Caribbean Art PDF

Caribbean Guidelines for
the Care and Treatment of

Persons with HIV Infection.
ABBREVIATIONS USED IN THIS DOCUMENT
3TC Lamivudine
ABC Abacavir
AFB Acid-Fast Bacillus
AFP Alfa-Fetoprotein
AIDS Acquired Immune Deficiency Syndrome
AIN Anal Intraepithelial Neoplasia
Anti-HBc Antibody to Hepatitis B Core Antigen
Anti-HBe Antibody to Hepatitis B e Antigen
Anti-HBs Antibody to Hepatitis B Surface Antigen
API Annual Parasitic Index
APV Amprenavir
ART Antiretroviral Therapy
ARV Antiretroviral (Drugs)
ASC-H Atypical Squamous Cells-Cannot Rule Out High-Grade Disease
ASCUS Atypical Squamous Cells of Uncertain Significance
ATL Adult T-Cell Leukaemia/Lymphoma
ATV Atazanavir
AZT Zidovudine (also abbreviated as ZDV)
b.i.d Twice Daily
b.i.w Twice Weekly
BAL Broncho-Alveolar Lavage
CAREC Caribbean Epidemiology Centre
CD4+ T CD4+ T-Lymphocyte (T-Helper Cell)
CDC United States Centers for Disease Control and Prevention
CHART Caribbean HIV/AIDS Regional Training Network
CIN Cervical Intraepithelial Neoplasia
CMC CARICOM Member Country
CMV Cytomegalovirus
CNS Central Nervous System
CRN+ Caribbean Regional Network of People Living with HIV/AIDS
CSF Cerebro-Spinal Fluid
CT Computerised Tomography
d4T Stavudine
ddC Zalcitabine
ddI Didanosine
DFA-TP Direct Fluorescent Antibody-T. pallidum
DKA Diabetic Ketoacidosis
DLV Delavirdine
DOT Directly Observed Therapy
DPT Diptheria-Pertussis-Tetanus
DR Dominican Republic
DS Double-Strength Tablet
EFV Efavirenz
EIA Enzyme-Linked Immuno-Assay
EMB Ethambutol
EPI WHO/PAHO/CAREC Expanded Programme on Immunisations
f-APV Fosamprenavir
FCSW Female Commercial Sex Worker
FDA United States Food and Drug Administration
14/03/2005 02:37 PM i
FTA-ABS Fluorescent Treponemal Antibody Absorption
FTC Emtricitabine
G-CSF Granulocyte Colony Stimulating Factor
GM-CSF Granulocyte Macrophage Colony Stimulating Factor
HAART Highly Active Antiretroviral Therapy
HAM/TSP Associated Myelopathy/Tropical Paraparesis
HAV Hepatitis A Virus
HBcAg Hepatitis B Core Antigen
HBeAg Hepatitis B e Antigen
HBIG Hepatitis B Immune Globulin
HBsAg Hepatitis B Surface Antigen
HBV Hepatitis B Virus
HCC Heptocellular Carcinoma
HCV Hepatitis C Virus
HDV Hepatitis Delta Virus
HELLP Syndrome Haemolysis, Elevated Liver Enzymes, Low Platelets
HHV-8 Human Herpes Virus 8
Hib Haemophilus influenzae Type B
HIV Human Immunodeficiency Virus
HPV Human Papillomavirus
HRA High-Resolution Anoscopy
HSIL High-Grade Squamous Intraepithelial Lesion
HSV-1 Herpes Simplex Virus 1
HSV-2 Herpes Simplex Virus 2
HTLV-1 Human T-Cell Lymphotrophic Virus 1
HU Hydroxyurea
IC Inhibitory Concentration
IDV Indinavir
IM Intramuscular
IMCI Current Integrated Management of Childhood Illness
INH Isoniazid
IPT Intermittent Preventative Treatment
IPV Inactivated Polio Vaccine
IRS Immune Reconstitution Syndrome
IRU Immune Recovery Uveitis
ITN Insecticide-Treated Bednets
IV Intravenous
IVDU Intravenous Drug Use
KS Kaposi’s Sarcoma
LEEP Loop Electrosurgical Excision Procedure
LIP Lymphoid Interstitial Pneumonia
LPV Lopinavir
LSIL Low-Grade Squamous Intraepithelial Lesion
LTBI Latent Tuberculosis Infection
MAC Mycobacterium avium Complex
MDR Multidrug Resistant
MMR Measles-Mumps-Rubella
MRI Magnetic Resonance Imaging
MSM Men Who Have Sex with Men
MTCT Mother-to-Child Transmission
NAA Nucleic Acid Amplification
14/03/2005 02:37 PM ii
NAM Nucleoside-Associated Mutations
NFV Nelfinavir
NNRTI Non-Nucleoside Reverse Transcriptase Inhibitor
NSAID Non-steroidal Anti-Inflammatory Drug
NRTI Nucleoside/Nucleotide Reverse Transcriptase Inhibitor
NsRTI Nucleoside Reverse Transcriptase Inhibitor
NtRTI Nucleotide Reverse Transcriptase Inhibitor
NUP Necrotising Ulcerative Peridontitis
NVP Nevirapine
OPV Oral Polio Vaccine
PAHO Pan-American Health Organisation
PAS Para-Aminosalicylic Acid
PCP Pneumocystis jiroveci Pneumonia
PCR Polymerase Chain Reaction
PCV Pneumococcal Conjugate Vaccine
PEP Post-Exposure Prophylaxis
PGL Persistent Generalised Lymphadenopathy
PI Protease Inhibitor
PI/r Ritonavir-Boosted Protease Inhibitor
PLWHA People Living with HIV/AIDS
PML Progressive Multifocal Leukoencephalopathy
PMTCT Prevention of Mother-to-Child Transmission
po By Mouth
PORN Progressive Outer Retinal Necrosis
PPD Purified Protein Derivative
PZA Pyrazinamide
q.d Daily
q.i.d Four Times a Day
q.m Monthly
q.o.d Every Other Day
q.o.w Every Other Week
q.w Weekly
RBC Red Blood Cell
RDR Relative Dose Response
RIF Rifampin
RPR Rapid Plasma Reagin
RSV Respiratory Syncytial Virus
RT Reverse Transcriptase
RTV Ritonavir
SC Subcoetaneous
SCD Sickle Cell Disease
SD Single Dose
SMX Sulfamethoxazole
SP Sulfadoxine-Pyrimethamine
SQV Saquinavir
SS Single-Strength Tablet
t.i.d Three Times a Day
t.i.w Three Times Weekly
TAM Thymidine Analogue Mutation
TB Tuberculosis
Td Tetanus and Diphtheria Toxiods
14/03/2005 02:37 PM iii

TDF Tenofovir Disoproxil Fumarate
TE Toxoplasmic Encephalitis
TMP Trimethoprim
TMP-SMX Trimethoprim-Sulfamethoxazole
TP-PA T. pallidum Particle Agglutination
TSH Thyroid-Stimulating Factor
TST Tuberculin Skin Test
USPHS United States Public Health Service
VCT Voluntary Counselling and Testing
VDRL Venereal Disease Research Laboratory Slide Test
VTR Vertical Transmission Rate
VZIG Zoster Immune Globulin (also abbreviated as ZIG)
VZV Varicella Zoster Virus
WBC White Blood Cell Count
WHO World Health Organisation
ZDV Zidovudine (also abbreviated as AZT)
ZIG Zoster Immune Globulin (also abbreviated as VZIG)
14/03/2005 02:37 PM iv
ACKNOWLEDGEMENTS
The authors would like to express, first and foremost, their gratitude to CAREC and to
Dr. Frank White and Dr. James Hospedales (Directors of CAREC), and Dr. Bilali
Camara (Director of the Special Programme on Sexually Transmitted Infections at
CAREC). CAREC, a PAHO/WHO center, sponsored a series of workshops and provided
ongoing critical guidance that led to the creation of these guidelines.
CO-CHAIRS OF THE GUIDELINES COMMITTEE AND LEAD WRITERS
Dr. Christopher Behrens, Clinical Assistant Professor and Medical Director,
International Training and Education Center on HIV (I-TECH), University of
Washington, Washington, USA
Dr. Herbert Orlander, Consultant Physician, Sexually Transmitted Infections and Skin
Clinic, Princess Margaret Hospital, Bahamas
SCIENTIFIC CONTRIBUTORS
Dr. Bilali Camara, PAHO/WHO Medical Epidemiologist; Head, Special Programme on
Sexually Transmitted Infections (SPSTI), Caribbean Epidemiology Centre
(CAREC)/Pan-American Health Organisation (PAHO)/World Health Organisation
(WHO)
Dr. Wendel Abel, Consultant Psychiatrist and Lecturer, Department of Community
Health and Psychiatry, University of the West Indies (UWI), Jamaica
Dr. Brendan Bain, Coordinator, University of the West Indies HIV/AIDS Response
Programme (UWI HARP) and Director, Regional Coordinating Unit, Caribbean
HIV/AIDS Regional Training Network (CHART), Jamaica
Dr. Paul Anton Best, Senior House Officer, Ladymeade Reference Unit, Barbados
Dr. Paula Brentlinger, Assistant Professor of Medicine, University of Washington
School of Public Health, Washington, USA
Dr. Jennifer Brown-Tomlinson, Dermatologist/Venereologist, Medical Management
Coordinator, Ministry of Health, Jamaica
Dr. Robert Cazal-Gamelsy, Head of the French HIV/AIDS Project for Caribbean States,
Special Programme on Sexually Transmitted Infections (SPSTI)
Dr. Celia Christie, Professor of Paediatrics and Infectious Diseases and Director,
Kingston Paediatric and Perinatal HIV/AIDS Programme, University of the West Indies
(UWI), Jamaica
Ms. Denise Clarke, Senior Technologist/Safety Officer, Laboratory Division, Caribbean
Epidemiology Centre (CAREC)
Ms. Arlene Darmanie, Technical Coordinator, Laboratory Division, Caribbean
Dr. Natalie Dayneka, Clinical Specialist, Pharmacy Department, Children’s Hospital of
Eastern Ontario, Ontario, Canada
Dr. Maria Dillon-Remy, Consultant Paediatrician, Scarborough General Hospital,
Tobago
14/03/2005 02:37 PM v
Dr. Georges Dos Santos, Virologiste, Hôpital Zobda Quitman – CHU La Meynard,
Laboratoire de Virologie Immunologie, Martinique
Dr. Jeffrey Edwards, Director, Caribbean Care, Prevention and Research Institute,
Trinidad & Tobago
Dr. Morris Edwards, Programme Manager, National AIDS Programme Secretariat,
Guyana
Ms. Jill Gatwood, Epidemiologist, Special Programme on Sexually Transmitted
Infections (SPSTI), Caribbean Epidemiology Centre (CAREC)
Dr. Perry Gomez, Consultant, Infectious Diseases, Princess Margaret Hospital, Bahamas
Ms. Radha Gosein, Laboratory Technologist, Laboratory Division, Caribbean
Dr. King Holmes, Professor of Medicine, University of Washington School of Medicine,
Washington, USA
Dr. Beryl Irons, Epidemiologist, Family and Child Health, Immunisation Unit, Pan-
American Health Organisation (PAHO)/Caribbean Epidemiology Centre (CAREC)
Dr. Noreen Jack, Consultant, HIV/AIDS Care and Treatment Team, Centers for Disease
Control (CDC)/Global AIDS Program (GAP) Caribbean Regional Office and Director,
Caribbean Care, Prevention and Research Institute, Trinidad & Tobago
Dr. Genevieve John, Senior Registrar and Clinical Specialist, HIV/AIDS Unit, Milton
Cato Memorial Hospital, St. Vincent & the Grenadines
Dr. Michael Johnson, U.S. Department of Health and Human Services (DHHS) Liaison
to the President's Emergency Plan for AIDS Relief (PEPFAR), Office of Global Health
Affairs
Ms. Wendy Kitson-Piggott, Training Manager, European Union (EU) Med-Lab Project,
Caribbean Epidemiology Centre (CAREC)
Dr. Wayne Labastide, Laboratory Information Systems Specialist, European Union
Med-Lab Project, Caribbean Epidemiology Centre (CAREC)
Dr. Robert Lee, Epidemiologist, Special Programme on Sexually Transmitted Infections
(SPSTI), Caribbean Epidemiology Centre (CAREC)
Dr. Paul Denis Leger, Research Clinician, GHESKIO Centers, Haiti
Dr. Percival McNeil, Consultant Paediatrician, Princess Margaret Hospital, Bahamas
Dr. Lynne M. Mofenson, Pediatric, Adolescent, and Maternal AIDS Branch, Center for
Research for Mothers and Children, National Institute of Child Health and Human
Development, National Institutes of Health, Maryland, USA
Dr. Nosa Everest Omo-Igbinomwanhia, Medical Officer-in-Charge, Cyril Ross (SVP)
Nursery for HIV/AIDS Orphans and Children, Trinidad
Prof. S. R. Prabhu, Professor of Oral Medicine, School of Dentistry, Faculty of Medical
Sciences, University of the West Indies, Trinidad & Tobago
14/03/2005 02:37 PM vi
Dr. Stanley Read, Professor of Paediatrics, University of Toronto and Infectious
Diseases Consultant and Director, HIV/AIDS Family Centered Care Program, The
Hospital for Sick Children, Ontario, Canada
Dr. Leslie K. Serchuck, Pediatric, Adolescent, and Maternal AIDS Branch, Centers for
Research on Mothers and Children, National Institute of Child Health and Human
Development, National Institutes of Health, Maryland, USA
Ms. Yolanda Y. Simon, Founder/Regional Coordinator, Caribbean Regional Network of
People Living with HIV/AIDS (CRN+)
Dr. Julianne Steel-Duncan, Paediatrician and Clinical Research Fellow, Paediatric
Infectious Diseases, Kingston Paediatric and Perinatal HIV/AIDS Programme, University
of the West Indies, Jamaica
Ms. Carol Trotman, Senior Technologist, Laboratory Division, Caribbean
Dr. Stephen Vreden, Internist and Infectiologist, National AIDS Treatment Physicians’
Group, Diakonessen Hospital, Suriname
Dr. Hans-Ulrich Wagner, Public Health Adviser, German Technical Cooperation (GTZ)
Project, Caribbean Epidemiology Centre (CAREC)
Ms. Katherine Williams, Director, Community Action Resource (CARe), Trinidad &
Tobago
Dr. Joseph Zunt, Assistant Professor of Neurology, University of Washington School of
Medicine, Center for AIDS Research, Washington, USA
THE PANEL OF CARIBBEAN REVIEWERS
Dr. Nicholas Adomakoh, Medical Director, Caribbean HIV/AIDS Regional Training
Network (CHART), Barbados
Dr. Brendan Bain, Coordinator, University of the West Indies HIV/AIDS Response
Programme (UWI HARP) and Director, Regional Coordinating Unit, Caribbean
HIV/AIDS Regional Training Network (CHART), Jamaica
Dr. Celia Christie, Professor of Paediatrics and Infectious Diseases and Director,
Kingston Paediatric and Perinatal HIV/AIDS Programme, University of the West Indies,
Jamaica
Dr. Peter Figueroa, Senior National Epidemiologist, Jamaica
Dr. Perry Gomez, Consultant, Infectious Diseases, Bahamas
Dr. Noreen Jack, Consultant, HIV/AIDS Care and Treatment Team, Centers for Disease
Control (CDC)/Global AIDS Program Caribbean Regional Office and Director,
Caribbean Care, Prevention and Research Institute, Trinidad and Tobago
Dr. Jose Ledesma, Clinical Coordinator, la Unidad Central de Atención Integral
(UCAI), la Secretaría de Salud (SESPAS), Dominican Republic
Dr. Jean Pape, Director, Group Haïtien d’Étude du Sarcome de Kaposi et des Infections
Opportunistes (GHESKIO), Haiti
Dr. Timothy Roach, Deputy Chairman, National HIV/AIDS Commission, Barbados
Dr. Margaret Anne St. John, Senior Consultant Paediatrician, Queen Elizabeth
Hospital, Barbados
14/03/2005 02:37 PM vii

Graphics
Mr. Roger McClean, A Little Sun, Trinidad
Typesetting and Layout
Karen Augustine
PUBLICATION COORDINATOR
Ms. Rosalind Saint-Victor
EDITORS
Ms. Kimberly Chase
Ms. Katherine Wiley
EDITOR/WRITERS
Dr. Violet Forsythe-Duke
Dr. Barbara Hull
Ms. Rosalind Saint-Victor
14/03/2005 02:37 PM viii

FOREWORD
Since the 1996 breakthrough identifying a combination of three antiretroviral drugs for the care and
treatment of people living with HIV/AIDS (PLWHA), HIV disease management has evolved
dramatically. With the introduction of highly active antiretroviral therapy (HAART), HIV infection has
become manageable as a chronic disease in many parts of the world. Opportunistic illnesses associated
with the disease have decreased, and the life expectancy of PLWHA, and their quality of life, has
significantly improved. It is in this context that these updated clinical guidelines on the care and
treatment of PLWHA in the Caribbean have been prepared.
Today, most CAREC member countries have either just begun to deliver comprehensive HIV/AIDS care
and treatment, including HAART, or are poised to do so. Designed to support these developments, these
guidelines provide regional clinicians with an up-to-date compendium of the very latest knowledge and
best practices in HIV/AIDS care and treatment from around the globe. Caribbean experts and their
international peers have contributed their cutting-edge skills and expertise to provide practising clinicians
with user-friendly, clinically-focused, and evidence-based guidelines. In addition, these guidelines have
been designed to address the Caribbean context directly and are flexible enough to accommodate the
variations in resources and healthcare infrastructures that characterise the region.
The main objective of these guidelines is to enable Caribbean clinicians to increase their index of
suspicion regarding HIV diagnosis and to facilitate their proficiency in the diagnosis and management of
HIV-infected individuals. When this objective is reached, Caribbean countries will have made significant
strides towards attaining:
improved quality of life and life expectancy for all PLWHA;
a reduction of the economic burden of HIV infection by preventing excessive use of
diagnostic tests and inappropriate treatment or prophylactic measures; and
enhanced HIV disease prevention and control through the effective management of
opportunistic infections and of HIV itself.
Although the Clinical Guidelines for the Care and Treatment of HIV-Infected Persons in the Caribbean is
intended primarily for use by clinicians, it is also a useful guide for other front-line healthcare
practitioners, medical students, and various healthcare workers in training. Furthermore, it is our hope
that Chief Medical Officers and National AIDS Programme Managers take these guidelines into
advisement as they plan for and manage the scale-up to comprehensive HIV/AIDS care and treatment in
their respective countries.
Finally, an important word: Prevention and care and treatment are inextricably linked, and there is no
place for false dichotomy between the two. As these guidelines indicate, prevention is an integral
component of any care and treatment programme. Thusly, CAREC and its partners urge all Caribbean
healthcare providers to utilise each encounter for the provision of HIV/AIDS care and treatment as an
opportunity to incorporate preventive counselling.
Dr. James C. Hospedales

Director
Caribbean Epidemiology Centre (CAREC)
14/03/2005 02:37 PM ix
ENDORSEMENT BY THE CARIBBEAN REGIONAL NETWORK OF PEOPLE LIVING WITH HIV/AIDS
(CRN+)
As a full and equal partner in the collaborative fight against HIV/AIDS in the region, the Caribbean
Regional Network of People Living with HIV/AIDS (CRN+) recognises the urgent need for improved
access to treatment, care, and support for persons living with HIV/AIDS. Accordingly, CRN+ is pleased
to endorse CAREC's publication Clinical Guidelines for the Care and Treatment of HIV-Infected Persons
in the Caribbean.
CRN+ views these guidelines as essential to the development of healthcare systems in the region. They
provide the foundation for quality care and treatment and represent a common ground for all Caribbean
territories. We applaud CAREC's foresight in establishing these guidelines.
CRN+ challenges all Caribbean healthcare practitioners and institutions to build on the principles outlined
in these guidelines in order to ensure full access to quality care and treatment for both the infected and
affected communities.
Ms. Yolanda Y. Simon

Regional Coordinator
Caribbean Regional Network of People Living with HIV/AIDS (CRN+)
14/03/2005 02:37 PM x
I. COMPREHENSIVE MANAGEMENT OF PERSONS WITH HIV INFECTION
TABLE OF CONTENTS
THE NEEDS-BASED APPROACH TO PERSONS WITH HIV INFECTION .................................................... I-1

MAXIMISING ADHERENCE TO ANTIRETROVIRAL THERAPY ................................................................. I-4
Introduction.......................................................................................................................................... I-4
The Dynamics of Adherence ............................................................................................................... I-4
Factors Affecting Adherence ............................................................................................................... I-4
Managing Adherence Effectively ........................................................................................................ I-5
HIV PREVENTION IN CARE AND SUPPORT SETTINGS: THE PUBLIC HEALTH BENEFIT ...................... I-7
Background .......................................................................................................................................... I-7
Ways to Incorporate Preventive Strategies into HIV/AIDS Care
and Support Programmes.................................................................................................................. I-8
CLINICAL CONSULTATION RESOURCES FOR THE CARIBBEAN ............................................................ I-11
CHART Initiative............................................................................................................................... I-11
Cliniserve ........................................................................................................................................... I-11
Websites............................................................................................................................................. I-11
REFERENCES............................................................................................................................................ I-27
TABLES
Table 1: Medical Needs of PLWHA ......................................................................................................... I-2
Table 2: Counselling Needs of PLWHA ................................................................................................... I-2
Table 3: Counselling Needs of Family and Friends of PLWHA .................................................................. I-2
Table 4: Self-Care Needs of PLWHA ....................................................................................................... I-3
Table 5: Social Support Needs of PLWHA ............................................................................................... I-3
Table 6: Factors Influencing Patient Adherence: Possible Negative Aspects .............................................. I-4
Table 7: Maintaining Adherence–Phase One: Starting Therapy ................................................................ I-6
Table 8: Maintaining Adherence–Phase Two: During Therapy ................................................................. I-7
Table 9: Sexual History-Taking: Examples of Open- and Closed-Ended Questions..................................... I-9
Table 10: Other Known Causes of Immunosuppression .................................................................................. I-25
Table 11: Diagnostic Methods for Indicator Diseases of AIDS ...................................................................... I-25
APPENDIX A: SAMPLE PATIENT ADHERENCE RISK ASSESSMENT QUESTIONNAIRE .............................. I-13

APPENDIX B: EPIDEMIOLOGY AND REPORTING OF HIV IN THE CARIBBEAN ......................................... I-18
APPENDIX C: CAREC HIV/AIDS CASE DEFINITIONS AND CLASSIFICATION SCHEMES ....................... I-21
APPENDIX D: WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN
ADULTS AND ADOLESCENTS .......................................................................................... I-26
I-1
I. COMPREHENSIVE MANAGEMENT OF PERSONS WITH HIV INFECTION
THE NEEDS-BASED APPROACH TO PERSONS WITH HIV INFECTION

The moment that an adult or child is suspected of having HIV infection, the issue of his/her care and
management is thrust into the spotlight. The responsibility for providing care is usually shared by the
professional team, the community, and the patient; there are moments when the balance of responsibility
lies solely in one quarter, but in other times, there is considerable overlap. Regarding the care of persons
living with HIV/AIDS (PLWHA), the concept of a continuum of care is most useful and applies to that
which starts at home or in the community and expands to the clinic, doctor’s office, or hospital. As such,
best practices in comprehensive care are achieved through a team approach; ideally, this team and its
resources are carefully planned.*
Most essential is good communication between the professional and nonprofessional team members, and
mutual understanding of roles, responsibilities, and relationships are an integral part of this
communication. Excellent communication between all parties becomes vital especially when the patient
is receiving antiretroviral drugs (ARVs), for they must be continued without interruption. Cange in rural
Haiti is an example of a best practice in such a situation; there, patients choose trustworthy persons from
the community to serve as accompagnateurs who complete regular, direct observation and documentation
of the patients taking their medications.
The first meeting between the healthcare professional and the patient is often at the request of the patient,
the family, or a concerned friend. From the first moment of meeting, the professional must focus on
beginning a cooperative partnership with the patient, for what often begins is a process of negotiation
between the professional caregiver and patient. From the caregiver’s perspective, the primary objective
of the partnership is adherence--not just to drug treatment, but to further clinical and laboratory
investigations and to any necessary aspects of lifestyle change.
Building trust between these parties is paramount, because the validity and reliability of communication
depends squarely on trust and trustworthiness. Furthermore, optimal care is based on optimal
communication. Understanding the patient’s mental and emotional status is vital to the success of
communication and, by extension, to the success of treatment. The healthcare worker must also get a
clear picture of the patient’s circumstances, including employment, economic status, and social support
network. For example, in some larger Caribbean countries, the cost of transportation to and from the
health clinic or hospital is prohibitive,† absorbing monies usually devoted to investigations and therapy.
Or, a patient living on the street may be less adherent to medications than someone who has a home.
Hence, the best care plan for each patient must be formed from the clearest appreciation of the patient’s
circumstances.
Many needs of PLWHA are identical to those of persons with other illnesses, but because of the aura and
stigma that often surrounds HIV/AIDS, the patient and the family may have additional requirements as
outlined in the following tables.
*
This article assumes that family members, friends, front-line healthcare workers, and others in the support team
(e.g. pharmacists, laboratory personnel, and administrators) have positive attitudes toward PLWHA. The care that
the patient experiences is proportional to these individuals’ knowledge, but it is also heavily dependent on their
attitudes. Willingness to give care and the degree of interest and concern are usually evident by general
deportment—therefore, it is imperative to maintain a helpful and caring attitude at all times.
†
This problem is obviated if funds have been provided to cover these costs, as is true in some situations.
I-1
Table 1: Medical Needs of PLWHA*
Access to health team
Means of transport
Medical monitoring (e.g. interviews, examinations, laboratory tests)
Patient education
Nutritional plan of action
Dietary and/or nutritional supplements
ARVs and drugs for opportunistic infection (OI) prophylaxis and treatment
Provision of condoms, when necessary
Crisis care and terminal care
Education of significant others (e.g. knowledge, skills, attitudes)
Supervision and supplies for caregivers at home, hospice, or hospital
Response to special needs
*
Adapted from a multidisciplinary focus group.
Table 2: Counselling& Needs of PLWHA†

Pre- and post-test counselling
Individual and group support for counselling concerning general life issues
Counselling regarding interpersonal relationships, sexuality, and sexual issues
Spiritual counselling
Discussion and clarification of issues related to personal and family confidentiality
Counselling and support in preparation for dying, and when necessary, including arrangements for
children
†
Table 3: Counselling& Needs of Family and Friends of PLWHA∞

Education about HIV, including reassurance about personal safety in long-term social contact situations
Emotional and spiritual support
Bereavement counselling
∞
&
A Special Note on Counselling
The purposes of counselling include: clarifying information related to the disease, helping the client
manage new circumstances, expressing negative and positive emotions, adjusting lifestyles, setting
realistic personal goals, and identifying and using available support systems. The client may be a
PLWHA; a contact of the primary case; someone who may suspect, rightly or wrongly, that he/she is
infected; a healthcare worker; or a family member or friend of a PLWHA.
I-2
The type of counselling described here is not synonymous with giving advice. Talking to a person or
talking at a person is often not enough to change his/her behaviour. Listening with empathy and
discerning the facilitators and obstacles to behaviour change are a starting point to what is often a
difficult process for the HIV-positive person. The changes that should occur in the person are often
multiple and long-term, requiring external support. The doctor or nurse alone may not be able to bring
about these changes.
Counselling may be carried out at many levels, sometimes by laypersons and at other times by
professionals. Professional counsellors are few in most Caribbean countries and, at the time of this
writing, there are even fewer of these persons in the region with training or experience in issues related
to HIV/AIDS. For this reason, the best substitutes must be engaged in this area of counselling while the
pool of professionals grows.
Table 4: Self-Care Needs of PLWHA*

Physical and mental:
• Keeping physically fit
• Maintaining the best possible nutrition
• Living a balanced life including work, rest, recreation, and sleep
• Good personal hygiene and sexual safety in order to avoid unnecessary contact with infection
Social
Economic and financial
Spiritual
*
Table 5: Social Support Needs of PLWHA†

Companionship
Legal advice and services
Employment
Income-generating activities
Occupational therapy
Cash and kind for short-term support
Food and shelter
Means of transport
Child welfare
Involvement in community life
†
I-3
MAXIMISING ADHERENCE TO ANTIRETROVIRAL THERAPY (ART)
INTRODUCTION
The goal of highly active antiretroviral therapy (HAART) -- clinical and immunologic stabilisation and
prevention of disease progression -- is most consistently achieved in patients who experience a sustained
drop in HIV viraemia to levels less than 50 copies/mL. Adherence to the HAART regimen appears to be
the single most important variable that predicts a patient’s ability to achieve and maintain suppression of
HIV viraemia to below the level of detection.1 Sustaining high levels of adherence to antiretroviral
therapy is difficult for many patients, but recent applied research among persons with HIV infection,
including a study carried out in Barbados, offers hope.2,3 These studies demonstrate that high-level
adherence to HAART is entirely possible with proper clinical management, strong patient confidence in
the clinician and in the treatment, and effective involvement of patients as active agents in their own care
and treatment.
THE DYNAMICS OF ADHERENCE
Two basic facts about the nature of adherence must be understood:
Achieving adherence is an interactive process. While the ultimate responsibility for adherence
to treatment rests with the patient, it is a complex process influenced by factors both internal and
external to the patient, and a process in which the patient must confront and come to terms with
those influences in a manner that is conducive to adherence.
Achieving adherence is not a one-time-only event. It is a dynamic and ongoing process that the
patient negotiates each time a dose of medication must be taken. Every day with every dose,
clients must navigate those influences, many of them negative and outside their sphere of
influence.
Therein lies the difficulty in achieving adherence: negotiating the interplay of influences that come to
bear upon the simple act of taking a medication AND the fact that, in the case of the HIV-infected person,
this negotiation must take place day after day, dose after dose, ad infinitum.
FACTORS AFFECTING ADHERENCE
What are those influences that intrude upon the client’s decision to adhere to treatment? The World
Health Organisation (WHO) characterises these factors as “interacting dimensions”4 that exert negative or
positive influences on treatment adherence. These factors and some of the attendant negative aspects that
could interfere with treatment adherence are delineated in Table 6.
Table 6: Factors Influencing Patient Adherence: Possible Negative Aspects5,6
INFLUENCING FACTOR POSSIBLE NEGATIVE ASPECTS
Social and Economic Socio-economic problems associated with being HIV-positive
Factors including unemployment, lack of money, adequate food,
housing, etc.
Stigma and discrimination against PLWHA
Having to travel long distances to access care and treatment or
medication
Healthcare Team- and Healthcare workers with a poor understanding of the dynamics
Health System-Related of adherence
Factors Healthcare workers with a poor understanding of the client
Stigma and discrimination from healthcare workers, not
I-4
necessarily those involved in the delivery of HAART
Inability or unwillingness to engage the client as an active agent
in his/her own therapy
Overworked staff with insufficient time or energy to engage the
patient effectively
Disjointed approach to care and treatment--workers not
functioning as a team
Poor linkages between the healthcare team and PLWHA
community support groups
Condition-Related Illness-related demands
Factors and Co- Severity of symptoms
Morbidities
Alcohol and other substance abuse
Psychiatric illness, including depression
Disease Therapies High pill burden
Difficult side effects
Complicated regimens
Poor fit between the medication regimen, patient’s lifestyle, and
eating patterns
Patient-Related Factors Low literacy or educational level
Poor self-confidence
Lack of confidence in the physician and in the team
Poor understanding of the details of the medication regimen
Beliefs about the disease
Beliefs about the efficacy of the treatment and alternate therapies
Medication fatigue
MANAGING ADHERENCE EFFECTIVELY

Preparing Healthcare Workers for Adherence
Before antiretroviral therapy is introduced, healthcare workers and the system must be ready to manage
treatment adherence effectively.
1. The HAART healthcare team (including clinicians, nurses, counsellors, social workers, pharmacists,
nutritionists, etc.) must be trained to understand and manage adherence successfully.
2. The team and all other workers who interface with PLWHA must be trained and sensitised to treat
them with dignity.
3. Systems must be established for efficient teamwork across disciplines AND also with community-
based supports.
Strategies for Managing Adherence
Tables 7 and 8 outline a process for the efficient management of HAART adherence.
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Table 7: Maintaining Adherence–Phase One: Starting Therapy7,8
OBJECTIVE: To take practical measures at the start of treatment therapy to ensure that the patient
takes the right medication, in the right dosage, at the right time, and under the right conditions,
always.
STRATEGIC ACTIONS:
1. ASSESS THE PATIENT’S READINESS FOR HAART. IDENTIFY:
Clinical status and other clinical factors that have a bearing on adherence;
Beliefs regarding health, illness, being infected with HIV, and HAART;
Attitudes toward medication, HAART, alternate therapies, etc.;
Knowledge on HIV/AIDS, living with HIV infection, and HAART; and
Elements in his/her lifestyle that may support or hinder adherence.
See Appendix A for a Sample Patient Adherence Risk Assessment Questionnaire.
2. ENGAGE THE PATIENT AS AN ACTIVE AGENT IN OWN THERAPY.
3. EDUCATE THE PATIENT: Fill in the gaps in patient knowledge on HIV/AIDS, living with
HIV infection, and HAART, etc.
4. TAILOR TREATMENT REGIMEN, WHERE POSSIBLE, TO THE PATIENT’S
LIFESTYLE AND NEEDS.
5. REVIEW POSSIBLE SIDE EFFECTS AND DEVELOP A CONCRETE PLAN FOR
PATIENT/CLINICIAN COMMUNICATION ON ADHERENCE AS THE NEED ARISES.
6. ENCOURAGE THE PATIENT TO UTILISE AT LEAST ONE SUPPORTIVE MEASURE
DESIGNED TO FACILITATE TREATMENT ADHERENCE. MEASURES COMMONLY
USED IN THE REGION INCLUDE:
A buddy or accompagnateur: usually a relative, friend, or community volunteer who
completes regular, direct observation and documentation of the patient taking his/her
medication. Partners in Health/Zanmi Lasante in rural Haiti is a best practice example.
A helper: a well-trained volunteer who ‘walks’ exclusively with a PLWHA providing
comprehensive support, including ensuring adherence. The Samaritan Ministries in the
Bahamas is a best practice example.
PLWHA support groups can be a source of weekly support sessions.
Patient hotlines that are easily contactable for advice, support, and guidance.
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Table 8: Maintaining Adherence–Phase Two: During Therapy9,10,11
OBJECTIVE: To ensure continued patient adherence to the HAART regimen.

STRATEGIC ACTIONS:
1. AT REGULAR INTERVALS, AT LEAST AT EVERY CLINIC VISIT, DETERMINE
PATIENT’S CAPACITY TO ADHERE TO THERAPY BY REVIEWING ADHERENCE
RECORD. THE SHORTER THE PERIOD BETWEEN MONITORING SESSIONS, THE
BETTER THE POSSIBILITY OF ACCURATE MONITORING REVIEWS. SOME
USEFUL APPROACHES INCLUDE:
Patient self-reporting: provide a treatment record form that the patient completes daily
and submits for review at each clinic visit.
Pharmacy logs are useful if the patient refills prescriptions at one pharmacy.
Directly observed therapy (DOT) and documentation by a trained relative, friend, or
community volunteer is a reliable method for monitoring, as well as supporting,
treatment adherence.
2. ADJUST TREATMENT REGIMEN, IF NECESSARY.
3. REINFORCE VALUE OF ADHERENCE WITH EACH VISIT:
Keep client informed of CD4+ T cell count and viral load response to treatment.
Continue to reinforce the role of exact HAART adherence in maintaining client’s
improved health status.
Again, high-level adherence to HAART is entirely possible, but it takes proper clinical management and a
trusting provider-patient relationship-–both of which demand that the clinician and other team members
assume a comprehensive role, beyond that solely of providers of medication and of clinical services.12
HIV PREVENTION IN CARE AND SUPPORT SETTINGS: THE PUBLIC HEALTH BENEFIT
BACKGROUND
Three new developments in the response to HIV/AIDS are coming together to create new opportunities
for HIV prevention: 1) several countries’ willingness to adopt widespread voluntary confidential
counselling and testing (VCT) for HIV; 2) the increasing availability of affordable and supervised
antiretroviral therapy; and 3) the emphasis on HIV prevention counselling and support targeted for the
HIV-infected person, as summarised in recently released guidelines13. This section will discuss VCT and
methods to include preventive approaches in HIV care and support programmes.
Knowing one’s HIV status in order to institute appropriate self-care, access medical treatment, and protect
others is always important. Now, however, more attention is being paid to improving care and treatment
of PLWHA. Because HAART is becoming more available and affordable, it is vital to persuade members
of the public, particularly adolescents and adults, to ascertain their HIV serostatus. In this regard, the
expansion of HIV VCT training and services in the Caribbean and elsewhere is timely.
With respect to prevention in care and support settings, it is recommended to strengthen the following
approaches and their regular use by healthcare workers in the Caribbean:
9 Screening HIV-infected patients for risk behaviours
9 Identifying and treating other sexually transmitted infections (STIs)
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9 Positively reinforcing changes to safer behaviours
9 Referring patients for associated services as necessary (e.g. substance abuse treatment)
9 Communicating prevention messages to the client
9 Facilitating partner notification, counselling, and testing
It is clear that the successful adoption of these approaches will require changes in current policy and
practice at points of service delivery. For example, health managers will have to reassess how services
are organised. Creating confidential spaces in clinics or offices may be necessary to bring new categories
of workers into the team and to improve the flow of confidential information between front-line staff and
the broader public health team. Practitioners may need to upgrade their skills in regard to prevention, and
some will need to learn entirely new skills. As policies and programmes gain momentum, healthcare
practitioners will be privy to a larger amount of private information, which needs to be handled with
maximum discretion.
In a busy fee-for-service-type practice or in an overflowing public clinic, primary caregivers may find it
challenging to incorporate many (if any) of these approaches into their work. Ideally, however, it is key
that every team member portray genuine interest in the incorporation of prevention into care. A
reasonable practical approach is to recognise the need in this area, determine how much the caregiver can
contribute, have a list of referral resources close at hand, and put the client into contact with other team
members who can address the preventive issues. Training programmes must be instituted to aid
healthcare workers in improving relevant skills and in boosting their own confidence levels.
Actual recommendations challenge the dichotomy that often exists between public health and ‘real-life’
medical practice. After all, who is more influential in the eyes of the client than his/her professional
caregiver, and who is therefore best-suited to deliver messages about safety? In addition, there is
evidence that brief, provider-delivered counselling messages, which can be delivered within the context
of a clinical encounter, can have a measurable effect on patient behaviour.14
To date, there are no published data from the Caribbean on practices such as screening and assessment of
behavioural risk or prevention counselling for HIV-infected persons. Few professional counsellors or
social workers are employed in health services in this part of the world. Anecdotal reports suggest that
few doctors, nurses, or pharmacists spend any time in preventive counselling or behavioural risk
assessment related to any disease, including HIV. In an unpublished study among Jamaican doctors,
more than 60% admitted their need to be trained in personal and family counselling.15 In another recent
study, sixty-four of eighty-nine pharmacists and pharmacy technicians admitted that no general
counselling about HIV/AIDS took place at their pharmacies.16
Data from the United States indicate that approximately one-third of HIV-infected patients report that
their providers have never counselled them about HIV prevention; in some settings, as many as three-
quarters of HIV medical care providers do not ask about sexual behaviour and as many as half do not ask
about recreational drug use.17 Apart from lack of time, as mentioned above, many practitioners confess
discomfort in raising personal matters, such as sex, with their patients. Recognising and acknowledging
such obstacles, however, are the first steps toward positive change. The practical notes below are written
against this background.
WAYS TO INCORPORATE PREVENTIVE STRATEGIES INTO HIV/AIDS CARE AND SUPPORT
PROGRAMMES
1. Screening Patients for Risk Behaviours
Ideally, a brief history should be taken at each regularly-scheduled clinic visit to ascertain the patient’s
sexual and drug-using behaviour; understanding of HIV transmission; and symptoms of an STI, such as
urethral or vaginal burning or discharge, dysuria, genital or anal ulcers, lower abdominal pain, or
intermenstrual bleeding in women. It is often necessary for the healthcare worker to build rapport with
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the patient before he/she will disclose details about risky behaviour. In addition, in a team setting, one or
more persons can interface with the patient in order to obtain a complete history. Questionnaires may be
useful in capturing such personal information, and can be given to the patient while he/she is waiting to
be seen (literacy level permitting). Research suggests that patients may provide more honest and detailed
responses to questionnaires not administered face-to-face. In this area of history-taking, it has been
shown, not surprisingly, that healthcare workers who have been trained to discuss sensitive sexual and
drug-using issues are likely to perform better than those who have not had such training. In reference to
HIV risk assessment, depending on the comfort levels of both the provider and the patient, either open- or
close-ended questions can be used. Examples of each are provided in Table 9.
Table 9: Sexual History-Taking: Examples of Open- and Closed-Ended Questions*
Open-Ended Questions
What do you know about HIV transmission?
What, if anything, are you doing that could result in transmitting HIV to another person?
Tell me about any sexual activity since your last clinic visit.
What do you know about the HIV status of each sex partner?
Tell me about condom use during any sexual activity.
Tell me about any drug use or needle sharing since your last clinic visit.
Closed-Ended Questions
Do you know the facts about how HIV is and is not transmitted?
Have you had sex (vaginal, anal, or oral) with any partner since your last clinic visit?
For each of your partners, do you know if he or she has HIV infection, doesn’t have HIV infection, or are
you not sure?
Did you use a condom every time, from start to finish of each sexual encounter?
Have you shared drug injection equipment (including needles, syringes, cotton, cookers, water) with
anyone?
*
Note: Symptoms of STIs (e.g. urethral or vaginal burning or discharge, dysuria, genital or anal ulcers,
intermenstrual bleeding, or lower abdominal pain among women) are asked in a closed-ended format,
regardless of behavioural question format.
Medical and Laboratory Screening
Symptoms or signs of STIs or known or suspected exposure to STIs should prompt immediate physical
and laboratory examinations. However, because STIs are often present without symptoms, every patient
should be screened for laboratory evidence of syphilis, trichomonads (women only), gonorrhoea, and
chlamydia at the initial visit and then at least annually.
Co-infection with HIV and certain strains of human papillomavirus (HPV) can increase the occurrence
and accelerate the clinical course of cervical cancer. Therefore, all HIV-positive women should be
screened at frequent intervals with Papanicolau smears. Current guidelines suggest that Pap smears be
performed every six months for HIV-infected women, though clinically asymptomatic women who have
CD4+ T cell counts >200 cells/mm3 and who have had two normal Pap smears may be screened annually.
Some experts also recommend type-specific testing for herpes simplex virus (HSV) type 2 because of its
association with a higher risk of HIV transmission and possible need for enhanced counselling. However,
this test is not commonly available in the Caribbean.
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More frequent screening for STIs is appropriate with evidence or suspicion of high-risk sexual behaviour
(e.g. sex with a new partner, sexual activity without consistent and correct condom use, or change in
intimate partners); however, there are no data to guide the precise frequency. More frequent screening
might also be appropriate in asymptomatic men who have sex with men (MSM) and younger women
because of a higher STI prevalence among these demographic groups. Where it is known, the local
prevalence of these infections should help to guide the frequency of screening.
Note: In some parts of the Caribbean, not all of these laboratory tests are available routinely. However,
taking cost and cost-benefit into account, it may be prudent to build such laboratory capacity over time.
In places where access to the laboratory is limited or whenever there is a risk of further spread of STIs, it
is practical and recommended by the Caribbean Epidemiology Centre (CAREC) and the Pan-American
Health Organisation (PAHO) to use a syndromic approach to the treatment of STIs.
2. Communicating Prevention Messages to the Client
Face-to-face talks, audio and videotapes, literature, and drama are among the methods that can be used to
communicate prevention messages in clinical settings. The principles of reinforcement of safe behaviour
include giving consistent and unambiguous messages; using “teachable moments”; using familiar and/or
attractive media; speaking in the “heart language” of the recipient; and pitching the message at a level
appropriate to the recipient. Guided discussions with groups of patients can be an effective way of
reinforcing behavioural messages and addressing genuine queries. Pictures or charts are useful both for
the literate and for the less literate; in situations where recipients are unable to read, leaflets with text
messages are relatively useless. Moreover, multimedia approaches, including wall posters, can help to
reinforce practical messages in the setting of an HIV/STI clinic. Please take caution, however, in regard
to overkill or message fatigue.
It is vital to evaluate the impact of each method and to put it into the context of the patient’s everyday life
when he/she is away from the clinic environment. Competing messages and other needs and drives can
hinder the success of transient education messages. From another perspective, it would be ideal if
messages given directly and indirectly in the popular mass media are consonant with the messages given
by healthcare workers.
A practical way to encourage or reinforce prevention messages is to highlight choices and potential
consequences of these choices, including abstinence, mutual fidelity, and the use of barrier methods such
as condoms. Many authorities recommend that condoms should be freely available at all HIV/STI points
of service.
3. Contact Tracing and Partner Notification
In some countries, the practices of confidential contact tracing and partner notification are used along
with other methods of tracking and attempting to curb the spread of HIV and some other STIs. Consistent
application of these methods is believed to augment other preventive approaches. However, carefully
designed studies are still needed to confirm the added value of contact tracing in the prevention of the
spread of HIV.
The practice of partner notification of HIV infection is humane and is to be encouraged. In several parts
of the United States, notification of partners is required by law; in Jamaica, health practitioners are asked
to provide a confidential list of the names and addresses of patients’ sexual partners. The responsibility
for notifying partners can be given to the patient, but many patients hesitate for fear of rejection or
reprisal, and notification is delayed in some instances when patients struggle with denial of the diagnosis.
It is not clear from the literature whether a single notification is sufficient to convince the partner of an
HIV-infected person.
4. PLWHA as Health Promoters
Now that groups or networks of PLWHA are becoming stronger in the Caribbean, it has been suggested
that some of these persons may be highly effective preventive counsellors at points of service delivery,
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without necessarily divulging their serostatus. A few Caribbean countries are starting to pilot test this
idea. Early results are very encouraging and should be immediately promoted by the Caribbean Regional
Network of People Living with HIV/AIDS (CRN+).
Note: There are definite limitations to the delivery of optimal care to every patient and family living with
HIV/AIDS, more so in resource-limited settings. For this reason, continued advocacy for improvements
in equipment, supplies, services (including self-help initiatives), education, and the alleviation of poverty
will continue to be crucial to improving the management of PLWHA.
CLINICAL CONSULTATION RESOURCES FOR THE CARIBBEAN

CHART INITIATIVE
The Caribbean HIV/AIDS Regional Training (CHART) network serves the region from national training
sites in the Bahamas, Barbados, Haiti, and Jamaica. Later expansion to Trinidad & Tobago and other
sites is planned. The CHART Regional Coordinating Unit is located on the Mona Campus of the
University of the West Indies in Kingston, Jamaica.
In addition to establishing centres for the ongoing training and development of healthcare workers, the
CHART initiative seeks to:
• Ensure that transfer of knowledge and technologies support the building of indigenous Caribbean
capacity to sustain training competence and responsibility within Caribbean regional and local
institutions; and
• Serve as a coordinating body and focal point for promoting the unique training needs and
resources of the Caribbean region.
CHART’s website is located at http://www.chartcaribbean.org.
CLINISERVE
A free, on-line forum sponsored by CAREC for exchanging clinical information on HIV/AIDS in the
Caribbean. Anyone may register by sending a registration e-mail request to http://cliniserve@carec.net.
WEBSITES
Clinician-Oriented
www.chartcaribbean.org: Website of the Caribbean HIV/AIDS Regional Training Network.
www.carec.paho.org: Website of the Caribbean Epidemiology Centre.
www.aidsinfo.nih.gov: Offering information on HIV/AIDS treatment, prevention, and research,
including care and treatment guidelines commonly used in the U.S. Sponsored by the U.S. Department of
Health and Human Services and the National Institutes of Health.
http://hivinsite.ucsf.edu: Comprehensive, up-to-date information on HIV/AIDS treatment,
prevention, and policy from the University of California San Francisco School of Medicine.
www.hivwebstudy.org: Interactive, case-based training modules related to the clinical care of
HIV-infected persons. Sponsored by the University of Washington and the Northwest AIDS Education
and Training Center.
www.hopkins-aids.edu: Website of the Johns Hopkins AIDS Service.
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www.medscape.com: A large, continuously-updated clinical knowledge base available to
physicians and health professionals.
www.emedicine.com: Another large, continuously-updated clinical knowledge base available to
physicians and health professionals.
www.cdc.gov: Website of the U.S. Centers for Disease Control and Prevention.
www.paho.org: Website of the Pan-American Health Organisation.
www.who.int: Website of the World Health Organisation.
Patient-Oriented
www.aidsmeds.com: Dedicated to providing people living with HIV the necessary information
they need to make empowered treatment decisions. The founder and some of the writers of this website
are living with HIV.
www.thebody.com: A service of Body Health Resources Corporation, The Body’s mission
includes using the Web to lower barriers between patients and clinicians, demystifying HIV/AIDS and its
treatment, improving patients' quality of life, and fostering community through human connections.
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APPENDIX A: SAMPLE PATIENT ADHERENCE RISK ASSESSMENT QUESTIONNAIRE
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Patient ID_________________________ Visit: □ Baseline □ 1 month □ 3 months □ 6 months
Date of Visit_______________________
The purpose of this questionnaire is to collect information on factors that affect your ability to take your antiretroviral
medicines as prescribed; to assess how best to measure your adherence, and to develop strategies to assist you better with
taking your medications exactly as prescribed.
________________________________________________________________________________
SECTION A: Socio-Demographic
1. Sex: □ Male □ Female
2. Age in years: □ 18-19 □ 20-30 □ 31-40 □ 41-50 □ over 51
3. Address:
4. Do you live: □ Alone □ with Family □ with Friends □ Other
5. Where you live:
5a. How many people live in the house including you?
□ less than 3 □ 3 to 6 □ 7 to 9 □ more than 10
5b. How many bedrooms are there in the house?
□1 □2 □3 □ more than 3
5c. Is your water supply source:
□ Piped into house □ A stand pipe □ Other
If Other, please specify:________________
5d. Is there electricity in your house?
□ Yes □ No
6. Are you employed? □Yes □ No
If Yes: □ Part-Time □ Full-Time

7. What is your average weekly income? (include pension, public assistance, support from family/friends, etc.)
□ less than $200 □ $200-$499 □ $500- $799
□ $800-$1,000 □ more than $1,000
8. How long has it been since you were diagnosed with HIV infection?
□ less than 1 year □ 1-3 years □ 4-6 years □ more than 6 years
9. Have you had HIV-related previous hospitalisations? □ Yes □ No
If Yes, what year?_________
If Yes, please specify the reason for hospitalisation:_________________________
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Date of Visit_______________________
10. To be completed by a physician:

Physician's clinical staging:__________________________
CD4+ T Cell Count CategoryCD4+ T Cell Count Category CD4+ T Cell Count Category 3
Clinical Category A
Clinical Category B
Clinical Category C
____________________________________________________________________________
SECTION B: Psychosocial History
11. Is your family aware of your HIV status?
□ Yes □ No □ Don’t Know
12. Are your friends aware of your HIV status?
□ Yes □ No □ Don’t Know
12a. If Yes and you are taking antiretroviral medication, do they help you take your medication?
□ A lot □ Somewhat □ A little □ Never □Not applicable
13. Have you ever been treated for a psychiatric illness?
□ Yes □ No
If Yes, please specify:_____________________________
14. In the past four (4) weeks, have you been unable to cope with all the things you need to do?
□ Never □ Sometimes □ Often □ Always
15. In the past four (4) weeks, have you felt down (depressed)?
□ Never □ Sometimes □ Often □ Always
16. If you are feeling down (depressed), is there someone you can talk to?
□ Yes □ No
16a. If Yes, is he/she (check as many as apply):
□ A family member □ A friend
□ A colleague at work □ A member of a support group
□ A doctor □ A nurse
□ A social worker □ Another member of the healthcare team
□ Other, please specify____________
16b. If you have no one to talk to, what do you do to relieve stress or when you have a
problem?________________________________________________
17. How often do you drink alcohol? 18. How often do you smoke cigarettes?
□ Daily, more than 3 drinks □ Regularly, more than 5 cigarettes/day
□ Daily, less than 3 drinks □ Regularly, less than 5 cigarettes/day
□ Weekly, less than 5 drinks □ Occasionally
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Date of Visit_______________________
□ Rarely/Occasionally □ Never
□ Never
19. Do you smoke marijuana? 20. Do you use crack/cocaine?
□ Regularly, more than 5 cigarettes/day □ Regularly, more than 5 times/day
□ Regularly, less than 5 times/day □ Regularly, less than 5 times/day
□ Occasionally □ Occasionally
□ Never □ Never
____________________________________________________________________________
SECTION C: HIV Knowledge
YES NO DON’T KNOW
21. Do you understand the difference between HIV and AIDS? ( ) ( ) ( )
If Yes, please explain:__________________________________
22. Do you know what a CD4+ T cell count measures? ( ) ( ) ( )
If Yes, please explain__________________________________
23. Do you know what viral load measures? ( ) ( ) ( )
24. Do you know how antiretrovirals work? ( ) ( ) ( )
25. The following statements are attempts to capture your knowledge and beliefs about taking antiretroviral
medicines.
Strongly Agree DK Disagree Strongly
Agree Disagree
25a. I have to take them for the rest ( ) ( ) ( ) ( ) ( )
of my life.
25b. Some antiretrovirals have to be ( ) ( ) ( ) ( ) ( )
taken on an empty stomach and
others may be taken with food.
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Date of Visit_______________________
Strongly Agree DK Disagree Strongly

Agree Disagree
25c. The time at which the medication ( ) ( ) ( ) ( ) ( )
is taken will influence its effectiveness.
25d. Missing doses and/or taking ( ) ( ) ( ) ( ) ( )
them late or incorrectly will
determine if the treatment works.
25e. For my medicine to work best, I ( ) ( ) ( ) ( ) ( )
should not miss a dose, nor take
it late or incorrectly.
25f. Drug resistance develops when my ( ) ( ) ( ) ( ) ( )
antiretrovirals are missed and/or
taken late or incorrectly.
__________________________________________________________________________
SECTION D: Antiretroviral Adherence Barriers
26. Which of the following reasons represent or would represent a major problem to you when you are taking
medication? (multiple responses are allowed)
□ Number of pills
□ Fear of side effects
□ Having side effects
□ Frequency of dosing
□ Interference with daily schedule
□ Privacy to take medication not available
□ Fear of disclosure of HIV status
□ Other Please specify:_______________________________
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APPENDIX B: EPIDEMIOLOGY AND REPORTING OF HIV IN THE CARIBBEAN
HIV/AIDS IN THE CARIBBEAN REGION

The Caribbean has the highest incidence of reported AIDS cases in the Americas.18 With approximately
350,000 to 590,000 PLWHA, the region has an adult HIV prevalence rate of between 1.9% and 3.1%,
second in the world only to Africa’s 7.5% to 8.5%. The most recent national estimates show HIV
prevalence among pregnant women reaching or exceeding 2% in eight Caribbean countries: the
Bahamas, Belize, the Dominican Republic, Guyana, Haiti, St. Lucia, Suriname, and Trinidad & Tobago.
Haiti and the Dominican Republic account for more than 79% of all Caribbean PLWHA.
HIV/AIDS IN CAREC MEMBER COUNTRIES

Between 99,000 and 121,000 PLWHA live in CAREC member countries (CMCs). From 1982 to the end
of 2002, the cumulative total of AIDS cases occurring in CAREC’s twenty-one member countries is
estimated to be between 30,000 and 35,000. Between 1991 and 2002, the AIDS incidence in CMCs
increased almost four-fold, up from an estimated 13.6 per 100,000 in 1991 to 54.32 per 100,000 in 2002.
AGE GROUP DISTRIBUTION
The epidemic is becoming more prevalent among younger age groups. Seventy-three percent of those
diagnosed with AIDS are between the ages of fifteen and forty-four, and AIDS is now the leading cause
of death among this age group. Close to 50% of AIDS diagnoses occur in individuals age twenty-five to
thirty-four.
GENDER DISTRIBUTION
Among AIDS cases in general, there is a predominance of males compared to females (ratio: 2:1);
however, young women are particularly vulnerable. Among women age fifteen to twenty-four, the annual
incidence of HIV is three to six times higher than in males of the same age. Moreover, several
seroprevalence surveys among pregnant women in this age group reveal rates that are double the national
average.
CATEGORIES OF TRANSMISSION
The predominant mode of HIV transmission is sexual (76%), with heterosexual transmission representing
65% of total transmissions by the end of 2002. Transmission through male-to-male sexual contact has
been declining since the beginning of the epidemic and now represents only 11% of the total reported
AIDS cases. However, it is believed that because of the strong social, cultural, and legal discrimination
against MSM and bisexuals, these transmission risk factors are underreported. It may also be true that
some report such transmissions as “unknown”, resulting in an increase of 16% to 40% in this category.
Transmission through intravenous drug use (IVDU) is low, ranging from 0% to 2%, except in Bermuda,
where IVDU represented 33.5% of reported AIDS cases in 2002. Rates of HIV transmission through
blood and blood products have been constant at 0.30% from 1992 to 2002, thanks to the implementation
of systematic blood screening and the application of universal precautions by healthcare personnel.
Mother-to-child transmission (MTCT) now accounts for 6% of reported AIDS cases.
The “unknown” category of transmission accounts for approximately 16% of the total cumulative AIDS
cases reported by CMCs. This varies from country to country, and in some, this figure represents 40% of
AIDS cases.
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HIV PREVALENCE AMONG PATIENTS WITH TUBERCULOSIS (TB), 1997-2002
The TB epidemic is fast growing in CMCs and the incidence rate between 1997 and 2002 increased
steadily from 200 to between 1,000 and 1,200 cases per year from 1998 to 2002. Between 1997 and
2002, a cumulative total of 5,025 TB cases were reported. Of these, 2,962 underwent HIV testing
(58.9%), and 785 were HIV-positive, reflecting an overall seroprevalence rate of 26.4%. Individual
country situational analyses show that declining rates of HIV prevalence among TB patients are being
observed in the Bahamas, in contrast to Belize, Guyana, Jamaica, Suriname, and Trinidad & Tobago, in
which increasing trends are observed.
Although the number of TB patients tested for HIV antibodies increased between 1997 and 2000, testing
declined during 2001 and 2002. CMCs should strive to test at least 80% of TB patients for HIV
antibodies on annual basis, and all such patients must have access to counselling. In addition to
improving patient management, testing would facilitate a better understanding of the epidemiological
pattern of HIV/TB co-infection in the Caribbean.
HIV SUBTYPING AND ARV RESISTANCE SURVEILLANCE AND MONITORING
In 2002, CAREC collaborated with University College London to conduct an HIV molecular survey
involving ten CMCs: Antigua & Barbuda, Dominica, Grenada, Guyana, Montserrat, St. Kitts & Nevis,
St. Lucia, St. Vincent & the Grenadines, Suriname, and Trinidad & Tobago. The survey found no drug
resistant HIV strains in the region and identified Subtype B as the most predominant strain of HIV-1,
which is also the most common subtype in North America and Western Europe. HIV 1 Subtype C was
also isolated in St. Lucia. A 2003 study in Barbados uncovered a single viral strain that harboured
resistance to zidovudine (AZT), zalcitabine (ddC), and didanosine (ddI).
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HIV/AIDS REPORTING ALGORITHM
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APPENDIX C: CAREC HIV/AIDS CASE DEFINITIONS AND CLASSIFICATION SCHEMES
Case definitions assist the clinician in making a diagnosis according to standardised criteria and are
needed as a basis for management and reporting.
CAREC CASE DEFINITION FOR HIV INFECTION

ADULTS
The diagnosis of HIV infection is generally based on a positive HIV antibody test (ELISA, rapid test),
confirmed by a second test using a different principle. In case of a discrepancy, a third test is done using
another antibody test (ELISA, IFA, WB) or by demonstration of viral material (PCR, p24-Ag test).
The first test should be repeated in case of inconclusive results or of an initially nonreactive result in a
patient with symptoms strongly suggestive of HIV-related disease.
CHILDREN
In cases of HIV-positive mothers, their children may carry maternal antibodies for up to eighteen months.
In order to make a definitive diagnosis of HIV infection, viral material needs to be demonstrated by, for
instance, PCR and p24-Ag test. Such a test should be carried out at least twice, at ages one month and
four months. The HIV infection is confirmed by the PCR at age four months. In the absence of such
facilities, HIV infection in infants born to HIV-infected mothers is defined as the persistence of HIV
antibodies beyond age eighteen months. Antibody testing in the absence of breastfeeding should be
carried out every three to six months until two consecutive negative results; or, infection is ruled out by
two consecutive nonreactive antibody tests to age eighteen months. In the special case that a nonreactive
infant has been exposed to breastmilk, testing of that child should be extended beyond the eighteen
months.
CAREC CASE DEFINITION FOR AIDS

ADULTS AND ADOLESCENTS (AGE 13 YEARS AND OLDER)
A confirmed case of AIDS is defined as an individual, age thirteen years or older, who, in the absence of
other known causes of immunosuppression (see Table 10) has a repeatedly positive screening test for HIV
by an enzyme-linked assay (ELISA) together with at least two major signs and at least one minor sign
or at least one indicator disease. Additionally, any HIV-infected adult or adolescent with an absolute
CD4+ T cell count of <200 cells/mm3 is defined as having AIDS, even if that individual is asymptomatic.
Major Signs:
• Involuntary weight loss of >10% of baseline body weight
• Chronic diarrhoea with at least two loose stools per day for more than thirty days
• Intermittent or constant fever for more than thirty days
Minor Signs:
• Persistent cough for more than thirty days
• Generalised pruritic dermatitis
• Herpes zoster (HZV), multidermatomal
• Oropharyngeal candidiasis
• Generalised lymphadenopathy
Indicator Diseases:
• Bacterial pneumonia, recurrent (at least two episodes per year)
• Cancer, cervical, invasive
• Candidiasis of bronchi, trachea, or lungs
I-21
• Candidiasis, oesophageal
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptosporidiosis, chronic intestinal for more than thirty days
• Cytomegalovirus disease (CMV) (other than liver, spleen, or nodes)
• CMV (with loss of vision)
• Encephalopathy with no other cause
• Herpes simplex (HSV): chronic ulcer(s) for more than thirty days; or bronchitis,
pneumonitis, or oesophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal for more than thirty days
• Kaposi’s sarcoma (KS) if under age sixty
• Lymphoma, Burkitt’s
• Lymphoma, immunoblastic
• Lymphoma, primary of brain under age sixty (or over age sixty)
• Mycobacterium avium complex (MAC) or M. kansasii, disseminated/extrapulmonary
• TB, any site (pulmonary or extrapulmonary)
• Pneumocystis jivoreci pneumonia (PCP)
• Progressive multifocal leukoencephalopathy (PML)
• Toxoplasmosis of brain (or of internal organ)
• Non-typhoid Salmonella septicaemia, recurrent
• Wasting syndrome (defined as ALL of major signs)
• Cryptococcosis, extrapulmonary
• Nocardiosis
• Strongyloidiasis, extra-intestinal
INFANTS AND CHILDREN (LESS THAN AGE 13 YEARS)
A confirmed case of AIDS is defined as an individual less than age thirteen years, who, in the absence of
other known causes of immunosuppression (see Table 10), has a repeatedly positive screening test for
HIV by ELISA together with at least two major signs AND at least two minor signs or at least one
indicator disease.
Major Signs:
• Weight loss of >10% of baseline or failure to thrive
• Chronic diarrhoea with at least two loose stools per day for more than thirty days
• Intermittent or constant fever for more than thirty days
Minor Signs:
• Oropharyngeal candidiasis
• Repeated common infections (otitis, pharyngitis, etc.)
• Persistent cough
• Generalised dermatitis
• Confirmed maternal HIV infection
Indicator Diseases:*
• Chronic (persisting over two months) lymphoid interstitial pneumonitis
• Bacterial infections, unexplained, serious, recurrent (more than two in a two-year period),
including sepsis, meningitis, pneumonia, abscess of an internal organ, and bone/joint
infections
*
For diagnosis of these conditions, please refer to Table 11.
I-22
• Candidiasis of bronchi, trachea, or lungs
• Candidiasis oesophageal
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptosporidiosis, chronic intestinal for more than thirty days
• CMV infection with onset after six months
• HSV infection, disseminated, with onset after one month of age
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal for more than thirty days
• KS
• Lymphoma, Burkitt’s
• Lymphoma, immunoblastic
• Lymphoma primary of brain
• TB, any site
• PCP
• PML
• Toxoplasmosis, disseminated, with onset after age one month
CAREC CLASSIFICATION OF HIV INFECTION IN ADOLESCENTS AND ADULTS

The determination of the stage of the disease and the monitoring of its progress over time are important to
guide clinical management. Two classification systems have been proposed; the first can be applied in
settings without facilities for measuring CD4+ T cell counts:
GROUP I: ACUTE HIV INFECTION
A mononucleosis-like syndrome, with or without aseptic meningitis, associated with seroconversion for
HIV antibody. Antibody seroconversion is required as evidence of initial infection; current viral isolation
procedures are adequately sensitive to be relied on for demonstrating the onset of infection.
GROUP II: ASYMPTOMATIC HIV INFECTION
The absence of signs or symptoms of HIV infection. To be classified in Group II, patients must have had
no previous signs or symptoms that would have led to classification in Groups III or IV. Patients whose
clinical findings caused them to be classified in Groups III or IV should not be reclassified in Group II if
those clinical findings resolve.
GROUP III: PERSISTENT GENERALISED LYMPHADENOPATHY (PGL)
Palpable lymphadenopathy (lymph node enlargement of >1cm) at two or more extra-inguinal sites
persisting for more than three months in the absence of a concurrent illness or condition other than HIV
infection to explain the findings.
GROUP IV: OTHER HIV DISEASE
The clinical manifestations of patients in this group may be designated by assignment to one or more
subgroups (A through E) listed below. Within Group IV, subgroup classification is independent of the
presence or absence of lymphadenopathy. Each subgroup may include patients who are minimally
symptomatic as well as patients who are severely ill. Increased specificity for manifestations of HIV
infection, if needed for clinical purposes, research purposes, or disability determinations, may be achieved
by creating additional divisions within each subgroup.
Subgroup A: Constitutional Disease. One or more of the following: fever persisting more than
one month, involuntary weight loss of >10% of baseline, or diarrhoea persisting more than one
I-23
month; and, the absence of a concurrent illness or condition other than HIV infection to explain the
findings.
Subgroup B: Neurologic Disease. One or more of the following: dementia, myelopathy, or
peripheral neuropathy; and, the absence of a concurrent illness or condition other than HIV
infection to explain the findings.
Subgroup C: Secondary Infectious Diseases. The diagnosis of an infectious disease associated
with HIV infection and/or at least moderately indicative of a defect in cell-mediated immunity.
Patients in this subgroup are further divided into two categories:
Category C-1. Includes patients with symptomatic or invasive disease due to one of twelve
specified secondary infectious diseases listed in the surveillance definition of AIDS (this
subgroup includes patients with one or more of the specified infectious diseases listed among
the indicator diseases).
Category C-2. Includes patients with symptomatic or invasive diseases due to one of six
other specified secondary infectious diseases: oral hairy leukoplakia, multidermatomal
HZV, recurrent Salmonella bacteraemia, nocardiosis, TB, or oral candidiasis (thrush).
Subgroup D: Secondary Cancers. The diagnosis of one or more kinds of cancer known to be
associated with HIV infection: KS, non-Hodgkin’s lymphoma (small, noncleaved lymphoma or
immunoblastic sarcoma), or primary lymphoma of the brain.
Subgroup E: Other Conditions in HIV Infection. The presence of other clinical findings or
diseases not classifiable above, which may be attributed to HIV infection and/or may be indicative
of a defect in cell-mediated immunity.
CDC HIV/AIDS CLASSIFICATION SCHEME

Where CD4+ T cell count testing is routinely available, some clinicians may find it useful to classify HIV
disease using the CDC classification system. Using this system, an HIV-infected individual’s status is
designated by a letter (A, B, or C) that corresponds to his/her most advanced clinical status, followed by a
number (1, 2, or 3) that corresponds to his/her nadir CD4+ T cell count, as outlined below:
Clinical Status*
NADIR CD4+ T CELL COUNT A B C
3
>500 cells/mm A1 B1 C1
200-500 cells/mm3 A2 B2 C2
<200 cells/mm3 A3 B3 C3
*Clinical Status Key:
A. Asymptomatic, PGL, or acute HIV infection
B. Having had symptoms judged to be attributable to HIV infection, but not an AIDS
indicator disease
C. Having had an AIDS indicator disease, as outlined above.
The boxes highlighted in red denote individuals classified as having AIDS, based on the presence of an
AIDS indicator disease or an absolute CD4+ T cell count of <200 cells/mm3.
I-24
Table 10: Other Known Causes of Immunosuppression
• Systemic corticosteroid therapy
• Other immunosuppressive or cytotoxic therapy
• Cancer of lymphoreticular or histiocytic tissue such as lymphoma (except for lymphoma
localised to the brain, Hodgkin’s disease, lymphocytic leukaemia, or multiple myeloma)
• Age under twenty-eight days (neonatal) at diagnosis
• Age under six months at diagnosis
• An immunodeficiency atypical of AIDS, such as one involving hypogammaglobulinaemia or
angioimmunoblastic lymphadenopathy, or an immunodeficiency of which the cause appears to
be a genetic or developmental defect rather than HIV infection
• Exogenous malnutrition (starvation due to food deprivation, not malnutrition due to
malabsorption or illness)
Table 11: Diagnostic Methods for Indicator Diseases of AIDS

Cryptosporidiosis Microscopy (histology or cytology)
Isosporiasis Microscopy (histology or cytology)
KS Microscopy (histology or cytology)
Lymphoma Microscopy (histology or cytology)
PCP Microscopy (histology or cytology)
PML Microscopy (histology or cytology)
Toxoplasmosis Microscopy (histology or cytology)
Candidiasis Gross inspection by endoscopy or autopsy or by microscopy
(histology or cytology) on a specimen obtained directly from the
tissues affected, not from culture
Coccidioidomycosis Microscopy (histology or cytology), culture, or detection of
antigen in a specimen obtained directly from the tissues affected
or a fluid from those tissues
Cryptococcosis Microscopy (histology or cytology), culture, or detection of
CMV Microscopy (histology or cytology), culture, or detection of
HSV Microscopy (histology or cytology), culture, or detection of
MAC Culture
Recurrent Bacterial Infection M. tuberculosis or smear, histology
HIV Encephalopathy Clinical findings of disabling cognitive or motor dysfunction
interfering with occupation of activities of daily living,
progressing over weeks to months, in the absence of a
concurrent illness or condition other than HIV infection that
could explain the findings. Methods to rule out concurrent
illness and conditions must include cerebrospinal fluid (CSF)
examination and either brain imaging (CT scan, MRI) or
autopsy.
I-25
APPENDIX D: WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN ADULTS AND
ADOLESCENTS
CLINICAL STAGE I
o Asymptomatic
o Persistent generalised lymphadenopathy
Performance Scale 1: Asymptomatic, normal activity
CLINICAL STAGE II
o Weight loss of <10% of body weight
o Minor mucocoetaneous manifestations (e.g. seborrhoeic dermatitis, prurigo, fungal nail
infections, recurrent oral ulcerations, angular cheilitis)
o Herpes zoster (HZV) within the last five years
o Recurrent upper respiratory tract infections (e.g. bacterial sinusitis)
Performance Scale 2: Symptomatic, normal activity
CLINICAL STAGE III

o Weight loss of >10% of body weight
o Unexplained chronic diarrhoea for >1 month
o Unexplained prolonged fever (intermittent or constant) for >1 month
o Oral candidiasis (thrush)
o Oral hairy leukoplakia
o Pulmonary TB within the past year
o Severe bacterial infections (e.g. pneumonia, pyomyositis)
Performance Scale 3: Bedridden <50% of the day during the last month
CLINICAL STAGE IV
o HIV wasting syndrome, as defined by the CDC
o Pneumocystis jiroveci pneumonia (PCP)
o Toxoplasmosis of the brain
o Cryptosporidiosis with diarrhoea for >1 month
o Cryptococcosis, extrapulmonary
o Cytomegalovirus (CMV) disease of an organ other than liver, spleen, or lymph nodes
o Herpes simplex viral (HSV) infection mucocoetaneous for >1 month or visceral any
duration
o Progressive multifocal leukoencephalopathy (PML)
o Any disseminated endemic mycosis (e.g. histoplasmosis, coccidioidomycosis)
o Candidiasis of the oesophagus, trachea, bronchi, or lungs
o Mycobacterium avium complex, disseminated
o Non-typhoid Salmonella septicaemia
o Extrapulmonary TB
o Lymphoma
o Kaposi’s sarcoma (KS)
o HIV encephalopathy as defined by the CDC
Performance Scale 4: Bedridden for >50% of the day during the last month
I-26
REFERENCES
1
Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in
patients with HIV infection. Ann of Int Med 2000;133(1):21-30.
2
Smith S, Marcus C, et al. A medication self-management program to improve adherence to HIV therapy
regimens. Pat Educ Couns 2003;50(2):187-99.
3
Adomakoh N. Adherence strategies in Barbados. Paper presented at the First CHART Caribbean
Conference on the Clinical Management of HIV/AIDS: A Multidisciplinary Team Approach, 16-19 Jun
2004, Kingston, Jamaica.
4
World Health Organisation. Adherence to long term therapies: evidence for action. 2003:27-32.
Available at: <http://www.who.int/chronic_conditions/ adherencereport/en/>. Accessed 2003.
5
Ibid.
6
American Public Health Association. Adherence to HIV treatment regimens: recommendations for best
practices. June 2004 version:20-25. Available at: < http://www.apha.org/ppp/hiv/>. Accessed 2004.
7
WHO, 2003.
8
APHA, 2004:34-40.
9
Ibid.
10
WHO, 2003:89-91.
11
Adomakoh, 2004.
12
Weller P. Adherence and ART: a summary of psychosocial issues. Paper presented at the First CHART
Caribbean Conference on the Clinical Management of HIV/AIDS: A Multidisciplinary Team
Approach. 16-19 Jun 2004, Kingston, Jamaica.
13
Centers for Disease Control and Prevention. Incorporating HIV prevention into the medical care of
persons living with HIV: recommendations of CDC, the Health Resources and Services Administration,
the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society
of America. MMWR [serial on the Internet] 2003 Jul 18 [cited 2005] 52(RR12):1-24. Available at:
http://www.cdc.gov/mmwr.
14
Kamb ML, Rhodes F, Hoxworth T, Rogers J, Lentz A, Kent C, et al. What about money? Effect of
small monetary incentives on enrollment, retention, and motivation to change behaviour in an HIV/STD
prevention counselling intervention. The Project RESPECT Study Group. Sex Trans Infect
1998;74(4):253-5.
15
Bain B and Reid M. An assessment of the readiness of Jamaican doctors to receive further training in
HIV/AIDS care. Paper presented at: Institute for Healthcare Improvement (IHI) International
Conference on Excellence In HIV/AIDS Education and Training, Sept 2002, Arlington, MD.
16
Bain B, McGaw A, et al. Jamaican Pharmacists and HIV/AIDS. Paper presented at the Eighth
Conference of the Commonwealth Pharmaceutical Society, 14-17 Aug 2003, Ochos Rios, Jamaica.
17
Natter J, Fiano T, Gamble B, Wood RW. Integrating HIV prevention and care services: the Seattle
"Collaboration Project". J Pub Health Manag Pract 2002;8(6):15-23.
18
Pan American Health Organisation. AIDS Surveillance in the Americas. Biannual Report, December
2001. Washington DC: PAHO, 2001.
I-27
II. COMMON CLINICAL MANIFESTATIONS OF UNDIAGNOSED
HIV INFECTION
TABLE OF CONTENTS
INTRODUCTION........................................................................................................................................ II-1
COMMON DERMATOLOGIC MANIFESTATIONS OF HIV INFECTION .................................................... II-1
COMMON ORAL AND DENTAL MANIFESTATIONS OF HIV INFECTION ............................................... II-6
TABLES
Table 1: Common Dermatologic Manifestations of HIV Infection ............................................................ II-2
Table 2: Summary of Oral Manifestations of HIV/AIDS .......................................................................... II-7
APPENDIX A: IMAGES OF COMMON MANIFESTATIONS OF HIV INFECTION ........................................... II-13
II-i
II: COMMON CLINICAL MANIFESTATIONS OF UNDIAGNOSED HIV INFECTION
INTRODUCTION
This chapter briefly describes several dermatologic and oral complications of HIV infection that may be
observed on routine examination in patients attending outpatient clinics. It is hoped that this chapter will
assist clinicians in recognising and properly treating these conditions, many of which may present in
individuals not yet diagnosed with HIV infection, prompting consideration of HIV testing. The appendix
to this chapter includes a number of photographs of these conditions to better serve the clinician at the
point of care.
For the sake of brevity, the list of conditions presented in this chapter is not intended to be
comprehensive, nor is the management presented in great detail; only general principles of therapy for
common presentations are offered. A more comprehensive review of many conditions presented herein
can also be found in Chapter V: Recommendations for the Treatment of Opportunistic Infections among
Adults and Adolescents and in Chapter X: Diagnosis and Treatment of Opportunistic Infections among
HIV-Exposed and –Infected Children. The reader is also encouraged to consult an HIV expert clinician
and/or other references for further information. Chapter I includes a list of some popular resources for
clinical consultation.
COMMON DERMATOLOGIC MANIFESTATIONS OF HIV INFECTION
Throughout the Caribbean, many patients infected with HIV initially present to a healthcare facility due to
a skin complaint. Physicians practising in the region should therefore be knowledgeable about the skin
conditions common in people living with HIV/AIDS (PLWHA). Many common skin disorders present in
an aggressive form in PLWHA, especially in those with advanced HIV disease. Hence, any unusually
aggressive skin condition should warrant consideration of undiagnosed HIV infection.
Long before the era of highly active antiretroviral therapy (HAART), physicians in the region had become
familiar with many of the characteristic dermatologic presentations of HIV/AIDS. A clinical study
conducted among HIV-infected patients attending a Bahamian dermatology clinic indicated that the
leading HIV-associated skin disorders were seborrhoeic dermatitis, papular pruritic eruption, herpes
zoster, hypo- and hyperpigmentation, xeroderma, folliculitis, and diffuse alopaecia with loss of the natural
peppercorn curl in Afro-Caribbean patients (e.g. the thinning and straightening of hair).
The introduction of HAART to the region reduced the incidence of skin diseases among patients
receiving antiretroviral therapy. However, close monitoring of the skin is still recommended for all
patients on HAART, as several of the antiretroviral (ARV) medications can cause severe drug eruptions
including toxic epidermal necrolysis and Stevens-Johnson syndrome. It is also important to note that
other skin eruptions may indicate treatment failure and clinical HIV disease progression. Referral to a
dermatologist experienced in HIV skin management is recommended.
The management of these dermatological conditions remains a challenge due to a relative lack of proper
diagnostic equipment and prescription skin medications in many islands through the region.
II-1
Table 1: Common Dermatologic Manifestations of Undiagnosed HIV Infection
SKIN CONDITION DIAGNOSTIC CLUES USUAL TREATMENT
FUNGAL AND YEAST INFECTIONS
Candidiasis Moist, scaling lesions with Topical imidazoles useful, but systemic
satellite papules. Intertriginous therapy may be needed, e.g.
infections common. Fingernail ketoconazole.
infection often presents with
paronychia.
Cryptococcosis Widespread, skin-coloured, Rule out Cryptococcal meningitis.
dome-shaped, translucent Systemic amphotericin B or
papules or nodules. Often fluconazole 400-800gm q.d x 8 weeks
resembles molluscum then 200gm q.d.
contagiosum on face and neck.
Histoplasmosis Slightly pink 2-6mm coetaneous Amphotericin B or itraconazole.
papules to larger reddish
plaques and multiple shallow
crusted ulcerations.
Seborrhoeic dermatitis Erythematous dermatitis, scaly, Mild topical steroid + imidazole usually
itchy plaques with indistinct effective. Oral imidazole occasionally
margins affecting scalp, face, needed. Regular use of dandruff
ears, hairline, chest, upper back, shampoo containing selenium sulphide
axillae, and groin. (Selsun®), zinc pyrithione (Head &
Shoulders®), zincon, sulphur and
salicyclic acid (Sebulex®), or polytar.
Dermatophytosis Scaly annular plaques with Topical imidazole or terbinafine. For
active borders and central nail involvement, systemic fluconazole
clearing, may become extensive 150mg q.w x 4 weeks or terbinafine
with confluent hyperpigmented 250mg q.d x 2 weeks (6-12 weeks for
patches. Anogenital and nail toenails).
involvement common.
VIRAL INFECTIONS
Herpes simplex Grouped vesicular lesions; large Oral acyclovir or valacyclovir until
erosions may be seen in lesions heal (approx. 1 week). IV
advanced HIV disease. therapy for CNS involvement. Chronic
suppressive therapy often necessary.
Herpes zoster Unilateral vesicular or bullous High-dose oral acyclovir (800mg 4-6x
dermatomal eruption, q.d), famciclovir 500mg po t.i.d, or
sometimes multidermal; bullae valacyclovir (Valtrex®) 1.0g t.i.d for 7-
may become haemorrhagic; 10 days. IV therapy in severe cases.
persistent pain. Adjuvant topical antibiotics may be
beneficial. Gabapentin, tri-cyclic
antidepressants for post-herpetic
neuralgia.
II-2
Molluscum contagiosum 2-5mm pearly, flesh-coloured Chemical cauterisation (silver nitrate,
papules typically on the face podophyllin, 5-fluorouracil, phenol,
and anogenital region, often tretinoin) or light cautery or
with central umbilication. cryotherapy of lesions. Often improves
with HAART.
Human papillomavirus (warts, Diffuse flat and filiform lesions Podophyllin chemical cautery,
condyloma acuminata) especially in anogenital region electrocautery, cryotherapy, surgery, or
though can occur elsewhere. laser ablation.
BACTERIAL INFECTIONS
Staphylococcus aureus Cellulitis, abscesses, bullous Oral antibiotics with adjuvant topical
impetigo, ecthyma, and therapy, drainage of abscesses;
folliculitis are all common. antipruritic therapy prn.
Secondary syphilis (due to Rash may take many forms. Benzathine penicillin (3 weekly IM
Treponema pallidum infection) Copper-coloured lesions are doses of 2.4 million U).
often present on palms and
soles. Serology may be
negative in advanced HIV
disease. CNS involvement
common.
Bacillary angiomatosis (due to Friable vascular papules, Erthyromycin 500mg po q.6h or
Bartonella henselae infection) plaques, and subcoetaneous doxycycline 100mg b.i.d x 12 weeks.
nodules, usually tender.
Lesions may be pedunculated,
verrucous, and bleed
extensively with trauma. Can
be confused with Kaposi’s
sarcoma.
OTHER SKIN DISORDERS
Scabies Excoriated, crusted, small Benzyl benzoate (12.5% in children
papules, burrows, intense and 25% in adults) or permethrin 5%
itching, worse at night. cream x 1 day. Repeat in 7days.
Antihistamines for relief of itching.
Crusted (Norwegian) scabies Highly contagious disseminated Isolate patient if possible until therapy
scabies infection characterised is complete. Permethrin 5% cream at
by erythema, hyperkeratosis, least weekly until coetaneous
and crusting. May be non- manifestations clear. Ivermectin 6%
pruritic; bacterial superinfection ointment daily may be added; oral
can lead to sepsis. ivermectin also effective.
Eosinophilic folliculitis Marked pruritus; discrete Astemizole 10mg q.d + topical steroid
erythematous or (oral imidazole use contraindicated
hyperpigmented follicular with astemizole); UV phototherapy;
papules on trunk, head, neck, permethrin; antihistamines for relief of
and proximal extremities. itching.
II-3
Kaposi’s sarcoma (KS) Early lesions are round or Numerous options depending on
irregular dark brown to location and severity including local
violaceous or pinkish red radiotherapy, cryotherapy, intralesional
macules, papules, or plaques. vinblastine, or interferon alpha; surgical
Usually non-tender. Often excision. Often improves and may
symmetrical along skin tension even remit with HAART. Look for
lines. Lesions can resemble visceral (e.g. GI, pulmonary)
ecchymoses. Oral lesions may involvement.
precede skin lesions.
Non-Hodgkin’s lymphoma Skin lesions are usually papules Chemotherapy.
or nodules.
Drug reactions and eruptions TMP-SMX, erythromycin, Withdraw suspected drug. Stevens-
dapsone, Dilantin®, NNRTIs Johnson syndrome and toxic epidermal
(NVP>EFV) are common necrolysis are managed as burns with
culprits. HIV+ patients have intensive inpatient supportive care.
increased frequency of skin
reactions to many drugs,
ranging from a fixed drug
eruption to generalised maculo-
papular eruption, exfoliative
dermatitis, and even Stevens-
Johnson syndrome, toxic
epidermal necrolysis, or
anaphylaxis.
Psoriasis Incidence and severity Topical steroid or tar preparations,
heightened in HIV disease. antimicrobial therapy for
Secondary bacterial infection superinfection. Often improves with
common. HAART.
Pruritic papular eruption Scattered itchy papules and Topical steroids may help. Doxepin
plaques predominantly on (starting at 10mg q.d and increased to
extremities. Recent research as much as 150mg q.d) may be an
suggests arthropod (insect) bites effective antipruritic. Anecdotal
followed by exaggerated evidence that condition improves with
immune response are HAART.
responsible.
Disturbance in pigmentation Areas of hypo- or Cosmetic cover creams. May improve
hyperpigmentation. with HAART. Consider substituting
Hyperpigmentation commonly another NRTI for AZT.
seen in nails, skin, or oral
mucosa of dark-skinned persons
taking AZT.
Diffuse hair loss (alopaecia) or Hair becomes thin and sparse; May improve with HAART.
change in hair appearance loss of natural tight curl in Afro-
Caribbean patients.
II-4
Xeroderma Severe dryness of the skin of Topical emollients prn (e.g. Aquaphor®
face, trunk, and extremities. ointment).
Prurigo nodularis Hyperpigmented, hyperkeratotic Oral antihistamines, potent topical
excoriated itchy papules and steroids under occlusion.
nodules.
Hyperpigmented or blue nails Common, but benign, side Reassurance; consider substituting
effect of AZT. another NRTI for AZT if distressing to
patient.
II-5
COMMON ORAL AND DENTAL MANIFESTATIONS OF HIV INFECTION
Oral lesions are an important component of the spectrum of disease seen in HIV infection. There are
almost forty different lesions reported in association with HIV disease. Presence of any of these lesions
may be an early diagnostic indicator of immunodeficiency and HIV infection. Some oral lesions are also
indicators of the disease’s progression.
Current classification of many oral lesions of HIV disease is based on their strength of association with
HIV infection:
Lesions Strongly Associated with HIV Infection:
¾ Fungal Infections:
Pseudomembranous Candidosis
Erythematous Candidosis
Candidal Angular Cheilitis
¾ Hairy Leukoplakia
¾ Linear Gingival Erythema
¾ Necrotising Ulcerative Gingivitis
¾ Necrotising Ulcerative Periodontitis
¾ Necrotising Ulcerative Stomatitis
¾ Kaposi’s Sarcoma
¾ Non-Hodgkin’s Lymphoma
Lesions Less Commonly Associated with HIV Infection:
¾ Viral Infections:
Herpes Simplex
Herpes Zoster
Condyloma Acuminata
Verruca Vulgaris
¾ Salivary Gland Disease:
Xerostomia
Salivary Gland Swelling
¾ Thrombocytopaenic Purpura
¾ Recurrent Aphthous Ulcers
¾ Melanotic Hyperpigmentation
¾ Cryptococcosis
¾ Histoplasmosis
II-6
Table 2: Summary of Oral Manifestations of HIV/AIDS
CONDITION/DISEASE SALIENT CLINICAL DIAGNOSIS TREATMENT REMARKS
FEATURES
Pseudomembranous Soft white/yellow, curd- Clinical grounds; Topical antifungals:
Candidosis like plaques on oral smear stained by
Mycostatin Pastilles: Contains nystatin 200,000
mucosa. Deposits easily Gram’s or PAS stain
units/tablet. Pastilles are more
removable by gentle show candidal Dissolve 1 tablet in mouth until gone, 4-5x q.d
effective than oral suspension due
scraping. hyphae; candidal x 14 days.
to prolonged contact.
culture.
Mycostatin Oral Suspension: Contains nystatin 100,000 units/ml.
Do not eat or drink for 30 minutes
Use 1 teaspoon 4-5x q.d, rinse and hold in
following application.
mouth as long as possible before swallowing
or spitting out (approximately 2 minutes).
Mycostatin Ointment or Cream: Contains nystatin 100,000 units/g.

Denture-wearers should apply to
Apply liberally to affected areas 4-5x q.d.
denture surface prior to each
insertion. For edentulous patients,
mycostatin powder can be sprinkled
on the denture.
Mycelex® Troche: Contains clotrimazole. Tablets

contain sucrose; risk of dental
10mg: dissolve 1 tablet in the mouth 5x q.d x
caries with prolonged use (>3
2 weeks.
months); care must be exercised in
diabetic patients.
Nizoral®: Contains ketoconazole. To be
taken if Candida infection does not
200mg: take 1 tablet q.d x 10-14 days.
respond to Mycostatin. Potential
for liver toxicity exists. LFT should
be monitored with long term use
(>3 months).
II-7
FEATURES
Nystatin: Contains nystatin.
(100,000 units) vaginal tablet dissolved in the
mouth t.i.d x 2 weeks.
Diflucan®: Contains fluconazole.
100mg: 2 tablets the first day and 1 tablet q.d
x 10-14 days.
Mycolog Cream: Contains nystatin and
triamcinolone. For candidal
Apply to affected area after each meal and
angular cheilitis. This often
before bedtime.
represents a mixed infection of
Candida and other organisms.
Fungizone® Oral Suspension: Contains amphotericin B. NOTE:
When amphotericin B is used,
1ml swish and swallow q.i.d between meals.
pharmacologic antagonism may
occur with ketoconazole and
miconazole. It may increase
toxicity of cyclosporin. Anti-
neoplastic agents may increase the
risk of toxicity of amphotericin-
induced nephrotoxicity,
bronchospasm, and hypotension.
Patients receiving digitalis may
present toxicity.
Erythematous Candidosis Flat red patches on the As above. As above. As above.
dorsal surface of the
tongue and hard palate.
Candidal Angular Cheilitis Red, ulcerated, and As above. Mycolog Cream: Occasionally this may be caused by
fissured lesion at the a mixed infection.
(See above.)
angle of the mouth.
II-8
FEATURES
Hairy Leukoplakia (Oral Asymptomatic bilateral, Clinical and Zovirax® (Acyclovir): Systemic administration causes
Hairy Leukoplakia) vertically corrugated or histological; some regression of HL. HL is not a
200mg: 1 capsule q.6h x 2 weeks. Surgery,
hairy white lesions on demonstration of the premalignant lesion.
cryotherapy, or application of podophyllin.
the lateral borders of the virus; (EBV) by in
tongue. situ hybridisation
techniques or PCR
Linear Gingival Erythema Well-demarcated, linear Clinical No treatment is necessary. Does not respond to oral
band of intense redness prophylaxis.
along the gingival
margins.
Necrotising Ulcerative Painful ulceration of the Clinical; smear for Metronidazole: Use with caution in patients with
Gingivitis interdental papillae identification of blood dyscrasias, liver impairment,
500mg: t.i.d x 7 days.
associated with halitosis fusospirochetal CNS/renal disease. Metronidazole
and spontaneous organisms. Oral prophylaxis (scaling and debridement) is increases the bleeding tendency in
gingival bleeding. needed for these patients. those on warfarin. No alcohol to be
consumed during the treatment with
metronidazole. May recur. Referral
to dentist for management.
Necrotising Ulcerative Rapidly progressive Clinical; radiological As above. Common cause of tooth loss;
Periodontitis (NUP) periodontal disease referral to dentist for management.
Debridement of necrotic tissue.
resulting in bone loss.
Necrotising Ulcerative Extension of NUP into Clinical; radiological As above. Referral to dentist for management.
Stomatitis soft tissues. Bone
Debridement of necrotic tissue.
sequestra.
Kaposi’s Sarcoma Painless Clinical; histological Surgery Referral to an oncologist or
purple/violaceous lesions specialist for management.
Cryotherapy
on palatal/anterior
gingival mucosa; later Radiotherapy and intralesional injection of
becomes raised and vincristine
ulcerated.
II-9
FEATURES
Non-Hodgkin’s Sarcoma Rapidly enlarging Clinical; histological Surgery Referral to an oncologist.
rubbery mass in the
Radiotherapy
tonsillar fossa, palate, or
gingival. Chemotherapy
Herpes Simplex (HSV) Clusters of painful, small Clinical; smear for Zovirax® (Acyclovir): Use with caution in patients with
vesicles/ulcers on palate viral inclusion bodies renal, neurologic, and hepatic
200mg: 1 capsule q.6h x 2 weeks.
or gingivae. Most cases diseases.
of HSV infections are Denavir® (Penciclovir) 1% Cream:
Contraindications: hypersensitivity
recurrent. Herpes Apply locally q.2h x 4 days. to the drug.
labialis lesions are on the
vermilion or Vira-A 1% (Vidarabine) Ointment:
mucocoetaneous Apply to affected areas q.i.d.
junction on the lips;
form crusts on rupture.
Herpes labialis is also
known as cold sores.
Herpes Zoster Prodrome of pain, Clinical As above.

multiple vesicles on
Carbamazepine (for post-herpetic neuralgia):
facial skin, lips, and
intraoral structures. 200mg: b.i.d to start; 800-1,200mg q.d (in
Follows the nerve divided doses) x 2 weeks.
distribution. May be
complicated by post-
herpetic neuralgia.
Condyloma Acuminata Warts are nodular or Clinical; histological Surgery Caused by human papillomavirus;
(Verruca Vulgaris) cauliflower-like in uncommon in oral tissues.
CO2 laser surgery
appearance, often
multiple.
II-10
FEATURES
Xerostomia Dry mouth, often with Clinical Artificial saliva Sucking ice cubes or lemon drops
fissured tongue. can be helpful.
Sodium Carboxymethylcellulose (Baker-
Promotes dental caries.
Perkins) 0.5% Aqueous Solution:
To be used as a rinse as needed.
Any of the following:
Xerolube®/Moi-Stir®/MouthKote®/
Optimoist™/Salivart®
Salivary Gland Swelling Unilateral/bilateral Clinical If xerostomia is present, as above. If xerostomia is present, as above.
salivary gland swellings.
Thrombocytopaenic Purpura Bleeding tendencies; Clinical; platelet Platelet transfusions in severe platelet No dental surgical intervention
petechiae on oral count deficiency. unless platelet numbers are
mucosa. restored.
Melanotic Melanotic linear lesions Clinical No treatment is necessary. Due to ARV drug reaction.
Hyperpigmentation on the gingivae.
Cryptococcosis Necrotic ulcerative Clinical; smear Antifungal treatment. Oral involvement is rare.
lesions. culture
Histoplasmosis Necrotic growth/ulcers. As above. As above. As above.
Erythema Multiforme Ulcerative lip and Clinical Withdrawal of the drug. Referral to a specialist.
intraoral lesions.
Sometimes antiviral drugs help.
Lichenoid Reactions White lace-like lesions Clinical; histological Topical steroid application. Withdrawal of cause if known.
on the oral mucosa. ®
Kenalog (triamcinolone acetonide) in
Orabase cream 3-4x q.d x 1 week.
Tuberculous Ulcers Ulcerative lesions usually Clinical; histological Treat the systemic disease with anti-TB drugs. Though TB is on the increase, oral
on the tongue or gingivae. (AFB stain); chest x- involvement is uncommon.
Usually patient has ray; tests for TB
pulmonary TB.
II-11
FEATURES
Trigeminal Neuralgia Shock-like pain along History Carbamazepine Uncommon
the distribution of the
trigeminal nerve.
Facial Palsy Unilateral paresthaesia History; clinical Sometimes antiviral medications help. Uncommon
of the face.
Dental Caries Dental decay. Clinical Early detection and appropriate treatment. Increased dental caries experience
in HIV patients due to poor oral
hygiene, xerostomia, etc.
II-12
III. SPECIAL CONSIDERATIONS FOR THE CARIBBEAN:
MANAGEMENT OF THE PATIENT WITH HIV AND SICKLE CELL
DISEASE, DENGUE FEVER, MALARIA, OR HTLV-1
TABLE OF CONTENTS
HIV AND SICKLE CELL DISEASE ........................................................................................................... III-1

Epidemiology ....................................................................................................................................... III-1
Clinical Manifestations ......................................................................................................................... III-1
Management of the Patient with Co-Morbid SCD and HIV Infection.................................................. III-1
Paediatric Considerations...................................................................................................................... III-2
HIV AND DENGUE FEVER ....................................................................................................................... III-2
Epidemiology ........................................................................................................................................ III-2
Management of the Patient with Dengue Fever and HIV Infection...................................................... III-2
Documentation ...................................................................................................................................... III-2
HIV AND MALARIA ................................................................................................................................. III-2
Diagnosis............................................................................................................................................... III-3
Management of the Patient with Malaria and HIV Infection ................................................................ III-3
Interactions between Malaria and HIV ................................................................................................. III-3
Considerations for Pregnant Patients with Malaria and HIV or at Risk for Co-Infection..................... III-4
Other Treatment Considerations for Patients with Malaria and HIV.................................................... III-4
Prevention Considerations..................................................................................................................... III-5
Policy Recommendations...................................................................................................................... III-5
HIV AND HTLV-1 ................................................................................................................................... III-5
Possible Interactions between HTLV-1 and HIV.................................................................................. III-6
Diagnosis............................................................................................................................................... III-6
Treatment .............................................................................................................................................. III-6
Prevention ............................................................................................................................................. III-6
REFERENCES............................................................................................................................................ III-7
III-
HIV AND SICKLE CELL DISEASE
EPIDEMIOLOGY
Sickle cell disease (SCD) is a genetic disorder that is characterised by a chronic anaemia occurring almost
exclusively in individuals of African descent. Individuals afflicted with SCD are homozygous for a key
mutation in haemoglobin, whereas individuals who are heterozygous for this mutation are generally
asymptomatic and are said to have sickle cell trait. SCD is relatively common throughout the Caribbean
and could present some unique clinical management issues as a co-morbidity with chronic HIV infection.
CLINICAL MANIFESTATIONS
The clinical manifestations of SCD are due to both anaemia and vaso-occlusive events that result in tissue
ischemia and infarction. SCD patients suffering from painful vaso-occlusive events are said to be in
sickle cell crisis. Common causes of death for individuals with SCD are intercurrent infections, multiple
pulmonary emboli, occlusion of a vessel supplying a major organ, and renal failure. The average life span
of SCD patients is age forty to forty-five years.
Anaemia in SCD is usually stable but acute exacerbation of anaemia occurs in the setting of aplastic
crisis, in which marrow red blood cell (RBC) production abruptly slows down. Aplastic crisis is usually
the result of an acute infection; hence immunocompromised patients may be at higher risk for this
complication. Individuals with sickle cell trait who are also HIV-infected are not expected to have
significant worsening of any manifestations of their HIV disease or of their sickle cell trait.
MANAGEMENT OF THE PATIENT WITH CO-MORBID SCD AND HIV INFECTION
General Principles of Management
Infection with encapsulated organisms is more common in SCD patients with functional asplaenia. HIV
co-infection also appears to increase susceptibility to these infections, especially in children. Prophylactic
antibiotics, pneumococcal vaccine, and early identification and treatment of serious bacterial infections
are therefore critical.
The use of hydroxyurea (HU) in SCD is well established, and its use for treatment of HIV disease has
been investigated. However, data from controlled clinical trials have revealed high rates of toxicity (e.g.
pancreatitis, neuropathy, hepatotoxicity, and cytopaenias) and blunted CD4+ T cell count responses in
patients receiving HU with antiretroviral therapy (ART). Current guidelines therefore suggest that HU
should generally not be offered as adjunctive therapy for HIV infection. Unfortunately, no data exist
from controlled clinical trials involving patients with SCD who receive HU with ART. Clinicians
considering the use of HU for HIV-infected patients with SCD should be aware of the potential additional
toxicity of this agent when administered with nucleoside reverse transcriptase inhibitors (NsRTIs).
Management of Anaemia
Anaemia is a common consequence of SCD, HIV disease, and some antiretroviral (ARV) agents,
especially zidovudine (AZT). Therefore:
√ Patients should be screened for anaemia prior to initiation of ART;
√ The design of ARV regimens for patients at risk for anaemia should take into account the potential
of individual agents to induce or exacerbate anaemia;
√ Monitoring of haemoglobin levels is warranted after initiation of therapy, especially for patients
with SCD or other risk factors for anaemia;
√ ARV-induced anaemia typically improves once the offending agent is discontinued. Thus,
appropriate modification of a patient’s ARV regimen is advisable in the case of anaemia that is
attributable to one or more of the prescribed ARV agents.
III-1
Management of Sickle Cell Crisis
Therapy is largely symptomatic for the sickle cell crisis. Standard interventions include rehydration,
analgesics, and oxygen therapy. The presence of HIV infection in a patient suffering from a sickle cell
crisis does not alter this general approach.
PAEDIATRIC CONSIDERATIONS
Splenic malfunction is common in both SCD and HIV infection. Therefore, several of the common
infections seen in SCD also occur in HIV-infected children. However, while these two patient
populations are not uncommon in the Caribbean, none of the publications on cohorts of children with HIV
disease or sickle cell anaemia have described children afflicted with both disorders. Caribbean studies of
pneumococcal and/or Haemophilus influenzae Type B infections have similarly failed to document
outcomes involving children with both SCD and HIV infection.
HIV AND DENGUE FEVER

EPIDEMIOLOGY
Dengue is endemic in the Caribbean. Many dengue fever outbreaks have been documented in the region
with all three types of viruses (type 1, 2 and recently type 3). However, not enough data exist to draw a
firm conclusion regarding the relationship between dengue fever and HIV. The natural history and
clinical manifestations of co-infection with HIV and dengue has not been established; CAREC therefore
encourages Caribbean clinicians and researchers to investigate this issue.
MANAGEMENT OF THE PATIENT WITH DENGUE FEVER AND HIV INFECTION
Caribbean clinicians should be careful when using ARV drugs or agents to treat HIV-related conditions
that may induce anaemia or haemorrhagic reactions since these two clinical manifestations are common
among patients infected with dengue. Close monitoring is warranted for these complications among HIV-
infected individuals who contract dengue fever.
DOCUMENTATION
Given the paucity of data on this topic, clinicians must document a history of dengue infection among
HIV-infected patients, as well as any observed unusual or unexplained clinical manifestations or adverse
effects of medications used to treat HIV and HIV-related conditions among persons co-infected with HIV
and dengue.
HIV AND MALARIA

EPIDEMIOLOGY
Malaria is endemic in Belize, the Dominican Republic, French Guiana, Guyana, Haiti, and Suriname.
Other countries may also see sporadic cases of malaria infection due to migration and tourism. In
endemic countries, the intensity and periodicity of malaria transmission and the predominant Plasmodium
species vary broadly. For example, in Haiti and the Dominican Republic, nearly all malaria is caused by
P. falciparum, and the annual parasitic index (API, or number of confirmed malaria cases per 1,000
population at risk) is 2.1. In contrast, in Suriname, where malaria transmission is more intense than
anywhere else in the Americas, the API is 370.8, with cases contributed by three different species of
malaria: P. falciparum (approximately 80% of cases), P. vivax (10%), and P. malariae (10%).1
Drug resistance patterns also vary within the region. Although chloroquine-susceptible malaria,
particularly P. vivax, still occurs, resistance to both chloroquine and sulfadoxine-pyrimethamine (SP) has
become widespread particularly in the Amazon River basin, where some degree of P. falciparum
III-2
resistance to mefloquine and P. vivax resistance to primaquine have also been observed.2 Because
antimalarial drug resistance is evolving rapidly in many sites, the Pan American Health Organization
(PAHO), in conjunction with the Centers for Disease Control and Prevention (CDC) and the United
States Agency for International Development (USAID), has recently established a network for ongoing
evaluation of antimalarial drug resistance, for the purpose of guiding antimalarial drug policy.3 Some
countries with particularly high burdens of antimalarial drug resistance are now introducing artemisinin-
based combination therapies, such as artemether/lumefantrine, as recommended by recent World Health
Organisation (WHO) guidelines.4,5
In both HIV-infected and -uninfected persons, clinical syndromes caused by malaria infection vary
depending on transmission patterns (stable vs. unstable), Plasmodium species (P. falciparum vs. others),
and host immunity (related to age, transmission intensity, nutritional status, and HIV infection). At its
most symptomatic, malaria causes acute febrile syndromes that may be complicated by seizures, coma,
renal failure, and/or death. The clinical spectrum of malaria also includes chronic, often severe, anaemia
in the otherwise asymptomatic person.6 Although often undiagnosed until its later stages, malaria-related
anaemia is associated with more fatalities than any other malaria-related syndrome.7 Because of the great
variation in malaria species and transmission patterns in the Caribbean region, predominant clinical
syndromes will vary by site. Increased vigilance for anaemia is warranted in HIV-infected patients at risk
for malaria (especially in those who have other risk factors for anaemia, such as AZT use), and clinical
suspicion of malaria is warranted in the HIV-infected patient with unexplained anaemia or fever.
DIAGNOSIS
Although rapid tests for detection of Plasmodium species are currently being developed and evaluated,
inspection of stained blood smears for the presence of malaria is still the standard means of diagnosis.
Where multiple Plasmodium species are endemic, laboratory diagnosis should seek both to detect malaria
and to classify the infecting species. Creation of new laboratory capacity may be required in some sites.
MANAGEMENT OF THE PATIENT WITH MALARIA AND HIV INFECTION
Malaria infection can be rapidly fatal, especially in non-immune patients. Therefore, prompt diagnosis
and rapid administration of effective treatment must be easily available to patients where malaria is
endemic. Appropriate treatment for malaria infection depends on several factors: the severity of
infection; the responsible Plasmodium species (bearing in mind that mixed infections may occur); the
pregnancy status of the patient; local antimalarial drug-resistance patterns; national drug policy and
availability; and the likelihood of interactions or overlapping toxicities involving antimalarials and other
medications the patient may be taking, including ARV agents and other medications used in the
management of AIDS and its complications. Clear treatment guidelines devised to respond to varying
local conditions should be created at national (or regional) levels and should be updated frequently in
response to changing drug-resistance and transmission patterns.
The differential diagnoses of fever and anaemia are broad in the HIV-infected patient. In order to avoid
the unnecessary prescription (with resultant risks of toxicity and resistance) of antimalarials, it is
important to encourage laboratory confirmation of malaria infection prior to treatment (other than
prophylaxis in pregnancy) and to discourage patients from self-treatment with antimalarials where these
agents are available without prescription.
INTERACTIONS BETWEEN MALARIA AND HIV
HIV infection appears to increase both the susceptibility to and the severity of malaria infection. Most of
our understanding of the interaction between malaria and HIV comes from studies performed in Africa,
primarily involving infection with P. falciparum.
III-3
International literature suggests that HIV-infected patients appear to be more susceptible to acquiring
malaria infection,8 particularly if they are pregnant. Both the prevalence of malaria parasitaemia and the
incidence of clinical attacks of malaria are greater in patients with HIV-induced immunosuppression.
Furthermore, the risks of severe malaria and malaria-related death appear to be increased significantly in
HIV-infected patients of all ages who live in regions where malaria transmission is unstable.9
The influence of malaria on HIV infection is not as well characterised, but malaria infection appears to
increase the HIV viral load, which could result in an increased rate of HIV disease progression as well as
an increased risk of HIV transmission to others.10
CONSIDERATIONS FOR PREGNANT PATIENTS WITH MALARIA AND HIV OR AT RISK FOR
CO-INFECTION
Malaria infection is more common in pregnancy, especially in primigravidae and in the HIV-infected of
any gravidity.11 Although malaria in pregnancy is commonly asymptomatic, its consequences may
include severe maternal anaemia, maternal death, and low infant birth weight, regardless of maternal HIV
status. Infants born to HIV-infected mothers with malaria are more likely to die12 and are approximately
twice as likely to be infected perinatally with HIV if a high placental burden of malaria exists in the
mother.13 Intermittent preventive treatment (IPT) with antimalarial agents (usually SP) during pregnancy
improves pregnancy outcomes in regions of intense transmission of P. falciparum, probably by reducing
maternal malaria parasitaemia and placental malaria burden. The WHO now recommends IPT for
malaria in pregnancy in countries with high burdens of P. falciparum malaria.14
IPT regimens are not yet well-defined in regions where P. falciparum is not the predominant strain of
malaria, where transmission is infrequent, or where there are high levels of resistance to SP and
chloroquine. Where the risk of malaria is low, WHO recommends aggressive management of
symptomatic malaria cases and regular use of insecticide-treated bednets (ITNs), rather than IPT. The
safety of many newer antimalarials has not yet been well-established for use in pregnancy.15 Therefore,
guidelines for treatment of symptomatic malaria in pregnancy may require frequent revision as new data
become available.
Prophylactic co-trimoxazole (TMP-SMX) has been shown to reduce the prevalence of malaria
parasitaemia and the incidence of symptomatic malaria in non-pregnant adults in some settings.16
Therefore, the WHO now recommends that preventive SP not be given to HIV-infected pregnant women
who take daily TMP-SMX.17 However, no studies have yet demonstrated the effectiveness of daily TMP-
SMX prophylaxis for prevention of malaria complications in pregnancy, and the eventual development of
malaria resistance to TMP-SMX could limit the durability of this drug's usefulness for malaria prevention.
OTHER TREATMENT CONSIDERATIONS FOR PATIENTS WITH MALARIA AND HIV
SP Treatment in Patients Taking Daily TMP-SMX
As noted above, TMP-SMX has antimalarial activity with an efficacy similar to that of chloroquine or SP
in some studies.18 Unfortunately, TMP-SMX and SP are chemically similar enough that clinically
significant cross-resistance between the two agents is common. Hence, patients on prophylactic TMP-
SMX probably should not be treated with SP for symptomatic malaria where better options exist. Some
fear that cross-resistance could hasten the loss of SP as an effective antimalarial agent in regions where
TMP-SMX use becomes widespread.19,20 However, as artemisinin-containing combination regimens
supplant chloroquine and SP as first-line antimalarial agents, this issue may become less important.
Management of Fever in Children
Current WHO Integrated Management of Childhood Illness (IMCI) guidelines for malaria-endemic
regions recommend presumptive treatment of fever in children age five years or younger. TMP-SMX is
endorsed because of its effectiveness for treatment of both pneumonia and malaria.21 Where TMP-SMX
is being used prophylactically in large populations over a long period of time, it may lose its efficacy in
III-4
treating pneumonia, otitis, and malaria due to the development of drug resistance.22,23 The introduction of
new paediatric AIDS treatment initiatives may require revision of local IMCI algorithms.
Drug-Drug Interactions and Overlapping Toxicities
Some ARVs and antimalarials are known to have overlapping side effect profiles. For example, both
nevirapine (NVP) and SP have been associated with Stevens-Johnson syndrome and hepatic
necrosis.24,25,26 SP and AZT have both been associated with bone marrow suppression, and the
manufacturers of pyrimethamine (PZA) note that severe anaemia may result from co-administration of
PZA and AZT.27 There is little published or anecdotal information on drug interactions between newer
antimalarials and ARVs, although concerns about potential drug-drug interactions have been raised
regarding the co-administration of lumefantrine or halofantrine with many protease inhibitors (PIs).
Similar concerns exist regarding the co-administration of quinine or atovaquone with various PIs and non-
nucleoside reverse transcriptase inhibitors (NNRTIs).28 Increased vigilance for adverse drug reactions is
advisable when treating malaria in the patient who is also taking ARVs.
PREVENTION CONSIDERATIONS
Use of ITNs prevents malaria-related morbidity and mortality.29 ITN use is strongly recommended by the
WHO and others for children age five years or younger and pregnant women in areas where malaria is
endemic.30 In malaria-endemic regions, ITN use should also be recommended to all HIV-infected
persons. Where feasible, indoor residual spraying of insecticides should also be considered to prevent
malaria transmission.
POLICY RECOMMENDATIONS
In malaria-endemic regions, management guidelines and policies must be based upon regional incidence,
prevalence, and transmission patterns, as well as patterns of antimalarial drug resistance. Where these
data do not exist, efforts should be made to collect them. Close collaboration between national and
regional malaria and HIV control programs is essential for effective, evidence-based policy making. This
collaboration will be especially critical in developing diagnostic and management guidelines for HIV-
infected persons who develop febrile syndromes and/or anaemia, and for HIV-infected pregnant women
who are simultaneously eligible for prophylactic antimalarial regimens and long-term ART. Because of
the paucity of available information on drug interactions involving newer antimalarial drugs, ARVs, and
other medications involved in management of AIDS, pharmacovigilance directed toward detection of
drug interactions involving these agents is also strongly advised.
HIV AND HTLV-I

EPIDEMIOLOGY
HTLV-1 seroprevalence rates in the Caribbean vary from 0.3% to 7% in the general population, to 2% to
7% in pregnant women, and 5% in HIV-infected persons.31 Although HTLV-1 and HIV have similar
routes of transmission (perinatal, parenteral, and sexual), transmission of HTLV-1 is less efficient.32
Sexual transmission is more frequent from male-to-female than vice versa.33 Perinatal transmission of
HTLV-1 occurs primarily via breastfeeding, and although breastfeeding for more than six months is a
significant risk factor for perinatal transmission, periods less than six months may, in fact, protect against
transmission.34
HTLV-1 is associated with adult T-cell leukaemia/lymphoma (ATL) and HTLV-1-associated
myelopathy/tropical spastic paraparesis (HAM/TSP), but 95% of those infected with HTLV-1 never
develop symptoms.35 Infective dermatitis is a common HTLV-1-associated condition in the Caribbean
characterised by persistent refractory coetaneous infections with saprophytic staphylococcal and
III-5
streptococcal bacteria.36 A variety of other clinical conditions, including uveitis, arthritis, and Sjogren’s
syndrome, have been anecdotally associated with HTLV-1 infection.37
POSSIBLE INTERACTIONS BETWEEN HTLV-1 AND HIV
Co-infection of the same cell by HTLV-1 and HIV is possible.38 Some studies suggest a more severe
clinical course with shortened survival for AIDS patients co-infected with HTLV-1, whereas others
demonstrated no detrimental effect of HTLV-1 upon progression of HIV infection.39
DIAGNOSIS
Diagnosis of HTLV-1 infection requires positive serum HTLV-1 ELISA with confirmatory Western blot
assay. PCR is more sensitive and specific than serologic testing, and could be considered for patients
seronegative by conventional testing.
TREATMENT
Although there is no curative treatment for HAM/TSP, mild to moderate beneficial effects have been
reported with corticosteroids, immunosuppressants, gamma-globulin, and vitamin C.40 The HTLV-1
protease enzyme is distinct from the HIV protease enzyme, suggesting that some medications used for
HIV infection may not be effective for HTLV-1 infection.41 In vitro studies of the PIs indinavir (IDV),
saquinavir (SQV), ritonavir (RTV), and nelfinavir (NFV), have demonstrated no effect of these
medications upon HTLV-1.42 Two nucleoside analogues, AZT and zalcitabine (ddC), inhibit the
production of proviral HTLV-1 DNA in vitro.43 In people with HAM/TSP, use of AZT was associated
with improvement in neurologic function, but no improvement was noted in non-ambulatory patients.44
Chemotherapy can be curative for ATL, but is less successful for acute and lymphoma-type ATL.
PREVENTION
Guidelines published by the CDC and the U.S. Public Health Service (USPHS) recommend that an
HTLV-1-infected person should: not donate blood, semen, body organs, or other tissues; not share
needles or syringes; not breastfeed infants; and consider using latex condoms to prevent sexual
transmission.45 In resource poor settings, or in areas where clean water is not available for baby formula,
breastfeeding for six months may be necessary. In HIV-infected persons, condom use would likely
prevent acquisition or transmission of HTLV-1.
III-6
REFERENCES
1
Pan American Health Organisation. Status report on malaria programs in the Americas (based on 2001
data). Washington, DC: Pan American Health Organisation; 2002 Report No. CSP26/INF/3 (Eng.).
2
Carter K. Avances de la Red Amazónica de Vigilancia de la Resistencia a las Drogas Antimaláricas
(Ravreda). Biomédica (Bogotá) 2003;23(Suppl 1):75-6.
3
Pan American Health Organisation. Pan American Health Organisation's proposed contribution to the
United States Agency for International Development (USAID)/Latin America and Caribbean Bureau's
Amazon Malaria Initiative (AMI): project proposal and workplans for years 2 & 3. Mar 2003. Last
accessed 9 November 2004, http://www.paho.org/english/hcp/hct/mal/Mar03-paho-ami-2.htm.
4
Suriname to get new malaria drug. PAHO Today [serial on the Internet] 18 Mar 2004 [cited 9 November
2004]:[about 1 pg]. Available from: http://www.paho.org/English/DD/PIN/ptoday18_mar04.htm.
5
World Health Organisation. Position of WHO's Roll Back Malaria Department on Malaria Treatment
Policy. Last accessed 9 November 2004 http://www.paho.org/English/AD/DPC/CD/mal-who-position-
paper.htm.
6
Ekvall H. Malaria and anemia. Curr Opin Hematol 2003;10:108-14.
7
Breman J, Alilio M, Mills A. Conquering the intolerable burden of malaria: what's new, what's needed: a
summary. Am J Trop Med Hyg 2004;71(Suppl 2):1-15.
8
Grimwade K, French N, et al. HIV infection as a cofactor for severe falciparum malaria in adults living
in a region of unstable malaria transmission in South Africa. AIDS 2004;18:547-554.
9
Grimwade K, French N, et al. Childhood malaria in a region of unstable transmission and high human
immunodeficiency virus prevalence. Ped Infect Dis J 2003;22:1057-1063.
10
Hoffman I, Jere C, et al. The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma
concentration. AIDS 1999;13:487-94.
11
Van Eijk A, Ayisi J, et al. HIV increases the risk of malaria in women of all gravidities in Kisumu,
Kenya. AIDS 2003;17:595-603.
12
Bloland P, Wirima J, et al. Maternal HIV infection and infant mortality in Malawi: evidence for
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III-10
IV. RECOMMENDATIONS FOR ANTIRETROVIRAL THERAPY FOR ADULTS
AND ADOLESCENTS WITH HIV INFECTION
TABLE OF CONTENTS
OVERVIEW OF ANTIRETROVIRAL THERAPY (ART).......................................................................................IV-1
Highly Active Antiretroviral Therapy (HAART) ........................................................................................IV-1
Classes and Characteristics of ARVs...........................................................................................................IV-2
PRINCIPLES OF HAART: INITIAL THERAPY ..................................................................................................IV-3
Timing of HAART Initiation .......................................................................................................................IV-4
Adherence ....................................................................................................................................................IV-5
Treatment of Co-Morbid Opportunistic Infections (OIs).............................................................................IV-6
Laboratory Monitoring Prior to Initiation of HAART.................................................................................IV-7
Selection of the Initial HAART Regimen....................................................................................................IV-7
Selection of Individual Agents in the HAART Regimen.............................................................................IV-8
Patient Follow-Up and Monitoring After Initiation of Therapy ..................................................................IV-12
TREATMENT FAILURE AND TREATMENT TOXICITY....................................................................................... IV-13
Treatment Failure: Clinical Definition........................................................................................................IV-13
Treatment Failure: Immunological Definition ............................................................................................IV-13
Treatment Failure: Virologic Definition .....................................................................................................IV-14
Treatment Toxicity.......................................................................................................................................IV-15
SECOND-LINE AND SALVAGE ANTIRETROVIRAL THERAPY ..........................................................................IV-17
HIV Resistance to Antiretroviral Therapy ...................................................................................................IV-17
Second-Line HAART Regimens .................................................................................................................IV-17
Salvage Therapy...........................................................................................................................................IV-20
HAART CONSIDERATIONS FOR PATIENTS WITH CO-MORBID DISEASES ....................................................IV-20
Patients with HIV and Tuberculosis (TB)....................................................................................................IV-20
Patients with HIV and Diabetes Mellitus.....................................................................................................IV-20
Patients with HIV and Chronic Liver Disease .............................................................................................IV-20
Patients with HIV and Renal Disease ..........................................................................................................IV-21
Patients with HIV and Other Sexually Transmitted Infections (STIs).........................................................IV-21
Patients with HIV and Neuropsychiatric Disorders .....................................................................................IV-21
METABOLIC COMPLICATIONS OF HAART AND HIV INFECTION .................................................................IV-21
Lactic Acidosis/Hepatic Steatosis................................................................................................................IV-21
Lipodystrophy ..............................................................................................................................................IV-22
Hyperlipidaemia...........................................................................................................................................IV-22
Insulin Resistance ........................................................................................................................................IV-22
Disorders of Bone Metabolism ....................................................................................................................IV-23
TABLES
Table 1: ARVs for Treatment of HIV Infection. .................................................................................................IV-3
Table 2: Combination NRTI/NNRTI Tablets for Antiretroviral Therapy. .............................................................IV-3
Table 3: General Recommendations of Initiation of HAART for HIV-Infected Adults and Adolescents ..................IV-5
Table 4: Selected Factors that Influence Adherence ..........................................................................................IV-6
Table 5: Advantages and Disadvantages of Different Types of HAART Regimens................................................IV-8
Table 6: Preferred Initial HAART Regimens .................................................................................................... IV-10
Table 7: Alternative Initial HAART Regimens .................................................................................................. IV-11
Table 8: Common Adverse Drug Reactions Associated with First-Line HAART Regimens and Recommended
Drug Substitutions....................................................................................................................................IV-16
Table 9: Second-Line Regimen Recommendations for Treatment Failure ...........................................................IV-19
Table 10: Selected Metabolic Complications in HIV ......................................................................................... IV-23
Table 11: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) ........................................................................IV-24
IV-i
Table 12: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) ..............................................................IV-28
Table 13: Protease Inhibitors (PIs) ................................................................................................................. IV-30
Table 14: Fusion Inhibitors ............................................................................................................................ IV-37
Table 15: Interactions between PIs ................................................................................................................. IV-38
Table 16: Interactions between PIs and NNRTIs .............................................................................................. IV-40
Table 17: Drug Interactions between ARVs and Other Drugs ............................................................................IV-41
Table 18: Major Mutations Associated with Reduced Susceptibility to NRTIs ......................................................IV-51
Table 19: Major Mutations Associated with Reduced Susceptibility to NNRTIs ....................................................IV-51
Table 20: Major Mutations Associated with Reduced Susceptibility to PIs...........................................................IV-52
APPENDIX A: CHARACTERISTICS OF ARVS ...................................................................................................... IV-24

APPENDIX B: DRUG-DRUG INTERACTIONS BETWEEN PIS AND NNRTIS .........................................................IV-38
APPENDIX C: DRUG INTERACTIONS BETWEEN ARVS AND OTHER DRUGS .....................................................IV-41
APPENDIX D: DRUGS THAT SHOULD NOT BE USED IN COMBINATION WITH PIS OR NNRTIS DUE TO DANGEROUS
DRUG INTERACTIONS .....................................................................................................................................IV-43
APPENDIX E: BASIC LABORATORY MONITORING FOR RECOMMENDED FIRST-LINE REGIMENS ...................IV-46
APPENDIX F: HIV RESISTANCE ........................................................................................................................ IV-48
Introduction..................................................................................................................................................IV-48
Resistance to Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) and Nucleotide Reverse Transcriptase
Inhibitors (NtRTIs) ......................................................................................................................................IV-48
Resistance to NNRTIs..................................................................................................................................IV-49
Resistance to PIs ..........................................................................................................................................IV-49
Resistance Testing .......................................................................................................................................IV-49
IV-ii
IV: RECOMMENDATIONS FOR ANTIRETROVIRAL THERAPY FOR
ADULTS AND ADOLESCENTS WITH HIV INFECTION
OVERVIEW OF ANTIRETROVIRAL THERAPY (ART)

HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (HAART)
HAART, defined as the combination of three or more antiretroviral (ARV) agents taken concurrently to
suppress HIV replication,* represents the current standard of care of antiretroviral therapy for individuals
infected with HIV. This strategy evolved from the recognition that treatment of chronic HIV infection
with only one or two ARV agents typically results in rapid treatment failure and the development of ARV
resistance, compromising future therapeutic options.
Ultimately, the goal of HAART is the prevention of HIV-associated morbidity and mortality. This is
most effectively achieved by suppressing HIV replication to a level below the limit of detection by viral
load assays (generally less than 50 copies/mL). Suppression of HIV replication with HAART is typically
associated with a significant rise in the CD4+ T cell count, reflecting partial reconstitution of the immune
system that results in reduced HIV-related morbidity and mortality and in improved quality of life.
Hence, for HIV-infected individuals initiating ARV therapy, full suppression of virologic replication
should be the goal. (See Figure 1 for a graphic depiction of the optimal response to HAART.) For highly
treatment-experienced patients who have developed significant resistance to various ARV agents,
© 2004 University of Washington
*
HAART can be more strictly defined as: (a) two or more NRTIs in combination with at least one PI or one NNRTI;
(b) one NRTI in combination with at least one PI and at least one NNRTI; (c) a regimen containing RTV and SQV
in combination with one NRTI and no NNRTIs; or (d) an ABC- or TDF-containing regimen of three or more NRTIs
in the absence of both PIs and NNRTIs. (Source: US DHHS. Guidelines for the use of antiretroviral agents in HIV-
1-infected adults and adolescents. 2004. Available at: http://AIDSinfo.nih.gov/guidelines. Accessed January 2005.)
IV-1
suppression of viral replication to an undetectable level may no longer be a realistic goal. However, an
appropriately designed HAART regimen for such patients will often result in stabilisation of HIV disease
progression, even in the absence of full virologic suppression.
CLASSES AND CHARACTERISTICS OF ARVs

HAART regimens are typically constructed using agents selected from two or three drug classes. These
classes are based on their mechanisms of action in suppressing HIV replication (see Figure 2). The three
main classes include the nucleoside reverse transcriptase inhibitors (NRTIs),* non-nucleoside reverse
transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). NRTIs and NNRTIs suppress HIV
replication by inhibiting the action of HIV reverse transcriptase, while PIs inhibit the HIV protease
enzyme. A fourth class of ARV agents has recently been introduced with enfuvirtide, a fusion inhibitor
that blocks HIV cell entry. However, enfuvirtide is not available in oral form, is very expensive, and is
generally only considered for patients with very few remaining ARV options (see Table 1 for a summary
of these ARV agents).
HAART regimens typically consist of two NRTIs (the nucleoside backbone) combined with an NNRTI or
one to two PIs. Choosing which combination to use depends on considerations of drug potency,
tolerability, potential for adherence, and resistance as discussed later in this chapter.
*
Tenofovir diproxil fumarate (TDF) is considered a member of the NRTI class, though technically, it is a nucleotide
reverse transcriptase inhibitor because it is monophosphorylated, whereas the nucleoside reverse transcriptase
inhibitors are not phosphorylated.
IV-2
Table 1: ARVs for Treatment of HIV Infection. (Agents in bold are commonly available in the
Caribbean. Commonly used abbreviations are in parentheses. Note that many of these agents are
available in combination forms of two or more medications combined into a single pill.)
NRTIs NNRTIs PIs FUSION
INHIBITORS
zidovudine (ZDV, nevirapine (NVP) nelfinavir (NFV) enfuvirtide (ENF)
AZT)
lamivudine (3TC) efavirenz (EFV, ritonavir (RTV)
EFZ)
stavudine (d4T) delavirdine (DLV) saquinavir (SQV)
didanosine (ddI) indinavir (IDV)
abacavir (ABC) lopinavir/ritonavir
(LPV/r)
tenofovir (TDF) atazanavir (ATV)
emtricitabine (FTC) amprenavir (APV)
zalcitabine (ddC) fos-amprenavir (fos-
APV)
Table 2: Combination NRTI/NNRTI Tablets for Antiretroviral Therapy. (Listed are common co-
formulations of ARV agents. Please note that this list may not be complete given that new formulations
may have been developed since these guidelines were published, and not all formulations may be readily
available in the region.)
COMBINATION TABLET NAME(S) COMPONENT MEDICATIONS
Combivir© AZT/3TC
Trizivir© AZT/3TC/ABC
©
Tri-immune d4T/3TC/NVP
©
Duovir AZT/3TC
Duovir-N© AZT/3TC/NVP
A more comprehensive review of these ARV agents, including adult dosing schedules, metabolism, and
common adverse effects can be found in Appendix A.
PRINCIPLES OF HAART: INITIAL THERAPY

Initiation of HAART represents a critical intervention for individuals infected with HIV. The potential
benefits of HAART (delayed progression of HIV disease, reconstitution of the immune system) must be
weighed against the potential drawbacks (medication toxicities, lifestyle changes, potential for developing
drug resistance). Though some controversy remains regarding the optimal time at which HAART should
be initiated (as well as the best initial treatment regimen), general guiding principles concerning these
decisions can be made and are presented below. Please note that specific circumstances may warrant
deviation from the guidelines for individual patients.
IV-3
TIMING OF HAART INITIATION
Four key variables should be considered when deciding if HAART should be initiated for an individual
infected with HIV: 1) HIV-related symptoms; 2) CD4+ T cell count; 3) HIV viral load; and 4) the
patient’s potential for adherence.
Patients with significant symptoms attributable to HIV infection should generally be offered HAART as
soon as possible. Initiation of therapy for those individuals with no symptoms or only mild HIV-related
symptoms should largely depend upon CD4+ T cell count measurements (or total lymphocyte count if
CD4+ T cell count testing is not available).
Some controversy remains as to the optimal CD4+ T cell count threshold for initiation of HAART in the
asymptomatic patient. When HAART first became available with the development of PIs in the late
1990s, most experts and guidelines advocated aggressive use of HAART, even for patients with relatively
high CD4+ T cell counts and low HIV viral load levels. However, it was soon discovered that while
HAART can suppress HIV replication to undetectable levels, HAART cannot fully eradicate the virus.
Furthermore, long-term adverse effects associated with ARV agents were increasingly recognised as
individuals continued therapy for several years. These factors have prompted most experts to favour a
less aggressive approach to HAART than was advocated in the past.
Several observational cohort studies of HIV-infected patients have suggested that patients who initiate
HAART before their CD4+ T cell count falls to <200 cells/mm3 have a higher likelihood of durable
virologic suppression, a lower likelihood of progression of HIV disease, and more robust immune
reconstitution as compared to patients who initiate HAART after their CD4+ T cell counts have dropped
to <200 cells/mm3. While these studies suggest a benefit associated with initiation of therapy at CD4+ T
counts >200 cells/mm3, studies have not consistently suggested a significant benefit of initiation of
HAART at higher CD4+ T cell counts (>350 cells/mm3). Earlier studies in the pre-HAART era
documented a relatively high rate of progression to AIDS among patients with viral loads of <55,000
copies/mm3, regardless of their CD4+ T cell count. More recent studies have also suggested that a high
baseline viral load (>100,000 copies/mm3) at the time HAART is initiated may be associated with less
favourable clinical outcomes, though this phenomenon has not been seen consistently in studies of more
potent regimens that include EFV or LPV/r.
These guidelines therefore recommend initiation of treatment (HAART) for patients with
significant or AIDS-defining symptoms, regardless of CD4+ T cell count or HIV viral load.
Initiation of HAART is also recommended for asymptomatic patients with a CD4+ T cell count of
<200 cells/mm3. For asymptomatic patients with a CD4+ T cell count between 200 and 350
cells/mm3, HAART should generally be offered, recognising that a better response to HAART is
likely if treatment is initiated before the CD4+ T cell count falls to <200 cells/mm3. Finally, for
patients who are asymptomatic and have a high CD4+ T cell count (>350 cells/mm3) or a high total
lymphocyte count (>1,200 cells/mm3), HAART may generally be deferred. Because the response to
HAART correlates strongly with adherence, the patient’s potential for adherence should be
assessed carefully, and attempts should be made to address and correct potential obstacles to
adherence prior to initiation of therapy.*
A patient’s baseline HIV viral load level is not as important as symptoms or CD4+ T cell count in
deciding when to initiate therapy. However, if available, this information can be used to estimate the
anticipated rate of disease progression: in the absence of therapy, higher viral loads typically correlate
with faster rates of disease progression and CD4+ T cell count decline. Furthermore, some studies
suggest that initiation of HAART at lower baseline viral loads is associated with a better clinical response
to treatment than in patients who initiate HAART at higher baseline viral loads. Some experts and
clinical guidelines therefore recommend initiation of HAART for patients with high viral loads (e.g.
>50,000 to 100,000 copies/mL), even if the CD4+ T cell count is >350 cells/mm3. Other experts might
*
Adherence is discussed in more detail later in this chapter, as well as in Chapter 1: Comprehensive Management of
Persons with HIV Infection.
IV-4
recommend simply following the CD4+ T cell count more carefully in patients with high baseline viral
loads to ensure that treatment is initiated before the CD4+ T cell count falls to <200 cells/mm3.
Table 3 summarises these guidelines for initiation of HAART. In regions where CD4+ T cell count
testing is not available, the total lymphocyte count (TLC) can be used as a marker of immunosuppression
in symptomatic patients. Because the TLC does not accurately reflect HIV-related immunosuppression in
asymptomatic patients, recommendations for initiation of HAART for asymptomatic patients cannot be
made on the basis of the TLC.
Table 3: General Recommendations for Initiation of HAART for HIV-Infected Adults and Adolescents.
Please refer to text for additional guidance and considerations.
IF CD4+ T CELL COUNT TESTING IS AVAILABLE
CD4+ T Cell
Viral Load
Symptoms of HIV Count Recommendation
(copies/mL)
(cells/mm3)
Symptomatic Any Any Treat
Asymptomatic <200 Any Treat
Treatment should generally be
Asymptomatic 200-350 Any
offered
Treatment decision controversial;
Asymptomatic >350 >100,000
monitor CD4+ T cell count closely
Asymptomatic >350 <100,000 Treatment not recommended
IF CD4+ T CELL COUNT TESTING IS UNAVAILABLE

Total Lymphocyte
Symptoms of HIV Infection Recommendation
Count (cells/mm3)
AIDS or Severe Symptoms Any Treat
WHO Stage II or III (minor symptoms) <1200 Treat
WHO Stage II or III >1200 Consider treatment
Asymptomatic Any Treatment not recommended
ADHERENCE
Studies have also consistently demonstrated that very high levels of adherence are required to maintain a
robust response to HAART with durable virologic suppression. In fact, recent data suggest that
adherence is a more important predictor of response to HAART than the baseline CD4+ T cell count or
HIV viral load. Furthermore, suboptimal adherence often rapidly leads to the development of ARV
resistance, limiting treatment options. Hence, adherence issues must be explored thoroughly before
initiation of HAART, and potential obstacles to adherence should be addressed and corrected if possible.
The selection of the HAART regimen itself should take into account patient preferences that favour
adherence. Research has identified several factors associated with adherence, as listed in Table 4.
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Table 4: Selected Factors that Influence Adherence
ASSOCIATED WITH POOR ASSOCIATED WITH BETTER ADHERENCE
ADHERENCE
Active alcohol or substance abuse Directly observed therapy (DOT)
Regimen complexity Once- or twice-daily regimens
Depression Not living alone
Lack of perceived efficacy of HAART Belief in efficacy of HAART
Lack of symptomatic disease History of OI or advanced HIV disease
Concern over side effects Belief in own ability to adhere to regimen
Work outside the home for pay Belief that non-adherence will lead to viral resistance
Lack of proper instructions to patient Dependence on a significant other for support
A multidisciplinary approach can be useful for exploring potential barriers to adherence with individual
patients. Ideally, any potential barriers to adherence should be corrected prior to initiation of HAART.
However, many potential barriers to adherence are not easily correctable, and patients are often able to
achieve excellent levels of adherence despite the presence of one or more factors associated with poor
adherence. Moreover, research has consistently shown that clinicians do not accurately predict their
patients’ levels of adherence. Hence, the presence of one or more potential barriers to adherence should
not prompt denial of HAART to patients who otherwise qualify for treatment.
Practical strategies to improve adherence prior to initiation of HAART include:
9 educating the patient regarding the anticipated benefits of HAART, the potential for treatment failure
and viral resistance associated with suboptimal adherence, and possible side effects of the
medications;
9 treating potential barriers to adherence prior to initiation of therapy, such as substance abuse or
mental health disorders;
9 recruiting support from other members of the healthcare team, members of the patient’s social
network of friends and family, and community-based organisations to reinforce the importance of
adherence and assist with overcoming barriers to adherence;
9 negotiating a treatment plan to which the patient is committed, taking into consideration the
patient’s daily routines, meal and work schedules, and co-morbid medical conditions;
9 simplifying the regimen as much as possible by favouring regimens that include a low pill burden,
once- or twice-daily dosing, and minimal food restrictions;
9 providing a written or pictorial schedule for taking the medications;
9 considering the use of automated reminders such as pagers, alarms, and pill boxes; and
9 considering a trial period of simulated therapy, using candy instead of actual pills, to identify
potential obstacles to adherence.
A more detailed discussion of adherence, including a sample patient adherence questionnaire, can be
found in Chapter I: Comprehensive Management of Persons with HIV Infection.
TREATMENT OF CO-MORBID OPPORTUNISTIC INFECTIONS (OIs)
Many patients will be diagnosed with HIV infection at the time they are diagnosed with an OI.
Development of an OI reflects significant damage to the immune system, implying that HAART should
be initiated as soon as possible. However, in such situations, it may be advantageous to initiate treatment
of the OI first and then to initiate HAART shortly thereafter (e.g. a few weeks later). The risks associated
with this slight delay in initiation of HAART are often outweighed by the advantages of 1) allowing time
for the patient to psychologically adjust to the diagnosis of HIV infection and to prepare for HAART; 2)
IV-6
allowing time for adherence issues to be adequately addressed; and 3) reduction in the likelihood of
significant immune reconstitution syndrome (IRS) involving the OI.
IRS represents an inflammatory response to an OI by an immune system that has been invigorated by the
recent initiation of HAART. Clinically, IRS typically presents as fevers, sweats, lymphadenopathy,
fatigue, and other features characteristic of the underlying OI. These signs and symptoms typically
develop within the first several weeks after initiation of HAART. Often, the OI responsible for IRS
represents a new diagnosis, having remained clinically ‘silent’ in the face of a severely depleted immune
system. Care must be taken to distinguish IRS from a truly new OI in the patient who has recently
initiated HAART. Management of IRS typically involves continuation of HAART, initiation or
continuation of treatment for the responsible OI, and use of non-steroidal anti-inflammatory drugs
(NSAIDs). Steroids, such as prednisone, are often used in the management of severe cases of IRS.
Further discussion of IRS can be found in Chapter V: Recommendations for the Treatment of
Opportunistic Infections (OIs) among Adults and Adolescents and in Chapter X: Diagnosis and
Treatment of Opportunistic Infections (OIs) among HIV-Exposed and –Infected Children.
LABORATORY MONITORING PRIOR TO INITIATION OF HAART
Prior to initiation of HAART, it is useful to check haematologic and chemistry indices in order to screen
for abnormalities and to establish baseline levels for future comparison. It is also helpful to check a
baseline CD4+ T cell count and (where available) an HIV viral load, so that the immunologic (and
virologic) response to HAART may be measured against pre-therapy baseline levels. However, if
clinically indicated, HAART should not be delayed where resources are scarce or laboratory testing is not
readily available to document baseline laboratory values. Pregnancy testing prior to initiation of HAART
is mandatory for women of childbearing potential.
SELECTION OF THE INITIAL HAART REGIMEN
The optimal HAART regimen provides potency and durability with a simple dosing schedule and
minimal adverse effects while preserving future treatment options in the event of treatment failure.
Fortunately, the introduction of additional ARV agents and the development of combination pills over the
past several years have resulted in a number of potent therapeutic options that are simpler and better
tolerated than earlier HAART regimens.
PI-Based vs. NNRTI-Based vs. Triple-NRTI Regimens
Initial HAART regimens typically consist of a combination of two NRTIs (the nucleoside backbone) plus
an NNRTI or a PI (which may or may not be boosted by low doses of RTV*). HAART regimens
consisting of a dual nucleoside backbone plus an NNRTI can be described as NNRTI-based regimens,
whereas PI-based regimens consist of a dual nucleoside backbone plus a PI (sometimes boosted by
RTV*). Either PI-based or NNRTI-based regimens are reasonable options for initial HAART; each has
distinct advantages and disadvantages (see Table 5). HAART regimens consisting of three NRTIs (triple
NRTI regimens) such as AZT plus 3TC plus ABC can also be considered for initial therapy, but are not
generally recommended unless significant contra-indications exist to more potent conventional PI- or
NNRTI-based regimens. Triple NRTI combinations that include TDF plus ABC or TDF plus ddI appear
to perform particularly poorly and should be avoided.
For most patients in the Caribbean region, the advantages of an NNRTI-based initial HAART regimen
outweigh those of a PI-based regimen, chiefly due to the simplicity of these regimens (low pill burden,
once- or twice-daily dosing schedule without significant food restrictions, no refrigeration requirements);
a wide availability of NVP and EFV (including combination tablets for NVP); generally favourable
tolerability; and potency.
*
See Appendix B for background and dosing information regarding the use of low-dose RTV to boost serum levels
of other PIs.
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Table 5: Advantages and Disadvantages of Different Types of HAART Regimens
REGIMEN TYPE ADVANTAGES DISADVANTAGES
EXAMPLES
NNRTI-based • Low pill burden • Low genetic barrier to
• 2 NRTIs + NVP • Simple dosing schedule resistance†
• 2 NRTIs + EFV • Few food restrictions • Cross-resistance among
NNRTIs‡
• No refrigeration requirements
• Potential for hepatic and skin
• Fewer metabolic toxicity (NVP>EFV)
complications than PI-based
regimens* • Potential teratogenicity (EFV)§
• Preserves PI options for • High potential for interactions
future regimens with other medications
PI-based • Longest prospective study • Higher pill burden
• 2 NRTIs + LPV/r data demonstrating survival • Gastrointestinal side effects
benefit common
• 2 NRTIs + NFV
• Preserves NNRTI options for • Metabolic complications
future regimens common
• High genetic barrier to • Refrigeration requirements for
resistance** some agents (RTV, LPV/r)††
• High potential for interactions
with other medications
Triple NRTI • Simple dosing • Lower potency/higher rates of
• AZT + 3TC + ABC • Low pill burden clinical failure than EFV-based
regimens
• d4T + 3TC + ABC • Low potential for metabolic
complications • Potential for ABC
hypersensitivity
• Low potential for interactions
with other medications
SELECTION OF INDIVIDUAL AGENTS IN THE HAART REGIMEN

The nucleoside backbone of an initial regimen typically includes 3TC due to its potency, few adverse
effects, and low pill burden (one pill once or twice daily) without food restrictions. 3TC is commonly
paired with AZT or d4T to complete the nucleoside backbone. 3TC can also be combined with other
agents such as ABC or TDF, but these agents are not as commonly available in the Caribbean. FTC can
be substituted for 3TC, but this agent is not yet commonly available in the region.
*
Dyslipidaemia, insulin resistance, and possibly lipodystrophy are metabolic complications of HAART most
commonly associated with PI-based regimens, though they may also be seen with NNRTI-based regimens as well.
†
A single point mutation in HIV reverse transcriptase can confer complete resistance to the NNRTI class. See
Appendix F for more information regarding HIV resistance.
‡
Resistance to EFV typically confers resistance to NVP and vice versa.
§
Severe neurological birth defects have been documented in the offspring of non-human primates exposed to EFV
during pregnancy.
**
Clinically significant resistance to most PIs requires multiple mutations. See Appendix F for more information
regarding HIV resistance.
††
RTV should be stored at 2° to 8°C (36° to 46°F) prior to dispensing. After dispensing, it can be stored at room
temperature (defined as less than 25°C, or 77°F) as long as it is used within thirty days (Source: Norvir® (ritonavir)
package insert. Abbott Park, Ill: Abbott Pharmaceuticals).
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The use of certain nucleoside combinations is specifically discouraged. AZT and d4T should not be
combined because these agents are antagonistic in vivo. The combination of ddI and d4T should be
avoided due to an overlapping toxicity profile that significantly raises the possibility of serious adverse
events such as lactic acidosis, pancreatitis, hepatitis, or peripheral neuropathy. 3TC and FTC should not
be combined since they are very similar drugs with identical resistance patterns.
Due to the risk of teratogenicity associated with EFV, NVP rather than EFV should be used in women
who are pregnant or at risk of becoming pregnant. However, a high incidence of symptomatic liver
toxicity (11%) has been reported in women with CD4+ T cell counts >250 cells/mm3 who initiate NVP-
based therapy; NVP should therefore be used cautiously in such women, and close laboratory monitoring
is recommended. Men with CD4+ T cell counts >400 cells/mm3 appear to be at increased risk for NVP-
induced hepatotoxicity as well. For individuals not at risk for pregnancy, EFV may be preferred over
NVP, because EFV has a generally more favourable toxicity profile and may be more potent than NVP
(EFV-based HAART regimens have generally performed better than NVP-based HAART regimens in
clinical trials, though a recent head-to-head trial failed to demonstrate a significant difference in efficacy
between the two agents). Nevertheless, the significant teratogenic potential of EFV renders this agent
unsuitable for women who are pregnant or may become pregnant while on the medication.
PI-based regimens are not as highly recommended in these guidelines for initial HAART, chiefly due to
the high pill burden and refrigeration requirements for some PIs. However, because numerous clinical
trials have confirmed the efficacy of PI-based HAART regimens, they can be considered as reasonable
alternative initial HAART regimens. Clinical trial data most strongly support the long-term efficacy and
potency of LPV/ritonavir (LPV/r). The potency of this agent is likely attributable at least in part to the
inclusion of RTV, which significantly boosts the circulating plasma levels of LPV by inhibiting its
metabolism. RTV will similarly boost the serum drug levels of other PIs, and many clinicians favour
routinely boosting PIs with a low dose of co-administered RTV in order to improve pharmacokinetics and
to simplify dosing and food requirements; see Appendix B for background and dosing information
regarding the use of low-dose RTV to boost serum levels of other PIs. Unfortunately, RTV requires
refrigeration,* making its use problematic in many parts of the Caribbean where a ‘cold chain’ of
distribution cannot be guaranteed. SQV also requires refrigeration, but other PIs do not. Where
refrigeration cannot be guaranteed and a PI-based regimen is indicated, NFV is an attractive alternative
due to its relatively simple dosing and favourable toxicity profile. ATV is a new PI with a lower pill
burden and higher potency than NFV but is not yet widely available in the region.
Recommendations
These guidelines therefore suggest a nucleoside backbone of AZT plus 3TC or d4T plus 3TC, combined
with EFV or NVP, as the initial HAART regimen. Due to the risk of teratogenicity associated with EFV,
NVP rather than EFV should be used in women who are pregnant or at risk of becoming pregnant. See
Table 6 for preferred initial regimens, along with their respective advantages and disadvantages; see
Table 7 for alternative initial HAART options. For HAART considerations in patients with co-morbid
conditions (e.g. hepatitis, diabetes, or tuberculosis (TB)), see the following chapter. For ART
considerations in pregnant women, see Chapter VII: Antiretroviral Therapy in Pregnant Women and
Prevention of Mother-to-Child Transmission of HIV.
*
RTV should be stored at 2° to 8°C (36° to 46°F) prior to dispensing. After dispensing, it can be stored at room
temperature (defined as less than 25°C, or 77°F) as long as it is used within thirty days (Source: Norvir® (ritonavir)
package insert. Abbott Park, Ill: Abbott Pharmaceuticals).
IV-9
Table 6: Preferred Initial HAART Regimens
REGIMEN ADVANTAGES DISADVANTAGES
• AZT + 3TC + EFV • Simple • Contra-indicated in women
• Highly potent who are pregnant or may
• Generally well-tolerated become pregnant (EFV)†
• Less potential for toxicities • Potential for EFV-associated
associated with mitochondrial CNS side effects‡
dysfunction** • Potential for AZT-associated
• Less potential for skin and liver anaemia
toxicity than NVP-based regimens
• May be more potent than NVP-
based regimens*
• AZT + 3TC + NVP§ • Simple • Higher potential for liver, skin
• Highly potent toxicity than EFV-based
• Generally well-tolerated regimens††
• Less potential for toxicities • Potential for AZT-associated
associated with mitochondrial anaemia
dysfunction** • May be less potent than EFV-
• Not contra-indicated in pregnancy based regimens*
• Less potential for EFV-associated
CNS side effects
• d4T + 3TC + EFV • Simple • Contra-indicated in women
• Highly potent who are pregnant or may
• Generally well-tolerated become pregnant (EFV)
• Unlikely to induce or worsen • Potential for EFV-associated
anaemia CNS side effects
• Less potential for skin and liver • Higher potential for toxicities
toxicity than NVP-based regimens associated with mitochondrial
• May be more potent than NVP- dysfunction**
based regimens
§
• d4T + 3TC + NVP • Simple • Higher potential for liver, skin
• Highly potent toxicity than EFV-based
• Generally well-tolerated regimens††
• Unlikely to induce or worsen • Higher potential for toxicities
anaemia associated with mitochondrial
• Not contra-indicated in pregnancy dysfunction**
• Less potential for EFV-associated • May be less potent than EFV-
CNS side effects based regimens*
*
EFV-based HAART regimens have generally performed better than NVP-based HAART regimens in clinical trials,
though a recent head-to-head trial failed to demonstrate a significant difference in efficacy between the two agents.
†
Severe neurological birth defects have been documented in the offspring of non-human primates exposed to EFV
during pregnancy.
‡
CNS effects commonly associated with EFV include dizziness, impaired concentration, and psychological changes;
these effects typically clear after the first few weeks of therapy.
§
NVP should be dosed at half-strength for the first two weeks of therapy, followed by escalation of the dose to full
strength, in order to minimise the risk of skin and liver toxicity.
**
Toxicities due to NRTI-induced mitochondrial dysfunction (lactic acidosis, peripheral neuropathy, pancreatitis,
and lipoatrophy) are more commonly associated with d4T than AZT.
††
Risk of NVP-induced hepatotoxicity is especially elevated in women with pre-HAART CD4+ T cell counts of
>250 cells/mm3 and in men with pre-HAART CD4+ T cell counts of >400 cells/mm3.
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Table 7: Alternative Initial HAART Regimens
REGIMEN ADVANTAGES DISADVANTAGES
EXAMPLES
TDF + 3TC + NNRTI* • Highly potent • TDF not widely available in
• TDF + 3TC + EFV • Low pill burden Caribbean
• TDF + 3TC + NVP • Once-daily option with • Potential for liver, skin
EFV may improve toxicity (NVP>EFV)
adherence • Teratogenicity (EFV)
• Second-line options may be
limited
2 NRTIs + LPV/r • Highly potent • LPV/r not commonly
• AZT + 3TC + LPV/r • Less potential for liver, available in the Caribbean
• d4T + 3TC + LPV/r skin toxicity than • High pill burden
NNRTI-based regimens • High potential for drug-drug
interactions
• GI side effects common
(LPV/r)
• Refrigeration requirement
(LPV/r)
2 NRTIs + NFV • Reasonably well- • High pill burden†
• AZT + 3TC + NFV tolerated • Lower potency than EFV- or
• d4T + 3TC + NFV • No refrigeration LPV/r-based regimens
requirements • Diarrhoea common (NFV)
• Fewer drug interactions
than other PI-based
regimens
2 NRTIs + ATV • Well-tolerated • ATV not widely available in
• AZT + 3TC + ATV • Low pill burden the Caribbean
• d4T + 3TC + ATV • No refrigeration • Unclear if potency equivalent
• TDF + 3TC + ATV requirements to EFV- or LPV/r-based
• Higher potency than regimens (though comparable
NFV-based regimens potency likely if ATV is
• Unlike other PIs, ATV boosted by low-dose RTV)
not associated with
dyslipidaemia
• TDF/3TC/ATV can be
dosed once-daily
3 NRTIs • Generally well-tolerated • Lower potency than EFV- or
• AZT + 3TC + ABC • Potentially fewer LPV/r-based regimens
• d4T + 3TC + ABC metabolic • Potential for ABC
complications‡ hypersensitivity
• Preserves PI and
NNRTI options
*
Do not use EFV in women who are pregnant or at risk for pregnancy.
†
New dose formulation of NFV (625mg/tablet) reduces pill burden to two NFV tabs b.i.d (where available).
‡
Triple-NRTI regimens have been associated with a lower risk of dyslipidaemia, lipodystrophy, and insulin
resistance than NNRTI- or PI-based regimens.
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Drug Interactions
Drug interactions between PIs and NNRTIs are common, and dosing adjustments are required for certain
combinations of ARV agents (see Appendix B for details). Drug interactions between these drugs and
medications used to treat other conditions are also common (see Appendix C). Potential drug interactions
must be investigated and appropriate modifications made prior to initiation of HAART. Appendix D lists
drugs that should not be used in patients on HAART due to potentially severe drug-drug interactions.
PATIENT FOLLOW-UP AND MONITORING AFTER INITIATION OF THERAPY
After HAART is initiated, close monitoring of the patient is warranted for toxicity and adherence. A
follow-up visit with the prescribing clinician or an associated community healthcare professional is
recommended within two weeks of initiation of ARV therapy. At this visit, adherence issues can be re-
addressed and the patient can be assessed for any clinical evidence of drug toxicity.
Adherence
The importance of adherence for those initiating HAART cannot be overemphasised. Studies suggest that
adherence is especially critical in the first few months of ARV therapy, when the HIV viral load is
expected to decline rapidly. Suboptimal adherence can rapidly lead to the development of drug
resistance, ultimately resulting in regimen failure as well as the loss of antiretroviral options for salvage
regimens.
Assessment of adherence should therefore be performed at every visit in order to identify and correct any
potential barriers. A trusting and non-judgmental relationship between the clinician and patient is critical
in this regard. Studies have found that clinicians do not reliably predict their patients’ levels of
adherence; more accurate methods of assessing adherence include patient recollection of missed doses
and pharmacy refill records. A sample patient adherence questionnaire, as well as a more thorough
discussion of adherence, can be found in Chapter I: Comprehensive Management of Persons with HIV
Infection.
Key strategies that may be useful in promoting adherence in patients who have recently initiated therapy
include:
9 establishing trust
9 closely monitoring adherence at routine visits
9 providing access between visits for questions or problems
9 involving patient’s social network to provide ongoing adherence support
9 adding adherence assessment and reinforcement to job descriptions of support team
members, such as nurses, pharmacists, case managers, and clinicians’ assistants
Laboratory Monitoring
Periodic laboratory monitoring is also recommended to screen for toxic effects of antiretroviral
medications and to assess the patient’s immunologic and (where available) virologic response to therapy.
However, clinical assessment without laboratory monitoring is reasonable if laboratory testing is not
readily available.
Appendix E summarises recommended laboratory testing for patients on HAART. The laboratory
monitoring that is recommended depends on the HAART regimen that is prescribed and on the patient’s
co-morbid conditions and past medical history. For example, increased vigilance for liver toxicity is
warranted in individuals with a history of chronic hepatitis who initiate antiretroviral therapy. Because
most drug-related toxicities appear within the first few months of introduction of the drug, it is reasonable
to decrease the frequency of monitoring in patients who initially display no evidence of toxicity.
Similarly, the frequency of CD4+ T cell count monitoring may be decreased in individuals who maintain
excellent adherence to their medications and who demonstrate sustained clinical improvement. While
HIV viral load testing is useful in assessing efficacy of treatment and early detection of treatment failure,
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it is not mandatory for the management of these patients. Obviously, clinical signs or symptoms that
suggest toxicity warrant prompt investigation. Hence, this table represents a rough guideline only and
should be tailored to the individual patient.
TREATMENT FAILURE AND TREATMENT TOXICITY

Treatment failure refers to the absence of a sustained favourable response to antiretroviral therapy.
Treatment failure can be suspected on the basis of clinical grounds, but confirmation of failure with
laboratory testing is strongly recommended before changing a patient’s HAART regimen. Consultation
with an expert HIV clinician is also highly recommended if treatment failure is suspected on the basis of
clinical, immunologic, or virologic criteria. Efforts should be made to confirm suspected treatment
failure as rapidly as possible in order to prevent HIV disease progression and the development of further
resistance to antiretroviral agents. Laboratory testing can be useful both to establish treatment failure and
to guide second-line treatment options.
In the event of treatment failure, re-assessment of adherence is indicated. After adherence issues have
been adequately addressed, a change in the HAART regimen to second-line therapy is usually warranted,
as detailed later in this chapter.
TREATMENT FAILURE: CLINICAL DEFINITION
Treatment failure should be suspected if progression of HIV disease continues following initiation of
HAART or if no clinical improvement occurs in three months following the initiation of therapy.
Clinical indicators of HIV disease progression include weight loss, papular prurigo, oral candidiasis,
fevers and night sweats, or chronic diarrhoea. Clinicians must be careful to distinguish suspected HIV
disease progression from IRS, which can also manifest with fevers, night sweats, and fatigue; however,
IRS typically resolves within a couple of months following initiation of HAART. Further discussion of
IRS can be found in the introduction to Chapter V: Recommendations for the Treatment of Opportunistic
Infections (OIs) among Adults and Adolescents.
Laboratory testing is highly recommended in the setting of suspected clinical treatment failure. Ideally, a
CD4+ T cell count and HIV viral load should be checked, and the results reviewed with an expert HIV
clinician, followed by immediate revision of the HAART regimen if indicated. If resources do not permit
CD4+ T cell count and viral load testing, these guidelines recommend addressing adherence and tolerance
issues, continuing the current regimen if tolerated, and re-assessing the patient in another three months.
DOT may also be considered where feasible. Laboratory testing, especially viral load testing, is strongly
recommended if treatment failure is still suspected six months following initiation of HAART.
Laboratory results should again be reviewed with an expert HIV clinician to guide management decisions.
If treatment failure is confirmed, a change in HAART to a second-line regimen is recommended, as
discussed below.
TREATMENT FAILURE: IMMUNOLOGICAL DEFINITION
Treatment failure should be suspected if the CD4+ T cell count declines or fails to rise within three
months following initiation of HAART. The World Health Organisation (WHO) defines immunologic
treatment failure as:
• a fall of over 30% in the CD4+ T cell count from the peak value; or
• a return of the CD4+ T cell count to or below the baseline (pre-HAART) CD4+ T cell count.
HAART-associated virologic suppression is typically associated with a significant rise in both the
absolute and percentage of CD4+ T cells within three to six months of starting HAART, as depicted in
Figure 1. However, discordant responses are sometimes observed in which full virologic suppression is
achieved on HAART but the CD4+ T cell count fails to rise significantly or even continues to decline.
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The reasons for these discordant responses remain unclear, and management options should be reviewed
with an expert HIV clinician. It is therefore strongly recommended that HIV viral load testing be
performed in the setting of immunological treatment failure.
TREATMENT FAILURE: VIROLOGIC DEFINITION
With successful initial HAART, the HIV viral load is expected to decline by at least tenfold (one log10)
every two to eight weeks, and should be below the limit of detection of most viral load assays within
approximately six months of HAART initiation, as depicted in Figure 1. Treatment failure can be defined
by the absence of such a decline in HIV viral loads following initiation of therapy (failure to suppress), or
by virologic suppression to below the lower limit of detection followed by a subsequent sustained rise in
HIV viraemia (virologic breakthrough), as depicted in Figures 3 and 4. If HIV viral load testing confirms
treatment failure, consideration of second-line therapy in consultation with an HIV expert is
recommended. Efforts should be made to change the HAART regimen as soon as possible in order to
discourage the development of drug resistance and to preserve effective treatment options.
Figure 3: Antiretroviral Therapy: Failure to Suppress
Antiretroviral Therapy:
Failure to Suppress
100000 Medications Started
HIV Viral Load (copies/mL)
10000
1000
100
50 50
10 Time
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Figure 4: Antiretroviral Therapy: Virologic Failure
Antiretroviral Therapy:
Virologic Failure
100000 Medications Started
HIV Viral Load (copies/mL)
10000
1000
100
50 50
10
Time
TREATMENT TOXICITY
While adverse effects from HAART are common, they can usually be managed symptomatically while
continuing the HAART regimen without interruption, as most adverse effects associated with
antiretroviral agents resolve within one to three months of initiation of therapy. If the adverse effect is
severe enough to require modification of the regimen, substitution of the offending drug with another
antiretroviral agent is an option if it can be reasonably deduced which agent is responsible for the side
effect in question. Table 8 presents options for drug substitution in the event of selected common adverse
reactions. Consultation with an expert HIV clinician is strongly recommended when a regimen change is
necessary.
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Table 8: Common Adverse Drug Reactions Associated with First-Line HAART Regimens and
Recommended Drug Substitutions*
REGIMEN TOXICITY DRUG SUBSTITUTION
d4T/3TC/NVP • d4T-related neuropathy or • Switch d4T Æ AZT
pancreatitis
• d4T-related lipoatrophy • Switch d4T Æ TDF or
ABC†
• NVP-related severe hepatotoxicity • Switch NVP Æ EFV‡
• NVP-related severe rash (but not • Switch NVP Æ EFV‡

life-threatening)
• NVP-related life-threatening rash • Switch NVP Æ PI§
(e.g. Stevens-Johnson syndrome)
AZT/3TC/NVP • AZT-related persistent GI • Switch AZT Æ d4T
intolerance or severe haematological
toxicity
• NVP-related severe hepatotoxicity • Switch NVP Æ EFV‡
• NVP-related severe rash (but not • Switch NVP Æ EFV‡

life-threatening)
• NVP-related life-threatening rash • Switch NVP Æ PI§
(e.g. Stevens-Johnson syndrome)
d4T/3TC/EFV • d4T-related neuropathy or • Switch d4T Æ AZT
pancreatitis
• d4T-related lipoatrophy • Switch d4T Æ TDF or
ABC†
• EFV-related persistent CNS toxicity • Switch EFV Æ NVP
AZT/3TC/EFV • AZT-related persistent GI • Switch AZT Æ d4T

intolerance or severe haematological
toxicity
• EFV-related persistent CNS toxicity • Switch EFV Æ NVP
Occasionally, severe HAART-related toxicity requires discontinuation of all ARV agents. In such
circumstances, it is best to discontinue all of the medications simultaneously, because continuation of
*
Adapted from the World Health Organisation. Table C: Major potential toxicities of first-line ARV regimens
recommended drug substitutions in Revised WHO guidelines for scaling up antiretroviral therapy in resource-
limited settings. 2003 revision. Available at: http://www.who.int/hiv/pub/prev_care/en/ arvrevision2003en.pdf.
†
Switching out d4T appears to reduce, and may even reverse, lipoatrophy (though very slowly). TDF and ABC
represent the best alternatives to d4T in this setting, but their availability in the Caribbean is limited; AZT is a
reasonable alternative where TDF and ABC are not available.
‡
Except in pregnancy. If the patient is pregnant or at risk for becoming pregnant, substitute a PI (preferred) or
ABC.
§
Recommended PIs include LPV/r or SQV/r; NFV and IDV/r are acceptable alternatives.
IV-16
therapy with only one or two ARV agents is associated with the development of drug resistance. If the
HAART regimen being discontinued contains an NNRTI (e.g. NVP or EFV), some expert clinicians
would recommend discontinuing the NNRTI three to seven days prior to discontinuing the NRTIs, owing
to the prolonged plasma half-life of NNRTIs. HAART should be withheld until the patient recovers, at
which time re-initiation of therapy with a different regimen can be considered in consultation with an HIV
expert.
SECOND-LINE AND SALVAGE ANTIRETROVIRAL THERAPY

Treatment failure of the initial HAART regimen is a common, though not inevitable, event. When initial
treatment fails, a second-line regimen is generally implemented. Salvage therapy refers to treatment
regimens designed for patients who have failed two or more HAART regimens. In general, each
successive HAART regimen is less likely than the previous regimen to achieve durable virologic and
immunologic success. Hence, treatment regimens must be selected carefully to maximise a patient’s
likelihood of a robust and durable response to HAART. However, it is also clear that many patients are
able to maintain clinical and immunologic stability on salvage HAART regimens, even if those regimens
fail to achieve an undetectable viral load.
HIV RESISTANCE TO ANTIRETROVIRAL THERAPY
Treatment failure often (though not always) occurs because a patient’s strain of HIV has developed
resistance to one or more of his/her antiretroviral medications. The manner by which HIV develops
resistance to ARVs is similar to the way in which bacteria or mycobacteria (e.g. TB) develop resistance to
antibiotics: insufficiently potent drug therapy selects for mutant strains that are resistant to the
medications administered to the patient. These mutant strains then replace the wild-type strain due to
their selective replication advantage in the face of drug pressure, leading to treatment failure. Resistance
to antiretroviral medications most commonly develops in the setting of suboptimal adherence, but can
occur even in patients who maintain very high levels of adherence to their medications. For example, a
patient with poorly controlled diarrhoea may not fully absorb his or her medications, leading to sub-
therapeutic drug levels in the blood, which could lead to the development of resistance.
Cross-resistance between ARVs within drug classes is common; for example, a strain of HIV that is
resistant to NVP is very likely to be highly resistant to EFV as well and vice versa. Cross-resistance is
not as common within the NRTI and PI classes, but can occur. Considerations of potential cross-
resistance must therefore be incorporated into the design of second-line and salvage treatment regimens.
Laboratory assays have been developed to estimate the patterns of resistance that have developed in a
given patient’s strain of HIV. Though imperfect, these assays have demonstrated clinical efficacy in
aiding the design of second-line treatment regimens following treatment failure. Unfortunately, these
assays are very expensive and not widely available in the Caribbean. However, where available, a
resistance assay can provide valuable information for patients experiencing treatment failure.
Even in the absence of resistance testing, knowledge of the patterns of resistance and cross-resistance that
commonly develop in patients failing specific regimens allows for reasonably accurate empiric decision-
making in designing a second-line regimen. For example, patients failing an NNRTI-based initial
treatment regimen commonly develop one or more mutations that confer high-level resistance to all
available NNRTI medications. Hence, a second-line regimen for these patients should be PI-based rather
than NNRTI-based. These concepts are discussed more fully below and are summarised in Table 9. A
more detailed discussion of antiretroviral resistance and resistance assays can be found in Appendix F.
SECOND-LINE HAART REGIMENS
Second-line HAART regimens are indicated for patients who are forced to discontinue their initial
treatment regimen as a consequence of treatment failure or severe toxicity. Consultation with an expert
IV-17
HIV clinician is highly recommended when designing a second-line regimen. If the initial regimen was
discontinued due to toxicity without evidence of treatment failure, then the second-line regimen should
involve substitution of the drug most likely to be responsible for the toxicity, as outlined in Table 8. For
example, if a patient develops a severe skin rash after starting an initial regimen of d4T plus 3TC plus
NVP, a second-line regimen can be constructed using the same nucleoside backbone but with a different
third agent, because it can be reasonably assumed that the NVP was responsible for the skin reaction.
If the initial HAART regimen was discontinued due to treatment failure, however, it is likely that drug
resistance to one or more ARVs in the initial regimen has developed. The next HAART regimen must be
constructed carefully to account for this potential resistance. Where available, antiretroviral resistance
testing is strongly recommended to help guide the design of the second-line regimen. If resistance-testing
is not available, empiric reasoning regarding the likelihood of resistance to agents in the initial regimen,
as well as considerations of cross-resistance, can be used to design a second-line regimen with the highest
likelihood of efficacy. Because the exact nature and extent of resistance is difficult to estimate
empirically, these guidelines suggest trying to replace as many of the agents in the initial regimen as
possible.
Resistance to 3TC and to NNRTIs commonly develops in patients who fail initial treatment regimens
containing these agents. Therefore, second-line regimens for patients who initiated an NNRTI-based
regimen generally involve replacement of the NNRTI with a PI. RTV-boosting of the PI is generally
recommended because this is associated with higher potency, reducing the risk of failure of the second-
line regimen. Conversely, initial PI-based regimens should generally be replaced with NNRTI-based
regimens.
Paradoxically, many HIV experts recommend including 3TC in second-line regimens of patients who
have failed initial 3TC-containing regimens. This is because the mutation that confers resistance to 3TC
also diminishes the replicative capacity of the virus. Including 3TC in the second-line regimen pressures
HIV to maintain this mutation, thereby indirectly helping to suppress viral replication. Furthermore, 3TC
is generally well-tolerated and has a low pill burden, so adding it to three other ARV agents is usually
well-tolerated. It should be noted, however, that clinical evidence substantiating this theoretical benefit is
lacking.
Most initial HAART regimens will also contain either AZT or d4T. Unfortunately, AZT and d4T share
very similar resistance patterns, and a high degree of cross-resistance between these two drugs limits the
utility of replacing one of them with the other. Hence, for patients failing AZT- or d4T-containing
HAART regimens, the best second-line options include a nucleoside backbone of ddI combined with
either TDF or ABC. Unfortunately, TDF and ABC are not commonly available in the Caribbean.
However, AZT and d4T will often retain at least partial efficacy in a second-line regimen, because
typically HIV must develop multiple resistance mutations before achieving full resistance to either of
these agents. Hence, where TDF and ABC are not available, AZT or d4T may be retained in second-line
regimens even if the initial regimen contained one of these agents.
Table 9 presents suggested second-line regimens for patients who have experienced treatment failure on
their initial HAART regimen in situations where resistance testing is not available to help guide decision-
making.
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Table 9: Second-Line Regimen Recommendations for Treatment Failure
FAILED FIRST-LINE SECOND-LINE REGIMEN COMMENTS
*******
REGIMEN OPTIONS
d4T + 3TC + EFV ABC + ddI + PI/r††††††† • ABC not widely available; beware
or or of ABC hypersensitivity
d4T + 3TC + NVP AZT + ddI + PI/r • TDF not widely available
or
TDF + ddI + PI/r
or
TDF + (AZT or d4T) + PI/r
or
ABC + ddI + AZT + PI/r
AZT + 3TC + EFV ABC + ddI + PI/r • TDF not widely available
or or • ABC not widely available; beware
AZT + 3TC + NVP AZT + ddI + PI/r of ABC hypersensitivity
or
TDF + ddI + PI/r
or
TDF + (AZT or d4T) + PI/r
or
ABC + ddI + AZT + PI/r
2 NRTIs + (PI or PI/r) 2 different NRTIs + (EFV or • See patterns above for NRTI
NVP) selection, bearing in mind that use
or of TDF + ddI + NNRTI no longer
2 different NRTIs + PI/r recommended for HAART
• Because PI resistance develops
relatively slowly, a PI/r–based
second-line therapy may be
effective even for patients who
failed initial PI-based therapy
AZT + 3TC + ABC TDF + ddI + PI/r • When TDF and ddI are taken
or together, ddI dose is lowered and
TDF + ddI + NFV no food restrictions
or • Use of TDF + ddI + NNRTI no
TDF + (AZT or d4T) + PI/r longer recommended for HAART
or • RTV-boosting of PI recommended
Substitute ABC for TDF in for higher potency
above options • Potency of ABC in this setting
or questionable but may retain some
Substitute d4T for TDF in activity despite failure of first-line
above options regimen
• d4T + ddI combination not
generally recommended due to
excess toxicity
*******
3TC may be added to any of the above regimens. Some expert clinicians suggest continuing 3TC therapy even
for patients in whom 3TC resistance is likely due to reduced replicative capacity induced by the signature 3TC
resistance mutation (see text for further explanation).
†††††††
PI/r = RTV-boosted PI (e.g. LPV/r; IDV/r; SQV/r)
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SALVAGE THERAPY
Following failure of two or more ARV regimens, durable virologic suppression is unlikely. However,
prevention of further immunologic deterioration is possible even in the absence of full virologic
suppression. Studies have demonstrated that highly treatment-experienced patients, including those with
demonstrably high levels of ARV resistance, generally fare better clinically if they remain on HAART
than if they discontinue HAART altogether. Hence, while full virologic suppression may not be a
realistic goal for highly treatment-experienced patients, attempts should be made to construct a regimen
that will still maintain some efficacy and hopefully prevent or slow further progression of HIV disease.
The design of salvage therapy regimens is exceedingly complex and should be performed in consultation
with an expert HIV clinician.
HAART CONSIDERATIONS FOR PATIENTS WITH CO-MORBID DISEASES

PATIENTS WITH HIV AND TUBERCULOSIS (TB)
Patients co-infected with HIV and TB present complex treatment issues, and consultation with an expert
in the management of these diseases is highly recommended. Significant drug interactions requiring dose
adjustments exist between many of the antiretroviral and antimycobacterial agents (especially the
rifamycins), as detailed in Appendix C.
Co-infected patients may also exhibit a paradoxical worsening of TB-related signs and symptoms (e.g.
night sweats, fevers, lymphadenopathy, and pulmonary findings) in the first several weeks after initiating
HAART. These paradoxical reactions reflect IRS, and can be severe enough to require steroid therapy.
The potential for severe IRS reactions to TB has prompted many expert clinicians to recommend that TB
therapy be generally initiated before HAART. Further discussion of IRS and of the management of
patients co-infected with HIV and TB can be found in Chapter V: Recommendations for the Treatment of
Opportunistic Infections (OIs) among Adults and Adolescents.
PATIENTS WITH HIV AND DIABETES MELLITUS
Many PIs, as well as the NNRTI EFV, have been associated with insulin resistance. Hence, diabetic
patients should be monitored closely for possible worsening of glucose control after starting PI-containing
HAART regimens, and the diabetic regimen may need to be intensified. Significant drug-drug
interactions between ARVs and diabetic agents have not been described. The use of metformin with
NRTI-containing ARV regimens may increase the risk of lactic acidosis, but this has not been clearly
documented in clinical practice.
PATIENTS WITH HIV AND CHRONIC LIVER DISEASE
All classes of ARV agents have been associated with liver toxicity, so extra caution is warranted in
prescribing HAART for patients with chronic liver disease. NVP and RTV have been associated with the
highest risk of liver toxicity and should therefore be avoided if other options exist, though the risk of liver
toxicity using low doses of RTV to boost another PI is not clear.
For patients with chronic hepatitis B (HBV) infection, inclusion of 3TC and/or TDF in the HAART
regimen should be considered because these agents are potent inhibitors of HBV replication and are
useful in the clinical management of this disease. However, patients who have a history of 3TC
monotherapy while co-infected with HBV and HIV likely developed HIV resistance to 3TC,
compromising the efficacy of this agent in HAART regimens. Discontinuation of either of these agents in
a patient with chronic HBV can be associated with an acute exacerbation of HBV. Further discussion of
the management of patients co-infected with HIV and HBV can be found in Chapter V:
Recommendations for the Treatment of Opportunistic Infections (OIs) among Adults and Adolescents.
IV-20
PATIENTS WITH HIV AND RENAL DISEASE
Dose adjustment of some ARVs, especially the NRTIs, must be performed for patients with renal
insufficiency or renal failure. Renal dosing for ARVs can generally be found in their respective
packaging information.
PATIENTS WITH HIV AND OTHER SEXUALLY TRANSMITTED INFECTIONS (STIs)
Co-morbid STIs are commonly encountered in persons infected with HIV. Prompt diagnosis and
treatment of STIs reduces the risk of HIV transmission to others. Recent data suggest that treatment of
chronic herpes simplex virus (HSV) infection reduces the risk of transmission of HSV, may reduce the
risk of HIV transmission, and likely reduces the level of HIV viraemia in patients not on HAART.
Further discussion of the management of patients co-infected with HIV and HSV can be found in Chapter
V: Recommendations for the Treatment of Opportunistic Infections (OIs) among Adults and Adolescents.
PATIENTS WITH HIV AND NEUROPSYCHIATRIC DISORDERS
Significant drug-drug interactions exist between many ARVs and medications used to treat seizure
disorders, bipolar affective disorder, and anxiety disorders, as described in Appendix C. Use of certain
agents in combination should be avoided altogether, while some agents can be combined safely as long as
the dosage is adjusted appropriately. EFV should be used with caution in patients with a history of
affective disorders.
METABOLIC COMPLICATIONS OF HAART AND HIV INFECTION

A number of metabolic disturbances have been described in HIV-infected patients on HAART. Patients
who have initiated treatment for HIV infection should be monitored carefully for development of these
complications and managed appropriately, as outlined below. The exact aetiology of these complications
is not clearly understood, and may reflect a multifactorial process involving antiretroviral medications,
HIV itself, and host factors.
LACTIC ACIDOSIS AND HEPATIC STEATOSIS
Lactic acidosis represents a rare but potentially fatal complication of antiretroviral therapy that has been
linked to NRTIs and to HIV infection. NRTIs can inhibit human mitochondrial DNA polymerase
gamma, an enzyme crucial for normal mitochondrial DNA replication. This inhibition results in depletion
of mitochondrial DNA that compromises cellular oxidative phosphorylation. Evidence of mitochondrial
DNA depletion can also be found in HIV-infected persons who have never received antiretroviral therapy,
suggesting that HIV infection itself may contribute to mitochondrial dysfunction.
Clinically, this syndrome can range from asymptomatic hyperlactataemia to fatal lactic acidosis, often
associated with hepatic steatosis. Development of this disorder appears to depend on the duration of
NRTI exposure and on the specific ARVs used. d4T appears to be most commonly associated with lactic
acidosis, followed by ddI and AZT, followed by 3TC and ABC. TDF appears to carry a low risk of
mitochondrial toxicity as well. Pregnant women appear to be at greater risk for developing lactic
acidosis, and deaths have been reported in women taking the combination of d4T plus ddI.
Physicians should maintain a high clinical suspicion for this syndrome, as symptoms are usually non-
specific. Symptoms may include nausea, vomiting, abdominal pain and distension, diarrhoea, fatigue,
myalgias, weight loss, and dyspnoea. An elevated lactic acid level establishes the diagnosis but requires
sampling without a tourniquet, rapid transportation to a laboratory on ice, and processing within a few
hours. Other helpful laboratory indicators include elevated CPK, LDH, amylase, and aminotransferases,
and low serum bicarbonate.
IV-21
Lactic acidosis is treated with supportive care and discontinuation of ARVs until the syndrome resolves.
Case reports have suggested that supplementation with high doses of vitamins involved in oxidative
phosphorylation, such as riboflavin or L-carnitine, may hasten the recovery process. Consultation with an
HIV expert is strongly recommended. Following resolution of the syndrome, HAART should be re-
initiated cautiously and in consultation with an HIV expert, avoiding NRTIs such as d4T and ddI that are
strongly associated with mitochondrial toxicity.
LIPODYSTROPHY
Lipodystrophy refers to changes in body habitus associated with HIV infection and antiretroviral therapy.
Two distinct syndromes have been characterised: subcoetaneous fat wasting (lipoatrophy) and central fat
deposition (lipohypertrophy). Lipoatrophy is typically most apparent in the face and extremities, and has
been associated with advanced HIV and with NRTIs, especially d4T. Central fat deposition in the
viscera, breasts, and dorsocervical fat pad (buffalo hump) have also been described, though the
pathophysiology of lipohypertrophy remains unclear. These changes in the distribution of fat are often,
though not always, associated with dyslipidaemia and insulin resistance; some definitions of
lipodystrophy include dyslipidaemia and insulin resistance, whereas others do not. A universally
accepted case definition of lipodystrophy has not yet been established.
The optimal management of lipodystrophy is not known at this time. Lipoatrophy appears to improve,
though very slowly, in patients who remove d4T from their ARV regimens and substitute NRTIs that
have less potential for mitochondrial toxicity. Similar medication switch strategies have failed to
consistently demonstrate a clinical benefit for patients with lipohypertrophy, though improvements have
been documented following dietary and exercise modifications. Cosmetic plastic surgery options exist
but are expensive and not widely available, and data regarding long-term outcomes are lacking.
HYPERLIPIDAEMIA
In the absence of ART, HIV infection can lead to dyslipidaemia, including lower HDL levels. HAART
has been associated with elevated total cholesterol, LDL, and triglycerides. PIs (with the exception of
ATV) have been most strongly associated with lipid abnormalities, though dyslipidaemia has also been
documented in patients on NNRTI-based regimens as well as in regimens that include d4T. Recent data
suggest that these abnormalities can lead to accelerated atherosclerosis and cardiovascular complications
among HIV-infected persons. In general, patients with HIV/HAART-associated dyslipidaemia should be
managed in a similar fashion as patients who are not infected with HIV. Low-fat diets, regular exercise,
and smoking cessation represent first-line interventions. Fibrates and HMG-CoA reductase inhibitors
(statins) can be helpful, but certain statins (e.g. simvastatin and lovastatin) should be avoided due to
dangerous drug interactions with PIs. Pravastatin is the preferred agent; atovarstatin may also be used at
reduced doses.
INSULIN RESISTANCE
Hyperglycaemia, new onset diabetes, exacerbation of pre-existing diabetes, and diabetic ketoacidosis
(DKA) have all been reported in HIV patients receiving HAART, especially in those receiving PIs.
Symptoms of hyperglycaemia have been reported as early as sixty days following initiation of PIs. EFV
has also been associated with insulin resistance. Routine fasting blood glucose measurements every three
to four months should be performed for patients with no previous history of diabetes that are receiving PIs
or EFV. Closer monitoring of glucose levels should be performed for pregnant women receiving PIs.
Patients should be counselled to recognise symptoms of hyperglycaemia, such as polyuria, polydipsia,
and polyphagia. Insulin resistance is usually treated by either switching to a non-PI-/non-EFV-based
regimen (if possible) or by supplementing the HAART regimen with oral hypoglycaemic agents or
insulin.
IV-22
DISORDERS OF BONE METABOLISM
Avascular necrosis and decreased bone density have been documented in HIV-infected adults and
children. It is unclear to what degree, if any, ARVs contribute to these disorders; some studies have
linked use of PIs to osteopaenia and osteoporosis, while other data suggest a protective effect of PIs on
bone mineralisation.
Recommended prevention and treatment measures for osteopaenia includes modification of other risk
factors (e.g. smoking cessation, weight-bearing exercise) and adequate intake of calcium and vitamin D.
Hormone replacement therapy may be considered in postmenopausal women. Bisphosphonates, such as
alendronate, have demonstrated clinical efficacy for HIV-infected patients with osteoporosis.
Avascular necrosis most commonly involves the femoral or humeral head, leading to hip or shoulder pain.
Risk factors for osteonecrosis include corticosteroid therapy, alcohol abuse, hyperlipidaemia, and
hypercoagulable states. The diagnosis is typically made by x-ray or CT scan. There is no accepted
medical therapy, and surgery may be needed to treat severe disabling symptoms.
Table 10: Selected Metabolic Complications in HIV
CONDITION CAUSE SYMPTOMS DIAGNOSIS TREATMENT
Hyperlactataemia/Lactic Depletion of Nausea ↑ venous lactate Withdraw NRTIs
Acidosis/Hepatic Steatosis mitochondrial level
DNA Vomiting (esp. ddI, d4T)
↑ CPK
Drugs (e.g. Abdominal pain Supportive
d4T, ddI, ↑ LDH therapy
Diarrhoea
AZT, 3TC, ↑ amylase Consider vitamin
and ABC) Fatigue supplementation
Dyspnoea ↑ amino- (e.g. folate, L-
transferases carnitine)
Weight loss
Low serum
Myalgias bicarbonate
Insulin Resistance HAART, Polyuria Fasting blood Continue HAART
mainly PIs glucose level
• Hyperglycaemia and EFV Polydipsia Diet/exercise
Monitor glucose
• New onset diabetes Polyphagia every 3-4 months Add oral
hypoglycaemic
• Exacerbation of pre- agents or insulin if
existing diabetes and necessary
DKA
Dyslipidaemia HAART; Associated with Monitor lipid Low-fat diets
linked to PIs, accelerated levels
↑ Total cholesterol EFV, and atherosclerosis Regular exercise
↑ LDL d4T and Smoking
cardiovascular cessation
↑ Triglycerides complications
HMG-CoA
Decreased HDL inhibitors (statins)
and/or fibrates
IV-23
APPENDIX A: CHARACTERISTICS OF ANTIRETROVIRAL AGENTS‡‡‡‡‡‡‡
Table 11: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
GENERIC NAME FORMULATION DOSING FOOD ORAL BIO- SERUM INTRA- ELIMINATION ADVERSE
AVAIL-
(ABBREVIATION)/TRADE RECOMMENDATIONS EFFECT HALF- CELLULAR EVENTS
ABILITY
NAME LIFE HALF-LIFE
Abacavir (ABC) Ziagen®: 300mg 300mg b.i.d; or 600mg Take 83% 1.5 12-26 hours Metabolised by Hypersensitivity
® ® tablets or q.d; without hours alcohol reaction that can
Ziagen ; Trizivir (w/ZDV be fatal;
20mg/mL oral regard to dehydrogenase
+ 3TC); Epzicom® (w/3TC) OR as Trizivir®, 1 symptoms may
solution meals; and glucuronyl
tablet b.i.d include fever,
alcohol transferase
Trizivir®: ABC, rash, nausea,
OR as Epzicom®, 1 increases
300mg + ZDV, Renal excretion vomiting,
tablet q.d ABC
300mg + 3TC, of metabolites malaise or
levels
150mg 82% fatigue, loss of
41%;
appetite,
Epzicom®: ABC has Trizivir® and respiratory
ABC, 600mg + no effect Epzicom® not symptoms such
3TC, 300mg on for patients as sore throat,
alcohol with CrCl cough, shortness
<50mL/min of breath
Didanosine (ddI) Videx EC®: 125, Body Weight >60kg: Levels 30-40% 1.5 >20 hours Renal excretion Pancreatitis
® ® 200 250, or 400mg q.d (buffered decrease hours 50%
Videx , Videx EC , generic Peripheral
400mg capsules tablets or EC capsule); 55%; neuropathy
ddI enteric-coated (dose Dosage
OR 200mg b.i.d take 1/2
same as Videx EC®) Videx® Buffered adjustment in Nausea
(buffered tablets); hour
Tablets: 25, 50, renal
before or Diarrhoea
100, 150, 200mg With TDF: 250mg/day insufficiency
2 hours
Videx® Buffered <60 kg: 250mg q.d after Lactic acidosis
Powders: 100, (buffered tablets or EC meal with hepatic
167, 250mg capsule); or 125mg b.i.d steatosis is a rare
(buffered tablets) but potentially
life-threatening
With TDF: Appropriate toxicity
dose not established; associated with
probably <250mg/day use of NRTIs
‡‡‡‡‡‡‡
Adapted from: United States Department of Health & Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults
& Adolescents. 29 Oct 2004. Last accessed 2 Mar 2005. Available at http://www.aidsinfo.nih.gov.
IV-24
AVAIL-
ABILITY
NAME LIFE HALF-LIFE
Emtricitabine (FTC) Emtriva™: Emtriva™: 200mg q.d Take 93% 10 >20 hours Renal excretion Minimal
™ ™ 200mg hard ™ without hours toxicity
Emtriva ; Truvada Truvada : 1 tablet q.d Dosage
gelatin capsule regard to
(w/TDF) adjustment in Lactic acidosis
meals
Truvada™: FTC, renal with hepatic
200mg + TDF, insufficiency steatosis (rare
300mg but potentially
Truvada™ not
life-threatening
for patients
toxicity with
with CrCl
use of NRTIs)
<30mL/min
Lamivudine (3TC) Epivir®: 150mg Epivir®: 150mg b.i.d Take 86% 5-7 18-22 hours Renal excretion Minimal
and 300mg OR 300mg q.d without hours toxicity
Epivir®; Combivir® Dosage
tablets or regard to
(w/ZDV); Epizicom® Combivir®: 1 tablet adjustment in Lactic acidosis
10mg/mL oral meals
(w/ABC); Trizivir® b.i.d renal with hepatic
solution
(w/ZDV + ABC) insufficiency steatosis (rare
Epizicom®: 1 tablet q.d
Combivir®: but potentially
Combivir®,
3TC, 150mg + Trizivir®: 1 tablet b.i.d life-threatening
Trizivir® not
ZDV, 300mg toxicity with
for patients
use of NRTIs)
Epizicom®: with CrCl
3TC, 300mg + <50mL/min
ABC, 600mg
Trizivir®:
<SUP® <sup>
3TC, 150mg
ZDV, 300mg +
ABC, 300mg
IV-25
AVAIL-
ABILITY
NAME LIFE HALF-LIFE
Stavudine (d4T) Zerit ®: 15, 20, Body Weight >60 kg: Take 86% 1.0 hour 7.5 hours Renal excretion Peripheral
® 30, 40mg 40mg b.i.d; without 50% neuropathy
Zerit
capsules or regard to
Body Weight <60 kg: Dosage Lipodystrophy
1mg/mL for oral meals
30mg b.i.d adjustment in
solution Rapidly
renal
progressive
insufficiency
ascending
neuromuscular
weakness (rare)
Pancreatitis
Lactic acidosis
with hepatic
steatosis (higher
incidence with
d4T than with
other NRTIs)
Hyperlipidaemia
Tenofovir Disoproxil Viread®: 300mg Viread®: 1 tablet q.d Take 25% in 17 >60 hours Renal excretion Asthaenia,
Fumarate (TDF) tablet without fasting hours headache,
Truvada®: 1 tablet q.d Dosage
® ® ® regard to state; diarrhoea,
Viread ; Truvada (w/FTC) Truvada : TDF, adjustment in
meals 39% nausea,
300mg + FTC, renal
with vomiting, and
200mg insufficiency
high-fat flatulence
meal Truvada® not
Renal
for patients
insufficiency
with CrCl
<30mL/min Lactic acidosis
with hepatic
steatosis (rare
but potentially
life-threatening
toxicity with
use of NRTIs)
IV-26
AVAIL-
ABILITY
NAME LIFE HALF-LIFE
Zalcitabine (ddC) 0.375, 0.75mg 0.75mg t.i.d Take 85% 1.2 N/A Renal excretion Peripheral
® tablets without hours 70% neuropathy
Hivid
regard to
Dosage Stomatitis
meals
adjustment in
Lactic acidosis
renal
with hepatic
insufficiency
steatosis (rare
but potentially
life-threatening
toxicity with
use of NRTIs)
Pancreatitis
Zidovudine (AZT, ZDV) Retrovir®: Retrovir®: 300mg b.i.d Take 60% 1.1 7 hours Metabolised to Bone marrow
® ® 100mg capsules, OR 200mg t.i.d without hours AZT suppression:
Retrovir ; Combivir
300mg tablets, regard to glucuronide macrocytic
(w/3TC); Trizivir® (w/3TC Combivir® or Trizivir®:
10mg/mL meals (GAZT) anaemia or
+ ABC) 1 tablet b.i.d
intravenous neutropaenia
Renal excretion
solution,
of GAZT Gastrointestinal
10mg/mL oral
intolerance,
solution Dosage
headache,
® adjustment in
Combivir : insomnia,
renal
3TC, 150mg + asthaenia
insufficiency
ZDV, 300mg
Lactic acidosis
Combivir®,
Trizivir®: 3TC, with hepatic
Trizivir® not
150mg + ZDV, steatosis (rare
for patients
300mg + ABC, but potentially
with CrCl
300mg life-threatening
<50mL/min
toxicity
associated with
use of NRTIs)
IV-27
Table 12: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
GENERIC NAME FORM DOSING FOOD EFFECT ORAL BIO- SERUM ELIMINATION ADVERSE
(ABBREVIATION)/TRADE RECOMMENDATIONS AVAILABILITY HALF- EVENTS
NAME LIFE
Delavirdine (DLV) 100mg 400mg t.i.d Take without 85% 5.8 Metabolised by Rash*
tablets or regard to meals hours cytochrome P450
Rescriptor® 4 100mg tablets can be Increased
200mg (3A inhibitor) transaminase
dispersed in >3 ounces
tablets levels
of water to produce 51% excreted in
slurry urine (<5% Headaches
unchanged)
200mg tablets should be
taken as intact tablets 44% in faeces
Separate dosing from
buffered ddI or antacids
by 1 hour
Efavirenz (EFV) 50, 100, 600mg q.d on an empty High-fat/high- Data not 40-55 Metabolised by Rash*
200mg stomach, at or before caloric meals available hours cytochrome P450 CNS symptoms†
Sustiva®
capsules or bedtime increase peak (3A mixed
600mg plasma inducer/inhibitor) Increased
tablets concentrations transaminase
14%-34% excreted levels
of capsules by
in urine
39% and tablets False-positive
(glucuronidated cannabinoid test
by 79%
metabolites, <1%
Take on an unchanged) Teratogenic in
empty stomach monkeys‡
16%-61% in faeces
Nevirapine (NVP) 200mg 200mg q.d for 14 days; Take without >90% 25-30 Metabolised by Rash including
® tablets or thereafter, 200mg po regard to meals hours cytochrome P450 Stevens-Johnson
Viramune syndrome*
50mg/5mL b.i.d (3A inducer)
oral Symptomatic
80% excreted in
suspension hepatitis,
urine including fatal
(glucuronidated hepatic necrosis,
metabolites; <5% have been
unchanged) reported‡
10% in faeces
IV-28
_______________________________
*During clinical trials, NNRTIs were discontinued because of rash among 7% of patients taking NVP, 4.3% of patients taking DLV, and 1.7% of patients
taking EFV. Rare cases of Stevens-Johnson syndrome have been reported with the use of all three NNRTIs, the highest incidence seen with NVP use.
†Adverse events can include dizziness, somnolence, insomnia, abnormal dreams, confusion, abnormal thinking, impaired concentration, amnaesia, agitation,
depersonalisation, hallucinations, and euphoria. Overall frequency of any of these symptoms associated with use of EFV was 52%, as compared with 26%
among control subjects; 2.6% of those persons on EFV discontinued the drug because of these symptoms. Symptoms usually subside spontaneously after 2-
4 weeks.
‡Symptomatic hepatic events (accompanied by rash in approximately 50% of cases) occur in significantly higher frequency in female patients with pre-NVP
CD4+ T cell counts of >250 cells/mm3 or in male patients with pre-NVP CD4+ T cell counts of >400 cells/mm3.
IV-29
Table 13: Protease Inhibitors (PIs)
GENERIC FORM DOSING FOOD ORAL BIO- SERUM ROUTE OF STORAGE ADVERSE
NAME/TRADE RECOMMEND- EFFECT AVAILABILITY HALF-LIFE METABOLISM EVENTS
NAME ATIONS
Amprenavir 50mg 1,400mg b.i.d High-fat meal Not 7.1-10.6 Cytochrome Room GI intolerance,
(APV) capsules (oral solution) decreases determined in hours P450 3A4 temperature nausea,
blood humans inhibitor (up to 25oC vomiting,
Agenerase® 15mg/mL Note: APV and diarrhoea
concentration inducer, and or 77oF)
oral solution RTV oral
21%; can be substrate Rash
solution should
(Capsules and taken with or
not be co- Dosage Oral
solution NOT without food,
administered due adjustment in paresthaesias
inter-change- but high-fat
to competition of hepatic
able on mg meals should Hyperlipi-
the metabolic insufficiency
per mg basis) be avoided daemia
pathway of the 2 recommended
vehicles Transaminase
elevation
Note: APV,
150mg capsule is Hypergly-
no longer caemia
available; Fat maldistri-
consider using f- bution
APV in these
patients Possible
increased
bleeding
episodes in
patients with
haemophilia
Note: Oral
solution contains
propylene
glycol; contra-
indicated in
pregnant women,
children age <4
years, patients
with hepatic or
renal failure, and
patients treated
with disulfiram
or metronidazole
IV-30
NAME ATIONS
Atazanavir 100, 150, 400mg q.d Administra- Not 7 hours Cytochrome Room Indirect
(ATV) 200mg tion with food determined P450 3A4 temper- hyperbili-
If Taken with
capsules increases inhibitor and ature (up to rubinaemia
Reyataz™ EFV (or TDF):
bioavailability substrate 25ºC or
RTV, 100mg + Prolong PR
77ºF)
ATV, 300mg q.d Take with Dosage interval–some
food; avoid adjustment in patients
taking with hepatic experienced
antacids insufficiency asymptomatic
recommended 1st-degree AV
block
Use with
caution in
patients with
underlying
condition
defects or on
concomitant
medications
that can cause
PR
prolongation
Hyper-
glycaemia
Fat maldistri-
bution
Possible
increased
bleeding
episodes in
patients with
haemophilia
IV-31
NAME ATIONS
fos- 700mg tablet ARV-Naïve No significant Not 7.7 hours Amprenavir is a Room Skin rash (19%)
amprenavir Patients: f-APV change in established (amprenavir) cytochrome temper-
Diarrhoea,
(f-APV) 1,400mg b.i.d; APV P450 3A4 ature (up to
nausea,
pharmaco- inhibitor, 25ºC or
Lexiva™ OR (f-APV, vomiting
kinetics in fed inducer, and 77ºF)
1,400mg + RTV,
or fasting substrate Headache
200mg) q.d;
state
Dosage Transaminase
OR (f-APV,
adjustment in elevation
700mg + RTV,
hepatic
100mg) b.i.d Hyper-
insufficiency
recommended glycaemia
PI-Experienced
Patients (once- Fat maldistri-
daily regimen bution and lipid
not abnormalities
recommended):
Possible
(f-APV, 700mg
+ RTV, 100mg) increased
b.i.d bleeding
episodes in
Co- patients with
Administration haemophilia
with EFV
(unboosted f-
APV not
recommended):
(f-APV, 700mg
+ RTV 100mg)
b.i.d;
OR (f-APV,
1,400mg +
RTV, 300mg)
q.d
IV-32
NAME ATIONS
Indinavir 200, 333, 800mg q8h For 65% 1.5-2 hours Cytochrome Room Nephro-lithiasis
(IDV) 400mg Unboosted P450 (3A4 temper-
With RTV: GI intolerance,
capsules IDV: Levels inhibitor; less ature 15-
Crixivan® [IDV, 800mg + nausea
decrease by than RTV) 30ºC (59-
RTV, 100mg or
77% 86ºF), Indirect
200mg] q12h Dosage
protect hyperbili-
Take 1 hour adjustment in
from rubinaemia
before or 2 hepatic
moisture
hours after insufficiency Misc.:
meals; may recommended headache,
take with asthaenia,
skim milk or blurred vision,
low-fat meal dizziness, rash,
metallic taste,
For RTV-
thrombo-
Boosted IDV:
cytopaenia,
Take with or
alopaecia, and
without food
haemolytic
anaemia
Hyper-
glycaemia
Fat
redistribution
Possible increased
bleeding episodes
in patients with
haemophilia
Lopinavir + Each capsule LPV, 400mg + Moderate fat Not 5-6 hours Cytochrome Refrig-erated GI intolerance,
Ritonavir contains RTV, 100mg (3 meal determined in P450 (3A4 capsules nausea,
(LPV/r) LPV, capsules or 5mL) increases humans inhibitor and and vomiting,
133.3mg + b.i.d AUC of substrate) solution are diarrhoea
Kaletra®
RTV, 33.3mg capsules and stable until
With EFV or Asthaenia
solution by date on
Oral Solution: NVP: [LPV,
48% and label if Hyper-
Each 5mL 533mg + RTV,
80%, stored at lipidaemia (esp.
contains 133mg] (4
IV-33
NAME ATIONS
LPV, 400mg capsules or respectively room hypertri-

+ RTV, 6.7mL) b.i.d temperature glyceridaemia)
Take with
100mg (up to 25oC
food Elevated serum
or 77oF)
Note: Oral trans-aminases
stable for 2
solution
months Hyper-
contains 42%
glycaemia
alcohol
Fat maldistri-
bution
Possible
increased
bleeding
episodes in
patients with
haemophilia
Nelfinavir 250mg tablets 1,250mg b.i.d Levels 20-80% 3.5-5 hours Cytochrome Room Diarrhoea;
(NFV) increase 2-3 P450 3A4 temperature
625mg tablets OR Hyper-
fold inhibitor and 15-30oC
Viracept® lipidaemia
50mg/g oral 750mg t.i.d substrate (59-86oF)
Take with
powder Hyper-
meal or snack
glycaemia
Fat
redistribution
Possible
increased
bleeding
episodes in
patients with
haemophilia
Serum
transaminase
elevation
IV-34
NAME ATIONS
Ritonavir 100mg 600mg q12h* Levels Not 3-5 hours Cytochrome Refrigerate GI intolerance,
(RTV) capsules (when RTV is increase by determined P450 capsules nausea,
used as sole PI) 15% (3A4>2D6; vomiting,
Norvir® OR Capsules
potent 3A4 diarrhoea;
As Pharmacokin- Take with can be left
600mg/7.5mL inhibitor)
etic Booster for food if at room Paresthaesias:
solution
Other PIs: possible; this temperature circumoral and
100mg- may improve (up to 25ºC extremities
400mg/day in 1- tolerability or 77ºF) for
Hyperlipi-
2 divided doses <30 days;
daemia, esp.
Oral hypertri-
solution glyceridaemia
should
Hepatitis
NOT be
refrigerated Asthaenia
Taste
perversion
Hyper-
glycaemia
Fat maldistri-
bution
Possible
increased
bleeding
episodes in
patients with
haemophilia
IV-35
NAME ATIONS
Saquinavir 200mg Unboosted SQV Take within 2 4% erratic 1-2 hours Cytochrome Room GI intolerance,
tablets and capsules -not hours of a (when taken P450 (3A4 temperature nausea and
hard gel recommended meal when as sole PI) inhibitor and 15-30oC diarrhoea
500mg tablets
capsules taken with substrate) (59-86oF) Headache
With RTV:
(SQV) RTV Elevated
(RTV, 100mg +
Invirase®
SQV, 1,000mg) transaminase
b.i.d enzymes
Hyperlipidaemia
Hyperglycaemia
Fat redistribution
Possible
increased
bleeding episodes
in patients with
haemophilia
Saquinavir 200mg Unboosted SQV- Levels Not 1-2 hours Cytochrome Refrigerate GI intolerance,
soft gel capsule capsules sgc: 1,200mg increase 6- determined P450 (3A4 or store at nausea,
(SQV-sgc) t.i.d fold inhibitor; less room diarrhoea,
abdominal pain,
than RTV) temper-ature
Fortovase® With RTV: Take with or and dyspepsia
<25oC pr
(RTV, 100mg + up to 2 hours
77oF) for Headache
SQV-sgc, after a meal
up to 3 Hyperlipi-daemia
1,000mg) b.i.d as sole PI or
months
with RTV Elevated
transaminase
enzymes
Hyper-glycaemia
Fat maldistri-
bution
Possible
increased
bleeding episodes
in patients with
haemophilia
*Dose Escalation for RTV When Used as Sole PI: Days 1 and 2: 300mg 2x; day 3-5: 400mg 2x; day 6-13: 500mg 2x; day 14: 600mg 2x
IV-36
Table 14: Fusion Inhibitors
GENERIC FORM DOSING BIO- SERUM ROUTE OF STORAGE ADVERSE EVENTS
NAME/TRADE RECOMMENDATIONS AVAILABILITY HALF- METABOLISM
NAME LIFE
Enfuvirtide Injectable: In 90mg (1mL) SC b.i.d 84.3% (SC 3.8 Expected to Store at room Local Injection Site
(T20) lyophilised powder compared to IV) hours undergo temperature (up Reactions: Almost
catabolism to to 25oC or 77oF) 100% of patients (pain,
Fuzeon™ Each single-use
its constituent erythema, induration,
vial contains Reconstituted
amino acids, nodules and cysts,
108mg of solution should
with subsequent pruritus, ecchymosis)
enfuvirtide to be be stored under
recycling of the
reconstituted with refrigeration at Increased rate of
amino acids in
1.1mL of sterile 2°C to 8°C (36°F bacterial pneumonia
the body pool
water for injection to 46°F) and
Hypersensitivity
for delivery of used within 24
Reaction (<1%):
approximately hours
Symptoms may include
90mg/1mL
rash, fever, nausea,
vomiting, chills, rigors,
hypotension, or elevated
serum transaminases;
rechallenge is not
recommended
IV-37
APPENDIX B: DRUG-DRUG INTERACTIONS BETWEEN PIS AND NNRTIS
PIs and NNRTIs are potent inhibitors and inducers of the cytochrome P450 (CYP450) enzymes in the liver, which are responsible for the metabolism of these
agents. For this reason, significant drug-drug interactions between PIs are common. Dosing adjustments are often necessary when two or more PIs and/or
NNRTIs are administered concurrently in an ARV regimen, as detailed in the tables below.
Table 15: Interactions between PIs

RTV is a potent inhibitor of the CYP450 system. RTV-mediated inhibition of the hepatic metabolism of other PIs can and often is used to therapeutic
advantage. When administered at low doses (e.g. 100-200mg once or twice daily), this agent will significantly boost the serum levels of a co-administered PI,
resulting in improved serum pharmacokinetics and higher clinical efficacy. Many PIs (e.g. IDV, SQV, LPV, APV, ATV) are therefore commonly co-
administered with low doses of RTV, as detailed in the table below.
DRUG AFFECTED RITONAVIR (RTV) SAQUINAVIR NELFINAVIR AMPRENAVIR LOPINAVIR/RITONAVIR ATAZANAVIR (ATV)
(SQV)* (NFV) (APV) (LPV/R)
PIs
Indinavir (IDV) Levels: IDV increase Levels: IDV no Levels: IDV Levels: APV AUC Levels: IDV AUC and Co-administration of these
2-5x. effect. increase 50%; increase 33%. Cmin increased. agents is not recommended
Dose: 400/400mg or SQV increase 4-7x. NFV increase Dose: No change. Dose: IDV 600mg b.i.d. because of potential for
800/100mg or Dose: Insufficient 80%. additive hyperbilirubinaemia.
800/200mg IDV/RTV data. Dose: Limited
b.i.d. data for IDV
Caution: Renal 1,200mg b.i.d
events may be + NFV
increased with 1,250mg b.i.d.
higher IDV
concentrations.
Ritonavir (RTV) Levels: RTV no Levels: RTV Levels: APV AUC LPV is co-formulated with ATV/r 300/100 increase ATV
effect. no effect; increase 2.5–3.5x. RTV as Kaletra™. AUC by 238%.
SQV increase NFV increase Dose: 600/100mg
20x†‡. 1.5x. APV/RTV b.i.d.
Dose: Dose: RTV or 1,200/200mg
1,000/100mg SQV 400mg b.i.d + APV/RTV q.d
sgc or hgc/RTV NFV 500-
b.i.d or 400/400mg 750mg b.i.d.
b.i.d.
IV-38
DRUG AFFECTED RITONAVIR (RTV) SAQUINAVIR NELFINAVIR AMPRENAVIR LOPINAVIR/RITONAVIR ATAZANAVIR (ATV)
(SQV)* (NFV) (APV) (LPV/R)
Saquinavir Levels: SQV Levels: APV AUC Levels: SQV† AUC and SQV 1,200 mg q.d + ATV
(SQV) increase 3-5x; decrease 32%. Cmin increased. 400 q.d; increase SQV AUC
NFV increase Dose: Insufficient Dose: SQV 1,000mg b.i.d, by 449%, no formal
20%†. data. LPV/r standard. recommendation.
Dose:
Standard
NFV;
Fortovase®,
800mg t.i.d or
1,200mg b.i.d.
Nelfinavir Levels: APV AUC Levels: LPV decrease
(NFV) increase 1.5x. 27%; NFV increase 25%.
Dose: Insufficient Dose: Insufficient data.
data.
Amprenavir (APV) APV: AUC and Cmin
increased relative to APV
without RTV; APV, AUC,
and Cmin are reduced
relative to APV + RTV;
LPV Cmin may be
decreased relative to
LPV/r.
Dose: APV 600-750mg
b.i.d; LPV/r standard or
consider dose increase to
533/133mg b.i.d; consider
monitoring PI
concentrations.
Lopinavir/Ritonavir (LPV/r) No information with
LPV/ATV; RTV 100 mg
increases ATV AUC 238%.
*Several drug interaction studies have been completed with SQV given as Invirase or Fortovase . Results from studies conducted with Invirase® may not be applicable
® ®
to Fortovase®.
†Study conducted with Fortovase®.
‡Study conducted with Invirase®.
IV-39
Table 16: Interactions between PIs and NNRTIs
DRUG AFFECTED NEVIRAPINE (NVP) DELAVIRDINE (DLV) EFAVIRENZ (EFV)
PIs and NNRTIs
Indinavir (IDV) Levels: IDV decrease 28%; NVP no effect. Levels: IDV increase >40%; DLV no Levels: IDV decrease 31%.
Dose: IDV 1,000mg q8h or consider effect. Dose: IDV 1.000mg q8h or consider IDV/RTV, EFV
IDV/RTV, NVP standard. Dose: IDV 600mg q8h. standard.
DLV: standard.
Ritonavir (RTV) Levels: RTV decrease 11%; NVP no effect. Levels: RTV increase 70%. Levels: RTV increase 18%.
Dose: Standard. DLV: no effect. EFV increase 21%.
Dose: DLV: standard. Dose: Standard.
RTV: no data.
Saquinavir (SQV) Levels: SQV decrease 25%. NVP no effect. Levels: SQV‡ increase 5 times; DLV no Levels: SQV‡ decrease 62%. EFV decrease 12%.
Dose: Consider SQV/RTV. effect. SQV is not recommended to be used as sole PI when
Dose: Fortovase® 800mg t.i.d, DLV EFV is used.
standard (monitor transaminase levels). Dose: Consider SQV/RTV.
Nelfinavir (NFV) Levels: NFV increase 10%. Levels: NFV increase 2 times; DLV Levels: NFV increase 20%.
NVP no effect. decrease 50%. Dose: Standard.
Dose: Standard. Dose: No data (monitor for neutropaenic
complications).
Amprenavir (APV) No data. Levels: APV AUC increase 130%. DLV Levels: APV AUC decrease 36%.
AUC decrease 61%. Dose: Administer APV/RTV with EFV, EFV
Dose: No data. standard.
Lopinavir/Ritonavir Levels: LPV Cmin decrease 55%. Levels: LPV levels expected to increase. Levels: LPV AUC decrease 40%; EFV no change.
(LPV/r) Dose: Consider LPV/r 533/133mg b.i.d in Dose: Insufficient data. Dose: Consider LPV/r 533/133mg b.i.d.
PI-experienced patients; NVP standard. EFV standard.
Atazanavir (ATV) No data. No data. Levels: ATV AUC decrease 74%, EFV no change.
A decrease in ATV levels is expected. Dose: Recommend ATV 300 + RTV 100mg each
given q.d with food; EFV standard.
Nevirapine (NVP) No data. Levels: NVP: no effect.
EFV: AUC decrease 22%.
Delavirdine (DLV) No data. No data.
‡
Study conducted with Invirase®.
IV-40
APPENDIX C: DRUG INTERACTIONS BETWEEN ARVS AND OTHER DRUGS
Table 17: Drug Interactions between ARVs and Other Drugs
DRUG INTERACTIONS REQUIRING DOSE MODIFICATIONS OR CAUTIOUS USE
Drugs Affected Indinavir (IDV) Ritonavir* (RTV) Saquinavir† (SQV)
ANTIFUNGALS
Ketoconazole Levels: IDV ↑ 68%. Levels: Ketoconazole ↑ 3x. Levels: SQV ↑ 3x.
Dose: IDV 600mg t.i.d. Dose: Use with caution; do not exceed Dose: If ketoconazole dose is
200mg ketoconazole daily. >200mg/day, monitor for excessive
diarrhoea, nausea, and abdominal
discomfort; adjust doses accordingly.
Voriconazole Levels: No significant changes in No data, but potential for bi-directional No data, but potential for bi-directional
AUC of azole or IDV (healthy inhibition between voriconazole and PIs; inhibition between voriconazole and
subjects). monitor for toxicities. PIs; monitor for toxicities.
Dose: Standard.
ANTIMYCOBACTERIALS
Rifampin (RIF)Σ Levels: IDV ↓ 89%. Levels: RTV ↓ 35%. Levels: SQV ↓ 84%.
Contra-indicated. Dose: No data; increased liver toxicity Contra-indicated, unless using RTV +
possible. SQV, then use RIF 600mg q.d or t.i.w.
Rifabutin Levels: IDV ↓ 32%. Rifabutin ↑ 2x. Levels: Rifabutin ↑ 4x. Levels: SQV ↓ 40%.
Dose: ↓ rifabutin to 150mg q.d or Dose: ↓ rifabutin to 150mg q.o.d. No rifabutin dose adjustment unless
300mg t.i.w. IDV 1,000mg t.i.d. or dose t.i.w. using RTV + SQV, then use rifabutin
RTV: Standard. 150mg t.i.w.
Clarithromycin Levels: Clarithromycin ↑ 53%. Levels: Clarithromycin ↑ 77%. Levels: Clarithromycin ↑ 45%.
No dose adjustment. Dose: Adjust clarithromycin dose for SQV ↑ 177%.
moderate and severe renal impairment. No dose adjustment.
ORAL CONTRACEPTIVES
Levels: Norethindrone ↑ 26%; Levels: Ethinyl estradiol ↓ 40%. Use No data.
ethinylestradiol ↑ 24%. alternative or additional method.
No dose adjustment.
LIPID–LOWERING AGENTS
Simvastatin Levels: Potential for large increase in Levels: Potential for large increase in Levels: Potential for large increase in
Lovastatin statin levels. Avoid concomitant statin levels. Avoid concomitant use. statin levels. Avoid concomitant use.
use.
IV-41
Atorvastatin Levels: Potential for increase in Levels: 450% ↑ when administered with Levels: 450% ↑ when administered
AUC. Use lowest possible starting SQV/RTV combination. Use lowest with SQV/RTV combination. Use
dose of atorvastatin with careful possible starting dose of atorvastatin with lowest possible starting dose of
monitoring. careful monitoring. atorvastatin with careful monitoring.
Pravastatin No data. Levels: 50% ↓ when administered with Levels: 50% ↓ when administered with
SQV/RTV combination. No dose SQV/RTV combination. No dose
adjustment needed. adjustment needed.
ANTICONVULSANTS
Carbamazepine Carbamazepine markedly ↓ IDV Carbamazepine: ↑ serum levels when Unknown, but may markedly ↓ SQV
Phenobarbitol AUC. Consider alternative agent. co-administered with RTV; use with levels.
Phenytoin caution; monitor anticonvulsant levels. Monitor anticonvulsant levels.
METHADONE
No change in methadone levels. Methadone ↓ 37%. Monitor and titrate No data.
dose if needed.
May require ↑ methadone dose.
ERECTILE DYSFUNCTION AGENTS
Sildenafil Sildenafil AUC ↑ 3x. Use cautiously. Sildenafil AUC ↑ 11x. Use cautiously. Sildenafil AUC ↑ 2x. Use a 25mg
Start with reduced dose of 25mg q48h Start with reduced dose of 25mg q48h starting dose of sildenafil.
and monitor for adverse effects. and monitor for adverse effects.
Vardenafil Vardenafil AUC ↑ 16x. Start with a Vardenafil AUC ↑ 49x. Start with a No data, but vardenafil AUC may be
2.5mg dose and do not exceed a 2.5mg dose, and do not exceed a single substantially increased. Start with a
single 2.5mg dose in 24 hours. Do 2.5mg dose in 72 hours. 2.5mg dose and do not exceed a single
not exceed 2.5mg in 72 hours if 2.5mg dose in 24 hours. Do not exceed
administered with RTV. a single 2.5mg dose in 72 hours if
administered with RTV.
MISCELLANEOUS
Grapefruit juice ↓ IDV levels by 26%.
Many possible interactions. Grapefruit juice ↑ SQV levels.
Desipramine ↑ 145%, reduce dose. Dexamethasone ↓ SQV levels.
Theophylline ↓ 47%, monitor
theophylline levels.
*Drugs for which plasma concentrations may be decreased by co-administration with RTV: anticoagulants (warfarin), anticonvulsants (phenytoin, divaproex,
lamotrigine), antiparasitics (atovaquone).
†
Some drug interaction studies were conducted with Invirase®. May not necessarily apply to use with Fortovase®.
Σ
There are limited data on RTV-SQV and RTV-LPV demonstrating that RTV compensates for RIF induction. In one small study, higher-boosting doses of RTV
(up to 400mg per dose) or an increased dose of LPV/RTV 800/200mg were needed to fully offset RIF-inducing activity of LPV. Of note, 28% of subjects
discontinued due to increases in LFTs. The safety of this combination is still under evaluation. Whether RTV can be used to offset RIF induction of all other
PIs, or whether this therapeutic manoeuvre is more broadly applicable, requires further study.
(Adapted from: US DHHS. Table 20: Drug Interactions Between Antiretrovirals and Other Drugs: PIs, NNRTIs, and NRTIs in Guidelines for the use of
antiretroviral agents in HIV-1-infected adults and adolescents. 2003. Available at: http://AIDSinfo.nih.gov/guidelines. Accessed 2003)
IV-42
APPENDIX D: DRUGS THAT SHOULD NOT BE USED IN COMBINATION WITH PIS OR NNRTIS DUE TO DANGEROUS DRUG INTERACTIONS
Drug Category# Calcium Cardiac Lipid- Antimycobacterial‡ Anti- Gastro- Neuroleptic Psychotropic Ergot Alkaloids Herbs Other
Channel Lowering histamine∂ intestinal (vasoconstrictor)
Blocker Agents Drugs∂
PIs
(none) (none) simvastatin RIF astemizole cisapride pimozide midazolamΣ dihydroergotamine St. ATV
lovastatin rifapentine terfenadine triazolam (D.H.E. 45) John’s
ergotamine† (various wort
Indinavir (IDV)
forms)
ergonovine
methylergonovine
bepridil amiodarone simvastatin rifapentine astemizole cisapride pimozide midazolamΣ dihydroergotamine St.
flecainide lovastatin terfenadine triazolam (D.H.E. 45) John’s
propafenone ergotamine† (various wort
Ritonavir (RTV)
quinidine forms)
ergonovine
methylergonovine
(none) (none) simvastatin RIF∆ astemizole cisapride pimozide midazolamΣ dihydroergotamine St.
lovastatin rifabutin∆ terfenadine triazolam (D.H.E. 45) John’s
Saquinavir rifapentine ergotamine† (various wort
(SQV) forms)
ergonovine
methylergonovine
(none) (none) simvastatin RIF astemizole cisapride pimozide midazolamΣ dihydroergotamine St.
Nelfinavir (NFV)
forms)
ergonovine
methylergonovine
bepridil (none) simvastatin RIF astemizole cisapride pimozide midazolamΣ dihydroergotamine St.
Amprenavir ergotamine† (various wort
(APV)* forms)
ergonovine
methylergonovine
(none) flecainide simvastatin RIF∫ astemizole cisapride pimozide midazolamΣ dihydroergotamine St.
propafenone lovastatin rifapentine terfenadine triazolam (D.H.E. 45) John’s
Lopinavir (LPV) ergotamine† (various wort
+ Ritonavir forms)
ergonovine
methylergonovine
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Drug Category# Calcium Cardiac Lipid- Antimycobacterial‡ Anti- Gastro- Neuroleptic Psychotropic Ergot Alkaloids Herbs Other
Channel Lowering histamine∂ intestinal (vasoconstrictor)
Blocker Agents Drugs∂
bepridil (none) simvastatin RIF astemizole cisapride pimozide midazolamΣ dihydroergotamine St. IDV
lovastatin rifapentine terfenadine proton pump triazolam (D.H.E. 45) John’s irinotecan
Atazanavir inhibitors ergotamine† (various wort
(ATV) forms)
ergonovine
methylergonovine
NNRTIs
(none) (none) (none) RIF (none) (none) (none) (none) (none) St.
Nevirapine rifapentine‡ John’s
wort
(none) (none) simvastatin RIF astemizole cisapride (none) alprazolam dihydroergotamine St.
lovastatin rifapentin‡ terfenadine H-2 blockers midazolamΣ (D.H.E. 45) John’s
Delavirdine rifabutin proton pump triazolam ergotamine† (various wort
(DLV) inhibitors forms)
ergonovine
methylergonovine
(none) (none) (none) rifapentine‡ astemizole cisapride (none) midazolamΣ dihydroergotamine St.
terfenadine triazolam (D.H.E. 45) John’s
Efavirenz (EFV)
forms)
ergonovine
methylergonovine
(Adapted from: US DHHS. Table 19: Drugs That Should Not Be Used With PI or NNRTI Antiretrovirals in Guidelines for the use of antiretroviral agents in HIV-
1-infected adults and adolescents. 2003. Available at: http://AIDSinfo.nih.gov/guidelines. Accessed 2003)
IV-44
#
Certain listed drugs are contra-indicated based on theoretical considerations. Thus, drugs with narrow
therapeutic indices and suspected metabolic involvement with P450–3A, 2D6, or unknown pathways are
included in this table. Actual interactions may or may not occur among patients.
‡
HIV patients being treated with rifapentine have a higher rate of TB relapse than those treated with other
rifamycin-based regimens; an alternative agent is recommended for this population.
∆
RIF and rifabutin are contra-indicated unless SQV is combined with RTV.
∫
In one small study, higher doses of RTV or LPV/r offset RIF-inducing activity of LPV. Of note, 28% of
subjects discontinued due to increases in LFTs. The safety of this combination is still under evaluation;
further studies are needed.
Σ
Midazolam can be used with caution as a single dose and given in a monitored situation for procedural
sedation.
†
This is likely a class effect.
∂
Astemizole and terfenadine are not marketed in the United States. The manufacturer of cisapride has a
limited-access protocol in place for patients meeting specific clinical eligibility criteria.
*
Each 150mg APV Agenerase® capsule has 109 IU (International Units) of vitamin E and 1mL of APV oral
solution has 46 IU of vitamin E. At FDA approved doses, the daily amount of vitamin E in Agenerase® is a
58-fold increase over the federal government’s reference daily intake for adults. Patients should be
cautioned to avoid supplemental doses of vitamin E. Multivitamin products containing minimal amounts of
vitamin E are likely acceptable.
Suggested Alternatives
Cerivastatin (no longer marketed in the United States), simvastatin, lovastatin: pravastatin and
fluvastatin have the least potential for drug-drug interactions; atorvastatin should be used with
caution, using the lowest possible starting dose and monitoring closely.
Rifabutin: clarithromycin, azithromycin (MAI prophylaxis); clarithromycin, azithromycin,
ethambutol (EMB) (MAI treatment)
Astemizole, terfenadine (no longer marketed in the United States): desloratadine, loratadine,
fexofenadine, cetirizine
Midazolam, triazolam: temazepam, lorazepam
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APPENDIX E: BASIC LABORATORY MONITORING FOR RECOMMENDED FIRST-LINE REGIMENS
This table is meant to serve as a general guide and should not replace clinical judgment for individual patients. Laboratory monitoring is
warranted outside of this schedule for any signs or symptoms suggestive of medication-related toxicity. Tolerance of a HAART regimen may
reasonably lead to a decreased frequency of laboratory monitoring. HAART should not be withheld in circumstances where scarce resources do
not permit laboratory monitoring as suggested below. Detection of abnormalities on laboratory testing should not necessarily lead to automatic
discontinuation or modification of the HAART regimen; rather, the results should be interpreted in the context of the patient’s clinical signs and
symptoms. Consultation with an expert HIV clinician is suggested.
HAART LABORATORY FREQUENCY STRENGTH OF REASON
REGIMEN TEST RECOMMENDATION
AZT + 3TC + EFV CD4+ T cell BL; q3-6m Highly recommended Assess response to therapy
Hgb/CBC BL; 4 weeks after initiation; Mandatory Potential for AZT-associated anaemia
Pregnancy BL; clinician discretion§§§§§§§ Mandatory Teratogenicity associated with EFV
AST BL; q3-6m; symptom-directed Recommended Potential for EFV-associated liver
toxicity
HIV viral load BL; q3-6m Optional but recommended in setting Assess response to therapy; confirm
of suspected treatment failure suspected treatment failure
Glucose BL; q6-12m Recommended Insulin resistance associated with EFV
Cholesterol BL; 3-6 months after initiation of Recommended for patients with other Dyslipidaemia associated with
treatment; clinician discretion risk factors for coronary artery NNRTIs and PIs
disease
AZT + 3TC + NVP CD4+ T cell BL; q3-6 months Recommended Assess response to therapy
Hgb/CBC BL; one month after initiation; Highly recommended Potential for AZT-associated anaemia
symptom-directed
BL; q3-6m; symptom-directed Highly recommended Potential for NVP-associated liver
AST toxicity
§§§§§§§
Due to its potential for severe teratogenicity, EFV should not be used in women who are pregnant (especially in the first and second trimesters) or in
women at risk for pregnancy (e.g. for whom effective contraception cannot be assured).
IV-46
HAART LABORATORY FREQUENCY STRENGTH OF REASON
REGIMEN TEST RECOMMENDATION
d4T + 3TC + EFV CD4+ T cell BL; q3-6m Highly recommended Assess response to therapy
********
Pregnancy BL; clinician discretion Mandatory Teratogenicity associated with EFV
AST BL; q3-6m; symptom-directed Recommended Potential for EFV-associated liver
toxicity
Glucose BL; q6-12m Recommended Insulin resistance associated with EFV
Cholesterol BL; 3-6 months after initiation of Recommended for patients with other Dyslipidaemia associated with
treatment; clinician discretion risk factors for coronary artery NNRTIs and PIs
disease
d4T + 3TC + NVP CD4+ T cell BL; q3-6m Recommended Assess response to therapy
AST BL; q3-6m; symptom-directed Highly recommended Potential for NVP-associated liver
toxicity
BL = baseline (before starting therapy)
********
Due to its potential for severe teratogenicity, EFV should not be used in women who are pregnant (especially in the first and second trimesters) or in
women at risk for pregnancy (e.g. for whom effective contraception cannot be assured).
IV-47
APPENDIX F: HIV RESISTANCE
INTRODUCTION
HIV resistance can be broadly defined as any change in the virus that improves its ability to replicate in
the presence of an antiretroviral drug. This resistance is always relative to the wild-type virus and is
rarely absolute. In specific terms, HIV resistance is an altered phenotype resulting from a change in a
viral genotype and can be measured both in vitro and in vivo.
In vivo, resistance is defined as failure of a drug to maintain viral suppression in a treated individual. This
is identified by a rising viral load when available, otherwise by a falling CD4+ T count, and may be
associated with phenotypic and/or genotypic evidence of drug resistance.
A more detailed review of HIV resistance, as well as an online algorithm for interpretation of genotypic
resistance assays, can be found at http://hivdb.stanford.edu.
RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NSRTIS) AND

NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NTRTIS)
The first data suggesting correlation between the emergence of viral resistance and clinical progression
was reported by Larder and colleagues* two years after AZT became available for clinical use.
AZT, ZDV:. Mutations emerge in a characteristic sequence, with a first single base mutation usually
appearing at codon 70. This appearance is temporary as it is typically replaced by a mutant at codon 215.
This mutation is commonly followed by the appearance of single base mutations at codons 41, 67, and
219. The mutation at codon 70 may reappear with prolonged AZT treatment, as can a mutation at codon
210. These mutations (M41L, D67N, K70R, L210W, T215Y/F, and K219Q/E) are known as thymidine
analogue mutations (TAMs) because they confer cross resistance to d4T, another thymidine analogue, as
well. Some experts favour the term nucleoside-associated mutations (NAMs) because some degree of
cross-resistance has been documented between these mutations and all members of the NRTI class.
Mutations at codon 69 and 151 have also been associated with broad resistance to nearly all members of
the NRTI class.
d4T: in addition to the TAMs and the mutations at codons 69 and 151 described above, mutations at
codon 75 may be associated with resistance.
ddI: Resistance to ddI is associated with a mutation at codon 74 (L74V) as well as the TAMS and the
mutations at codons 69 and 151. In addition, the K65R mutation may be associated with resistance.
3TC: In vitro, high-level resistance (500- to 1,000-fold) develops rapidly when the virus carries the
single mutation M184V/I. This mutation is also observed in vivo. Furthermore, insertion at codon 69 is
associated with resistance to 3TC.
ABC: In vitro selection for resistance to ABC has been associated with the TAMS and mutations at
codon 184. Insertion mutations at codon 69 are also associated with resistance to ABC.
TDF: In vitro selection for reduced sensitivity to TDF has been associated with a mutation at codon 65
(K65R). In vivo, the mutation K65R has also been documented in patients failing TDF treatment. In
addition, multiple TAMs and/or an insertion mutation at codon 69 can result in resistance to TDF.
*
Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged
therapy. Science 243:1731-1734; 1989.
IV-48
As shown in Table 18, many mutations of the reverse transcriptase gene elicited by one ARV induce
cross-resistance to other NRTIs.
RESISTANCE TO NNRTIS
Despite their structural differences, all NNRTIs bind to the same site, a hydrophobic pocket of the HIV
reverse transcriptase. A single mutation in this region of the enzyme can result in a conformational
change that confers high-level resistance. Cross-resistance between NNRTIs is unfortunately very
common; resistance to NVP typically confers cross-resistance to EFV, and vice-versa.
Mutated codons contributing to resistance to NNRTIs are shown in Table 19.
RESISTANCE TO PIS
Mutations of at least twenty-five different codons have been implicated in the development of HIV
resistance to PIs. There is also a significant degree of cross-resistance among the members of the PI
class.
SQV: Reduced sensitivity to SQV is most often associated with three mutations in the protease gene at
codons 48 (G48V), 84 (I84V), and 90 (L90M). Additional mutations at codons 54, 71, 73, 77, and 82
have also been observed in patients receiving SQV. When SQV is administrated with RTV, mutations at
codons 24, 62, and 90 have been reported in patients failing treatment.
RTV: Resistance to RTV involves multiple mutations, usually at greater than three sites and up to eleven.
Resistant viruses generally show mutation at codons 46, 82, 84, and 90, with the mutation at codon 82
appearing first in most patients. Others mutations have been observed in patients at codons 20, 24, 32,
36, 54, 71, 73, and 77.
IDV: Resistance to IDV is very similar to RTV resistance, with multiple mutations required usually at
greater than three sites and up to eleven. Mutations at codon 82 or codon 46 (M46I or M46L) are the
most commonly seen (with or without other mutations).
NFV: The most common mutations observed in vivo are D30N and L90M. D30N occurs more
commonly and does not induce cross-resistance with other PIs. Reduction in susceptibility is also
displayed by isolates harbouring a mutation at codon 82 in association with other mutations.
APV: A specific mutation at codon 50 induces resistance to APV. Otherwise, up to three mutations at
codons 10, 32, 46, 47, 54, 73, 82, 84, and 90 are required to induce resistance to APV. When APV is
administrated with RTV, up to five of these mutations are needed.
LPV: LPV is co-formulated with RTV, which boosts the serum drug levels of LPV. Multiple mutations
in the protease gene are required to generate significant resistance to LPV/RTV, making this a useful
agent for initial as well as salvage therapy.
RESISTANCE TESTING
TEST METHODS
There are two types of tests: phenotypic and genotypic assays.
Phenotypic Assays
In vitro, resistance is based on the ability of the virus to grow in the presence of an inhibitor compared
with a more susceptible control virus (wild-type).
IV-49
These assays measure the ability of HIV to replicate at different concentrations of a tested ARV agent.
The method involves isolation, amplification, and insertion of the reverse transcriptase (RT) and protease
genes from the patient into a backbone laboratory clone by cloning or by recombination. Replication is
then monitored at various drug concentrations and compared with a reference. Results are reported as the
IC50 (50% inhibitory concentration) for the test strain relative to that of a reference or a wild-type strain.
Genotypic Assays
The genotype is defined as the nucleotide sequence from which a protein’s amino acid sequence can be
deduced. This sequence can be compared to a reference wild-type genotype. Any change from the wild-
type is usually reported as a change in amino acid at a specific residue (codon) of the protein.
Genotypic assays identify mutations into the RT and protease gene. The methodology is: 1) amplification
of the RT and/or protease gene by RT PCR; 2) DNA sequencing of amplicons generated for the dominant
species; and 3) reporting of mutations for each gene.
The results of these assays can be obtained in one to two weeks and are reproducible. Limitations are
viral load >500 - 1,000 copies/mL and identification of mutations present in >10% - 20% of plasma
virions.
Due to the continuous rising of the number of mutations associated with resistance, only assays allowing
the complete determination of nucleotides sequences of the RT and protease gene should be used.
Commercial kits exist, but many laboratories utilise their own sequencing methods.
Interpretation of Genotypic Assays
Resistance to ARV drugs is due to complex combinations of mutations in the HIV genes coding for the
RT or protease. The interpretation of the mutations observed and of their combinations needs the
expertise of the analyst and algorithms regarding each ARV. As the interpretation algorithms are quickly
evolving with time, the following links should be consulted:
Table from IAS-USA updated at <http://www.iasusa.org>; see also
<http://hivdb.stanford.edu/pages/seqAnalysis.html>.
Table from ANRS updated at <http://www.hivfrenchresistance.org>.
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Table 18: Major Mutations Associated with Reduced Susceptibility to NRTIs
SEQUENCE OF THE REVERSE TRANSCRIPTASE
Wild
M41 E44 K65 D67 T69 K70 L74 V75 Y115 Q151 M184 L210 T215 K219
Codons
MUTATED CODONS ASSOCIATED WITH RESISTANCE TO:
Y/F/
INSERTION AT
AZT L N R M W A/C/D/E/G Q/E
CODON 69
/H/I/L/N/S/V
Y/F/
INSERTION AT
d4T L N R M/S/A/T M W A/C/D/E/G Q/E
CODON 69
/H/I/L/N/S/V
INSERTION AT
ddI L N R V M W Y/F Q/E
CODON 69
INSERTION AT
3TC R M V/I
CODON 69
INSERTION AT
ABC L R N R V F M V/I W Y/F
CODON 69
INSERTION AT
TDF L D R N D/N/S V W Y/F
CODON 69
Table 19: Major Mutations Associated with Reduced Susceptibility to NNRTIs
SEQUENCE OF THE REVERSE TRANSCRIPTASE GENE

Wild Codons L100 K101 K103 V106 Y181 Y188 G190 P225
EFV I E H/N/S/T M C/I C/L A/C/E/Q/S/T/V H
NVP I E H/N/S/T M/A C/I C/H/L A/C/E/Q/S/T/V
IV-51
Table 20: Major Mutations Associated with Reduced Susceptibility to PIs
SEQUENCE OF THE PROTEASE GENE
Wild
L10 K20 L24 D30 V32 L33 M36 M46 G48 I50 F53 I54 I62 L63 A71 G73 V77 V82 I84 N88 L90
Codons
IDV M/R I I I V/L/M/T V/T S/A I A/F/S/T A/V M
I/L
SQV I V V A/F/S/T A/V M
NFV I I I/L V/L/M/T I A/F/S/T A/V

N S/D M
RTV M/R I I I V/L/M/T I A/F/S/T A/V M

I/L
APV F/I/V M/R V P A/F/S/T A/V

V
LPV/r F/I/V/R M/R I F I/L V L V/L/M/T P I/L/V/T A/F/S/T V M
ATV F/I/V I/M/R I F/I/V I/L/V I/L V L L/V P I/L/V/T A/C/S/T A/F/S/T V M
V-52
V: RECOMMENDATIONS FOR THE TREATMENT OF
OPPORTUNISTIC INFECTIONS (OIS) AMONG ADULTS AND
ADOLESCENTS∗
TABLE OF CONTENTS
INTRODUCTION .....................................................................................................................................................V-1
THE EFFECT OF HAART ON OIS AND IMMUNE RECONSTITUTION SYNDROME (IRS) ...................................V-1
INITIATION OF HAART FOR THE TREATMENT-NAÏVE PATIENT IN THE SETTING OF AN ACUTE OI.............V-2
MANAGEMENT OF ACUTE OIS IN THE SETTING OF RECENTLY-INITIATED HAART......................................V-2
TREATMENT RECOMMENDATIONS: WHEN TO INITIATE THERAPY IN THE SETTING OF AN ACUTE OI........V-3
SPECIAL CONSIDERATIONS IN PREGNANCY ....................................................................................................... V-3
DISEASE-SPECIFIC RECOMMENDATIONS ........................................................................................................... V-4
Pneumocystis jiroveci (Formerly carinii) Pneumonia (PCP)..........................................................................V-4
Toxoplasma gondii Encephalitis .....................................................................................................................V-7
Cryptosporidiosis ............................................................................................................................................V-10
Isosporiasis......................................................................................................................................................V-11
Cyclospora ......................................................................................................................................................V-12
Microsporidiosis..............................................................................................................................................V-13
Mycobacterium tuberculosis (TB) .................................................................................................................. V-15
Disseminated Mycobacterium avium Complex (MAC) Disease..................................................................... V-23
Bacterial Respiratory Disease .........................................................................................................................V-25
Bacterial Enteric Disease ................................................................................................................................V-28
Bartonellosis....................................................................................................................................................V-30
Syphilis............................................................................................................................................................V-31
Mucocoetaneous Candidiasis ..........................................................................................................................V-34
Cryptococcosis ................................................................................................................................................V-36
Histoplasmosis ................................................................................................................................................V-38
Coccidioidomycosis ........................................................................................................................................V-40
Aspergillosis V-55 .........................................................................................................................................V-41
Cytomegalovirus (CMV) Disease ...................................................................................................................V-42
Herpes Simplex Virus (HSV) Disease ............................................................................................................V-44
Varicella Zoster Virus (VZV) Disease............................................................................................................V-46
Human Herpesvirus-8 (HHV-8) Disease ........................................................................................................V-47
Progressive Multifocal Leukoencephalopathy (PML) Due to JC Virus .........................................................V-47
Human Papillomavirus (HPV) Disease...........................................................................................................V-48
Hepatitis B Virus (HBV) Disease ...................................................................................................................V-50
REFERENCES ........................................................................................................................................................V-96
TABLES
Table 1: Recommended Dose Adjustments When Patients Are Administered Rifabutin Concurrently with ARVs ......V-19
Table 2: ARV-Anti-Infective Drug Combinations that Should Be Avoided .............................................................V-20
Table 3: Recommended Regimens for the Treatment of Syphilis in HIV-Infected Patients....................................... V-32
∗
This chapter has been adapted with permission from the following document:
Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and
adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine
Association/Infectious Diseases Society of America. MMWR Weekly [serial on the Internet] 2004
December 17 [cited 2004] 53(RR15);1-112. Available at:
http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5315al.htm.
V-i
Table 4: Treatment of Anal Condyloma or Anal Intraepithelial Neoplasia (AIN) ...................................................V-49
APPENDIX A: SUMMARY OF PRE-CLINICAL AND HUMAN DATA ON OI DRUGS IN PREGNANCY ........................V-56

APPENDIX B: TREATMENT OF AIDS-ASSOCIATED OIS IN ADULTS .....................................................................V-64
APPENDIX C: DOSAGE ADJUSTMENT IN RENAL INSUFFICIENCY .........................................................................V-83
APPENDIX D: COMMON TOXICITIES OF SYSTEMIC AGENTS FOR TREATMENT OF OIS ........................................V-86
APPENDIX E: SIGNIFICANT PHARMACOKINETIC DRUG-DRUG INTERACTIONS FOR DRUGS IN THE
TREATMENT OF OIS ............................................................................................................................................V-88
V-ii
V: RECOMMENDATIONS FOR THE TREATMENT OF OPPORTUNISTIC
INFECTIONS (OIS) AMONG ADULTS AND ADOLESCENTS
INTRODUCTION
Opportunistic Infections (OIs) are responsible for significant morbidity and mortality among HIV-
infected persons in the Caribbean. Clinical studies of adults or children with HIV infection in Barbados,1
Haiti,2 Cuba,3 Puerto Rico,4 Guadeloupe,5 and elsewhere indicate that OIs commonly seen in the region
include tuberculosis;6 pneumocystis pneumonia; toxoplasmosis encephalitis; cryptococcal meningitis;
histoplasmosis; mucocoetaneous candidiasis; Mycobacterium avium complex disease; bacterial
respiratory infections; bacterial and parasitic enteric infections; syphilis; and viral infections caused by
cytomegalovirus, herpes simplex virus, varicella zoster virus, human herpesvirus type I, and human
papillomavirus.
In the foreseeable future, OIs will remain a principal reason that HIV-infected persons seek medical
attention. The management of OIs remains challenging; treatment strategies continue to evolve as new
drugs are developed and as more data about efficacy, toxicity, and drug-drug interactions emerge.
THE EFFECT OF HAART ON OIS AND IMMUNE RECONSTITUTION SYNDROME (IRS)

Data from randomised, controlled trials and observational cohort studies demonstrate that HAART
reduces the incidence rates of OIs and improves survival among people with HIV infection, independent
of the use of antimicrobial prophylaxis. The clinical benefit of HAART in reducing the risk of OIs over
the short term has been most clearly documented for those with CD4+ T cell counts of <200 cells/mm3.
Studies also support benefit in patients with CD4+ T cell counts of >200 cells/mm3, although there is
debate over the desirability of starting HAART in this population. While HAART does not replace the
need for antimicrobial prophylaxis in patients with severe immune suppression, it remains the cornerstone
of the overall strategy to reduce morbidity due to complications of HIV infection.
In addition to preventing OIs, HAART often results in improvement in or resolution of many OIs. This is
especially important regarding conditions for which specific treatment options are suboptimal.
However, initiation of HAART in the setting of an OI can also result in IRS. IRS occurs when a patient’s
immune system, newly strengthened by the recent initiation of HAART, mounts an exuberant
inflammatory reaction against one or more OIs. OIs for which IRS has been described include
mycobacterial infections (including disease due to both Mycobacterium avium complex (MAC) and
Mycobacterium tuberculosis (TB)), Pneumocystis jiroveci pneumonia (PCP), toxoplasmosis, hepatitis B
and hepatitis C infections, cytomegalovirus (CMV) infection, varicella zoster virus (VZV) infection,
cryptococcal infection, and progressive multifocal leukoencephalopathy (PML). Often the OI responsible
for IRS is not diagnosed until after HAART is initiated, having been clinically inapparent due to the lack
of an inflammatory response from the debilitated immune system. IRS is usually characterised by fever
and other clinical manifestations of the underlying OI, and typically develops within the first six weeks of
initiation of HAART, though later manifestations have been described. Clinicians must be vigilant for
IRS, because it may present with atypical signs and symptoms, and distinguishing between IRS versus
drug toxicity versus a new OI can be challenging. IRS is typically treated by adding non-steroidal anti-
inflammatory agents (NSAIDs) or corticosteroids to alleviate the inflammatory reactions, though clinical
guidelines have not been developed. The condition may take weeks or months to subside.
V-1
INITIATION OF HAART FOR THE TREATMENT-NAÏVE PATIENT IN THE SETTING OF AN ACUTE
OI
Initiation of HAART in the setting of an acute OI offers the potential for improvement in immune
function that could result in faster resolution of the OI. This benefit is most obvious for OIs for which
there are limited or no effective therapies. Reports detailing the resolution of cryptosporidiosis,
microsporidiosis, PML, and Kaposi’s sarcoma (KS) after the initiation of HAART provide evidence that
improving immune function can lead to improved outcomes in the setting of an acute OI. Immediate
initiation of HAART during an acute OI also reduces the risk of developing a second OI.
Arguments against the immediate initiation of HAART concurrent with the diagnosis of an OI include:
potentially complex drug regimens with a heavy pill burden; additive drug toxicities, including difficulty
in distinguishing the specific drug responsible for toxicity; the potential for drug interactions between
antiretrovirals (ARVs) and antimicrobials that target the OI; and the potential for IRS to complicate the
management of the OI. Much simpler HAART regimens are now available for the treatment of HIV,
diminishing the argument to delay therapy for reasons of complexity, but overlapping toxicities between
OI treatments and HAART regimens persist. Drug interactions pose the biggest problem for the treatment
of patients with TB, but HAART regimens compatible with TB treatments are available.
Most published reports regarding IRS involve patients with TB. These patients can develop high fevers,
worsening lymphadenopathy or transient to severe worsening of pulmonary infiltrates, and expanding
central nervous system (CNS) lesions. Reduction of HIV RNA levels and marked increases in CD4+ T
cell counts have been associated with the occurrence of paradoxical reactions in patients with TB or
MAC.
Currently, there are no randomised, controlled trials demonstrating that initiation of HAART improves
the outcome for patients treated with specific therapies for their acute OIs, nor are there data
demonstrating that initiation of HAART in the setting of an acute OI worsens the prognosis or treatment
of that OI. Trials are underway to evaluate the most appropriate timing for initiation of HAART in this
context.
MANAGEMENT OF ACUTE OIS IN THE SETTING OF RECENTLY INITIATED HAART

Specific guidelines have not been developed regarding management options for patients who develop an
acute OI shortly after HAART is initiated. Management generally depends on the degree of virologic and
immunologic disease progression prior to initiation of HAART, the virologic and immunologic benefit
resulting from HAART, the duration of HIV disease prior to and time since starting HAART, and the
potential for drug-drug interactions between the HAART regimen and the treatment needed for the OI.
OIs that develop after patients have been started on HAART can be categorised into three groups. The
first group includes OIs that occur shortly after initiating HAART (within twelve weeks). These cases are
thought to represent an IRS against a previously undiagnosed subclinical infection and are therefore not
considered to represent early failure of HAART.
The second group includes the rare reports of OIs occurring more than twelve weeks after initiation of
therapy among patients despite fully suppressed HIV RNA levels and sustained CD4+ T cell counts of
>200 cells/mm3. It is difficult to determine whether these represent late IRS versus a new OI. The
presence of organisms by stain and culture suggests that, in either situation, specific therapy is indicated.
The third group includes OIs that develop among patients who are experiencing virologic and
immunologic failure while on HAART. These represent a clinical failure of HAART.
V-2
TREATMENT RECOMMENDATIONS: WHEN TO INITIATE THERAPY IN THE SETTING OF AN
ACUTE OI
There is no consensus regarding the optimal time to begin HAART in the presence of a recently
diagnosed OI. The decision regarding initiation of HAART should consider the availability of effective
therapy for the OI, the risk of drug interactions and overlapping drug toxicities, the risk for and potential
consequences of the development of IRS, and the willingness and ability of the patient to adhere to the
HAART regimen. Despite this lack of consensus, however, the following specific recommendations can
be made:
In cases of cryptosporidiosis, microsporidiosis, PML, and KS, the early benefits of potent
HAART would appear to outweigh any increased risk; hence, potent HAART should be started as
soon as possible.
In the setting of TB, MAC, PCP, and cryptococcal meningitis, awaiting a response to OI therapy
is usually warranted prior to initiating HAART.
When an OI occurs within twelve weeks of starting HAART, IRS should be suspected; treatment
for the OI should be started, and HAART should be continued.
When an OI occurs despite complete virologic suppression (late OI), therapy for the OI should be
initiated; potent HAART should be continued; and if the CD4+ T cell response to HAART has
been suboptimal, modification of the HAART regimen may be considered.
When an OI occurs in the setting of virologic failure, OI therapy should be started; antiretroviral
resistance testing is recommended where available; and the HAART regimen should be modified,
if possible, to achieve better virologic control.
SPECIAL CONSIDERATIONS IN PREGNANCY

No large studies have been conducted that describe the epidemiology or manifestations of HIV-associated
OIs in pregnant women. No data suggest that the spectrum differs from that among non-pregnant women
with comparable CD4+ T cell counts. Absolute CD4+ T cell counts characteristically drop during
pregnancy, probably due to dilutional effects of the increased plasma volume. CD4+ T cell percentages
are generally more stable and are preferred over absolute CD4+ T cell counts to describe the degree of
immune suppression during pregnancy.
A number of physiologic changes occur during pregnancy that may influence the presentation of acute
OIs and the considerations for implementing OI treatment and/or HAART. These changes include the
following:
Cardiac output increases by 30% to 50% with concomitant increase in glomerular filtration rate
and renal clearance.
Plasma volume increases by 45% to 50% while red cell mass increases only by 20% to 30%,
leading to dilutional anaemia.
Increased tidal volume and pulmonary blood flow may lead to increased absorption of aerosolised
medications. Changes in late pregnancy may affect distribution of aerosolised medication. The
tidal volume increase of 30% to 40% must be considered if ventilatory assistance is required.
Placental transfer of drugs, increased renal clearance, altered gastrointestinal absorption, and
metabolism by the foetus may affect maternal drug levels.
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Limited pharmacokinetic data are available on the effects of pregnancy on levels of OI therapy
drugs. Use usual adult doses based on current weight, monitor levels if available, and consider
increasing the dosage if the patient is not responding as expected.
In general, given the morbidity and mortality associated with OIs in HIV-infected persons, OI treatment
should not be withheld during pregnancy. Therapy should generally be the same as that for non-pregnant
women, but treatment options that minimise toxicity may be preferred. Currently available reproductive
data on drugs potentially indicated for therapy of OIs are summarised in Appendix A.
For pregnant women diagnosed with an OI and not currently on HAART, prompt initiation of OI therapy
and HAART should be encouraged. Decisions regarding immediate versus delayed initiation of HAART
in pregnancy should take into account gestational age, maternal HIV RNA levels and clinical condition,
and potential toxicities and interactions between HAART and OI drugs.
Pregnant women with active OIs who receive drugs for which information about their use in pregnancy is
limited should have additional evaluation of foetal growth and well-being. Weekly foetal non-stress
testing should be initiated at thirty-two weeks of gestation where possible, unless indicated sooner based
on clinical or ultrasound findings. A summary of preclinical and human data on OI drugs in pregnancy is
provided in Appendix A.
DISEASE SPECIFIC RECOMMENDATIONS

PNEUMOCYSTIS JIROVECI (FORMERLY CARINII) PNEUMONIA (PCP)
Epidemiology
PCP is caused by Pneumocystis jiroveci, a ubiquitous organism that is classified as a fungus but shares
biological characteristics with protozoa. (P. carinii now refers only to the pneumocystis that infects
rodents, while P. jiroveci refers to the distinct species that infects humans. The abbreviation “PCP” is
still used to designate Pneumocystis pneumonia.)
PCP is widespread in the Caribbean. Among twenty Haitians studied in 1980 to 1982, PCP was among
the most common OIs seen.7 In a cohort of children with HIV infection in Barbados, PCP was the most
common cause of death (65.2%).8 In AIDS patients in Puerto Rico, PCP (26.8%) was one of the three
main diagnoses for AIDS9.
Over 90% of cases of PCP occur in patients with CD4+ T cell counts of <200 cells/mm3. Other factors
associated with a higher risk of PCP include CD4+ T cell percentage of <15%, prior episodes of PCP,
oral thrush, recurrent bacterial pneumonia, unintentional weight loss, and higher plasma HIV RNA. The
incidence of PCP has declined dramatically with widespread use of prophylaxis and effective HAART.
Most cases now occur in patients unaware of their HIV infection or not receiving ongoing HIV care, or in
those with advanced immunosuppression (e.g. CD4+ T cell counts of <100 cells/mm3).
Clinical Manifestations
The most common manifestations of PCP in HIV-infected persons are the subacute onset of progressive
exertional dysapnea, fever, non-productive cough, and chest discomfort that worsens over a period of
days to weeks. In mild cases, pulmonary examination is usually normal at rest. With exertion,
tachypnea, tachycardia, and diffuse dry (cellophane) rales may occur. Oral thrush is a common co-
infection. Fever is apparent in most cases and may be the predominant symptom in some patients.
Hypoxaemia, the most characteristic laboratory abnormality, may range from mild or moderate (room air
arterial oxygen [pO2] of >70mmHg or alveolar-arterial O2 difference [(A-a)DO2] of <35mmHg) to more
severe levels (pO2 of <70mmHg or [A-a]DO2 of >35mmHg). Oxygen desaturation with exercise is
suggestive of an abnormal A-a gradient, but is non-specific. The chest radiograph typically demonstrates
diffuse, bilateral, symmetrical interstitial infiltrates emanating from the hili in a butterfly pattern;
however, patients with very early disease may have a normal chest x-ray. In addition, atypical
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presentations with nodules, asymmetric disease, blebs and cysts, upper lobe localisation, and
pneumothorax can occur. Cavitation or pleural effusion is uncommon in the absence of other pulmonary
pathogens or malignancy, and the presence of a pleural effusion may be a clue to an alternative diagnosis.
Between 13% and 18% of patients with documented PCP have had another concurrent cause of
pulmonary dysfunction such as TB, KS, or bacterial pneumonia. Pneumothorax in a patient with HIV
infection should raise the suspicion of PCP.
Diagnosis
Because the clinical presentation, blood tests, or chest x-ray are not pathognomonic for PCP and the
organism cannot be routinely cultivated, histopathologic demonstration of organisms in tissue,
bronchoalveolar lavage fluid, or induced sputum samples are required for a definitive diagnosis.
Spontaneously-expectorated sputum has very low sensitivity and should not be submitted to the
laboratory to diagnose PCP. Cresyl violet, Giemsa, Diff-Quik, and Wright stains detect both the cyst and
trophozoite forms but do not stain the cyst wall, while Gomori’s Methenamine Silver, Gram-Weigert, and
Toluidine Blue stain the cyst wall. Many laboratories prefer direct immunofluorescent staining. Stained
respiratory tract samples obtained by various methods indicate the following relative diagnostic
sensitivities: induced sputum <50% to >90% (the sensitivity and specificity depends heavily on the
quality of the specimens and the experience of the microbiologist or pathologist); bronchoscopy with
bronchoalveolar lavage 90% to 99%; transbronchial biopsy 95% to 100%; and open lung biopsy 95% to
100%.
Because many processes can present with similar clinical manifestations, a specific diagnosis of PCP
should be sought rather than relying on a presumptive diagnosis. Treatment can be initiated prior to
making a definitive diagnosis since organisms persist in clinical specimens for days or weeks after
effective therapy is initiated.
Treatment Recommendations
Trimethoprim-sulfamethoxazole (TMP-SMX) is the treatment of first choice (see Appendix B). The dose
must be adjusted for abnormal renal function. Adding leucovorin to prevent myelosuppression during
acute treatment is not recommended due to questionable efficacy and some evidence of a higher failure
rate. Oral outpatient therapy of TMP-SMX is highly effective in patients with mild to moderate disease.
Patients who develop PCP despite TMP-SMX prophylaxis are usually effectively treated with standard
doses of TMP-SMX.
Patients with documented PCP and moderate to severe disease as defined by pO2 of <70mmHg or [A-
a]DO2 of >35mmHg should receive corticosteroids as early as possible and certainly within seventy-two
hours after starting specific PCP therapy. If steroids are started at a later time, it is not clear that they
provide any benefit, although most clinicians would use them in such circumstances for patients with
severe disease. The preferred corticosteroid dose and regimen is prednisone 40mg by mouth twice daily
for days one through five, 40mg daily for days six through ten, and 20mg daily for days eleven through
twenty-one. Methylprednisolone at 75% of the respective prednisone dose can be used if parenteral
administration is necessary.
Alternative therapeutic regimens include: a) dapsone plus TMP for mild to moderate disease (this
regimen may have similar efficacy and fewer side effects than TMP-SMX but is less convenient because
of the number of pills); b) primaquine plus clindamycin (this regimen is also effective in mild to moderate
disease, and the clindamycin component can be administered intravenously for more severe cases;
however, primaquine is only available orally); c) intravenous (IV) pentamidine (generally the drug of
second choice for severe disease); d) atovaquone suspension (this is less effective than TMP-SMX for
mild to moderate disease but has fewer side effects); and e) trimetrexate with leucovorin (this is less
effective than TMP-SMX but may be used if the latter is not tolerated and an IV regimen is needed),
although leucovorin must be continued three days after the last trimetrexate dose. The addition of
dapsone, SMX, or sulfadiazine to trimetrexate may improve efficacy based on the sequential enzyme
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blockade of folate metabolism, although there are no study data available to confirm this.
Aerosolised pentamidine should not be used for the treatment of PCP because of limited efficacy and
more frequent relapse.
The recommended duration of therapy for PCP is twenty-one days. Overall, the probability and rate of
response to therapy depends on the agent used, number of prior episodes, severity of illness, degree of
immunodeficiency, and timing of initiation of therapy.
Although the overall prognosis of patients whose degree of hypoxaemia requires ICU admission or whose
mechanical ventilation remains poor, survival in up to 40% of patients requiring ventilatory support has
been reported in recent years. Because long-term survival is possible for those patients for whom
HAART is effective, many patients with AIDS and severe PCP should be offered ICU admission or
mechanical ventilation when appropriate, e.g. when they have good functional status and no concurrent
life-threatening processes.
Because of the potential for additive or synergistic toxicities associated with anti-PCP and HAART, many
experts delay initiation of HAART until after the completion of anti-PCP therapy despite some suggestion
of potential benefit for early HAART. An inflammatory IRS has been described for PCP and may
complicate the concurrent administration of anti-PCP treatment and HAART.
Monitoring and Adverse Events
Careful monitoring during therapy is important to evaluate response to treatment and to detect toxicity as
soon as possible. Follow-up after therapy includes assessment for early relapse, especially when therapy
has been with an agent other than TMP-SMX or was shortened for toxicity. PCP prophylaxis should be
initiated promptly and maintained until the CD4+ T cell count rises to >200 cells/mm3. If PCP occurred
at a CD4+ T cell count of >200 cells/mm3, it may be prudent to maintain PCP prophylaxis for life
regardless of the CD4+ T cell response, although data regarding the most appropriate approach in this
setting are limited. Adverse reaction rates in patients with AIDS are high for TMP-SMX (20% to 85%),
although may be less common among dark-skinned people in the Caribbean. Common adverse effects
(see Appendix D) are rash (30% to 55%) including, rarely, Stevens-Johnson syndrome; fever (30% to
40%); leukopaenia (30% to 40%); thrombocytopaenia (15%); azotaemia (1% to 5%); hepatitis (20%); and
hyperkalaemia. Supportive care for common adverse effects should be tried before abandoning TMP-
SMX. Rashes may often be “treated through” with antihistamines, nausea can be controlled with
antiemetics, and fever can be managed with antipyretics.
The most common adverse effects of alternative therapies include methemoglobinaemia and haemolysis
with dapsone or primaquine (especially in those with G6PD deficiency); rash and fever with dapsone;
azotaemia, pancreatitis, hypo- or hyperglycaemia, leukopaenia, fever, electrolyte abnormalities, and
cardiac dysrhythmia with pentamidine; anaemia, rash, fever, diarrhoea, and methemoglobinaemia with
primaquine and clindamycin; headache, nausea, diarrhoea, rash, fever, and transaminase elevations with
atovaquone; and bone marrow suppression, fever, rash, and hepatitis with trimetrexate.
Management of Treatment Failure
Clinical failure is defined by the lack of improvement or worsening of respiratory function documented
by arterial blood gases after at least four to eight days of anti-PCP treatment.
Treatment failure attributed to treatment-limiting toxicities occurs in up to one-third of patients. Failure
due to lack of drug efficacy occurs in 10% or more of those with mild to moderately severe disease.
Adding or switching to another regimen is the appropriate management for treatment-related toxicity.
There are no convincing clinical trials published upon which to base well-founded recommendations for
the management of treatment failure due to lack of drug efficacy. It is important to wait at least four to
eight days prior to switching therapy for lack of clinical improvement. In fact, in the absence of
corticosteroid therapy, early and reversible deterioration within the first three to five days of therapy is
typical; this is likely due to the inflammatory response caused by antibiotic-induced lysis of organisms in
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the lung. Other concomitant infections must be excluded as a cause for such deterioration. Bronchoscopy
with bronchoalveolar lavage is optimal and should be considered whenever possible.
If TMP-SMX has failed or must be avoided for toxicity in moderate to severe disease, the common
practice is to use primaquine combined with clindamycin or clindamycin plus primaquine (with or
without oral dapsone) plus leucovorin. For mild disease, atovaquone is a reasonable alternative.
Although one meta-analysis concluded that trimetrexate may be the most effective regimen for salvage
therapy, no prospective clinical trials have evaluated the optimal approach to patients who fail therapy
with TMP-SMX.
Prevention of Recurrence
Patients who have a history of PCP should be administered secondary prophylaxis for life with TMP-
SMX unless immune reconstitution occurs as a consequence of HAART. For patients intolerant of TMP-
SMX, alternatives include dapsone, dapsone combined with pyrimethamine, atovaquone, or aerosolised
pentamidine.
Secondary prophylaxis should be discontinued for adult and adolescent patients whose CD4+ T cell count
has increased from <200 cells/mm3 to >200 cells/mm3 for at least three months as a result of antiretroviral
therapy. Secondary prophylaxis should be re-introduced if the CD4+ T cell count decreases to <200
cells/mm3 or if PCP recurs at a CD4+ T cell count of >200 cells/mm3.
Special Considerations in Pregnancy
Diagnostic considerations and indications for therapy in pregnancy are the same as in non-pregnant
adults. The preferred initial therapy during pregnancy is TMP-SMX, although alternate therapies may be
used if patients are unable to tolerate or are unresponsive to TMP-SMX. Neonatal care providers should
be informed of maternal sulfa or dapsone therapy if used near delivery because of the theoretical
increased risk of hyperbilirubinema and kernicterus.
Pentamidine is embryotoxic but not teratogenic in rats and rabbits. Trimetrexate should not be used
because of teratogenicity at low doses in multiple animal studies, foetopathy in humans associated with
use of the biochemically similar agents methotrexate and aminopterin, and potential negative effects on
placental and foetal growth (see Appendix A for information on specific drugs).
Adjunctive corticosteroid therapy should be used as indicated in non-pregnant adults. Maternal fasting
and postprandial glucose levels should be monitored closely when corticosteroids are used in the third
trimester, as the risk of glucose intolerance is increased.
Rates of pre-term labour and pre-term delivery are increased with pneumonia in pregnancy. Pregnant
women with pneumonia after twenty weeks of gestation should be monitored for evidence of
contractions.
TOXOPLASMA GONDII ENCEPHALITIS

Epidemiology
Toxoplasmic encephalitis (TE), caused by the protozoan Toxoplasma gondii, has been documented in
HIV-infected patients in and from the Caribbean.10 In a study conducted in Martinique, TE was the most
frequent presenting complication of AIDS.11 The disease occurs exclusively due to re-activation of latent
tissue cysts; there is no transmission of the organism by person-to-person contact. The development of
clinical disease is rare in patients with CD4+ T cell counts of >200 cells/mm3. The greatest risk is among
patients with CD4+ T cell counts of <50 cells/mm3.
The most common clinical presentation of T. gondii infection in patients with AIDS is a focal encephalitis
with headache, confusion or motor weakness, and fever. Physical examination may demonstrate focal
neurological abnormalities, and, in the absence of treatment, disease progression results in seizures,
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stupor, and coma. Retinochoroiditis, pneumonia, and evidence of other multifocal organ system
involvement can be seen following dissemination of infection but are rare manifestations in this patient
population. Primary infection is occasionally associated with acute cerebral or disseminated disease.
Diagnosis
Computerised tomography (CT) or magnetic resonance imaging (MRI) of the brain will typically show
multiple contrast-enhancing lesions, often with associated oedema. No imaging technique is completely
specific in distinguishing between TE and primary CNS lymphoma.
HIV-infected patients with TE are almost uniformly seropositive for anti-Toxoplasma IgG antibodies.
The absence of the IgG antibody makes a diagnosis of toxoplasmosis unlikely but not impossible. Anti-
Toxoplasma IgM antibodies are usually absent, and quantitative antibody titers are not diagnostically
useful. Definitive diagnosis of TE requires a compatible clinical syndrome; identification of one or more
mass lesions by CT, MRI, or other radiographic testing; and detection of the organism in a clinical
sample, e.g. by brain biopsy. However, patients suspected to have TE on the basis of serology, clinical
symptoms, radiologic findings, and the absence of a likely alternative diagnosis are generally treated
empirically; confirmation of the diagnosis can be reasonably inferred from clinical and radiographic
improvement in response to specific anti-T. gondii therapy. Brain biopsy is generally reserved for
patients failing to respond to specific therapy.
In the presence of neurologic disease, the differential diagnosis includes CNS lymphoma, mycobacterial
infection (especially TB), fungal infection (e.g. cryptococcosis), Chagas disease, and bacterial abscess.
PML can usually be distinguished based on imaging studies, for PML lesions typically involve white
matter rather than grey matter, are non-contrast enhancing, and show no mass effect.
The initial therapy of choice consists of the combination of pyrimethamine plus sulfadiazine plus
leucovorin. Use of leucovorin prevents the haematologic toxicities associated with pyrimethamine
therapy. The preferred alternative regimen for patients unable to tolerate or who fail to respond to first-
line therapy is pyrimethamine plus clindamycin plus leucovorin.
For patients who cannot take an oral regimen, there are no well-studied options. There is no parenteral
formulation of pyrimethamine; the only widely available parenteral sulfonamide is the SMX component
of TMP-SMX. Thus, some experts will treat severely ill patients requiring parenteral therapy initially
with oral pyrimethamine plus parenteral TMP-SMX or parenteral clindamycin.
The following regimens have been shown to have activity in the treatment of TE in at least two non-
randomised, uncontrolled trials, though their relative efficacy compared to the above regimens is
unknown: 1) atovaquone (with meals or oral nutritional supplements) plus pyrimethamine plus
leucovorin; 2) atovaquone combined with sulfadiazine or, for patients intolerant of both pyrimethamine
and sulfadiazine, as a single agent; and 3) azithromycin plus pyrimethamine plus leucovorin daily.
The following regimens have been reported to have activity in the treatment of TE in small cohorts of
patients or in case reports of one or a few patients: clarithromycin plus pyrimethamine; 5-fluoro-uracil
plus clindamycin; dapsone plus pyrimethamine plus leucovorin; and minocycline or doxycycline
combined with either pyrimethamine plus leucovorin, sulfadiazine, or clarithromycin.
Acute therapy should be continued for at least six weeks if there is clinical and radiologic improvement.
Longer courses may be appropriate if clinical or radiologic disease is extensive or response is incomplete
at six weeks. Adjunctive corticosteroids (e.g. dexamethasone) should be administered when clinically
indicated only for treatment of a mass effect due to focal lesions or associated oedema. Because of the
potential immunosuppressive effects of corticosteroids, they should be discontinued as soon as clinically
feasible. Patients receiving corticosteroids should be closely monitored for the development of other OIs
including CMV retinitis and TB. Anticonvulsants should be administered to patients with a history of
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seizures, but should not be administered prophylactically to all patients. Anticonvulsants, if administered,
should probably be continued at least through the period of acute therapy.
Patients should be routinely monitored for adverse events and clinical and radiologic improvement.
Common pyrimethamine toxicities include rash, nausea, and bone-marrow suppression (neutropaenia,
anaemia, and thrombocytopaenia) that can often be reversed by increasing the dose of leucovorin to 50 to
100mg daily, administered in divided doses.
Common sulfadiazine toxicities include rash, fever, leukopaenia, hepatitis, nausea, vomiting, diarrhoea,
and crystalluria. Common clindamycin toxicities include fever, rash, nausea, diarrhoea (including
pseudomembranous colitis or diarrhoea related to C. difficile toxin), and hepatotoxicity. Common TMP-
SMX toxicities include rash, fever, leukopaenia, thrombocytopaenia, and hepatotoxicity. Drug
interactions between anticonvulsants and ARV agents should be carefully evaluated and doses be adjusted
according to established guidelines.
For patients who fail to respond to initial therapy as defined by 1) clinical or radiologic deterioration
during the first week despite adequate therapy, or 2) a lack of clinical improvement within two weeks, a
brain biopsy, if not previously performed, should be strongly considered. For those who undergo brain
biopsies and have confirmed histopathologic evidence of TE, a switch to an alternative regimen as
previously described should be considered. Recurrence of disease during secondary maintenance therapy
following an initial clinical and radiographic response is unusual if patients are adherent to their
regimens.
Patients who have successfully completed a six-week course of initial therapy for TE should be
administered lifelong suppressive therapy (e.g. secondary prophylaxis or chronic maintenance therapy)
unless immune reconstitution occurs due to HAART.
Adult and adolescent patients receiving secondary prophylaxis for TE appear to be at low risk for
recurrence of TE when they have successfully completed initial therapy for TE, remain asymptomatic
with respect to signs and symptoms of TE, and have a sustained increase in their CD4+ T cell counts to
>200 cells/mm3 following six months or more of HAART. Discontinuing chronic maintenance therapy
among such patients is a reasonable consideration. However, secondary prophylaxis should be re-started
if the CD4+ T cell count decreases to <200 cells/mm3.
Treatment should be the same as in non-pregnant adults. Although pyrimethamine has been associated
with birth defects in animals, limited human data have not suggested an increased risk of defects;
therefore, it can be administered to pregnant women. Paediatric providers should be notified if
sulfadiazine is continued until delivery since its use may increase the risk of neonatal hyperbilirubinema
and kernicterus.
While perinatal transmission of T. gondii normally occurs only with acute infection in the
immunocompetent host, case reports have documented occurrences of transmission, albeit at very low
rates, with re-activation of chronic infection in HIV-infected women with severe immunosuppression.
Since risk of transmission with chronic infection appears low, routine evaluation of the foetus for
infection with amniocentesis or cordocentesis is not indicated.
Where available, detailed ultrasound examination of the foetus specifically evaluating for hydrocephalus,
cerebral calcifications, and growth restriction should be performed for HIV-infected women with
suspected primary or symptomatic re-activation of T. gondii during pregnancy.
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CRYPTOSPORIDIOSIS
Epidemiology
Cryptosporidiosis is caused by Cryptosporidium species, a group of protozoan parasites that infect the
small bowel mucosa, and in immunosuppressed individuals, the large bowel and extraintestinal sites.
Those at greatest risk for this disease are patients with advanced immunosuppression, e.g. with CD4+ T
cell counts generally <100 cells/mm3. Among forty Cuban patients with HIV infection, cryptosporidiosis
was among the most commonly found OIs.12
Transmission occurs through ingestion of Cryptosporidium oocysts. Faeces from infected animals,
including humans, can contaminate water supplies and recreational water with viable oocysts despite
standard chlorination. Person-to-person transmission, primarily among men who engage in oral-anal sex,
has also been observed. Young children with cryptosporidial diarrhoea may also infect adults, especially
in the course of nappy-changing. Scrupulous handwashing, use of barriers during anal sex, and other
hygiene measures may help to prevent person-to-person transmission.
The most common manifestation is the acute or subacute onset of profuse, non-bloody watery diarrhoea
frequently accompanied by nausea, vomiting, and lower abdominal cramping. Fever is present in
approximately one-third of patients. Malabsorption is often present. Cholangitis and pancreatitis occur in
patients with prolonged disease.
Diagnosis
Diagnosis of cryptosporidiosis is primarily based on microscopic identification of the oocysts in stool or
tissue; there is no consensus on the optimal oocyst detection method in faecal samples. Oocysts stain red
with varying intensities with a modified acid-fast technique; this technique allows for differentiation of
the Cryptosporidium oocysts from yeasts that are similar in size and shape but are not acid-fast. Oocysts
can also be detected by direct immunofluorescent or enzyme-linked immunosorbent assays. The
modified acid-fast stain and fluorescein-labelled monoclonal antibody technique show comparability for
diarrhoeal samples, but the immunofluorescent method is probably preferable for formed stool specimens.
In individuals with profuse diarrhoeal illness, a single stool specimen is usually adequate to make the
diagnosis. In individuals with less severe disease, repeat stool sampling is recommended, although there
have been no controlled studies showing the utility of three consecutive stool samples as is the case in
Giardia duodenalis infection.
HAART with immune restoration (an increase of CD4+ T cell count to >100 cells/mm3) is associated
with complete resolution of cryptosporidiosis, and all patients with cryptosporidiosis should be offered
HAART as part of the initial management of their infection.
At present, there is no consistently effective pharmacologic or immunologic therapy directed specifically
against C. parvum. More than ninety-five interventional agents have been tried for the treatment of
cryptosporidiosis with no consistent success.
Paromomycin, a non-absorbable aminoglycoside that is indicated for the treatment of intestinal amebiasis,
is effective in very high doses for the treatment of cryptosporidiosis in animal models. A meta-analysis
of eleven published paromomycin studies in humans reported a response rate of 67%. However, relapse
was common in the few studies that evaluated this, with long term success rates of only 33%. Two
randomised, controlled trials have compared paromomycin with placebos in patients with AIDS and
cryptosporidiosis; modest, but statistically significant, improvement in symptoms and oocyst shedding
was demonstrated in one, but no difference from the placebo was observed in the other. Thus, efficacy
data do not support a recommendation for the use of paromomycin for therapy, although the drug appears
to be safe.
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Treatment of individuals with cryptosporidiosis should include symptomatic treatment of diarrhoea.
Rehydration and repletion of electrolyte losses by either the oral or IV route is of paramount importance.
Severe diarrhoea, which may be over 10L/d in patients with AIDS, often requires intensive support.
Aggressive efforts at oral rehydration should be made with oral rehydration solutions that contain
glucose, sodium bicarbonate, potassium, magnesium, and phosphorus. Treatment with antimotility agents
can play an important adjunctive role in therapy, but these agents are not consistently effective.
Loperamide or tincture of opiate will often palliate symptoms.
Patients should be closely monitored for signs and symptoms of volume depletion, electrolyte and weight
loss, and malnutrition and should receive supportive treatment. Total parenteral nutrition may be
indicated in some patients.
At this time, there are no alternatives to HAART and supportive treatment that are demonstrated to be
useful.
No drug regimens are currently proven to be effective in preventing the recurrence of cryptosporidiosis.
ISOSPORIASIS
Epidemiology
Isosporiasis results from ingestion of food or water contaminated by oocysts of the protozoan Isosopora
belli. Infection occurs worldwide, but the prevalence of infection is higher in tropical and subtropical
regions. Infection can occur in both immunocompetent and immunocompromised hosts.
Infection primarily involves the small intestine. The most common clinical manifestation of the disease is
diarrhoea, which can result in severe dehydration. Systemic symptoms of fever, headache, malaise,
abdominal pain, vomiting, and weight loss are also common. Colitis and haematochezia are rare.
Diagnosis
The diagnosis of isosporiasis can be made by stool examination for ova and parasites. Oocysts are ovoid
in shape and are 23 to 36 by 12 to 17µM in size. Isospora oocysts autofluoresce a blue-green colour
under an epifluorescence microscope, enhancing their detection in wet-mount preparations. The
organisms also stain red with the same modified acid-fast technique used for diagnosis of
cryptosporidiosis. No commercial antigen-detection systems have been developed. Schizonts,
merozoites, macrogamonts, microgamonts, microgametes, and oocysts can be demonstrated in
enterocytes in biopsies of the small or large intestine. Extraintestinal infections with tissue cyst-like
stages have been demonstrated in lymph nodes adjacent to the intestine in patients with AIDS.
Fluid support should be administered if dehydration has developed. Nutritional supplementation is indicated
for malnutrition and wasting.
The drug of choice for therapy is TMP-SMX. Dosing options include 160mg TMP plus 800mg SMX
administered four times a day for ten days or 320mg TMP plus 1,600mg SMX administered twice a day
for ten to fourteen days. Treatment results in clearance of parasites, decrease in the volume of diarrhoea,
and decreased abdominal pain within a mean of two and a half days after initiation of therapy.
No alternative treatment with proven efficacy exists for patients unable to tolerate sulfonamides, but the
following agents have been used with anecdotal success:
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Pyrimethamine in doses of 50 to 75mg daily appears comparable to treatment with TMP-SMX.
Folinic acid (5 to 10mg daily) should also be given to prevent bone marrow suppression.
Ciprofloxacin and other fluoroquinolones have demonstrated activity against other Apicomplexa
in animal studies and may represent second-line alternatives for treatment of isosporiasis. In a
small, randomised clinical trial comparing ciprofloxacin with TMP and SMX in HIV-infected
patients with isosporiasis, all treated with TMP-SMX cleared the organism and had cessation of
diarrhoea within a median of two days, while ciprofloxacin was effective in 83% of patients with
a median time to cessation of diarrhoea of four and a half days.13
Macrolide antibiotics have marginal efficacy in treating I. belli enteritis. Spiramycin (1.5g twice
daily) and roxithromycin (2.5mg/kg every twelve hours) have been effective in a small number of
patients with AIDS and chronic refractory isosporiasis. Diclazuril (200 to 300mg daily for seven
days), nitazoxanide (500mg twice daily for seven to ten days), and albendazole coupled with
ornidazole were effective in small numbers of patients with AIDS and I. belli diarrhoea, and may
be tried in patients intolerant of (or unresponsive to) TMP and SMX.
Treatment with other anti-protozoal agents such as metronidazole, tinidazole, quinacrine, and
furazolidone are probably of little value and are not recommended.
Immune restoration following initiation of HAART in patients with AIDS is associated with more
rapid resolution of symptoms and fewer relapses. HAART is therefore recommended as part of the
treatment for patients with isosporiasis.
Treatment failure is defined as persistence or worsening of diarrhoea and systemic symptoms after five to
seven days of appropriate treatment. Re-treatment with a second-line alternative agent may result in
improvement in those who fail initial therapy.
Infections tend to be chronic and relapsing, particularly in patients with AIDS and advanced
immunosuppression. Treatment is usually effective in controlling symptoms but recurrences are common
after treatment is stopped. This is most likely because the agents used to treat the infection are not active
against the extra-intestinal tissue cyst stage of the parasite.
Patients with CD4+ T cell counts of <200 cells/mm3 should receive secondary prophylaxis with TMP
(320mg) and SMX (1,600mg) once daily or three times a week. Pyrimethamine, 25mg daily, has also
been used successfully for secondary prophylaxis following primary isosporiasis. Although not evaluated
in any clinical trial or observational cohort setting, it is likely, as with other similar OIs, that secondary
prophylaxis can be safely discontinued after an increase in CD4+ T cell counts to levels of >200
cells/mm3 sustained for at least three to six months following initiation of HAART.
The incidence, clinical manifestations, and course of I. belli infection do not appear to differ with
pregnancy. Diagnosis and therapy should be the same as in non-pregnant adults.
CYCLOSPORA
Epidemiology
Cyclospora cayetanensis has been implicated in outbreaks of diarrhoeal illness around the world and
appears to be common in the Caribbean. A study of HIV-infected patients in Haiti revealed that over
10% of HIV-infected adults with diarrhoea in Haiti were infected with Cyclospora.14 Infection occurs via
the faecal-oral route, and outbreaks attributable to contaminated water, fruits, and vegetables have been
documented.
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Signs and symptoms resemble those associated with Cryptosporidium and Isospora infections. Nausea,
vomiting, anorexia, cramping abdominal pain, fever, malaise, and diarrhoea are common, though some
patients may experience constipation as well. Unlike immunocompetent patients in whom the illness is
self-limited, immunocompromised patients, such as those with AIDS, may experience severe and chronic
infections. The small intestine is the primary site of infection.
Diagnosis
Microscopic examination of the stool can establish the diagnosis, though shedding of Cyclospora may be
intermittent. Cyclospora oocysts may be seen with acid-fast staining of stool specimens, and resemble
Cryptosporidium oocysts in shape but are roughly twice as large. Autofluorescence using epifluorescence
microscopy can also establish the diagnosis.
Treatment Recommendations and Management of Treatment Failure
Supportive therapy includes fluid support if dehydration has developed and nutritional supplementation for
malnutrition and wasting. TMP-SMX (320mg TMP plus 1,600mg SMX) twice a day for seven to ten days
is generally effective; alternatively, ciprofloxacin 500mg twice a day for ten days may be used for
patients who fail initial therapy with TMP-SMX or are intolerant of this agent. A small clinical trial in
Haiti involving patients with diarrhoea due to Cyclospora or Isospora found that a seven-day course of
TMP-SMX resulted in clinical cure in 100% of treated patients, while a seven-day course of ciprofloxacin
was nearly as effective.15
TMP-SMX (320mg TMP plus 1,600mg SMX) once daily or ciprofloxacin 500mg daily can be used for
secondary prophylaxis. Effective reconstitution of the immune system with HAART will also reduce
susceptibility to Cyclospora.
Diagnosis and therapy should be the same as in non-pregnant adults.
MICROSPORIDIOSIS
Epidemiology
The Microsporidia reported as pathogens in humans include Encephalitozoon cuniculi, E. hellem, E.
(Septata) intestinalis, Enterocytozoon bieneusi, Trachipleistophora hominis, T. anthropopthera,
Pleistophora species, P. ronneeafyi, Vittaforma (Nosema) corneae, Microsporidium sp., Nosema
ocularum, Brachiola (Nosema) connori, B. vesiculatum, and B. (Nosema) algerae.
In the pre-HAART era, reported prevalence rates of microsporidiosis varied between 2% and 70% in
HIV-infected patients with diarrhoea, depending on the diagnostic techniques employed and the patient
population described. The incidence of microsporidiosis has declined dramatically with the widespread
use of effective HAART.
In the immunosuppressed host, microsporidiosis is most commonly seen when the CD4+ T cell count is
<100 cells/mm3.
The most common manifestation of microsporidiosis is gastrointestinal tract infection with diarrhoea;
however, encephalitis, ocular infection, sinusitis, myositis, and disseminated infection are also described.
Clinical syndromes may vary with the infecting species. E. bieneusi is associated with malabsorption,
diarrhoea, and cholangitis. E. cuniculi is associated with hepatitis, encephalitis, and disseminated disease. E.
(Septata) intestinalis is associated with diarrhoea, disseminated infection, and superficial keratoconjuctivitis.
E. hellem is associated with superficial keratoconjunctivitis, sinusitis, respiratory disease, prostatic abscesses,
and disseminated infection. Nosema, Vittaforma, and Microsporidium are associated with stromal keratitis
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following trauma in immunocompetent hosts. Pleistophora, Brachiola, and Trachipleistophora are
associated with myositis. Trachipleistophora is associated with encephalitis and disseminated disease.
Diagnosis
Although microsporidia belonging to the genera Encephalitozoon, Brachiola (B. algerae), Vittaforma (V.
corneae), and Trachipleistophora have been cultivated in vitro; E. bieneusi has not been successfully
cultivated in vitro. In biopsy specimens, microsporidia can be visualised with Giemsa, Brown-Hopps
gram stain, acid-fast staining, Warthin-Starry silver staining, haematoxylin and eosin, or Chromotrope
2A.
In gastrointestinal disease, examination of three stools with chromotrope and chemofluorescent stains is often
sufficient for diagnosis. If stool examination is negative and microsporidiosis is suspected, a small bowel
biopsy should be performed. If the aetiologic agent is Encephalitozoonidae or Trachipleistophora,
examination of urine often reveals the organism.
HAART with immune restoration (an increase of CD4+ T cell count to >100 cells/mm3) is associated
with resolution of symptoms of enteric microsporidiosis including those due to E. bieneusi. All patients
should be offered HAART as part of the initial management of their infection. Nevertheless, available
data suggest that microsporidia are suppressed but not eliminated by immune restoration.
Albendazole, a benzimidazole that binds to β-tubulin, has activity against many species of microsporidia, but
it is not effective for Enterocytozoon infections. Fumagillin, a water-insoluble antibiotic made by Aspergillus
fumigatus, also has activity in vitro and in vivo. Albendazole is recommended for initial therapy of intestinal
and disseminated (not ocular) microsporidiosis due to microsporidia other than E. bienuesi.
Itraconazole may also be useful in disseminated disease when combined with albendazole, especially in
infections due to Trachipleistophora or Brachiola. Ocular infections due to microsporidia should be treated
topically with Fumidil B® (fumagillin bicylohexylammonium) in saline (to achieve a concentration of
70µg/mL of fumagillin). Metronidazole and atovaquone are not active in vitro or in animal models and
should not be used to treat microsporidiosis. Fluid support should be offered if diarrhoea has resulted in
dehydration. Malnutrition and wasting should be treated with nutritional supplementation.
Albendazole side effects are rare but hypersensitivity (rash, pruritis, fever), neutropaenia (reversible), CNS
effects (dizziness, headache), gastrointestinal disturbances (abdominal pain, diarrhoea, nausea, vomiting),
hair loss (reversible), and elevated hepatic enzymes (reversible) have been reported. Albendazole is not
carcinogenic or mutagenic. Topical fumagillin has not been associated with significant side effects. Oral
fumagillin has been associated with thrombocytopaenia, which is reversible upon stopping the drug.
Optimising HAART to attempt to achieve full virologic suppression is currently the only feasible
approach to management of patients who fail specific therapy.
Treatment for ocular microsporidiosis should be continued indefinitely as recurrence or relapse may follow
treatment discontinuation. It is not known if treatment can be safely discontinued following immune
restoration with HAART, although it is reasonable, based on the experience with discontinuation of
secondary prophylaxis for other OIs during advanced HIV disease, to discontinue chronic maintenance
therapy if patients remain asymptomatic with regard to signs and symptoms of microsporidiosis, and have a
sustained (e.g. six months or longer) increase in their CD4+ T cell counts to levels >200 cells/mm3 after
HAART.
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In animals (rats and rabbits), albendazole is embryotoxic and teratogenic at dosages of 30mg/kg. Thus,
albendazole is not recommended for use in pregnant women. However, well-controlled studies in human
pregnancy have not been performed.
Systemic fumagillin has been associated with increased resorption and growth retardation in rats. No data on
use in human pregnancy are available. However, given the known anti-angiogenic effect of fumagillin, this
drug should not be used in pregnant women. Topical fumagillin has not been associated with embryotoxic or
teratogenic effects in pregnant women, and may be considered when therapy with this agent is appropriate.
MYCOBACTERIUM TUBERCULOSIS (TB)

Epidemiology
The World Health Organisation (WHO) estimates that TB is the cause of death for 11% of all AIDS
patients in the world and has developed policy guidelines to rapidly scale up a collaborative approach to
fight TB and HIV16 through expansion of voluntary counselling and testing for HIV in TB programmes,
intensified TB case-finding in HIV-infected patients, and other measures. These actions will be
especially important in parts of the Caribbean where the overall HIV seroprevalence rates among patients
with TB have been quite high. Although declining rates were seen in the Bahamas and in Trinidad &
Tobago during the late 1990s, increasing rates were witnessed in Guyana and Suriname. There are
currently 30% to 40% HIV seroprevalence rates among TB patients in Guyana, Trinidad, Tobago, and the
Bahamas. TB has also been a common AIDS-defining illness in a number of other Caribbean countries.17
TB occurs in HIV-infected persons at all CD4+ T cell count levels. The clinical manifestations may be
altered depending on the degree of immunosuppression. Those with more advanced immunosuppression
(CD4+ T cell counts of <200 cells/mm3) are more likely to have extrapulmonary or disseminated disease.
In areas where TB is endemic, many patients have higher CD4+ T cell counts at the time HIV-related TB
develops.
TB in persons with HIV infection can develop immediately after exposure (primary disease) or as a result
of progression following establishment of latent TB infection (LTBI), sometimes called re-activation
disease. Primary TB has been reported in a number of outbreaks—frequently in individuals with
advanced immune suppression—and may account for one-third or more of cases of TB in the HIV-
infected population.
Progression to disease among those with latent TB infection has been dramatically more likely in HIV-
infected persons than in HIV-uninfected persons in the Caribbean.18 HIV-uninfected persons with a
positive tuberculin skin test (TST) result have a 5% to 10% lifetime risk of developing TB, compared
with a 7% to 10% yearly risk in HIV-infected persons with a positive TST result.19 Patients with TB have
been shown to have higher HIV viral loads and a more rapid progression of their HIV illness than
comparable HIV-infected patients without TB.
With CD4+ T cell counts of >350 cells/mm3, HIV-related TB presents like TB among HIV-uninfected
persons. Most patients have the disease limited to the lungs, and common chest radiographic
manifestations include upper lobe fibronodular infiltrates with or without cavitation. However,
extrapulmonary disease is more common in HIV-infected individuals than in non-HIV-infected persons.
When extrapulmonary disease does occur in HIV-infected persons, clinical manifestations are not
substantially different from those described in HIV-uninfected patients.
With increasing immunodeficiency, extrapulmonary TB—with or without pulmonary involvement—
becomes increasingly common. At CD4+ T cell counts of <50 cells/mm3, extrapulmonary involvement
(pleuritis, pericarditis, and meningitis) is common.
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Among severely immunocompromised patients, TB can be a critical systemic disease with high fevers,
rapid progression, and sepsis syndrome. The chest radiographic findings of TB in advanced AIDS
patients are markedly different, however, than those among patients with less severe HIV infection.
Lower lobe, middle lobe, and miliary infiltrates become common with advancing immunodeficiency, and
cavitation becomes uncommon. Finally, patients with HIV infection and pulmonary TB can have sputum
smears and culture results of positive for AFB or M. tuberculosis respectively, even with a normal chest
radiograph.
Histopathological findings are affected by the degree of immunodeficiency. Patients with relatively intact
immune function have typical granulomatous inflammation associated with TB. With progressive
immunodeficiency, granulomas become poorly formed or can be completely absent.
Diagnosis
The evaluation of suspected HIV-related TB should always include a chest radiograph; pulmonary
involvement is common at all stages of HIV disease. Sputum samples for AFB smear and culture should
be obtained from patients with pulmonary symptoms, cervical adenopathy, or chest radiographic
abnormalities. Sputum samples from a substantial fraction of cases of pulmonary TB are negative by
direct smear microscopy. Nucleic-acid amplification (NAA) tests have been used as an adjunct to sputum
smear and culture for rapid detection of M. tuberculosis in the French Caribbean.20
For patients with signs of extrapulmonary TB, needle aspiration of skin lesions, nodes, pleural, or
pericardial fluid may allow for rapid diagnosis, culture, and susceptibility testing. Tissue biopsy can be
helpful among patients with negative fine-needle aspirates. Among patients with signs of disseminated
disease, mycobacterial blood cultures may allow a definitive diagnosis. mycobacterial blood cultures
become increasingly sensitive for TB diagnosis among severely immunodeficient patients.
Among patients with relatively intact immune functions, the yield of sputum smear and culture exams is
similar to that of HIV-uninfected adults, with positive smear results being more common among patients
with cavitary pulmonary involvement. TST is positive in most patients with pulmonary disease and
CD4+ T cell counts of >200 cells/mm3. Among patients with more severe immunodeficiency, sputum
smear and culture exams become somewhat less sensitive, and TST has little diagnostic value because it
is often negative. However, the yield of mycobacterial stain and culture of specimens from
extrapulmonary sites (node aspirates, pleural and pericardial fluid) is higher among patients with
advanced immunodeficiency compared to HIV-uninfected adults.
A positive smear result in any of these specimens (sputum, needle aspirate, tissue biopsy) represents some
form of mycobacterial disease but does not always represent TB. However, because TB is the most
virulent mycobacterial pathogen and can be spread from person to person if pulmonary involvement is
present, patients with smear-positive results should be treated for TB until definitive mycobacterial
species identification has been made.
Drug susceptibility testing and adjustment of the treatment regimen based on the results is recommended
to ensure the successful treatment of TB and to prevent transmission of drug resistant M. tuberculosis in
the community. Major outbreaks of multidrug resistant (MDR)-TB have so far occurred in HIV-infected
patients in hospital and hospital clinic settings in the United States; Buenos Aires, Argentina; and Lima,
Peru. Therefore, for all HIV-infected patients with TB, testing for susceptibility to first-line agents
(isoniazid (INH), rifampin (RIF), rifabutin, or ethambutol (EMB)) should be performed wherever
possible, regardless of the source of the specimen. Pyrazinamide (PZA) susceptibility testing should be
performed on an initial isolate if there is a sufficiently high prevalence of PZA resistance in the
community.
Treatment of HIV-related TB should follow the general principles developed for TB treatment in the
HIV-uninfected individual. Early diagnosis and treatment are critical. Because of the severity of TB
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among immunocompromised patients, directly observed therapy (DOT) is strongly recommended for
patients with HIV-related TB. Multiple drugs and DOT are used to provide effective therapy, to prevent
acquired drug resistance during treatment, and to allow a cure with a relatively short course of treatment
(six to nine months).
HIV-infected patients have other social and medical needs and treatment success is enhanced by a case-
management approach, which incorporates assistance with all of these needs (enhanced DOT) in addition
to providing DOT.
There are several special considerations in the treatment of HIV-associated TB:
• Treatment is very effective, but the optimal duration of treatment is uncertain.
• Acquired drug resistance is unusual with the use of DOT, but does occur in HIV-infected persons.
• The risk of acquired rifamycin resistance has led to specific recommendations regarding dosing
frequency (see below).
• The use of HAART among patients being treated for TB is complicated by overlapping drug
toxicity profiles, drug-drug interactions, and an increase in TB manifestations during immune
reconstitution (paradoxical reactions). Recent studies suggest that with careful attention to these
complicating factors, the prognosis of HIV-related TB can be markedly improved with the
provision of HAART, although the optimal relative timing between anti-TB and HIV therapy is
uncertain.
Treatment of drug-susceptible TB in HIV-infected adults should include the use of a six-month regimen
consisting of an initial phase of INH, RIF or rifabutin, PZA, and EMB given for two months followed by
INH and RIF for four months, when the disease is caused by organisms known or presumed to be
susceptible to first-line anti-TB drugs. Once the organism is shown to be susceptible to INH, RIF, and
PZA, then EMB should be discontinued.
The optimal duration of therapy for HIV-related TB remains controversial. Studies in several developing
countries have shown that patients with HIV-related TB respond well to standard six-month treatment
regimens, with rates of treatment failure and relapse similar to those of HIV-uninfected patients.
Concerns remain, though, that these results may not be applicable to patients with advanced HIV disease
and TB. While awaiting definitive randomised comparisons in HIV-infected patients with TB, six
months of therapy is probably adequate for most cases, but prolonged therapy (up to nine months) is
recommended (as in HIV-negative patients) for patients with a delayed clinical or bacteriological
response to therapy (symptomatic or positive culture results at or after two months of therapy,
respectively) or perhaps with cavitary disease on chest radiograph.
Intermittent dosing (twice- or thrice-weekly) facilitates DOT by decreasing the total number of
encounters required between the patient and the provider, making observed therapy more practical to
deliver. However, once- or twice-weekly dosing has been associated with an increased rate of acquired
rifamycin resistance among patients with advanced HIV disease (CD4+ T cell counts of <100 cells/mm3).
Acquired rifamycin resistance was relatively common with once-weekly rifapentine plus INH and also
occurred in trials of twice-weekly rifabutin plus INH and twice-weekly RIF plus INH. Therefore, once-
weekly rifapentine is contra-indicated in HIV-infected patients, and it is recommended that RIF- and
rifabutin-based regimens be given at least three times weekly for patients with TB and advanced HIV
disease (CD4+ T cell counts of <100 cells/mm3). Although treatment approaches to this population need
to be further evaluated in prospective trials, a prudent management strategy consists of daily DOT during
the first two months of therapy and thrice-weekly DOT during the continuation phase of anti-TB therapy.
Close follow-up, consisting of clinical, bacteriological, and occasionally, laboratory and radiographic
evaluations, is essential to ensure treatment success. In patients with pulmonary TB, at least one sputum
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specimen for microscopic examination and culture should be obtained at monthly intervals until two
consecutive specimens are negative on culture. Drug susceptibility tests should be performed on isolates
from patients who have positive cultures after three months of treatment. Patients who have positive
cultures after four months of treatment should be considered as having failed therapy and be managed
accordingly. For patients with extrapulmonary TB, the frequency and types of evaluations will depend on
the sites involved and the ease with which specimens can be obtained.
A detailed clinical assessment should be performed at least monthly in order to identify possible
medication intolerance and to assess adherence. As a routine, it is not necessary to monitor blood tests for
patients being treated with first-line drugs unless baseline abnormalities were identified. More frequent
clinical and laboratory monitoring is indicated for patients with underlying liver disease, including
hepatitis C co-infection, who are being treated for TB.
INH, RIF, and PZA all can cause drug-induced hepatitis, and the risk may be increased in patients taking
other potentially hepatotoxic agents or in persons with underlying liver dysfunction. However, because
of the effectiveness of these drugs (particularly INH and RIF), they should be used, if at all possible, even
in the presence of pre-existing liver disease. Frequent clinical and laboratory monitoring should be
performed to detect any exacerbation of hepatitis.
In general, independent of HIV status for all patients with TB, several treatment options exist if serum
aminotransaminases are more than three times the upper limit of normal prior to the initiation of treatment
(and the abnormalities are not thought to be caused by TB). One option is to use standard therapy with
frequent monitoring. A second option is to treat with RIF, EMB, and PZA for six months, avoiding INH.
A third option is to treat with INH and RIF for nine months, supplemented by EMB for the first two
months, thereby avoiding PZA. For patients with severe liver disease, a regimen with only one
hepatotoxic agent, generally RIF plus EMB, could be given for twelve months, preferably with another
agent, such as a fluoroquinolone, for the first two months. As previously indicated, treatment may need
to be lengthened for patients who are HIV-infected. For patients who develop worsening hepatic function
on treatment, an expert should be consulted.
Tests to monitor hepatotoxicity (aminotransferases, bilirubin, alkaline phosphatase), renal function (serum
creatinine), and platelet count should be obtained for all patients started on treatment for TB. At each
monthly visit, patients taking EMB should be questioned regarding possible visual disturbances including
blurred vision or scotomata; monthly testing of visual acuity and colour discrimination is recommended
for patients taking doses that on a milligram per kilogram basis are greater than those listed in
recommended doses and for patients receiving the drug for longer than two months.
Patients who have TB caused by strains of M. tuberculosis resistant to at least INH and RIF are at high
risk for treatment failure and for further acquired drug resistance. Such patients should be referred to or
have consultation obtained from specialised treatment centres. Although patients with strains resistant to
RIF alone have a better prognosis than patients with MDR strains, they are also at increased risk for
treatment failure and for developing additional resistance and should be managed in consultation with an
expert.
HAART in the Management of TB and Paradoxical Reactions
Rifamycin drugs are essential components of short-course regimens for the treatment of TB. However,
substantial adverse pharmacologic interactions occur between rifamycins and commonly-used ARV
drugs, such as protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), as a
consequence of changes in drug metabolism resulting from induction or inhibition of the hepatic
cytochrome P-450 (CYP450) enzyme system (see Appendix E). Of the available rifamycins, RIF is the
most potent CYP450 inducer, and rifabutin has substantially less inducing activity. Despite such
interactions, rifamycin should generally not be excluded from the TB treatment regimen in patients
receiving HAART except in unusual circumstances.
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Table 1: Recommended Dose Adjustments When Patients Are Administered Rifabutin Concurrently with
ARVs
ARV REGIMEN RIFABUTIN DOSE* ARV DOSE ADJUSTMENT
PI Regimens
NFV: use 1,250mg q12h
Nelfinavir (NFV), indinavir (IDV), or Decrease daily dose to IDV: consider increase to
amprenavir (APV) (+ 2 NRTIs) 150mg; use 300mg t.i.w 1,000mg q8h
APV: no change
Ritonavir (RTV) (+ 2 NRTIS, other PIs, Decrease to 150mg b.i.w or
None
and/or NNRTIs) t.i.w†
Lopinavir (LPV) (+ 2 NRTIs and/or a Decrease to 150mg b.i.w or
None
NNRTI) t.i.w †
NNRTI Regimens
Efavirenz (EFV) (+ 2 NRTIs) Increase to 450mg q.d or None
600mg b.i.w or t.i.w
Nevirapine (NVP) (+ 2 NRTIs) 300mg q.d or t.i.w None
NRTI Regimens
Dual or triple (e.g. zidovudine (AZT), 300mg q.d or t.i.w None

lamivudine (3TC), and abacavir (ABC))**
PI + NNRTI Regimens
EFV or NVP + PI (except RTV, see above) 300mg q.d or t.i.w Consider increased dose of
IDV to 1,000mg q8h
*Avoid twice-weekly rifabutin therapy among patients with CD4+ T cell counts of <100 cells/mm3 at the time of TB
diagnosis.
†
When the dose of rifabutin is decreased, it is important to monitor adherence with RTV, because discontinuation of
RTV may result in underdosing with rifabutin.
**RIF increases concentrations of AZT and probably ABC. While the clinical significance of these changes is not
clear, it is prudent to use rifabutin with triple NRTIs.
Either RIF or rifabutin can be used with NRTIs.* Rifabutin can be used with certain PIs or NNRTIs
(other than delavirdine (DLV)) and has fewer problematic drug interactions than RIF. Adjustments in
rifabutin or elements of the HAART regimen may be necessary with certain combinations (see Table 1).
Two ARV drug regimens have been associated with a favourable outcome when administered with RIF:
1) EFV (potentially using an increased dose of 800mg daily) plus two NRTIs, and 2) RTV (600mg twice
daily) plus two NRTIs. Serum concentrations of NVP may be adequate even in the presence of
concentrations of RIF associated with enzyme induction, but clinical data are lacking. RIF should not be
used with NFV, saquinavir (SQV), IDV, APV, atazanavir (ATV), or dual PI combinations using low-dose
RTV (<200mg twice daily) for which dosing guidelines are not available (see Table 2). In 2004, the CDC
provided updated guidelines for the use of rifamycins in the treatment of TB in HIV-infected patients
taking PIs or NNRTIs.21
*
In this chapter, the term "NRTI" encompasses both NsRTI (nucleoside reverse transcriptase inhibitor) and NtRTI
(nucleotide reverse transcriptase inhibitor).
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Table 2: ARV-Anti-Infective Drug Combinations That Should Be Avoided
FIRST DRUG SECOND DRUG REASON
Rifabutin Atovaquone Atovaquone conc. ↓ 34%;
rifabutin conc. ↓ 19%
Itraconazole Itraconazole conc. ↓ 70%;
potential for inhibition of rifabutin metabolism and ↑
rifabutin conc.
SQV (as sole PI) SQV AUC ↓ 43%; if used, consider addition of RTV
and/or monitor SQV concentration;
no change in rifabutin conc.
Voriconazole Voriconazole AUC ↓ 79%;
rifabutin AUC ↑ 3-fold
RIF APV APV AUC ↓ 82%; Cmin ↓ 92%;
no change in RIF conc.
ATV Pharmacokinetic study not available. Expect RIF to ↓
ATV concentrations substantially (up to 90%↓), as seen
with other PIs
Atovaquone Atovaquone conc. ↓ 52%;
RIF conc. ↑ 37%
Clarithromycin ↓ mean clarithromycin conc. 87%
DLV DLV AUC ↓ 95%,
Fosamprenavir No study done with fosamprenavir to date. APV AUC ↓
82%; Cmin ↓ 92%
IDV IDV AUC ↓ 89%;
RIF conc. slightly ↑
Itraconazole Itraconazole AUC ↓ 64-88%;
Ketoconazole Ketoconazole levels ↓ 50%;
RIF peak conc. ↓ 40%-50% probably due to impaired RIF
oral absorption
LPV/ritonavir (LPV/r) LPV AUC ↓ 75% & Cmin ↓ 99%; ritonavir AUC may be
increased
NFV NFV AUC ↓ 82%;
SQV (as sole PI) SQV AUC ↓ 84%;
Voriconazole Voriconazole AUC ↓ 96%
The optimal time for initiating HAART during TB treatment is not known. Because of the risk of
prolonged airborne transmission of M. Tuberculosis, initiation of treatment for TB should never be
delayed. Early initiation of HAART (within the first two to four weeks after the start of TB therapy) may
decrease HIV disease progression, but may be associated with a relatively high incidence of side effects
and paradoxical reactions (some severe enough to warrant discontinuation of both ARV and anti-TB
drugs). Delaying the initiation of HAART for four to eight weeks after starting TB treatment has the
potential advantages of being better able to ascribe a specific cause for a drug side effect, decreasing the
severity of paradoxical reactions, and decreasing the adherence challenge for the patient. Until there have
been controlled studies evaluating the optimal time for starting antiretroviral therapy in patients with
HIV-associated TB, this decision should be individualised, based on the patient’s initial response to TB
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therapy, occurrence of side effects, and acceptance of multidrug HAART. For these considerations,
physicians should avoid beginning the simultaneous administration of both HAART and combination
chemotherapy for TB; most experts would wait at least four to eight weeks.
Patients receiving HAART at the time treatment for TB is started require a careful assessment of the
HAART regimen and, if necessary, changes to ensure optimum treatment of the HIV infection in the
setting of TB therapy.
Because of the difficulties associated with the accurate diagnosis of an adverse drug reaction and in
determining the responsible agent, the first-line anti-TB drugs should not be stopped permanently without
strong evidence that the anti-TB drug was the cause of the reaction. In such situations, consultation with
an expert in treating TB in HIV-infected persons is recommended.
Patients may experience temporary exacerbation of symptoms, signs, or radiographic manifestations of
TB after beginning anti-TB treatment. This phenomenon is termed a paradoxical (or immune
reconstitution) reaction. This reaction occurs in non-HIV-infected persons, but it is more common among
those with HIV infection, particularly those who receive HAART. These reactions presumably develop
as a consequence of reconstitution of immune responsiveness brought about by HAART or perhaps by
treatment of TB itself. Signs of a paradoxical reaction may include high fevers, increase in size and
inflammation of involved lymph nodes, new lymphadenopathy, expanding CNS lesions, worsening of
pulmonary parenchymal infiltrations, and increasing pleural effusions. Such findings should be attributed
to a paradoxical reaction only after a thorough evaluation has excluded other possible causes, especially
TB therapy failure.
A paradoxical reaction that is not severe should be treated symptomatically with NSAIDs, without a
change in anti-TB therapy or HAART. Approaches to the management of severe reactions, such as high
fever, airway compromise from enlarging lymph nodes, enlarging serosal fluid collections, and sepsis
syndrome have not been studied. However, case reports have documented improvements with the use of
prednisone or methylprednisolone used at a dose of approximately 1mg/kg and gradually reduced after
one to two weeks.
Management of Drug Resistance and Treatment Failure
If resistance to INH (with or without resistance to streptomycin) is detected, INH (and streptomycin, if
used) should be discontinued and the patient treated with a six-month regimen of RIF, PZA, and EMB,
which is nearly as effective as the conventional INH-containing regimen. Alternatively, treatment with
RIF and EMB for twelve months may be used, preferably with PZA during at least the initial two months.
Treatment regimens for TB due to RIF mono-resistant strains are less effective, and patients infected with
these strains are at increased risk of relapse and treatment failure. A minimum of twelve to eighteen
months of treatment with INH, EMB, and a fluorquinolone (e.g. levofloxacin) with PZA given during the
first two months is recommended. An injectable agent (e.g. amikacin or capreomycin) may be included
in the first two to three months for patients with severe disease.
Patients with MDR-TB, defined as resistance to both INH and RIF, are at high risk of treatment failure
and relapse and require especially close follow-up during (and often after) treatment. Treatment regimens
for MDR-TB must be individualised, taking into account the resistance pattern, relative activities of
available anti-TB agents, the extent of disease, and presence of co-morbid conditions. The management
of MDR-TB is complex and should be undertaken only by an experienced specialist or in close
consultation with specialised treatment centres.
Chronic suppressive therapy for patients who have successfully completed a recommended regimen of
treatment for TB, as outlined above, is generally considered unnecessary. Re-infection, however, can
occur. A study conducted in the late 1990s in Haiti22 demonstrated that in HIV-infected persons
completing treatment for active pulmonary TB, those assigned to post-treatment INH prophylaxis for one
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year had a significant reduction in recurrent TB during the twenty-four months after completing initial
treatment, compared to those assigned to post-treatment placebo. Today, with increasing availability of
HAART in the Caribbean, this approach might be considered most appropriate only for those with
persistent immunosuppression despite use of HAART.
HIV-infected pregnant women who lack documentation of negative TST results within the past year
should be tested during pregnancy. The frequency of anergy is not increased during pregnancy, and
routine anergy testing for HIV-infected pregnant women is not recommended. The diagnostic evaluation
for TB in pregnant women is the same as for non-pregnant adults. Chest radiographs with abdominal
shielding result in minimal foetal radiation exposure.
An increase in pregnancy complications, including preterm birth, low birth weight, and intrauterine
growth retardation may be observed in pregnant women with both pulmonary and extrapulmonary TB not
confined to the lymph nodes, especially when treatment is not begun until late in pregnancy.
In general, therapy of TB during pregnancy should be the same as for the non-pregnant adult but with
attention given to the following considerations.
• INH is not teratogenic in animals or humans. Hepatotoxicity may occur more frequently in
pregnancy and the postpartum period. Some experts recommend monthly monitoring of
transaminases during pregnancy and the postpartum period.
• RIF is not teratogenic in humans. Because of a potential increased risk of RIF-related
haemorrhagic disease in neonates born to women receiving anti-TB therapy during pregnancy,
prophylactic vitamin K, 10mg, should be administered to the neonate.
• PZA is not teratogenic in animals. There is limited experience with use in human pregnancy.
There are international recommendations by WHO and the International Union Against
Tuberculosis and Lung Diseases for the routine use of PZA in pregnant women. If PZA is not
included in the initial treatment regimen, the minimum duration of therapy should be nine
months.
• EMB is teratogenic in rodents and rabbits at doses much higher than those used in humans. No
teratogenicity has been observed in humans. Ocular toxicity has been reported in adults taking
EMB, but changes in visual acuity have not been detected in infants born after exposure in utero.
Experience during pregnancy with most of the second-line drugs for TB is limited. MDR-TB in
pregnancy should be managed in consultation with an expert; therapy should not be withheld because of
pregnancy. The following issues should be considered when selecting second-line anti-TB drugs for use
in pregnant women:
• Although no longer a first-line agent, streptomycin use has been associated with a 10% rate of
VIII nerve toxicity in infants exposed in utero; its use during pregnancy should be avoided if
possible.
• Hearing loss has been detected in approximately 2% of children exposed to long-term kanamycin
therapy in utero; like streptomycin, this agent should generally be avoided if possible. There is a
theoretical risk of ototoxicity in the foetus with in utero exposure to amikacin and capreomycin,
but this risk has not been documented, and these drugs may be alternatives when an
aminoglycoside is required for treatment of MDR-TB.
• Because arthropathy has been noted in immature animals with the use of quinolones during
pregnancy, quinolones are generally not recommended in pregnancy or in children age eighteen
years or younger. However, more than 200 cases of ciprofloxacin use in pregnancy have been
reported to various pregnancy registries, and its use has not been associated with arthropathy or
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birth defects after in utero exposure. Thus, quinolones may be used in pregnancy for drug
resistant TB if required based on susceptibility testing.
• Para-aminosalicylic acid (PAS) has been associated with occipital bone defects when
administered during pregnancy to rats. PAS is not teratogenic in rats or rabbits. A possible
increase in limb and ear anomalies was reported among 143 pregnancies with first-trimester
exposure in one study. No specific pattern of defects and no increase in rate of defects have been
detected in other human studies, suggesting that this agent may be used with caution if needed.
• Ethionamide has been associated with an increased risk of several anomalies in mice, rats, and
rabbits following high-dose exposure; no increased risk of defects was noted with doses similar to
those used in humans, but there is very limited experience with use in human pregnancy.
• There are no data available from animal studies or reports of cycloserine use in humans during
pregnancy.
DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX (MAC) DISEASE

Epidemiology
Organisms of MAC are ubiquitous in the environment, and disseminated MAC infection has been clearly
documented among HIV-infected patients in the Caribbean.23 MAC infection is thought to be acquired
through inhalation, ingestion, or inoculation via respiratory or gastrointestinal tract portals of entry.
Household or close contacts of those with MAC disease are not at increased risk of developing the
disease.
In the absence of effective HAART or chemoprophylaxis in those with advanced immunosuppression, the
incidence of disseminated MAC disease in persons with AIDS ranges from 20% to 40%. Most cases of
MAC disease occur in individuals with CD4+ T cell counts of <50 cells/mm3. Other factors associated
with increased susceptibility to MAC disease are high plasma HIV RNA levels (>100,000 copies/mL),
prior OIs (particularly CMV disease), and/or prior colonisation of the respiratory or gastrointestinal tract
with MAC.
MAC disease in patients with AIDS, in the absence of antiretroviral therapy, is generally a disseminated
multi-organ infection. Early symptoms may be minimal and may precede detectable intermittent or
continuous mycobacteraemia by several weeks. Symptoms include fever, night sweats, weight loss,
fatigue, diarrhoea, and abdominal pain.
Inflammatory IRS, characterised by focal lymphadenitis with fever, is a systemic inflammatory response
with signs and symptoms clinically indistinguishable from active infection, and is similar to paradoxical
reactions observed with TB. Bacteraemia is absent. The syndrome has been described in patients with
subclinical or established MAC disease and advanced immunosuppression who begin HAART and have a
rapid and marked increase in CD4+ T cell counts (of >100 cells/mm3). This syndrome may be benign and
self-limited, or may be severe and require systemic anti-inflammatory therapy to alleviate clinical
symptoms.
Other localised manifestations of MAC disease have been reported most commonly among those who are
receiving and who have responded to HAART. Localised syndromes include cervical or mesenteric
lymphadenitis, pneumonitis, pericarditis, osteomyelitis, skin or soft tissue abscesses, genital ulcers, or
CNS infection.
Laboratory abnormalities particularly associated with disseminated MAC disease include anaemia (often
out of proportion to that expected for stage of HIV disease) and elevated liver alkaline phosphatase.
Hepatomegaly, splenomegaly, or lymphadenopathy (paratracheal, retroperitoneal, para-aortic, or, less
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commonly, peripheral) may be found on physical examination or by radiographic or other imaging
studies. Other focal physical findings or laboratory abnormalities may occur in the context of those
localised disease syndromes previously described.
Diagnosis
A confirmed diagnosis of disseminated MAC disease is based on compatible clinical signs and symptoms
coupled with the isolation of MAC from cultures of blood, bone marrow, or other normally sterile tissue
or body fluids.
Other ancillary studies provide supportive diagnostic information, including AFB smear and culture of
stool or biopsy material obtained from tissues or organs, radiographic imaging of the abdomen or
mediastinum for detection of lymphadenopathy, or other studies aimed at isolation of organisms from
focal infection sites.
Initial treatment of MAC disease should consist of two antimycobacterial drugs to prevent or delay the
emergence of resistance. Clarithromycin is the preferred first agent; it has been studied more extensively
than azithromycin and appears to be associated with more rapid clearance of MAC from the blood.
However, azithromycin may be substituted for clarithromycin when drug interactions or clarithromycin
intolerance preclude the use of clarithromcyin. EMB is the recommended second drug.
Some clinicians would add rifabutin as a third drug to improve survival and reduce emergence of drug
resistance. The addition of rifabutin could be considered in individuals with advanced
immunosuppression (CD4+ T cell counts of <50 cells/mm3), high mycobacterial loads (>2 log10 colony
forming µ/mL of blood), or settings in which mortality is increased and emergence of drug resistance
most likely. Table 1 lists recommended dose adjustments when patients are administered rifabutin
concurrently with ARV drugs. If rifabutin cannot be used due to drug interactions or intolerance, a third
or fourth drug may be selected from among either the fluoroquinolones (ciprofloxacin or levofloxacin) or
parenteral amikacin, although data supporting a survival or microbiologic benefit when these agents are
added have not been compelling.
Patients diagnosed with disseminated MAC disease who have not previously received or are not currently
receiving HAART should generally have HAART initiated simultaneously within one to two weeks of
initiation of anti-mycobacterial therapy for MAC disease. If HAART has already been instituted, it
should be continued and optimised for patients with disseminated MAC disease, unless drug interactions
preclude the safe concomitant use of ARV and antimycobacterial drugs. For those who experience
symptoms of moderate to severe intensity due to an inflammatory IRS in the setting of HAART,
symptomatic treatment initially with NSAIDs is recommended. If symptoms fail to improve, short-term
(four to eight weeks) systemic corticosteroid therapy, in doses equivalent to 20 to 40mg of oral
prednisone once daily, have been successfully employed.
Adverse effects observed with clarithromycin and azithromycin consist of nausea, vomiting, abdominal
pain, abnormal taste, and rarely elevations of liver transaminase levels or hypersensitivity reactions.
Doses of clarithromycin in excess of 1g daily for treatment of disseminated MAC disease have been
associated with increased mortality and should not be used. Adverse effects of rifabutin are described in
the section on TB. Rifabutin doses of 450mg daily or higher have been associated with an increased of
adverse drug interactions when used with clarithromycin or other drugs that inhibit cytochrome p450
isoenzyme 3A4, and may be associated with a higher risk of developing uveitis or other adverse drug
reactions.
Improvement in fever and a decline in the quantity of mycobacteria in blood or tissue can be expected
within two to four weeks after initiation of appropriate therapy. However, for those with more extensive
disease or advanced immunosuppression, clinical response may be delayed. A repeat blood culture for
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MAC should be performed if possible on patients who fail to demonstrate clinical improvement
(reduction in fever or systemic symptoms) within four to eight weeks of initiation of antimycobacterial
therapy.
Treatment failure is defined by the absence of a clinical response and the persistence of Mycobacteraemia
after four to eight weeks of treatment. Although the majority of patients who failed clarithromycin- or
azithromycin-primary prophylaxis in clinical trials had isolates susceptible to these drugs at the time
MAC disease was detected, the number of drugs with demonstrated clinical activity against MAC is
limited, and results of susceptibility testing should be used whenever possible to construct a new
multidrug regimen consisting of at least two new drugs not previously used and to which the isolate is
susceptible from among the following: EMB, rifabutin, ciprofloxacin or levofloxacin, or amikacin. It is
not known whether continuing clarithromycin or azithromycin in the face of resistance provides
additional benefit. Clofazimine should not be used based on the lack of efficacy demonstrated in
randomised trials and the association with increased mortality.
For patients who have failed initial treatment for MAC disease, or who have antimycobacterial drug
resistant MAC disease, optimising HAART is an important adjunct to second-line or salvage therapy for
MAC disease.
Adult and adolescent patients with disseminated MAC disease should receive lifelong therapy (e.g.
secondary prophylaxis or maintenance therapy), unless immune reconstitution occurs as a consequence of
HAART. Apparently, patients are at low risk for recurrence of MAC when they have completed a course
of twelve months or longer of treatment for MAC, remain asymptomatic with respect to MAC signs and
symptoms, and have a sustained increase (e.g. six months or longer) in their CD4+ T cell counts to >100
cells/mm3 after HAART. Discontinuing chronic maintenance therapy among such patients is reasonable.
Secondary prophylaxis should be reintroduced if the CD4+ T cell count decreases to <100 cells/mm3.
Indications for treatment are the same as in non-pregnant adults. Azithromycin is preferred over
clarithromycin as the second agent with EMB or rifabutin due to the occurrence of birth defects in mice
and rats associated with clarithromycin, not seen with azithromycin.
BACTERIAL RESPIRATORY DISEASE

Epidemiology
Bacterial pneumonia has been a common cause of HIV-related morbidity, especially in developing
countries. In a study comparing rates among cohorts with similar risk factors for bacterial pneumonia,
those with HIV infection were 7.8 times more likely to develop bacterial pneumonia than HIV-uninfected
persons.
For many individuals, bacterial pneumonia is a presenting symptom of HIV disease. Studies have shown
that patients can develop serious pneumococcal infections with relatively preserved CD4+ T cell counts.
The high rates of bacterial pneumonia and other pyogenic respiratory tract infections are likely due to
multiple factors including qualitative B-cell defects that impair the ability to produce pathogen-specific
antibodies; weakened neutrophil function or numbers or both; as well as non-HIV-related factors such as
cigarette smoking, use of crack cocaine, IV drug use, alcoholism, or liver disease. The most consistent
predictor of bacterial infections is the CD4+ T cell count.
The aetiology of bacterial pneumonia in patients with HIV infection has been reported in several studies.
Consistent among these has been the relative prominence of Streptococcus pneumoniae, followed by
Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. In most studies, the
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pathogens of atypical pneumonia (Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydia
pneumoniae) are rarely encountered.
Based on data derived from studies of pneumococcal bacteraemia, infection with S. pneumoniae has been
estimated to occur 150 to 300 times more commonly among patients with HIV infection than in age-
matched HIV-uninfected populations. Recurrent pneumococcal pneumonia, either with the same or
unrelated serotype, is also more common among HIV-infected patients, with a rate of 8% to 25% within
six months. Recent data suggest that re-infection with a different strain is more common than relapse.
In most series, H. influenzae (usually non-typable) is generally the second most common cause of
bacterial pneumonia.
In patients with advanced immunosuppression, S. aereus and P. aeruginosa can cause particularly
aggressive invasive pneumonias, sometimes associated with bacteraemia and frequent relapses after
cessation of therapy.
As in pneumonia studies of HIV-uninfected patients, a high proportion (up to 33%) of patients with HIV
infection will have no specific microbiologic aetiology defined. Importantly, many of these undefined
cases are believed to be of possible bacterial aetiology.
HIV-infected patients with bacterial pneumonia generally present in a similar fashion to those without
HIV infection. Lobar consolidation on chest radiograph is commonly seen and is a predictor of bacterial
pneumonia, although atypical presentations with multilobar, nodular, or reticulonodular patterns are
occasionally described. Patients ill over a period of weeks to months are more likely to have PCP, TB, or
an endemic chronic fungal infection.
Diagnosis
The pace of the respiratory disease, the underlying CD4+ T cell count, the circulating neutrophil count,
and the appearance of the infiltrate should guide the diagnostic evaluation for bacterial pneumonia. At a
minimum, a chest radiograph, blood cultures, a white blood cell (WBC) count, and, if available, a Gram’s
stain and culture of an adequate expectorated sputum sample should be obtained prior to antibiotic
administration if possible, though antibiotic administration should not be delayed more than thirty
minutes after initial diagnosis of pneumonia. Since PCP is a common HIV-related respiratory infection
and may co-exist with bacterial pneumonia, an induced sputum examination for P. jiroveci staining
should be performed if there is a known CD4+ T cell count of <250 cells/mm3, other sign of advanced
immunodeficiency (such as thrush), a prior history of PCP or another AIDS-related condition, or diffuse
infiltrates on CXR.
For both clinical and infection-control purposes, sputum samples (either expectorated or induced) for
AFB staining and TB cultures should be obtained on all HIV-infected, hospitalised patients with
pulmonary infiltrates in most Caribbean settings, especially where TB is common. A possible exception
to this rule would be the patient who clearly has an acute onset of an illness consistent with bacterial
pneumonia, has no exposure to TB, has a prior negative TST, and has not lived in or been exposed to
high-prevalence areas for TB.
Therapy for HIV-related bacterial pneumonia should target the most commonly identified pathogens, in
particular S. pneumoniae and H. influenzae. In general, treatment guidelines appropriate for HIV-
uninfected patients are applicable to those with HIV infection as well. Specific recommended regimens
include either an extended-spectrum cephalosporin (such as cefotaxime or ceftriaxone) or a
fluoroquinolone with activity against S. pneumoniae (levofloxacin, moxifloxacin, or gatifloxacin).
Combination therapy with macrolide or quinolone plus a cephalosporin regimen should be considered in
those with severe illness. It is important to determine whether or not meningitis is present, since the
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recommended fluoroquinolones do not reliably attain adequate cerebro-spinal fluid (CSF) levels for
treating pneumococcal meningitis. For patients with severe immunodeficiency (CD4+ T cell counts of
<100/mm3), a known history of prior Pseudomonas infection, bronchiectasis, or relative or absolute
neutropaenia, broadening empiric coverage to include P. aeruginosa and other gram-negative bacilli
should be considered. Possible options for therapy would include ceftazidime, cefepime, piperacillin-
tazobactam, a carbepenem, or high-dose ciprofloxacin or levofloxacin. For ceftazidime and
ciprofloxacin, other antimicrobial agents would be needed to provide optimal coverage for gram-positive
infections.
A clinical response, defined by a reduction in fever and improvement in laboratory studies, physical
findings, and respiratory symptoms, is generally seen within forty-eight to seventy-two hours following
initiation of appropriate therapy. Radiographic improvement may require additional time.
Management of Treatment Failure.
HIV-infected patients who fail to respond to appropriate antimicrobial therapy, as determined by a lack of
reduction in fever, failure of the total WBC to return toward normal, persistent or worsening pulmonary
signs, symptoms or radiographic abnormalities, progressive hypoxaemia, or other evidence of progressive
disease should undergo further evaluation to search for other infectious and non-infectious causes of
pulmonary dysfunction. Broader spectrum antimicrobial therapy may be required while additional
diagnostic testing is pursued. Management in consultation with an infectious disease expert is
recommended.
The preventive strategy most effective against bacterial pneumonia in HIV-infected patients is the use of
HAART. There is no well-documented benefit for maintenance therapy following successful completion
of antibiotic treatment for bacterial respiratory tract infections. Adults and adolescents who have CD4+ T
cell counts of >200 cells/mm3 should be administered a single dose of 23-valent polysaccharide
pneumococcal vaccine if they have not received it during the previous five years. Yearly administration
of influenza vaccine may be useful in preventing pneumococcal superinfection of influenza respiratory
tract infections.
Administration of antibiotic chemoprophylaxis to HIV-infected patients who have frequent recurrences of
serious bacterial respiratory infections may be considered. TMP-SMX, administered for PCP
prophylaxis, and clarithromycin or azithromycin, administered for MAC prophylaxis, can prevent
recurrent bacterial pneumonia caused by drug-sensitive organisms. However, using antibiotics solely for
preventing the recurrence of serious bacterial respiratory infections carries the potential for development
of drug resistant micro-organisms and drug toxicity.
The diagnosis of bacterial respiratory tract infections in pregnant women is the same as for non-pregnant
adults, with appropriate shielding of the abdomen during radiographic procedures.
Clarithromycin should be avoided due to the occurrence of birth defects associated with its use in mice
and rats. Because arthropathy has been observed in immature animals with the use of quinolones during
pregnancy, quinolones are generally not recommended in pregnancy and in children age eighteen years or
younger. However, quinolones may be used in pregnancy for drug resistant disease when other
alternatives are not available.
Pneumococcal and influenza vaccines may be given during pregnancy, and influenza vaccine is
recommended for all women who will be in the second or third trimester of pregnancy during the peak of
influenza season. Since administration of vaccines may be associated with a transient rise in HIV RNA
levels, vaccination of pregnant women is best done after HAART has been initiated to minimise increases
in HIV RNA levels that may raise the risk of perinatal HIV transmission.
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BACTERIAL ENTERIC DISEASE
Epidemiology
The three most common causes of bacterial diarrhoea in patients with HIV infection are Salmonella,
Campylobacter, and Shigella species. Patients with HIV infection are at a markedly increased risk of
developing salmonellosis.
Campylobacter jejuni has a reported incidence among HIV-infected individuals, particularly men who
have sex with men (MSM), which is up to thirty-nine times higher compared with the general population.
Persons with HIV infection, particularly sexually active MSM, are at markedly increased risk of
developing shigellosis. Data also suggest that Shigella bacteraemia is more common in HIV-infected
persons and may occur in both mild and severe cases of clinical shigellosis. Relapses in gastroenteritis
and bacteraemia after appropriate treatment have also been reported.
Three major clinical syndromes of salmonellosis have been described in patients with HIV infection: a) a
self-limited gastroenteritis; b) a more severe and prolonged diarrhoeal disease associated with fever,
bloody diarrhoea, and weight loss; and c) Salmonella septicaemia, which may present with or without
gastrointestinal symptoms. Bacteraemia can occur with each of these syndromes and is more likely to
occur in those with advanced immunosuppression. Since non-typhoidal Salmonella bacteraemia is rare in
immunocompetent hosts, its diagnosis should prompt consideration of HIV testing. Salmonella
bacteraemia in patients with AIDS has marked propensity for relapse. Early in the AIDS epidemic, the
rate of recurrent bacteraemia was approximately 45% unless chronic suppressive therapy was given.
Campylobacter disease in those with severe or progressive immunodeficiency is often associated with
more prolonged diarrhoea, invasive disease, bacteraemia, and extraintestinal involvement. The
development of antimicrobial resistance during therapy, often associated with clinical deterioration or
relapse, also occurs more frequently among HIV-infected individuals.
Shigellosis in persons with HIV infection generally causes an acute, febrile, diarrhoeal illness with
prominent upper and lower gastrointestinal symptoms. Bloody diarrhoea is more common with Shigella
infection than with Salmonella.
Diagnosis
Bacterial enteric infection is diagnosed through cultures of stool and blood. Given the high rate of
bacteraemia associated with Salmonella gastroenteritis–-in particular in patients with advanced HIV
disease-–blood cultures should be obtained whenever possible in any HIV-infected patient presenting
with diarrhoea and fever. Persons with HIV are also at risk for disease due to non-jejuni Campylobacter
species, including C. foetus, C. upsaliensis, C. laridis, C. cineadi, and C. fennelliae. While blood culture
systems will generally grow these organisms, routine stool cultures performed by most laboratories will
fail to identify these more fastidious Campylobacter species. If a lower endoscopy is performed,
ulcerations similar to those seen with CMV colitis may be evident and can only be distinguished through
histopathologic examination and culture.
Immunocompetent hosts without HIV infection seldom require treatment for Salmonella gastroenteritis;
the condition is self-limited and treatment may prolong the carrier state. With HIV infection, the risk of
bacteraemia is sufficiently high that most experts recommend antimicrobial treatment of all HIV-
associated Salmonella infections. The initial treatment of choice for Salmonella infection is a
fluoroquinolone. Ciprofloxacin is the preferred agent. Other fluroquinolones (levofloxacin, gatifloxacin,
and moxifloxacin) would also likely be effective in treatment of salmonellosis in HIV-infected persons.
For HIV-related Salmonella infection presenting with mild gastroenteritis without bacteraemia, seven to
fourteen days of treatment is reasonable in an effort to reduce the risk of extraintestinal spread. For
patients with advanced HIV disease (CD4+ T cell counts of <200/mm3) and/or who have Salmonella
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bacteraemia, at least four to six weeks of treatment is recommended. Depending on antibiotic
susceptibility, alternatives to the fluoroquinolone antibiotics for Salmonella infections include TMP-SMX
or expanded spectrum cephalosporins, such as ceftriaxone or cefotaxime.
The optimal treatment of campylobacteriosis in persons with or without HIV infection is poorly defined.
For mild disease, some clinicians might withhold therapy unless symptoms persist for more than several
days. Rising resistance to fluoroquinolones makes the choice of therapy especially problematic. For mild
to moderate disease, initiating therapy with a fluoroquinolone (ciprofloxacin) or a macrolide
(azithromycin), pending susceptibility test results, and treating for seven days is a reasonable approach.
Patients with bacteraemia should be treated for at least two weeks, and it may be prudent to add a second
active agent, such as an aminoglycoside, in such cases.
Therapy of shigellosis is indicated both to shorten the duration of illness and to prevent the spread of the
infection to others. The recommended treatment is with a fluoroquinolone for three to seven days.
Alternatives include TMP-SMX for three to seven days or azithromycin for five days. Shigella acquired
in the Caribbean has high rates of TMP-SMX resistance; as a result, fluoroquinolones are preferred as
first-line treatments. Treatment of patients who have Shigella bacteraemia is less well-defined.
Depending on the severity of infection, it may be reasonable to extend treatment to fourteen days using
the agents described above.
Patients should be monitored closely for improvement in systemic signs and symptoms and resolution of
diarrhoea. A follow-up stool culture to demonstrate clearance of the organism is not generally required if
a complete clinical response has been demonstrated, but should be considered for those who fail to
clinically respond to appropriate antimicrobial therapy or when public health considerations dictate the
need to assure microbiologic cure (e.g. healthcare or food service workers).
Treatment failure is defined by the lack of improvement in clinical signs and symptoms of diarrhoeal
illness coupled with the persistence of organisms in stool, blood, other relevant body fluids, or tissue after
completion of appropriate antimicrobial therapy for the recommended duration. Many patients with
Salmonella bacteraemia may remain febrile for five to seven days despite effective therapy. Therefore,
careful observation is required to determine the adequacy of the response. Treatment is best guided by
drug susceptibility testing of isolates recovered in culture. An evaluation of other factors that may
contribute to failure or relapse, such as malabsorption of oral antibiotics, a sequestered focus of infection
(such as an undrained abscess), or adverse drug reactions that interfere with antimicrobial activity, should
be undertaken as indicated.
HIV-infected persons who have Salmonella bacteraemia should receive long-term therapy (e.g. secondary
prophylaxis or chronic maintenance therapy) to prevent recurrence. Fluoroquinolones, primarily
ciprofloxacin, are the drugs of choice for susceptible organisms. Chronic suppressive or maintenance
therapy is not generally recommended for Campylobacter or Shigella infections in persons with HIV
infection.
Household contacts of HIV-infected persons who have salmonellosis or shigellosis should be evaluated
for persistent asymptomatic carriage of Salmonella or Shigella so that strict hygienic measures or
antimicrobial therapy can be instituted and recurrent transmission back to the HIV-infected person can be
prevented.
Because arthropathy has been observed in immature animals with the use of quinolones during
pregnancy, quinolones are generally not recommended in pregnancy and in children age eighteen years or
younger. Therefore, expanded spectrum cephalosporins, TMP-SMX, or azithromycin, depending on the
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organism and the results of susceptibility testing, should generally be considered as first-line therapy.
However, quinolones may be used in pregnancy for drug resistant disease. Neonatal care providers
should be informed of maternal sulfa therapy if used near delivery due to the theoretical increased risk of
hyperbilirubinema and kernicterus to the newborn.
BARTONELLOSIS
Epidemiology
Bacillary angiomatosis, first recognised in 1983, and associated illnesses such as peliosis hepatica, are
caused by bacteria of the genus Bartonella, most commonly Bartonella henselae and Bartonella
quintana. Cases of bacillary angiomatosis in patients with HIV/AIDS have been linked to cat exposure.
It is seen in increased frequency in the homeless and under conditions of poor sanitation.
Bacillary angiomatosis occurs most frequently late in HIV infection in patients with a median CD4+ T
cell count of <50 cells/mm3 and has been documented in an HIV-infected patient in Nassau (Orlander,
personal communication). Bartonellosis is often a chronic illness with disease lasting for months to years
in most patients.
Bartonella species have been associated with infections involving every organ system, but the
characteristic presentation is bacillary angiomatosis of the skin. Bacillary angiomatosis resembles KS.
Lesions are often papular, red, with smooth or eroded surfaces, vascular, and bleed if traumatised.
Nodules may be seen in the subcoetaneous tissue and can erode through the skin. Bone infection has
been reported and such infections are notable in that they are lytic and painful. Bartonella infection of the
liver produces hepatic bacillary peliosis characterised by vascular masses in the liver or spleen. Although
isolated organ systems may be affected, infection results from haematogenous dissemination, and
systemic symptoms of fever, sweats, fatigue, malaise, weight loss, and other symptoms may accompany
localised syndromes.
Diagnosis
The diagnosis is confirmed by histopathologic examination of tissue biopsy specimens. Lesions produce
vascular proliferative histopathology; modified Silver stain demonstrates numerous bacilli. Tissue
Gram’s stain or acid-fast staining are negative.
Erythromycin and doxycycline have been used successfully to treat bacillary angiomatosis, peliosis
hepatica, bacteraemia, and osteomyelitis and are considered first-line treatment for bartonellosis based on
reported experience in case series. The duration of therapy should be at least three months. Doxycyline
is the treatment of choice for CNS bartonellosis. Clarithromycin or azithromycin have been associated
with clinical response in some cases, and are considered second-line alternatives, although treatment
failures have been reported with both drugs. Quinolones have variable in vitro activity and clinical
response in case reports; they are not recommended as first-line therapy but may be tried as second-line
alternatives.
Management of Treatment Failure and Prevention of Recurrence
For patients who fail to respond to initial treatment, one or more of the second-line alternative regimens
should be considered. For patients who relapse, lifelong suppression of infection with erythromycin or
doxycycline should be considered.
Pregnancy has been associated with a more severe course and possible increased risk of death with acute
infection due to B. bacilliformis in immunocompetent patients. Similarly, B. bacilliformis infections
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during pregnancy may increase the risk of spontaneous abortion and stillbirth and may be transmitted to
the foetus.
Treatment during pregnancy should be with erythromycin rather than tetracyclines due to increased
hepatotoxicity and staining of foetal teeth and bones associated with tetracycline use during pregnancy.
Cephalosporins are not recommended.
SYPHILIS
Epidemiology
Although the incidence of syphilis has declined since the mid- to late 1980s in the Caribbean region, the
incidence remains relatively high in several Caribbean countries24 where syphilis has been seen with
increased incidence in HIV-infected individuals, sex workers, and MSM.25 HIV infection appears to alter
the diagnosis, natural history, management, and outcome of Treponema pallidum infection.
As in HIV-uninfected individuals, primary syphilis commonly presents as a single, painless nodule at the
site of contact that rapidly ulcerates to form a classic chancre; however, in HIV-infected persons, multiple or
atypical chancres occur, and primary lesions may be absent or missed.
Progression to secondary syphilis generally follows in two to eight weeks after primary inoculation, and
is a reflection of ongoing replication and dissemination of T. pallidum in the absence of an effective host
immune response. Although more rapid progression to secondary syphilis or severe disease may be more
common in HIV-infected persons with advanced immunosuppression than in immunocompetent persons,
the clinical manifestations are, in general, similar to those in HIV-uninfected individuals. Secondary
syphilis, and in particular, acute syphilitic meningitis, must be distinguished from acute primary HIV
infection. Constitutional symptoms, along with non-focal CNS symptoms and CSF abnormalities
(lymphocytic pleocytosis with a mildly elevated CSF protein), are common to both.
Some of the manifestations of neurologic complications or neurosyphilis progress more rapidly or occur
earlier in the course of disease in persons with HIV infection, and thus are not truly “late” complications
or manifestations. However, concomitant uveitis and meningitis may be more common in HIV-infected
patients with syphilis.
Diagnosis
The diagnosis of syphilis depends on a variety of tests that either directly detect the organism (e.g.
darkfield microscopy or Direct Fluorescent Antibody-T. Pallidum (DFA-TP)) or serum antibodies against
it (e.g. FTA-ABS and TP-TA), or indirectly indicate the presumptive presence of T. pallidum by detecting
non-treponemal antibodies generated during infection (e.g. VDRL and RPR). Concurrent HIV infection
probably does not change the performance of standard tests for the diagnosis of syphilis.
In early-stage disease (primary, secondary, and early-latent syphilis), responses to non-treponemal
serologic tests (i.e., VDRL and RPR) may be atypical (e.g. higher, lower, or delayed) in HIV-infected
versus HIV-uninfected patients with early-stage syphilis, but treponemal tests do not perform differently
in HIV-infected compared to HIV–uninfected patients.
By definition, patients presenting with latent syphilis have serological evidence of disease in the absence
of clinical or other laboratory abnormalities (e.g. normal CSF profiles).
The diagnosis of neurosyphilis is established by examination of the CSF, which may show mild
mononuclear pleocytosis (10-200 cells/mm3), normal or mildly elevated protein concentrations, or a
reactive CSF-VDRL. The CSF-VDRL is specific but not sensitive, and a reactive test establishes the
diagnosis of neurosyphilis but a non-reactive test does not exclude the diagnosis. In contrast, CSF
treponemal tests, such as the CSF FTA-ABS, are sensitive but not specific, and a non-reactive test
excludes the diagnosis of neurosyphilis, but a reactive test does not establish the diagnosis. A reactive
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CSF-VDRL and a CSF WBC of >10 cells/mm3 support the diagnosis of neurosyphilis; most experts
would not base the diagnosis solely on elevated CSF protein concentrations in the absence of these other
abnormalities. HIV infection itself may be associated with mild mononuclear CSF pleocytosis (5 to 15
cells/mm3), particularly in individuals with peripheral blood CD4+ T cell counts of >500 cells/mm3; thus,
establishing the diagnosis of neurosyphilis may be more difficult in such individuals. If neurosyphilis
cannot be excluded by a non-reactive CSF treponemal test, such individuals should be treated for
neurosyphilis, despite the acknowledged uncertainty of the diagnosis.
The management of HIV-infected patients with syphilis is similar to the management of HIV-uninfected
persons with the disease (see Table 3). However, closer follow-up is recommended to detect potential
treatment failures or disease progression.
Table 3: Recommended Regimens for the Treatment of Syphilis in HIV-Infected Patients
Early-Stage: Benzathine penicillin G, 2.4MU intramuscular (IM) x
(Primary, secondary, and early-latent) 1
Late-Latent Benzathine penicillin G, 2.4MU IM q.w x 3 weeks
Late-Stage: Infectious diseases consultation
(Aortitis and gummata)
Neurosyphilis: Infectious diseases consultation
(CNS and ocular)
Crystalline penicillin G, 18-24MU q.d, administered
3-4MU IV q4h or by continuous infusion for 10-14
days
or
Procaine penicillin, 2.4MU IM q.d plus probenecid,

500mg orally q.i.d x 10-14 days
Each +
Benzathine penicillin G, 2.4MU IM q.w x 3 weeks

after completion of above
For all patients with syphilis, regardless of disease stage, those with neurological or ocular symptoms or
signs should undergo CSF examination to rule out neurosyphilis. CSF examination is also recommended
for HIV-infected patients with late-latent syphilis, including those with syphilis of unknown duration.
Similar to the HIV-uninfected population, HIV-infected patients with active tertiary syphilis (aortitis and
gumma) or who fail treatment for non-neurological syphilis should undergo CSF examination. Patients
with CSF abnormalities consistent with neurosyphilis should be treated for neurosyphilis.
HIV-infected individuals with early-stage (primary, secondary, or early-latent) syphilis should receive a
single IM injection of 2.4 million units of benzathine penicillin G. Alternative therapies, including oral
doxycycline, ceftriaxone, and azithromycin have not been sufficiently evaluated in HIV-infected patients
to warrant use as first-line treatment. If an alternative to penicillin is used, treatment must be undertaken
with close clinical monitoring.
In HIV-infected patients with late-latent syphilis for whom the CSF examination excludes the diagnosis
of neurosyphilis, treatment is recommended with three weekly IM injections of 2.4 million units
benzathine penicillin G. Alternative therapy with doxycycline 100mg orally twice a day for twenty-eight
days has not been sufficiently evaluated in HIV-infected patients to warrant use as first-line treatment. If
an alternative to penicillin is used, treatment must be undertaken with close clinical monitoring.
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HIV-infected patients with clinical or laboratory evidence of neurosyphilis (CNS involvement including
otic and ocular disease, even with a normal CSF) should receive IV aqueous crystalline penicillin G, 18 to
24 million units daily, administered 3 to 4 million units IV every four hours or by continuous infusion for
ten to fourteen days, or procaine penicillin 2.4 million units IM once daily plus probenecid 500mg orally
four times a day for ten to fourteen days. HIV-infected patients allergic to sulfa-containing medications
should not be given the IM alternative because they are very likely to be allergic to probenecid. IM
procaine penicillin without probenecid does not achieve sufficient penicillin levels in CSF to treat
neurosyphilis. Some experts recommend following neurosyphilis treatment with three weeks of
benzathine penicillin, 2.4 million units IM weekly. For penicillin-allergic patients, penicillin
desensitisation followed by one of the penicillin regimens listed above is the preferred approach.
However, limited data suggest that ceftriaxone (2g daily IV for ten to fourteen days) may be an alternative
regimen.
Clinical and serological responses to treatment of early-stage (primary, secondary, and early-latent)
disease should be monitored at three, six, nine, twelve, and twenty-four months after therapy. Serological
responses to treatment in HIV-infected patients may differ from responses in HIV-uninfected individuals,
including temporal pattern of response and proportion of subjects achieving serologically-defined
treatment success (at least a four-fold decrease in titer).
After successful treatment for syphilis in HIV-infected and HIV-uninfected patients, some remain
serofast, meaning that serum non-treponemal test titers remain reactive at low and unchanging titers,
generally <1:8, for extended periods of time (up to the lifetime of the patient). The serofast state probably
does not represent treatment failure. Serologic evidence of potential re-infection should be based on at
least a four-fold increase in titer above the established serofast baseline.
Response to therapy of late-latent syphilis should be monitored using non-treponemal serologic tests at
three, six, twelve, eighteen, and twenty-four months to assure at least a four-fold decline in titer.
Concomitant HIV infection may be associated with poorer CSF and serological responses to
neurosyphilis therapy. Repeat CSF examination is recommended at three and six months after
completion of therapy for neurosyphilis where possible, and then every six months until the CSF WBC is
normal and the CSF-VDRL is non-reactive. Treatment should be undertaken in consultation with an
expert, where possible.
Re-treatment of patients with early-stage syphilis should be considered for those who: 1) do not
experience at least a four-fold decrease in serum non-treponemal test titers six to twelve months after
therapy; 2) have a sustained four-fold increase in serum non-treponemal test titers after an initial
reduction after treatment; or 3) have persistent or recurring clinical signs or symptoms of disease. If CSF
examination does not confirm the diagnosis of neurosyphilis, such patients should receive 2.4 million
units IM benzathine penicillin G administered at one-week intervals for three weeks. If titers fail to
appropriately respond after re-treatment, repeat CSF evaluation or re-treatment may not be beneficial.
Patients with late-latent syphilis should have a repeat CSF examination and be retreated if they develop
clinical signs or symptoms of syphilis, have a four-fold increase in serum non-treponemal test titer, or
experience an inadequate serologic response (less than four-fold decline in non-treponemal test titer)
within twelve to twenty-four months of therapy. If the CSF exam is consistent with CNS involvement,
re-treatment should follow the neurosyphilis recommendations; those without a profile suggesting CNS
disease should receive a repeat course of benzathine penicillin, 2.4 million units IM weekly for three
weeks, although some experts recommend following the neurosyphilis recommendations in this setting.
Re-treatment of neurosyphilis should be considered if the CSF WBC count has not decreased after six
months following completion of treatment, or if the CSF-VDRL remains reactive two years after
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treatment.
All pregnant women should be screened for syphilis at the first prenatal visit. All women delivering a
stillborn infant after twenty weeks of gestation should also be tested for syphilis. Syphilis screening
should also be offered at sites providing episodic care to pregnant women at high risk including
emergency departments, jails, and prisons. No infant should leave the hospital without documentation of
maternal syphilis serology status during pregnancy. The rate of transmission and adverse outcomes of
untreated syphilis are highest with primary, secondary, and early latent syphilis during pregnancy and
decrease with increasing duration of infection thereafter. Concurrent syphilis infection may increase the
risk of perinatal transmission of HIV to the infant although an increased risk has not been consistently
reported.
Treatment during pregnancy should consist of the same penicillin regimen as recommended for the given
disease stage in non-pregnant, HIV-infected adults. Given concerns regarding the efficacy of standard
therapy in HIV-infected individuals, a second injection one week after the first for HIV-infected pregnant
women should be considered.
No alternatives to penicillin have been proven effective and safe for treatment of syphilis during
pregnancy or for prevention of foetal infection. Pregnant women who have a history of penicillin allergy
are best referred for skin testing and desensitisation and treatment with penicillin. Erythromycin does not
reliably cure foetal infection; tetracyclines should not be used during pregnancy because of hepatotoxicity
and staining of foetal bones and teeth. Efficacy data with azithromycin or ceftriaxone are insufficient to
support a recommendation for their use in this setting.
The Jarisch-Herxheimer reaction, associated with fever within hours after treatment, may precipitate
preterm labour or foetal distress during the second-half of pregnancy. Consideration should be given to
providing foetal and contraction monitoring for twenty-four hours after initiation of treatment for early
syphilis of pregnant women who are at or beyond twenty weeks of gestation, especially in the setting of
abnormal ultrasound findings indicative of foetal infection. Alternatively, women should be advised to
seek obstetric attention after treatment if they notice contractions or a decrease in foetal movement.
Repeat serologic titers should be performed in the third trimester and at delivery for women treated for
syphilis during pregnancy.
MUCOCOETANEOUS CANDIDIASIS
Epidemiology
Most oropharyngeal and oesophageal candidiasis is caused by Candida albicans. Fluconazole (or azole)
resistance is predominantly the consequence of previous exposure to fluconazole (or other azoles),
particularly with repeated and long-term exposure. With such exposure, C. albicans resistance has been
accompanied by a gradual emergence of non-albicans Candida species, particularly C. glabrata, as a
cause of refractory mucosal candidiasis, particularly in patients with advanced immunosuppression.
Oesophageal candidiasis is a frequent presenting symptom of AIDS in the Caribbean.26
Oropharyngeal and oesophageal candidiasis are recognised as indicators of immune suppression and are
most often observed in patients with declining CD4+ T cell counts of >200 cells/mm3. In contrast,
vulvovaginal candidiasis is common in healthy, adult women, and is unrelated to HIV status.
Oropharyngeal candidiasis is characterised by painless, creamy white, plaque-like lesions of the buccal or
oropharyngeal mucosa or tongue surface. Lesions can be easily scraped off with a tongue depressor or
other instrument. Less commonly, erythematous patches without white plaques can be seen on the
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anterior or posterior upper palate or diffusely on the tongue. Angular chelosis is also noted on occasion
and may be due to Candida.
Oesophageal candidiasis is occasionally asymptomatic but often presents with fever, retrosternal burning
pain or discomfort, and odynophagia. Endoscopic examination reveals whitish plaques similar to those
observed with oropharyngeal disease that may progress to superficial ulceration of the oesophageal
mucosa, with central or surface whitish exudates.
Vulvovaginitis may be mild to moderate and sporadic, similar in presentation to that in normal hosts, and
characterised by a creamy to yellow-white adherent vaginal discharge associated with mucosal burning
and itching. In those with more advanced immunosuppression, episodes may be more severe, more
frequently recurrent, of longer duration, or refractory to treatment.
Diagnosis
The diagnosis of oropharyngeal candidiasis is usually a clinical one based on the appearance of the
lesions. The feature that distinguishes these from oral hairy leukoplakia is the ability to scrape off the
superficial whitish plaques. Scraping for microscopic examination for yeast forms using a potassium
hydroxide (KOH) preparation provides supportive diagnostic information. Cultures of clinical material
identify the species of yeast present. The definitive diagnosis of oesophageal candidiasis requires
endoscopic visualisation of lesions with histopathologic demonstration of characteristic Candida yeast
forms in tissue and culture confirmation of the presence of Candida species. Although symptoms of
oesophageal candidiasis may be mimicked by other pathogens, a diagnostic trial of antifungal therapy is
often appropriate before endoscopy is undertaken to search for other causes of oesophagitis. The
diagnosis of vulvovaginal candidiasis is based on the demonstration of characteristic hyphae or
pseudohyphae forms in vaginal secretions examined microscopically after KOH preparation. Culture
confirmation is rarely required. As self-diagnosis of vulvovaginitis is unreliable, microscopic
confirmation is required to avoid unnecessary exposure to inappropriate treatments.
Although initial episodes of oropharyngeal candidiasis can be adequately treated with topical therapy,
including clotrimazole troches or nystatin suspension or pastilles, oral fluconazole is as effective and in
some studies, superior to topical therapy and is more convenient and generally better tolerated.
Itraconazole oral solution for seven to fourteen days is as effective as oral fluconazole but less well-
tolerated. Ketoconazole and itraconazole capsules are less effective than only fluconazole due to their
more variable absorption and should be considered second-line alternatives.
Systemic therapy is required for effective treatment of oesophageal candidiasis. A fourteen to twenty-one
day course of either fluconazole or itraconazole solution is highly effective. As with oropharyngeal
candidiasis, ketoconazole and itraconazole capsules are less effective than fluconazole because of variable
absorption. Although caspofungin and voriconazole are effective in treating oesophageal candidiasis in
HIV-infected patients, experience is limited and the expensive is high. As such, fluconazole remains the
preferred agent.
Vulvovaginal candidiasis in HIV-infected women is uncomplicated in 90% of cases and responds readily
to short-course oral or topical treatment with any of the following therapies including single-dose
regimens: topical azoles (clotrimazole, butoconazole, miconazole, ticonazole, or terconazole) for three to
seven days; topical nystatin 100,000µ daily for fourteen days; oral itraconazole 200mg twice daily for one
day or 200mg once-daily oral solution for three days; or one dose of oral fluconazole. Complicated
vaginitis (prolonged or refractory episodes) is seen in approximately 10% of cases and requires
antimycotic therapy for more than seven days.
Most patients respond rapidly to adequate therapy, with improvement in signs and symptoms within
forty-eight to seventy-two hours. Short courses of topical therapy rarely result in adverse effects,
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although occasional patients experience coetaneous hypersensitivity reactions with rash and pruritis.
Patients may experience gastrointestinal upset with oral azole treatment. Treatment for longer than seven
to ten days with azoles orally may produce hepatotoxicity. If prolonged therapy is anticipated (more than
twenty-one days), periodic monitoring of liver chemistry studies should be considered.
Treatment failure is generally defined as signs and symptoms of oropharyngeal or oesophageal
candidiasis that persist for more than seven to fourteen days of appropriate therapy. Fluconazole-
refractory oropharyngeal candidiasis will respond at least transiently to itraconazole solution in
approximately two-thirds of individuals. Amphotericin B oral suspension (1 mL four times daily of the
100mg/mL suspension) is sometimes effective in patients with oropharyngeal candidiasis who do not
respond to itraconazole. However, amphotericin B solution is not widely available. IV amphotericin B is
usually effective and may be used in patients with refractory disease. Fluconazole-refractory oesophageal
candidiasis should be treated with caspofungin or IV amphotericin B, either conventional, liposomal, or
lipid complex formulations.
Most HIV specialists do not recommend chronic prophylaxis of recurrent oropharyngeal or vulvovaginal
candidiasis. However, if recurrences are frequent or severe, an oral azole, fluconazole, or itraconazole
solution (or for recurrent vulvovaginal candidiasis, daily prophylaxis with any topical azole) should be
considered. Factors that influence choices related to such therapy include impact of recurrences on the
patient’s well-being and quality of life, the need for prophylaxis for other fungal infections, cost,
toxicities, drug interactions, nutritional status, and potential to induce drug resistance among Candida and
other fungi.
Prolonged use of systemically absorbed azoles, specifically among patients with low CD4+ T cell counts
(<100 cells/mm3) increases the risk for developing azole resistance. However, those with a history of one
or more episodes of documented oesophageal candidiasis can be considered as candidates for chronic
suppressive therapy: fluconazole 100 to 200mg daily.
Pregnancy increases the risk of vaginal colonisation with Candida species. In general, invasive or
refractory oesophageal Candida infections should be treated the same in pregnancy as in the non-pregnant
adult, with the exception that amphotericin B should be substituted for fluconazole or itraconazole (if
indicated) in the first trimester if similar efficacy is to be expected.
This is because fluconazole is teratogenic in high doses in animal studies. In humans, four cases of an
unusual cluster of defects (craniofacial and skeletal) have been reported after prolonged use at high doses
in the first trimester of pregnancy; however, anomalies do not appear to be increased among infants born
to women receiving single-dose fluconazole treatment in the first trimester. Itraconazole is teratogenic in
rats and mice (skeletal defects, encephalocele, macroglossia) at high doses. Similar to fluconazole, no
increase in anomalies has been noted among women exposed to treatment doses in the first trimester.
CRYPTOCOCCOSIS
Epidemiology
Virtually all HIV-associated cryptococcal infections are caused by Cryptococcus neoformans var.
neoformans. Most cases of infection are seen in patients who have CD4+ T cell counts of <50 cells/mm3.
Cases of cryptococcosis have been clearly documented among HIV-infected patients in the Caribbean.27
Cryptococcosis in patients with AIDS most commonly presents as a subacute meningitis or
meningoencephalitis with fever, malaise, and headache. Classic meningeal symptoms and signs (such as
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neck stiffness or photophobia) occur in only about one-quarter to one-third of patients. Some patients
may present with encephalopathic symptoms such as lethargy, altered mentation, personality changes, and
memory loss. Analysis of the CSF usually shows a very mildly-elevated serum protein, normal or
slightly low glucose, a few lymphocytes, and numerous organisms. The opening pressure in the CSF is
elevated (with pressures exceeding 200mm H2O) in up to 75% of patients. Disseminated disease is a
common manifestation, with or without concurrent meningitis. About one-half of patients with
disseminated disease have pulmonary rather than meningeal involvement. Symptoms and signs of
pulmonary infection include cough or dyspnoea and abnormal chest radiographs. Skin lesions may be
observed.
Diagnosis
Cryptococcal antigen is almost invariably detectable in the CSF at high titers in patients with meningitis
or meningoencephalitis. The serum cryptococcal antigen is also usually positive and detection of
cryptococcal antigen in serum may be useful in initial diagnosis. As many as 75% of patients with HIV-
associated cryptococcal meningitis have positive blood cultures; if disseminated or other organ disease is
suspected in the absence of meningitis, a fungal blood culture is also diagnostically helpful.
Untreated, cryptococcal meningitis is fatal. The recommended initial treatment for acute disease is
amphotericin B, usually combined with flucytosine, for two weeks followed by fluconazole alone for a
further eight weeks. This approach is associated with a mortality of less than 10% and a mycologic
response of approximately 70%.
The addition of flucytosine to amphotericin B during acute treatment does not improve immediate
outcome, but is well tolerated for two weeks and decreases the risk of relapse. Lipid formulations of
amphotericin B appear effective. AmBisome® has been effective at doses of 4mg/kg daily. Combination
therapy with fluconazole (400 to 800mg daily) and flucytosine has been effective in the treatment of
AIDS-associated cryptococcal meningitis but, owing to the toxicity of this regimen (especially
myelotoxicity and gastrointestinal toxicity), it is recommended only as an alternative option for those
unable to tolerate or unresponsive to standard treatment.
The opening pressure should always be measured when a lumbar puncture is performed. Increased
intracranial pressure may cause clinical deterioration despite a microbiologic response, probably due to
cerebral oedema, and is more likely if the CSF opening pressure is >200mm H2O. In a recent large
clinical trial, 93% of deaths occurring within the first two weeks of therapy and 40% of deaths occurring
within weeks three through ten were associated with increased intracranial pressure. The principal
intervention for reducing symptomatic elevated intracranial pressure initially is repeated daily lumbar
punctures. CSF shunting should be considered for patients in whom daily lumbar punctures are no longer
being tolerated or whose signs and symptoms of cerebral oedema are not being relieved. It has not yet
been established that reduction in opening pressure leads to a reduction in the mortality and morbidity
associated with cerebral oedema.
After a two-week period of successful induction therapy, consolidation therapy should be initiated with
fluconazole administered for eight weeks or until CSF cultures are sterile. Itraconazole is an acceptable,
albeit less effective, alternative.
A repeat lumbar puncture to assure clearance of the organism is not required for those with cryptococcal
meningitis who have improvement in clinical signs and symptoms after initiation of treatment. If new
symptoms or clinical findings occur after two weeks of treatment, a repeat lumbar puncture should be
performed. Serum cryptococcal antigen is not helpful in management as changes in titer do not correlate
with clinical response. Serial measurement of CSF cryptococcal antigen may be more useful but requires
repeated lumbar punctures and is not routinely recommended for monitoring response. Patients treated
with amphotericin B should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances.
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Supplemental colloidal fluids may reduce the risk of nephrotoxicity during treatment. Infusion-related
adverse reactions such as fever, chills, renal tubular acidosis, hypokalaemia, orthostatic hypertension,
tachycardia, nausea, headache, vomiting, anaemia, anorexia, and phlebitis may be ameliorated pre-
treatment with acetaminophen, diphenhydramine, and/or corticosteroids given approximately thirty
minutes before the infusion. Lipid formulations of amphotericin B are less toxic. As previously
indicated, those treated with fluconazole should be monitored for hepatotoxicity, though this toxicity is
rare.
Treatment failure is defined as clinical deterioration despite appropriate therapy (assuming increased
intracranial pressure is being adequately treated as described above), the lack of improvement in signs and
symptoms after two weeks of appropriate therapy, or relapse after an initial clinical response. A repeat
lumbar puncture should be performed (if a shunt is not already in place) to ascertain whether or not
intracranial pressure has increased. Fluconazole resistance of C. neoformans is exceedingly rare, and
susceptibility testing is not routinely recommended.
The optimal therapy for those with treatment failure is not known. Those who have failed on fluconazole
should be treated with amphotericin B with or without flucytosine as indicated above, and therapy should
be continued until there is a clinical response. Higher doses of fluconazole in combination with
fluctyosine may also be useful. Voriconazole has activity against Cryptococcus in vitro; caspfungin does
not.
Patients who have completed initial therapy for cryptococcosis should be administered lifelong
suppressive treatment, unless immune reconstitution occurs as a consequence of HAART. Fluconazole is
superior to itraconazole for preventing relapse of cryptococcal disease and is the preferred drug. Adult
and adolescent patients appear to be at low risk for recurrence of cryptococcosis when they have
successfully completed a course of initial therapy, remain asymptomatic with regard to signs and
symptoms of cryptococcosis, and have a sustained increase (e.g. six months or greater) in their CD4+ T
cell counts to >100 to 200 cells/mm3 after HAART. Discontinuing chronic maintenance therapy among
such patients is a reasonable consideration. Maintenance therapy should be re-initiated if the CD4+ T cell
count decreases to <100 to 200 cells/mm3.
Considerations regarding the use of amphotericin B, fluconazole, and itraconazole are the same as those
for mucocoetaneous and invasive candidiasis; i.e., amphotericin B should be used in the first trimester to
avoid the potential for teratogenicity with fluconazole or itraconazole. Flucytosine was teratogenic in rats
at high doses, but not at doses similar to human exposure. There are no reports of its use in the first
trimester of pregnancy in humans. Flucytosine may be metabolised to 5-fluoruracil. It should be used in
pregnancy only if clearly indicated.
HISTOPLASMOSIS
Epidemiology
Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum. The disease occurs in 2% to
5% of patients with AIDS from endemic areas, and has been clearly documented in the Caribbean.28 In
non-endemic areas, it most often occurs in those who have previously lived in an endemic region.
Histoplasmosis is acquired by inhalation of microconidia of the mycelial phase of the organism, but re-
activation of latent infection may be a mechanism for disease in some patients. Disseminated
histoplasmosis usually occurs in individuals with CD4+ T cell counts of >150 cells/mm3; localised
pulmonary histoplasmosis may be seen in individuals with CD4+ T cell counts of >300 cells/mm3.
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The most common clinical presentation in patients with AIDS is disseminated multi-organ disease.
Patients usually present with fever, fatigue, and weight loss; respiratory tract symptoms of cough, chest
pain, and dyspnoea may occur in up to 50% of patients. Symptoms and signs may be limited to the
respiratory tract for those with higher CD4+ T cell counts and localised pulmonary histoplasmosis.
Fewer than 10% of patients present with a “septic shock” syndrome. CNS, gastrointestinal, and
coetaneous manifestations each occur in <10% of cases, and other sites may be less commonly involved.
Diagnosis
Detection of Histoplasma antigen in blood or urine is a sensitive method for rapid diagnosis of
disseminated histoplasmosis but insensitive for pulmonary infection. Antigen is detected in the urine of
95% and serum of 85% of cases of disseminated histoplasmosis, and may be present in bronchoalveolar
lavage fluid or CSF of patients with pulmonary or meningeal involvement. Fungal stain of blood smears
or tissues may also yield a rapid diagnosis, but the sensitivity is <50%. H. capsulatum can be isolated
from blood, bone marrow, respiratory secretions, or localised lesions in over 85% of cases, but isolation
may take two to four weeks. Serologic tests are positive in over two-thirds of cases but are rarely helpful
in the acute diagnosis of histoplasmosis disease. Diagnosis of meningitis poses added difficulties. Fungal
stains are usually negative, and CSF cultures are positive in no more than half of cases. Antigen or anti-
Histoplasma antibodies may be detected in the CSF in up to 70% of cases. A presumptive diagnosis of
Histoplasma meningitis may be appropriate if the patient has disseminated histoplasmosis and findings of
CNS infection cannot be explained by another cause.
Patients with severe disseminated histoplasmosis who meet one or more of the following criteria
(temperature >39oC, systolic blood pressure <90mmHg, pO2 <70 torr, weight loss >5%, Karnofsky
performance score <70, haemoglobin <10gm/dl, neutrophil count <1,000/mm3, platelet count
<100,000/mm3, aspartate aminotransferase >2.5 times normal, bilirubin or creatinine >2 times normal,
albumin <3.5 gm/dL, coagulopathy, presence of other organ system dysfunction, or confirmed
meningitis) should be treated with IV amphotericin B, either the deoxycholate formulation or liposomal
amphotericin B, for the first three to ten days until they clinically improve. Liposomal amphotericin B
has been more effective than the standard deoxycholate formulation, inducing a more rapid and more
complete response, lowering mortality, and reducing toxicity. IV itraconazole 200mg daily after an initial
loading period may be used for persons who cannot tolerate amphotericin B.
Patients responding well after completion of initial amphotericin B therapy for three to ten days may be
switched to oral therapy with itraconazole capsules to complete twelve weeks of treatment and then
placed on maintenance treatment as indicated below. Itraconazole solution would be logical to use, but
there are no trials documenting efficacy and tolerability in this setting. Fluconazole 800mg daily is less
effective than itraconazole, but is recommended as an alternative if patients cannot tolerate itraconazole.
For those with confirmed meningitis, amphotericin B should be continued for twelve to sixteen weeks
followed by maintenance therapy as described below. Fluconazole has been recommended previously for
HIV-uninfected individuals with meningitis following amphotericin B; however, itraconazole may be
considered in this setting.
In persons with mild illness, therapy with itraconazole capsules for twelve weeks is recommended. Acute
pulmonary histoplasmosis in an HIV-infected patient with intact immunity, as indicated by a CD4+ T cell
count of >500 cells/mm3, may require no therapy and should be managed in a similar way to infection in
an otherwise non-compromised host.
Patients who complete initial therapy for histoplasmosis should be administered lifelong suppressive
treatment with itraconazole 200mg twice daily.
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Although patients receiving secondary prophylaxis (chronic maintenance therapy) might be at low risk for
recurrence of systemic mycosis when their CD4+ T cell counts increase to >100 cells/mm3 in response to
HAART, the number of patients who have been evaluated is insufficient to warrant a recommendation to
discontinue prophylaxis.
Treatment is the same as for non-pregnant adults. Because fluconazole has been shown to be teratogenic
in high doses in animal studies, and itraconazole is teratogenic in high doses in rats and mice,
amphotericin B should be substituted for itraconazole or fluconazole (if indicated) in the first trimester.
COCCIDIOIDOMYCOSIS
Epidemiology
Coccidioidomycosis is caused by Coccidioides immitis and is seen predominantly in endemic regions,
which include Central and South America; cases have been documented in the Caribbean as well.29
Sporadic cases may be diagnosed from non-endemic areas due to re-activation of prior infection. Both
localised pneumonia and disseminated infection are usually observed in those with CD4+ T cell counts of
<250 cells/mm3.
The two most common clinical presentations of coccidioidomycosis are disseminated disease and
meningitis. Disseminated disease is associated with generalised lymphadenopathy, skin nodules or
ulcers, peritonitis, liver abnormalities, and bone and joint involvement. Localised meningeal disease
results in symptoms of lethargy, fever, headache, nausea or vomiting, and/or confusion, and occurs in
about 10% of patients. In those with meningeal involvement, CSF analysis typically demonstrates a
lymphocytic pleocytosis with CSF glucose levels of <50mg/dL. CSF protein may be normal or mildly
elevated.
Diagnosis
The diagnosis of coccidioidomycosis is confirmed by culture of the organism from clinical specimens or
by demonstration of the typical spherule on histopathological examination of involved tissue. Blood
cultures are positive in a minority of patients. C. immitis serology is frequently positive in HIV-infected
patients with coccidioidomycosis and is useful in diagnosis. Complement fixation serology (IgG) is
generally positive in the CSF in coccidioidal meningitis.
For non-meningeal pulmonary or disseminated disease, amphotericin B is the preferred initial therapy.
Data evaluating lipid formulations of amphotericin B are limited such that appropriate dosing
recommendations cannot be made. Therapy with amphotericin B should continue until there is clinical
improvement; this usually occurs after administration of 500 to 1,000mg. Some experts would use an
azole antifungal concurrently with amphotericin B. Fluconazole or itraconazole may be appropriate
alternatives for patients with mild disease.
Coccidioidal meningitis should be treated with fluconazole, which has been reported to be successful in
approximately 80% patients with this disease. Consultation with a specialist is recommended. Intrathecal
amphotericin B is the most accepted alternative but is quite toxic.
Patients who complete initial therapy for coccidioidomycosis should be administered lifelong suppressive
therapy using either fluconazole 400mg daily or itraconazole 200mg twice daily.
Although patients receiving secondary prophylaxis (chronic maintenance therapy) might be at low risk for
recurrence of systemic mycosis when their CD4+ T cell counts increase to >100 cells/mm3 in response to
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HAART, the number of patients who have been evaluated are insufficient to warrant a recommendation to
discontinue prophylaxis.
Coccidioides infections appear to be more likely to disseminate if acquired during pregnancy in HIV-
uninfected women, with the risk increasing with increasing gestational age.
In general, invasive fungal infections should be treated the same in pregnancy as in the non-pregnant
adult, with the exception that amphotericin B is the preferred agent in the first trimester because of the
potential teratogenic risks of the azoles.
ASPERGILLOSIS
Epidemiology
Aspergillosis is most frequently caused by Aspergillus fumigatus but occasionally by other Aspergillus
species. Specific risk factors previously identified include neutropaenia, low CD4+ T cell counts,
corticosteroid use, exposure to broad-spectrum antibacterial therapy, and prior pneumonia or other
underlying lung disease. Patients diagnosed with HIV-associated aspergillosis have extremely low CD4+
T cell counts (<50 cells/mm3), a history of other AIDS-defining OIs, and are not receiving HAART.
Two major syndromes have been described in patients with AIDS-respiratory tract disease: 1) either
semi-invasive pseudomembranous tracheitis or invasive pneumonitis and 2) CNS infection presenting as
a febrile diffuse meningoencephalitis syndrome with vascular infarction as a central feature (based on the
predilection of Aspergillus organisms to invade blood vessel walls).
Semi-invasive pseudomembranous tracheitis is associated with fever, cough, dyspnoea, stridor, and
wheezing due to airway constriction, culminating in airway obstruction if untreated. Endoscopic
examination demonstrates a confluent, exudative pseudomembrane adherent to the tracheal wall.
Invasive pneumonitis presents with fever, cough, dyspnoea, chest pain, haemoptysis, and hypoxaemia;
chest radiograph demonstrates either a diffuse interstitial pneumonitis or a localised “wedge-shaped”,
dense infiltrate representing pulmonary infarction, again related to the predilection of the organisms for
invasion of vascular endothelium.
Diagnosis
A definitive diagnosis requires the presence of relevant clinical signs and symptoms coupled with the
histopathologic demonstration of organisms in biopsy specimens obtained from involved sites or from a
site that is expected to be sterile, e.g. liver or brain. A presumptive diagnosis of respiratory tract disease
can be made in the absence of a tissue biopsy if Aspergillus sp. are cultured from a respiratory sample, a
compatible lesion or syndrome is present, and no alternative causative process is identified. Serologic
testing is not helpful.
The recommended treatment for invasive aspergillosis is voriconazole, though this agent has not been
studied in HIV-infected patients with this disease. Amphotericin B, either conventional or lipid
formulation, in doses equivalent to 1mg/kg daily of standard amphotericin B, is an alternative regimen.
Itraconazole represents another alternative option, while caspofungin is approved for patients failing to
tolerate or improve with standard therapy.
Rarely, airway obstruction results from extensive pseudomembrane formation in those with tracheitis.
Pulmonary infarction and progressive interstitial pneumonitis may lead to respiratory failure.
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The overall prognosis is poor in patients with advanced immunosuppression and in the absence of
effective HAART. Treatment failure is generally defined as failure to respond to initial therapy or
progression of clinical signs and symptoms despite appropriate therapy. There are no data to guide
recommendations for the management of treatment failure. If amphotericin B was used initially,
substitution with voriconazole may be considered; similarly, substitution of amphotericin B for
voriconazole would be rational for those who began therapy with voriconazole.
There are no data upon which to base a recommendation for or against chronic maintenance or
suppressive therapy in those who have successfully completed an initial course of treatment.
As with other invasive fungal infections, in general, aspergillosis should be treated the same in pregnancy
as in the non-pregnant adult, with the exception that amphotericin B is the preferred agent in the first
trimester due to the potential teratogenic risks of the azoles.
CYTOMEGALOVIRUS (CMV) DISEASE

Epidemiology
CMV is a double-stranded DNA virus in the herpes virus family that may reactivate to cause disseminated
or localised end-organ disease in patients with advanced immunosuppression who have been previously
infected with CMV. The majority of infections are thought to derive from re-activation of latent
infection. In the era before HAART, it was estimated that 30% of patients with AIDS developed CMV
retinitis some time between the diagnosis of AIDS and death. End-organ disease due to CMV occurs in
persons with advanced immunosuppression, typically those with CD4+ T cell counts of <50 cells/mm3,
who are either not receiving or have failed to respond to HAART. Other risk factors include prior OIs,
particularly MAC disease.
Retinitis is the most common clinical manifestation of CMV end-organ disease in the patient population.
CMV retinitis usually presents as unilateral disease, but in the absence of therapy, viraemic dissemination
results in bilateral disease in the majority of patients. Peripheral retinitis may be asymptomatic or present
with floaters, scotomata, or peripheral visual field defects. Central retinal lesions or lesions impinging on
the macula are associated with decreased visual acuity or central field defects. The characteristic
ophthalmologic appearance of CMV lesions includes perivascular fluffy yellow-white retinal infiltrates,
typically described as a focal necrotising retinitis, with or without intraretinal haemorrhage, and with little
inflammation of the vitreous unless immune recovery with HAART intervenes. In the absence of
HAART or specific anti-CMV therapy, retinitis invariably progresses, usually within ten to twenty-one
days following presentation. Progression of retinitis occurs in “fits and starts” and causes a characteristic
“brushfire” pattern, with a granular, white leading edge advancing before an atrophic, gliotic scar.
Colitis is the second most common manifestation, occurring in 5% to 10% of persons with AIDS and
CMV end-organ disease. The most frequent clinical manifestations are fever, weight loss, anorexia,
abdominal pain, debilitating diarrhoea, and malaise. Extensive mucosal haemorrhage and perforation can
be life-threatening complications.
Oesophagitis due to CMV occurs in less than 5% to 10% of persons with AIDS who develop CMV end-
organ disease, causing fever, odynophagia, nausea, and occasionally mid-epigastric or retrosternal
discomfort.
CMV neurologic disease causes dementia, ventriculoencephalitis, or ascending polyradiculomyelopathy.
Patients with dementia typically present with lethargy, confusion, and fever but the clinical presentation
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may mimic that of HIV dementia. The CSF generally demonstrates lymphocytic pleocytosis (although a
mixture of neutrophils and lymphocytes may be seen), low to normal glucose levels, and normal to
elevated protein levels. Patients with ventriculoencephalitis have a more acute course, with focal
neurologic signs, often including cranial nerve palsies or nystagmus. There is a rapid progression to
death. Periventricular enhancement of CT or MRI images is suggestive of CMV ventriculoencephalitis
rather than HIV-related neurologic disease. CMV polyradiculomyelopathy causes a Guillan Barré-like
syndrome characterised by urinary retention and progressive bilateral leg weakness. The clinical
symptoms generally progress over several weeks to include loss of bowel and bladder control and flaccid
paraplegia. A spastic myelopathy has been reported and sacral paresthaesia may occur. The CSF
generally shows a neutrophilic pleocytosis (often there are 100 to 200 neutrophils/mm3 and some
erythrocytes), accompanied by low CSF glucose and elevated protein levels.
CMV pneumonitis is uncommon, but when it occurs, it presents with shortness of breath, dyspnea on
exertion, a non-productive cough, and hypoxaemia, associated with interstitial infiltrates on chest
radiograph.
Diagnosis
The diagnosis of CMV retinitis is generally made based on recognition of characteristic retinal changes
observed on funduscopic examination by an experienced ophthalmologist.
The demonstration of mucosal ulcerations on endoscopic examination, coupled with colonoscopic or
rectal biopsy demonstrating histopathological identification of characteristic intranuclear and
intracytoplasmic inclusions are required for the diagnosis of CMV colitis.
The diagnosis of CMV oesophagitis is established by the presence of extensive large, shallow ulcers of
the distal oesophagus and by biopsy evidence of intranuclear inclusion bodies in the endothelial cells with
an inflammatory reaction at the ulcer’s edge. Culturing CMV from a biopsy or cells brushed from the
colon or the oesophagus is not sufficient to establish the diagnosis of CMV colitis or oesophagitis because
some persons with low CD4+ T cell counts may be viremic and have positive cultures for CMV in the
absence of clinical disease.
CMV neurologic disease is diagnosed on the basis of a compatible clinical syndrome and on the presence
of CMV in CSF or brain tissue. Detection of CMV in CSF is greatly enhanced by PCR testing.
Diagnosis of CMV pneumonitis should be made in the setting of pulmonary interstitial infiltrates, through
identification of multiple CMV inclusion bodies in lung tissue, and by the absence of other pathogens that
are more commonly associated with pneumonitis in this population.
The choice of initial therapy for CMV retinitis should be individualised, based on the location and
severity of the lesion(s), the level of underlying immune suppression, and other factors such as
concomitant medications and ability to adhere to treatment. Oral valganciclovir, IV ganciclovir, IV
ganciclovir followed by oral valganciclovir, IV foscarnet, IV cidofovir, and the ganciclovir intraocular
implant coupled with valganciclovir are all effective alternatives, as summarised in Appendix B. Prior to
the availability of HAART, these medications were administered for CMV retinitis in a course of acute
induction therapy, followed by secondary prophylaxis (chronic maintenance therapy) for life--
prohibitively expensive for many Caribbean settings. However, with the increasing availability of
HAART, simultaneous initiation of acute induction therapy together with HAART has become an
attractive option. This offers the possibility of stopping the progression of CMV retinitis to preserve
vision, followed by a time-limited course of maintenance therapy, with the potential for discontinuing the
maintenance therapy after a sustained (six months or greater) increase in CD4+ T cell counts to >100
cells/mm3 in response to HAART.
Some clinicians would not treat small peripheral CMV retinitis lesions if HAART is soon to be initiated,
as immune recovery may ultimately control the retinitis. However, there is a suggestion that immune
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recovery uveitis (IRU) is more common among patients given less aggressive anti-CMV therapy.
Similarly, some HIV specialists would withhold therapy for mild to moderately severe CMV colitis or
oesophagitis if HAART is soon to be initiated or can be optimised unless moderate to severe symptoms
justify the use of systemic anti-CMV therapy treatment.
There are no data demonstrating that starting HAART in treatment-naïve patients with CMV retinitis
would have an adverse effect on retinitis, gastrointestinal disease, or pneumonitis, or worsen IRU should
this occur. Thus, there is no reason to delay initiation of appropriate HAART, which should be
administered based on standards of care in the community, to those with acute CMV retinitis,
gastrointestinal disease, or pneumonitis.
Management of CMV retinitis requires close monitoring by an experienced ophthalmologist as well as by
the primary clinician. Dilated indirect ophthalmoscopy should be performed at the time of diagnosis of
CMV retinitis, after completion of induction therapy, one month after the initiation of therapy, and
monthly thereafter while the patient is on anti-CMV treatment. Adverse effects of anti-CMV medications
are summarised in Appendix D.
IRU is an immunologic reaction to CMV characterised by inflammation in the anterior chamber and/or
vitreous in the setting of immune reconstitution, and is generally observed in those with a substantial rise
in CD4+ T cell counts in the four to twelve weeks following initiation of HAART. Ocular complications
of uveitis include macular oedema and epiretinal membranes, which can cause loss of vision. Treatment
usually requires periocular corticosteroids or short courses of systemic corticosteroids. Estimated
response rates are about 50%.
Indications for treatment of CMV infection during pregnancy are the same as for those in non-pregnant
HIV-infected adults. For retinal disease, use of intraocular implants or intravitreous injections for local
therapy should be considered in pregnancy if possible to limit foetal exposure to systemically
administered antiviral drugs.
Ganciclovir is embryotoxic in rabbits and mice and teratogenic (cleft palate, anophthalmia, aplastic
kidney and pancreas, hydrocephalus) in rabbits. There are case reports of safe use in human pregnancy
after organ transplantation.
HERPES SIMPLEX VIRUS (HSV) DISEASE

Epidemiology
Infections with human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are common. Herpes
simplex virus infections in the Caribbean have been well-described in several studies of HIV-negative
persons and also in one Jamaican study of immunocompromised HIV-infected patients.30 As many as
95% of HIV-infected persons are seropositive for either HSV-1 or HSV-2, although in most infected
persons, HSV infections are asymptomatic. Regardless of the clinical severity of infection, reactivation
on mucosal surfaces occurs intermittently and can result in transmission.
HSV orolabialis is the most common manifestation of HSV-1 infection, presenting with a sensory
prodrome in the affected area, rapidly followed by the evolution of lesions from papule to vesicle, ulcer,
and crust stages on the lips. Ulcerative lesions are usually the only stage observed on mucosal surfaces.
The course of illness in untreated subjects is seven to ten days; lesions recur one to twelve times per year
and can be triggered by sunlight or physiologic stress.
HSV genitalis is the more common manifestation of HSV-2 infection. Genital mucosal or skin lesions are
similar in appearance and evolution to external orofacial lesions. Local symptoms include a sensory
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prodrome consisting of pain and pruritis. Ulcerative lesions are usually the only stage observed on
mucosal surfaces. Mucosal disease is occasionally accompanied by dysuria and vaginal or uretheral
discharge; inguinal lymphadenopathy, particularly in primary infection, is common with genital herpes.
In profoundly immunocompromised patients, extensive, deep, non-healing ulcerations may occur. These
lesions have been most often reported in those with CD4+ T cell counts of <100 cells/mm3 and also might
be more commonly associated with acyclovir resistant virus. HSV encephalitis occurs among HIV-
infected persons, but no evidence exists to suggest that it is more severe or common than among HIV-
uninfected persons.
Diagnosis
Though HSV infections are often diagnosed and treated empirically on the basis of characteristic skin,
mucus membrane, or ophthalmic lesions, laboratory confirmation is required to definitively diagnose
mucosal HSV infection. Viral culture, HSV DNA PCR, or HSV antigen detection are available methods
for diagnosis of mucocoetaneous lesions caused by HSV. Type-specific serologic assays that distinguish
between HSV-1 and HSV-2 antibody can be used in asymptomatic persons or those with atypical lesions.
Orolabial lesions can be treated with oral famciclovir, valacyclovir, or acyclovir for five to ten days (AII).
Severe mucocoetaneous HSV lesions are best treated initially with IV acyclovir (435--437) (AII).
Patients may be switched to oral therapy after the lesions have begun to regress; therapy should be
continued until the lesions have completely healed. Initial or recurrent genital HSV should be treated
with oral famciclovir, valacyclovir, or acyclovir for seven to fourteen days (AII).
Trifluridine and IV acyclovir are indicated for the treatment of herpes keratitis and HSV encephalitis,
respectively. These conditions should be treated in consultation with an expert in HSV management.
Famciclovir, valacyclovir, and acyclovir are generally well-tolerated but are occasionally associated with
nausea or headache. Rarely, patients receiving higher doses of famciclovir, valacyclovir, or acyclovir
might experience renal dysfunction. For patients receiving high-dose IV acyclovir, monitoring of renal
function is recommended at initiation of treatment, and once or twice weekly for the duration of treatment
particularly for those with underlying renal dysfunction or those receiving prolonged therapy.
Thrombotic thrombocytopaenic purpura-haemolytic uremic syndrome resulting in death has been reported
among HIV-infected patients treated with high-dose (8g/day) valacyclovir but has not been reported at
doses used for therapy of HSV infection.
Treatment failure related to resistance to antiviral drugs should be suspected if lesions do not indicate
signs of resolution within seven to ten days after initiation of therapy. Among immunocompromised
patients with suspected acyclovir resistant HSV, a lesion culture should be obtained and, if the virus is
isolated, susceptibility testing performed to confirm drug resistance. Foscarnet is the treatment of choice
for acyclovir resistant HSV. Topical trifluridine or cidofovir also has been used successfully for lesions
on external surfaces, although prolonged application for twenty-one to twenty-eight days or longer may
be required.
Chronic therapy with acyclovir is not required after lesions resolve. However, most recurrences can be
prevented by use of daily anti-HSV therapy and is recommended for persons who have frequent or severe
recurrences.
Acyclovir is the first choice for therapy of HSV infections in pregnancy. The predominant risk,
regardless of HIV-co-infection, is from maternal genital shedding at delivery. Caesarean delivery is
recommended for women with prodrome or visible HSV genital lesions at the onset of labour.
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VARICELLA ZOSTER VIRUS (VZV) DISEASE
Epidemiology
Up to 95% of the adult population is seropositive for VZV, and recurrent disease in the form of herpes
zoster occurs in 3% to 5% of all adults but becomes more prevalent in the elderly and the
immunocompromised host. The incidence of herpes zoster is fifteen to twenty-five times greater in HIV-
infected persons than in the general population, and three to seven times greater in the elderly. Zoster in
HIV-infected adults can occur at any CD4+ T cell count; more advanced immunosuppression may be
associated with altered manifestations of VZV infection as described below, but does not appear to
substantially alter the overall incidence of VZV.
Herpes zoster (shingles) may follow a prodrome of pain that resembles a burn or muscle injury in the
affected dermatome; skin lesions, which are similar to chickenpox in appearance and evolution, develop
in the same dermatome. Extensive coetaneous dissemination and visceral involvement occur rarely.
Progressive outer retinal necrosis is a VZV-associated entity that typically occurs in HIV-infected persons
with CD4+ T cell counts of <50 cells/mm3. This rapidly-progressive necrotising herpetic retinopathy is
often associated with dermatomal zoster and is characterised by multifocal retinal opacification with little
or no ocular inflammation and rapid visual loss.
VZV has been associated with transverse myelitis, encephalitis, and vasculitic stroke in HIV-uninfected
individuals. There are rare anecdotal reports of these syndromes in HIV-infected patients.
Diagnosis
Zoster and chickenpox are generally diagnosed empirically based on the appearance of characteristic
lesions.
The recommended treatment for localised dermatomal herpes zoster is acyclovir, famciclovir, or
valacyclovir for seven to ten days. If coetaneous lesions are extensive or if there is clinical evidence of
visceral involvement, IV acyclovir should be initiated and continued until coetaneous lesions and visceral
disease are clearly resolving. Due to its immunosuppressive effects and the absence of data to support
benefit with its use in this patient population; adjunctive corticosteroid therapy to prevent post-herpetic
neuralgia is not recommended.
Progressive outer retinal necrosis is rapidly progressive and leads to profound loss of vision. Because of
the rapidity of disease progression, recommended treatment is with high-dose IV acyclovir in
combination with foscarnet.
IV acyclovir for seven to ten days is the recommended initial treatment for immunocompromised adults
and adolescents with chickenpox. It may be permissible to switch to oral therapy after the patient has
defervesced if there is no evidence of visceral involvement. Oral acyclovir is the recommended oral
treatment (20mg/kg up to a maximum dose of 800mg four times daily), but valacyclovir or famciclovir
would be reasonable alternatives.
Same as for HSV.
Treatment failure due to drug resistance should be suspected if lesions do not show signs of resolution
within ten days of initiation of therapy or if they evolve to a verrucous appearance. In patients with
suspected or proven acyclovir resistant VZV infections, treatment with IV foscarnet is the recommended
alternative therapy.
No drug has been proven to prevent the recurrence of zoster among HIV-infected individuals.
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Treatment of zoster in pregnancy should be the same as for non-pregnant adults.
HUMAN HERPESVIRUS-8 (HHV-8) DISEASE

Epidemiology
Human herpesvirus-8 (HHV-8) is a transmissible DNA virus with a seroprevalence in the United States of
1% to 5%. The seroprevalence is considerably greater among MSM regardless of HIV infection, and is
also much higher in certain Mediterranean countries (10% to 20%) and in parts of sub-Saharan Africa
(30% to 80%). The dermatovenereology clinic at the Princess Margaret Hospital in Nassau has
documented three cases of KS all involving the lower limbs in HIV-infected young men (Orlander and
Woods-Cargill, personal communication). HHV-8 is associated with all forms of KS (classic, endemic,
transplant-related, and AIDS-related), as well as certain rare neoplastic disorders such as primary effusion
lymphoma and multicentric Castleman’s disease. The precise pathogenesis is unclear even though
seroconversion to HHV-8 precedes the development of these tumours.
There are anecdotal reports of lesion regression in patients who have been treated with HAART, and the
overall incidence of KS has declined dramatically in the United States following the introduction of PIs
and HAART.
KS, primary effusion lymphoma, and multicentric Castleman’s disease are described most frequently in
HIV-infected persons with more advanced immunosuppression (CD4+ T cell counts of <200 cells/mm3),
although they can occur at any CD4+ T cell count level.
Clinical Manifestations and Treatment
As the principal clinical manifestations of HHV-8 infection are neoplastic diseases, the presentation,
diagnosis, and treatment recommendations for these entities are beyond the scope of this document.
HAART that suppresses HIV replication reduces the frequency of occurrence of KS among HIV-infected
persons and should be considered for all persons who qualify for such therapy.
Effective suppression of HIV replication with HAART among HIV-infected patients with KS might
prevent KS progression or occurrence of new lesions and should be considered for all persons with KS.
The seroprevalence of HHV-8 infection among HIV-infected pregnant women does not appear to impact
pregnancy outcome.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) DUE TO JC VIRUS

Epidemiology
PML is an AIDS-defining neurologic disease caused by the JC virus, a ubiquitous polyoma virus; the
name is derived from the initials of the first patient from which this virus was isolated. Most humans are
infected early in life, and most adults have detectable serum antibodies.
PML is the only known disease caused by the JC virus. This disease has an insidious onset and produces
a neurologic syndrome that progresses relatively rapidly over weeks or months characterised by cognitive
dysfunction, dementia, seizures, ataxia, aphasia, cranial nerve deficits, hemiparesis or quadriparesis, and
eventually coma. Typical CT abnormalities include single or multiple hypodense, non-enhancing
cerebral white matter lesions, although cerebellum and brain stem are occasionally involved.
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Diagnosis
A confirmed diagnosis of PML requires a compatible clinical syndrome and radiographic findings
coupled with a brain biopsy demonstrating characteristic pathologic foci of demyelination and
oligodendrocytes with enlarged nuclei and basophilic-staining intranuclear material. Whether a brain
biopsy will yield information that will alter the clinical course of a patient presenting with a
demyelinating disease is a clinical judgment.
There is no effective therapy for JC virus. However, when HAART is initiated and CD4+ T cell counts
rise, some patients will experience neurologic improvement. Others may simply become neurologically
stable. There are several reports, however, of patients developing worse neurologic manifestations after
initiation of HAART. In some instances, this worsening is due to inflammatory IRS; other cases
represent simply the natural history of PML.
HUMAN PAPILLOMAVIRUS (HPV) DISEASE

Epidemiology
HPV infection of the genital tract and anus results in a spectrum of disease ranging from self-limited,
transient infection to squamous cell cancer.
HPV is the aetiologic agent of genital warts (condyloma acuminata). Only a small number of HPV types
produce warts on the external genital or anal skin; types 6 and 11 account for nearly 90% of such lesions.
The incidence of genital warts is increased by more than ten times in HIV-infected women compared with
uninfected women.
In parallel with the increased prevalence of genital HPV infection, cervical intraepithelial neoplasia
(CIN), and anal intraepithelial neoplasia (AIN) associated with certain other HPV subtypes (16, 18, 31, 35
and others), occur with increased frequency in HIV-infected women compared with HIV-uninfected
women. A 2000 study of female sex workers (FSW) in Guyana found that HIV-positive women have
anal sex more frequently and would therefore also be at risk for anal HPV infection.31 The relative risk of
CIN is increased five- to ten-fold for HIV-positive women, and the risk of cervical cancer may also be
increased.
HIV-infected women with CIN manifest higher grade lesions than HIV-negative women, particularly
those with lower CD4+ T cell counts and higher plasma HIV RNA levels, and are at higher risk of having
HPV-associated lesions elsewhere in the vagina, vulva, and anus.
MSM have a high prevalence of anal HPV infection and of AIN, and those who are HIV-infected,
particularly those with lower CD4+ T cell counts, are at an even higher risk. The incidence of anal cancer
is also higher in MSM than in the general population.
The principal manifestations of genital and anal HPV infections are the presence of genital or anal warts
or of CIN or AIN detected by cytology or inspection with magnification (e.g. colposcopy or anoscopy).
In HIV infection with immunosuppression, genital and anal warts sometimes grow much larger and
increase greatly in number and may extend to involve a large area of epithelium.
Diagnosis
HPV disease can be diagnosed by clinical inspection. The entire anal and genital areas should be
carefully inspected for visual signs of warts. Digital examination should be performed after collection of
a cervical Papanicolou smear, as lubricant may obscure the interpretation of Pap smears.
Testing for HPV DNA is available, but there is currently no clinical indication for routine testing of
anogenital warts for the presence or type of HPV. Current guidelines should be followed for routine Pap
smear monitoring to detect cervical dysplasia in HIV-infected women. If a Pap smear is performed and
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returns with a cytologic interpretation reporting atypical squamous cells of uncertain significance
(ASCUS) or atypical squamous cells-cannot rule out high-grade disease (ASC-H), or a low-grade
squamous intraepithelial lesion (LSIL) or a high grade SIL (HSIL), colposcopic evaluation and directed
biopsy are recommended.
Although formal guidelines recommending anal Pap smear screenings have not been adopted, anal
cytologic screenings should be considered for HIV-infected men and women. High-resolution anoscopy
(HRA) should be considered if the anal Pap smear shows ASCUS or ASC-H and should be performed if
an individual has LSIL or HSIL on an anal Pap smear. Visible lesions should be biopsied to determine
the level of histologic changes and to rule out invasive cancer.
There are a number of treatments available for genital warts, but none are uniformly effective.
Recurrences are frequent with most modalities. There are limited data on the response of HIV-infected
patients to the available treatments for genital warts. The treatment options are briefly summarised
below, divided into patient-applied treatments and provider-applied treatments.
Patient-applied treatments are generally recommended for uncomplicated external lesions and consist of
the following options:
Podofilox is an anti-mitotic agent that should be applied topically to wart lesions as a 0.5%
solution or a 0.5% gel; twice-daily applications for three consecutive days can be repeated weekly
for up to four weeks. The efficacy is 40% to 60% in immunocompetent subjects.
Imiquimod recruits an inflammatory response to the site of the wart. A 5% cream formulation is
applied to lesions at bedtime and removed in the morning by washing. The drug should be
applied on three non-consecutive nights weekly for up to sixteen weeks. The efficacy of
imiquimod in immunocompetent individuals is 30% to 70%; the overall response in HIV-positive
individuals may be lower than in immunocompetent persons.
Provider-applied treatments are generally recommended for complex or multcentric lesions or those
lesions inaccessible to patient-applied treatments. Options are summarised as follows:
Cryotherapy with liquid nitrogen should be applied until each lesion is thoroughly frozen. Some
experts recommend allowing the lesion to thaw and freezing a second time in each session.
Cryotherapy sessions can be repeated every one to two weeks up to three to four times. The
efficacy of cryotherapy is 60% to 80%.
Trichloroacetic or bichloroacetic acids act as caustic agents to kill wart tissue. They can be made
in an 80% to 95% aqueous solution and applied to each lesion. The treatment can be repeated
weekly for three to six weeks. The expected efficacy is 60% to 80%.
Surgical treatments include excision by scissor, shave, curette, or electrosurgery. The efficacy of
surgical removal can approach 100% depending on the location of the lesions.
Podophyllin resin is a crude extract that contains podophyllotoxin and other cytotoxins and
induces wart necrosis after topical application. It is prepared as a 10% to 25% suspension in
tincture of benzoin. It is applied by the provider to all lesions (up to 10 cm2 of skin area) and then
removed by washing a few hours later. Applications can be repeated weekly for three to six
weeks. Efficacy ranges from 20% to 80%.
In general, the management of CIN in HIV-infected patients does not differ from management in other
women. Most experts recommend observation without specific intervention for CIN 1 unless lesions
persist over an eighteen to twenty-four month period of follow-up, evolve to CIN 2 or worse, or there is
poor adherence to routine monitoring. Conventional therapies used for treatment of CIN 2 or 3 include
cryotherapy, laser therapy, cone biopsy, and a loop electrosurgical excision procedure (LEEP)--generally
V-49
the preferred mode of treatment. Recurrence rates of 40% to 60% after treatment have been reported in
HIV-infected women undergoing these procedures.
For anal condyloma and AIN, there are insufficient data to recommend a specific treatment approach,
although experienced clinicians follow approaches listed in Table 4.
Table 4: Treatment of Anal Condyloma or Anal Intraepithelial Neoplasia (AIN)
A. CONDYLOMA OR AIN-1 LESION LOCATION
Lesion Size Perianal Intra-Anal
2
Discrete, <1cm at base A,B,C,D,E A,B,E,F,G,H
Discrete lesion >1cm2 at base, not circumferential A,B,C,D,E,F,G,H E,F,G,H
Diffuse or circumferential lesions C,D,E,F,G,H H
B. AIN-2/AIN-3
Lesion Size Perianal Intra-Anal
Discrete, <1cm2 at base A,B,E,F A,B,E,F,G
Discrete lesion >1cm2 at base, not circumferential E,F,G E,F,G
Diffuse or circumferential lesions E,F,G,H H
Key:
A: 85% trichloroacetic acid
B: Liquid nitrogen
C: Imiquimod
D: Podophyllotoxin
E: Electrocautery
F: Laser
G: Surgical cold scalpel excision
H: Observation only
There is no evidence to suggest that HAART should be instituted or modified for the sole purpose of
treating CIN or AIN, although there are limited data to suggest that HAART may be associated with
improved response rates.
Monitoring and Adverse Effects
Recurrences of CIN and cervical cancer after conventional therapy are more frequent in HIV-infected
individuals; therefore, patients should be carefully followed after treatment with frequent cytologic
screening and colposcopic examination when indicated as per published guidelines.
There is currently no indication for secondary prophylaxis with any of the conventional modalities to
prevent recurrence of genital warts. Patients with CIN should be monitored with frequent cytologic
screening and, when indicated, colposcopic examination for recurrent lesions.
Podophyllin and podofilox should not be used in pregnancy. Use of podophyllin has been associated with
an increased risk of foetal death in several animal models and with case reports in humans but not with
congenital anomalies. No experience with imiquimod in human pregnancy has been reported, so its use
in pregnancy is not recommended.
HEPATITIS B VIRUS DISEASE (HBV)

Epidemiology
HBV is the leading cause of chronic liver disease worldwide. In developed countries, HBV shares risk
factors for transmission, such as sexual contact and injection drug use, and is transmitted more efficiently
than HIV. Although up to 90% of HIV-infected persons have at least one serum marker of prior exposure
V-50
to HBV, only approximately 10% have chronic HBV, as evidenced by the detection of hepatitis B surface
antigen (HBsAg) in the serum persisting for a minimum of six months.
HIV infection is associated with an increased risk for the development of chronic HBV after HBV
exposure. Limited data suggest that co-infected patients with chronic HBV have higher HBV DNA levels
and are more likely to have detectable HBeAg, accelerated loss of protective hepatitis B surface antibody
(anti-HBs), and an increased risk of liver-related mortality and morbidity.
While many patients are asymptomatic, symptoms of acute HBV infection include fatigue, right upper
quadrant abdominal pain, nausea, vomiting, fever, and arthralgias, followed by jaundice. Although
persons with chronic HBV may have non-specific symptoms such as fatigue and right upper quadrant
abdominal pain, chronic HBV is often clinically inapparent until the onset of end-stage liver disease
(ESLD) manifested as ascites, coagulopathy, caput medusa, palmar erythema, jaundice, hepatomegaly,
splenomegaly, variceal bleeding, or hepatic encephalopathy. Ancillary manifestations of chronic HBV
also include polyarteritis nodosa, glomuerulonephritis, and vasculitis.
Diagnosis
All HIV-infected individuals should be tested for HBV. The optimal testing strategy for co-infected
individuals has not been determined. Testing for HBsAg, hepatitis B core antibody (anti-HBc), and anti-
HBs is recommended as this strategy will detect the majority of persons chronically infected with HBV,
although serum HBV DNA has been detected in some persons without HBsAg; in addition, in some
persons anti-HBc may be the only serum marker of infection. The interpretation of an isolated anti-HBc
is difficult both because false positive tests for anti-HBc occur and because the clinical significance of
anti-HBc alone or with low levels of HBV DNA, even in those with elevated ALT (alanine
aminotransferase) levels, is not known.
Chronic HBV infection is defined as positive serologies for HBsAg and total anti-HBc but negative for
IgM anti-HBc, or persistence of HBsAg for six or more months. Patients with chronic HBV infection
should be tested for HBeAg and antibody to HBeAg (anti-HBe). Some experts would also obtain a test
for circulating HBV DNA in patients diagnosed with chronic HBV. A number of assays for HBV DNA
are available, but results are not interchangeable. Viral loads are usually high in chronic infection, 108–
1010 copies/mL of blood; however, available data indicate that HBV DNA levels do not predict
progression of liver disease or response to therapy in a manner analogous to plasma HIV RNA levels.
Severity of liver disease should be assessed initially and at least every six months with ALT, albumin,
prothrombin time, platelet count, complete blood count, and bilirubin. Transient or persistent elevations
in liver transaminases may occur just prior to loss of HBeAg; upon discontinuation of anti-HBV therapy,
in association with 3TC resistance; with hepatotoxicity from anti-HIV therapy or other drugs; or with the
acquisition of another hepatitis virus infection such as hepatitis A virus (HAV), hepatitis C virus (HCV),
or hepatitis delta virus (HDV).
Patients with chronic HBV are at increased risk for hepatocellular carcinoma (HCC). In HIV-negative
patients, some experts recommend monitoring patients with chronic HBV every six to twelve months
with an alfa-fetoprotein (AFP) and/or ultrasound of the liver, especially if the patient is in a high-risk
group (e.g. age forty-five years or older, cirrhosis, or a family history of HCC); however, the
effectiveness of this screening strategy has not been determined. In HIV-infected patients, the risk and
natural history of HBV-related HCC have not been studied, hence the optimal HCC screening method and
interval are not known.
Liver biopsy remains the only definitive test to assess the grade (necro-inflammatory activity) and stage
(degree of fibrosis) of liver disease. The rate of progression of chronic HBV in patients with HIV-co-
infection has not been studied, and the optimal indications for liver biopsy are not known. However,
because fibrosis grade and stage are currently the most reliable means to assess prognosis and to inform
V-51
decisions regarding the need for initiation of therapy, in the absence of a contraindication, most experts
recommend a liver biopsy for all HIV-infected persons with chronic HBV-co-infection who are
candidates for antiviral therapy (see below). Some HIV specialists would initiate therapy for chronic
HBV without a pretreatment liver biopsy.
All patients with chronic HBV should be advised to avoid or limit alcohol consumption due to the effects
of alcohol on the liver. In addition, they should be counselled about the risk of household, sexual, and
needle-sharing transmission and the need for such contacts to be vaccinated against HBV B infection.
Because fulminant hepatic failure from HAV infection occurs at increased frequency in persons with
chronic liver disease, vaccination is indicated for persons susceptible to HAV. If possible, the vaccine
should be administered before the CD4+ T cell count declines to <200 cells/mm3 in order to maximise the
likelihood of a response.
Antiviral treatment is recommended for patients who have any of the following: 1) actively replicating
virus in blood (as defined by a positive HBeAg or HBV DNA levels of >105 copies/mL), 2) an elevated
serum ALT (at least two times the upper limit of normal), or 3) histopathologic evidence of moderate
disease activity and/or fibrosis on liver biopsy. The response to therapy is poor for those with a
pretreatment ALT level of less than two times the upper limit of normal; hence, therapy should generally
be deferred in such patients. The goals of anti-HBV therapy are sustained suppression of HBV
replication, prevention of liver disease progression, and clearance of HBeAg. Treated patients rarely
become HBsAg-negative as HBV reservoirs are not affected by anti-HBV therapy. There are only very
limited data to suggest that treatment reduces the risk of HCC.
There is no “preferred” treatment that can be uniformly recommended for all HIV-co-infected persons
with chronic HBV. Therapy should be individualised taking into account patient-specific considerations.
For HIV-infected persons who are HAART-naïve and require HAART, 3TC 150mg twice daily is the
preferred treatment for chronic HBV because of its relative safety, anti-HIV activity, wealth of data
regarding its use in HIV-infected individuals, and the potential toxicity associated with IFN-alfa. 3TC
should be used together with other ARV drugs in a fully suppressive HAART regimen. Due to the high
rate of development of HBV resistance to 3TC monotherapy, some experts further recommend the use of
3TC in combination with either adefovir or tenofovir (TDF) (as described below), although data are
limited to support this approach.
Seroconversion of HBeAg occurs in 22% of HBeAg-positive, HIV-infected patients with chronic HBV
who are treated with 3TC for one year. In HIV-negative patients, HBeAg seroconversions are sustained
in approximately 80% if 3TC is continued several months after seroconversion. Based on limited data on
the duration of treatment, HBeAg-positive, HIV/HBV-co-infected patients who become HBeAg-negative
and anti-e-positive on 3TC therapy should be treated for a minimum of one year, or at least six months
beyond HBeAg seroconversion. In HIV-negative, HBeAg-negative patients with chronic HBV who are
treated with 3TC, ALT and HBV DNA levels may decline, but high rates of relapse have been reported
when therapy is stopped. Thus, the optimal duration of treatment of HBeAg-negative patients, whether
HIV-infected or not, is unknown.
Adefovir dipivoxil, 10mg daily, has no anti-HIV activity at this dose and is unlikely to select for HIV
resistance; thus, it is an appropriate alternative to interferon alfa for co-infected patients who require
treatment for chronic HBV but do not yet require HAART. However, the long-term safety of adefovir
has not been established in HIV-infected individuals.
TDF has similar in vitro anti-HBV activity to adefovir, and limited human data suggest it is also active
against 3TC resistant HBV. Although TDF is not approved for use in the treatment of HBV infection and
there are sparse data in HIV/HBV-co-infected patients, some experts would use TDF for both the
treatment of HIV infection and chronic HBV (in conjunction with a fully suppressive HAART regimen).
V-52
Until long-term data are available that demonstrate the absence of HBV resistance, it may be prudent to
use TDF in combination with 3TC. TDF, if used for treatment of HBV in patients receiving HAART,
should be added as a single agent for this purpose only if plasma HIV RNA levels are undetectable to
avoid selection pressure that engenders drug resistance. If therapy is indicated for HIV infection but not
for chronic HBV, some experts would withhold TDF, if possible, to allow for its future use for treatment
of HBV.
For HBV treatment-naïve patients who require treatment of both HIV infection and chronic HBV, many
experts would recommend use of a HAART regimen that includes 3TC, adefovir, or TDF, or a
combination of 3TC with either adefovir or TDF, although combination therapy for treatment of HBV in
this population is not yet supported by data.
Emtricitabine (FTC) (200mg once daily) is also active against HBV replication and thus could potentially
be substituted for 3TC, but there are sparse data for its use for this indication and it is not active against
3TC resistant HBV.
IFN-alfa 2a and 2b, administered in subcoetaneous doses of 5MU daily or 10MU three times per week,
are approved for the treatment of chronic HBV in HIV-uninfected individuals but not in HIV-infected
patients. IFN-alfa should not be used in patients with decompensated liver disease. Approximately one-
third of HIV-negative patients will clear HBeAg with either of these interferon regimens, and the
response is durable in 80% to 90% of persons followed for four to eight years. If used for treatment in
HBeAg-positive patients, sixteen to twenty-four weeks of therapy is recommended, whereas for HBeAg-
negative patients (who respond less well), a minimum of twelve months and possibly longer is
recommended. Patients who have a substantial decrease (some experts suggest >2 log10 copies/ml) or
clearance of HBV DNA in response to IFN-alfa 2a or 2b at week sixteen but have persistent HBeAg may
also be candidates for longer-term treatment of twelve months or longer; however, the data are
insufficient to make a firm recommendation in HIV-infected patients. Studies of pegylated interferon
alpha in HIV-uninfected patients with chronic HBV are in progress, and it will likely become the
preferred interferon formulation.
Some experts recommend that IFN-alfa be used in HIV-co-infected patients who are candidates for
treatment for chronic HBV but not HIV. This strategy preserves 3TC and/or TDF for later treatment of
HIV and avoids some potential complications of HAART. The combination of 3TC and interferon does
not appear to be superior to either medication alone and is not recommended.
In patients infected with HBV, HCV, and HIV, consideration of the need for HAART should be the first
priority. If HAART is not required, the treatment of HCV should be considered before HBV treatment
because IFN therapies for HCV may also treat HBV. If IFN-based therapy for HCV has failed, treatment
of chronic HBV therapy with nucleoside or nucleotide analogs can be considered.
A virologic response is defined as a substantial (some experts suggest >2 log10 copies/mL) decrease in
HBV DNA and loss of HBeAg at the end of treatment. A sustained virologic response is defined as a
decrease in HBV DNA and loss of HBeAg sustained for more than six to twelve months after the end of
treatment. In HIV-uninfected persons, the response rates to IFN-alfa or 3TC-containing regimens are
50% or greater in patients with ALT levels more than five times the upper limit of normal, and 20% to
35% in patients with ALT levels between two to five times the upper limit of normal. Patients for whom
therapy is not initiated should be monitored regularly for changes in ALT levels (e.g. every four to six
months).
Other markers of treatment success include improvement in liver histology, normalisation of hepatic
transaminases, and, in those with loss of HbeAg, the development of HBe antibody (HBeAg
seroconversion). Sustained loss of HBsAg is considered by some to be a “complete response.” Although
V-53
a decline in HBV viral load correlates with response, no threshold HBV viral load has been established
that clearly defines a virological response.
Hypo- or hyperthyroidism, which may be irreversible, may occur three to six months after initiation of
therapy with IFN-alfa, hence a serum TSH level should be monitored at baseline and periodically (e.g.
every three months) for the duration of treatment. Side effects of IFN-alfa include flu-like symptoms
(fever, headaches, chills, nausea) and fatigue, which can be reduced by premedication with
acetaminophen or a non-steroidal medication. Other common side effects include weight loss, alopaecia,
thrombocytopaenia, anaemia, leukopaenia (decreased total CD4+ T cell count but not percent),
depression, and auto-immune disorders.
Adefovir causes renal tubular disease and renal excretion of carnitine in a substantial proportion of
patients at higher doses, but these side effects are uncommon at the 10mg per day dose. Significant renal
toxicity with TDF has not been reported, although isolated cases of increased serum creatinine or renal
tubular dysfunction have been observed. Given the potential for overlapping toxicities and their similar
structure, TDF and adefovir should not be used in combination.
Once anti-HBV therapy with 3TC, adefovir, or TDF is begun, whether for the purpose of treating chronic
HBV or for the treatment of HIV infection, discontinuation is associated with a flare of liver disease in
approximately 15% of cases, with loss of the benefit accrued from prior anti-HBV treatment. Some
experts recommend that once anti-HBV therapies are begun, they should be continued unless contra-
indicated or unless the patient has been treated for more than six months beyond loss of HBeAg
positivity. However, the risks and benefits of this practice are unknown. If anti-HBV therapy is
discontinued and a flare occurs, reinstitution of anti-HBV therapy is appropriate since it can be potentially
life saving.
The rate of development of 3TC resistance is approximately 20% per year among HIV/HBV-co-infected
persons treated with 3TC. In HIV-infected patients who have been on 3TC and are currently candidates
for treatment of chronic HBV, some experts recommend use of adefovir or TDF. How long 3TC should
be continued beyond initiation of a new treatment is unknown.
For HIV-infected persons previously treated with a 3TC-containing HAART regimen, uncontrolled data
suggest that the combination of adefovir with continued 3TC has substantial antiviral effects even in the
presence of 3TC resistant HBV. Many experts would use adefovir to treat chronic HBV in HIV-infected
patients who have had an inadequate response to a course of 3TC therapy as evidenced by high plasma
HBV DNA levels or persistent serum HBeAg. Whether 3TC should be continued (or restarted) if not
needed as part of the ARV regimen is unknown.
Although there are sparse data and the drug is not approved for this indication, some experts would
recommend TDF to treat chronic HBV in HIV-infected patients who require HAART and remain HBeAg
positive or have high levels of circulating HBV DNA despite twelve or more months of 3TC. Whether
3TC should be used (or restarted) in such patients is unknown.
Flares of liver disease have been reported with development of resistance to 3TC. If this occurs, addition
of TDF or adefovir may be life-saving. HBV DNA testing may be useful in this setting, since increasing
levels are associated with emergence of 3TC resistance or relapse, while stable levels should suggest an
alternative cause of acute deterioration.
ESLD in HBV- and HIV-co-infected patients is managed as it is in HIV-negative patients. Interferon is
contra-indicated in ESLD, but limited data suggest that 3TC and adefovir can be safely used. Liver
transplantation has been performed with limited success in selected patients with HBV and HIV infection.
If a patient is thought to be a candidate for liver transplantation, early consultation with a transplant centre
should be obtained because transplantation does not cure HBV infection and adequate posttransplant
treatment is required.
V-54
Prevention of Relapse and Recurrence
In HIV-negative, HBeAg-negative patients with chronic HBV who are treated with 3TC, ALT and HBV
DNA levels may decline, but high rates of relapse have been reported when therapy is stopped. Thus, the
optimal duration of treatment of HBeAg-negative patients, whether HIV-infected or not, is unknown.
There are no known effective means to prevent recurrence or flares of chronic HBV.
All pregnant women should be screened for HBsAg. Treatment of symptomatic acute HBV infection
during pregnancy should be supportive with special attention given to maintaining blood glucose levels
and normal clotting status. Risk of preterm labour and delivery may be increased with acute HBV
infection.
Treatment of chronic HBV infection is generally not indicated in pregnancy. Hepatitis A vaccination,
indicated for persons with chronic HBV infection, can be given during pregnancy.
Infants born to HBsAg-positive women should receive hepatitis B immune globulin and HBV vaccine
within twelve hours of birth. The second and third doses of vaccine should be given at age one and six
months, respectively. This regimen is 95% or more effective in preventing HBV infection in these
infants. Post-vaccination testing for anti-HBs and HBsAg should be performed at age nine to fifteen
months because of the infant’s ongoing exposure to HBV.
If treatment for chronic HBV is necessary, 3TC is the preferred agent, as it has not been shown to be
teratogenic in animals or based on human experience including over 1,000 first trimester exposures
reported to the Antiretroviral Pregnancy Registry. 3TC should only be used in HIV-infected pregnant
women as part of a fully suppressive HAART regimen.
Only limited information is available regarding adefovir. It is embryotoxic in mice and caused neonatal
thymic lymphoid tissue destruction with use in later pregnancy in mice. No reports of its use in human
pregnancy are available. Cases of exposure during pregnancy should be reported to the Antiretroviral
Pregnancy Registry at (910) 256-0263, email: registry@inveresk.com or www.APRegistry.com.
Limited information is available regarding TDF. No birth defects have been seen in studies of rats,
rabbits, and monkeys. Decreased foetal weights are increased bone prosity were seen in monkeys after
high-dose exposure in utero. Nineteen cases of first trimester exposure in humans without birth defects
have been reported. Cases of exposure during pregnancy should be reported to the Antiretroviral
Pregnancy Registry at (910) 256-0263, email: registry@inveresk.com or www.APRegistry.com.
V-55
APPENDIX A: SUMMARY OF PRE-CLINICAL AND HUMAN DATA ON OI DRUGS IN PREGNANCY
DRUG FDA PREG- PLACENTAL ANIMAL CONCERNS IN HUMAN RECOMMENDED USE IN
NANCY PASSAGE REPRODUCTION PREGNANCY PREGNANCY
CATEGORY (NEWBORN/M STUDIES
ATERNAL
RATIO)
Acyclovir B Yes (1.2-1.4) Impaired fertility, Large experience in Treatment of frequent or severe
foetal death, and pregnancy (>700 first symptomatic herpes outbreaks or
growth retardation trimester exposures varicella. Use for prevention of
in rats at high reported to Registry); recurrences at term
doses. No well-tolerated. investigational.
teratogenicity in
mice, rats, or
rabbits at human
levels.
Adefovir C Unknown Embryotoxic in No experience with Not recommended. Report
mice; caused human use. exposures during pregnancy to
thymic lymphoid Antiretroviral Pregnancy
tissue destruction in Registry, (910) 256-4263.
mice later in the
neonate with use in
later pregnancy.
Albendazole C Unknown Teratogenic No experience, animal Consider in second, third
(skeletal data concerning. trimester for severe diarrhoea
malformations) in with documented Microsporidia
rats and rabbits, but infection.
not in mice.
Amikacin C Moderate Not teratogenic in Theoretical risk of Drug resistant TB, severe MAC
(0.15-0.5) mice, rats, or ototoxicty in foetus; infections.
rabbits. reported with
streptomycin but not with
amikacin.
Amphotericin B B Yes (0.4-1.0) No effect on No studies. No evidence Documented invasive fungal
fertility; no of teratogenicity. May be disease.
teratogenicity in preferred over fluconazole
rats or rabbits. in first trimester.
Antimonials, Not FDA Unknown Antimony not One case report of use in Therapy of visceral leishmaniasis
pentavalent approved teratogenic in rats, human pregnancy in not responsive to amphotericin B
chicks, or sheep. second trimester with or pentamidine.
good outcome. Labelled
as contra-indicated in
pregnancy.
Atovaquone C Yes, in rats Not teratogenic in Limited experience. PCP, T. gondii infections.
and rabbits rats or rabbits.
(0.18-0.6)
Azithromycin B Low No effect on Moderate experience with Preferred agent for MAC
fertility; no use for treatment of prophylaxis or treatment (with
teratogenicity in Chlamydia trachomatis in EMB); Chlamydia trachomatis
rodents. pregnancy. infection.
Benznidazole Not FDA Yes, in rats No specific studies Increase in chromosomal Not indicated in chronic
approved of teratogenicity. aberrations in children infections. Seek expert
receiving treatment; consultation if acute infection or
uncertain significance. No symptomatic reactivation of T.
human pregnancy data. cruzi is diagnosed in pregnancy.
Capreomycin C Unknown Possible increase in Limited experience in Drug resistant TB.
skeletal variants in human pregnancy.
rats. Theoretical risk of foetal
ototoxicity.
V-56
ATERNAL
RATIO)
Caspofungin C Yes, in rats Incomplete No experience with Invasive Candida or Aspergillus
and rabbits ossification in rats human use. infections refractory to
and rabbits at amphotericin and azoles.
similar to human
doses.
Cephalosporins B Yes, moderate No teratogenicity in No evidence of Bacterial infections, alternate
to high rodents or rabbits. teratogenicity in humans. treatment for MAC.
Cidofovir C Unknown Embryotoxic and Unknown risk; animal Alternate treatment or secondary
teratogenic studies concerning. prophylaxis of life-threatening or
(meningocele, sight-threatening CMV
skeletal infections.
abnormalities) in
rats and rabbits.
Ciprofloxacin, C Yes, in rabbits Arthropathy in Because of cartilage Severe MAC infections, MDR-
other quinolones immature animals; changes in immature TB. (Anthrax)
not embryotoxic or animals, use in pregnant
teratogenic in mice, women and children age
rats, rabbits, or <18 years not
monkeys. recommended. No
increase in anomalies with
<200 first trimester
exposures.
Clarithromycin C Unknown Teratogenic in one Animal data concerning, Treatment or secondary MAC
strain of rats limited human experience. prophylaxis if other choices
(cardiovascular No increase in anomalies exhausted.
defects) and mice in 156 infants with first
(cleft palate). Not trimester exposure but
teratogenic in increased rate of first
rabbits or monkeys. trimester spontaneous
Intrauterine growth abortions noted.
retardation in
monkeys.
Clindamycin B Yes (0.5) No effect on No concerns specific to Treatment of anaerobic bacterial
fertility; no pregnancy. infections. Alternate agent for
teratogenicity in secondary prophylaxis of
rodents. Toxoplasma encephalitis.
Clofazimine C Yes Not teratogenic in Limited experience No current indications.
mice, rats, or reported (19 cases). No
rabbits. anomalies noted but red-
brown skin discolouration
reported in several infants
exposed throughout
pregnancy.
Cycloserine C Unknown No data available. No data available. MDR-TB.
Dapsone C Unknown No animal studies Limited human experience Alternate choice for primary or
of teratogenicity. does not suggest secondary PCP prophylaxis.
teratogenicity. May
displace bound bilirubin in
the neonate, increasing the
risk of kernicterus.
Diphenoxylate/atr C Unknown Increased foetal Limited data do not Symptomatic treatment of
opine (Lomotil®) death in rats at suggest teratogenicity. diarrhoea.
extremely high
doses; no
teratogenicity.
V-57
ATERNAL
RATIO)
Doxycycline, D Passage in Incorporated into Risk of hepatic toxicity None.
other animal studies foetal bones, teeth increased with
tetracyclines with staining. No tetracyclines in pregnancy.
birth defects in Bone and tooth changes
mice, rats, or contra-indicate use in
rabbits. pregnancy.
Erythromycin B Limited No evidence of Hepatotoxicity with Bacterial and chlamydial
passage teratogenicity. erythromycin estolate in infections.
pregnancy, other forms
acceptable. No evidence
of teratogenicity.
EMB B Yes (0.75) Teratogenic, at high No evidence of Active TB, MAC treatment.
doses, in mice (cleft teratogenicity in 320 cases
palate, of human use for
exencephaly, treatment of TB. Avoid in
vertebral first trimester if possible.
abnormalities), rats
(vertebral
abnormalities), and
rabbits
(monophthalmia,
cleft lip, palate).
Ethionamide C Unknown Increased rate of Limited human data. Active TB.
defects Avoid in first trimester if
(omphalocele, possible.
exencephaly, cleft
palate) in rats,
mice, and rabbits
with high doses; not
seen with usual
human doses.
Famciclovir B Unknown No evidence of Limited human Recurrent genital herpes, primary
teratogenicity in experience. Report varicella infection.
rats or rabbits. exposures during
pregnancy to ARV
Registry: (910) 256-0238.
Fluconazole C Unknown Abnormal Case reports of rare Only for documented systemic
ossification, pattern of craniofacial, disease, not prophylaxis; not for
structural defects in skeletal abnormalities in 4 treatment of vaginal or oral
rats and mice at infants born to 3 women Candida. Consider use of
high doses. with prolonged exposure amphotericin B in first trimester.
during pregnancy. No
increase in defects seen in
several series after single-
dose treatment.
Flucytosine C Yes, in rats Facial clefts and No reports of use in first Use after first trimester if
skeletal trimester of human indicated for life-threatening
abnormalities in pregnancy. May be fungal infections.
rats; no defects in metabolised to 5-
mice or rabbits. fluorouracil, which is
teratogenic in animals and
possibly in humans.
Fomivirsen C Unknown No animal studies. No data in human Intravitreous injection probably
pregnancy. safe in pregnancy as minimal
systemic levels.
V-58
ATERNAL
RATIO)
Foscarnet C Unknown Teratogenic No data in human Treatment or secondary
(skeletal pregnancy. prophylaxis of life-threatening or
abnormalities) in sight-threatening CMV infection.
rats and rabbits.
Fumagillin Not Unknown Caused complete No data in human Topical solution may be used for
approved litter destruction or pregnancy. ocular infections.
growth retardation
in rats depending
on when
administered.
Ganciclovir, C Low Embryotoxic in Case reports of safe use in Treatment or secondary
valganciclovir rabbits and mice. human pregnancy after prophylaxis of life-threatening or
Teratogenic in transplants. sight-threatening CMV infection.
rabbits: cleft Preferred agent for therapy in
palate, children.
anophthalmia,
aplastic kidney and
pancreas,
hydrocephalus.
G-CSF, GM-CSF C Yes Not teratogenic in Case reports of use in Treatment of leukopaenia.
rats or rabbits. human pregnancy without
adverse effects.
Imiquimod B Low, in No teratogenicity in No experience with use in Given lack of experience, other
rabbits rats or rabbits. human pregnancy. treatment modalities such as
cryotherapy or trichloracetic acid
recommended for wart treatment
during pregnancy.
Interferons: alfa, C Unknown Abortifacient at Over 30 cases of use of Treatment of HCV should be
beta, gamma high doses in alfa-interferon in delayed until after delivery if
monkeys and mice. pregnancy reported; 14 in possible.
Not teratogenic in first trimester without
monkeys, mice, increase in anomalies.
rats, or rabbits. Possible increased risk of
intrauterine growth
retardation.
INH C Yes, high Not teratogenic in Possible increased risk of Active TB; prophylaxis for
rodents, rabbits. hepatotoxicity during exposure or skin test conversion.
pregnancy. Prophylactic
pyridoxine, 50mg/day,
should be given to prevent
neurotoxicity.
Prophylactic vitamin K
recommended at birth to
prevent haemorrhagic
disease.
Itraconazole C Unknown Teratogenic in rats Case reports of Only for documented systemic
(skeletal defects) craniofacial, skeletal fungal disease, not prophylaxis.
and mice abnormalities in humans
(encephalocele, with prolonged
macroglossia) at fluconazole exposure
high doses. during pregnancy. No
increase in defect rate
noted among 156 infants
born after first trimester
itraconazole exposure.
V-59
ATERNAL
RATIO)
Kanamycin D Yes Club feet in mice. Hearing loss in 2.3% of Drug resistant TB.
No defects in rats, 391 children after long
rabbits, or monkeys term in utero therapy.
except inner ear
changes in multiple
species.
Ketoconazole C Low in Teratogenic (VSD, Inhibits androgen and None.
animals cleft palate) in rats. corticosteroid synthesis,
Increased foetal may impact foetal male
death in mice, genital development.
rabbits. Case reports of
craniofacial, skeletal
abnormalities in humans
with prolonged
fluconazole exposure
during pregnancy.
3TC C High No evidence of No evidence of Hepatitis B therapy, only as part
teratogenicity in teratogenicity with nearly of a combination ARV regimen.
multiple species. 1,000 first trimester
exposures to ARV doses.
Loperamide B Unknown Not teratogenic in No increase in birth Symptomatic treatment of
rats, rabbits. defects among infants diarrhoea.
born to 89 women with
first trimester exposure.
Miltefosine Not FDA Unknown Embryotoxic in rats No experience with Not recommended.
approved and rabbits. human use.
Complete
embryolethality in
rabbits at doses of
6mg/kg/day.
Metronidazole B Yes Multiple studies do Studies in several hundred Anaerobic bacterial infections,
not suggest women with first trimester bacterial vaginosis,
teratogenesis; one exposure do not show trichomoniasis, giardiasis,
study with positive increase in birth defects. amebiasis.
findings in rodents
and guinea pigs.
Nifurtimox Not FDA Unknown Not teratogenic in Increase chromosomal Not indicated in chronic
approved mice and rats. aberrations in children infection. Seek expert
receiving treatment; consultation if acute infection or
uncertain significance. No symptomatic reactivation of T.
experience in human cruzi diagnosed in pregnancy.
pregnancy.
Nitazoxamide Approved Unknown No data. No experience in human Experimental agent for
for use in pregnancy. cryptosporidiosis.
children
Octreotide B Yes (0.5) Not teratogenic in 4 case reports with use in Symptomatic treatment of
rats or rabbits. early pregnancy and diarrhoea.
normal outcomes.
p-aminosalicylic C Unknown Occipital bone Possible increase in limb Drug resistant TB.
acid (PAS) defects in one study and ear anomalies in one
in rats. Not study with 143 first
teratogenic in trimester exposures. No
rabbits. specific pattern of defects
noted, several studies did
not find increased risk.
V-60
ATERNAL
RATIO)
Paromomycin C Unknown Not teratogenic in Poor oral absorption Experimental agent for
mice or rabbits. makes toxicity and cryptosporidiosis.
teratogenicity unlikely.
Penicillin B High Not teratogenic in Vast experience with use Syphilis, other susceptible
multiple animal in human pregnancy does bacterial infections.
species. not suggest teratogenicity.
Pentamidine C High in rats Embryocidal but Limited systemic Alternate therapy for PCP,
not teratogenic in absorption with aerosol leishmaniasis.
rats or rabbits with use. Limited experience
systemic use. with systemic use in
pregnancy.
Podophyllin, C Unknown Increased Case reports of maternal Since alternative treatments for
podofilox embryonic and and foetal deaths after use genital warts in pregnancy are
foetal deaths in rats of podophyllin resin in available, use not recommended.
and mice but not pregnancy are concerning. Inadvertent use in early
teratogenic. No clear increase in birth pregnancy is not indication for
defects with first trimester abortion.
exposure.
Prednisone B Minimal Dose-dependent Human data inconsistent Adjunctive therapy for severe
increased risk of in finding increased risk of PCP. Multiple other non-HIV
cleft palate in mice, cleft palate. Risk of related indications.
rabbits, and growth retardation, low
hamsters; dose- birth weight may be
dependent increase increased with chronic
in genital anomalies use. Monitor blood sugars
in mice. with use in third trimester.
Primaquine C Unknown Not available. Limited experience with Alternate therapy for PCP.
use in human pregnancy.
Theoretical risk of
haemolytic anaemia if
foetus has G6PD
deficiency.
PZA C Unknown Not teratogenic in Limited experience with Active TB.
mice. use in human pregnancy.
Pyrimethamine C Unknown Teratogenic in Limited human data have Treatment and secondary
mice, rats, and not suggested an increased prophylaxis of TE; alternate
hamsters (cleft risk of birth defects. treatment of PCP.
palate, neural tube Folate antagonist, use with
defects, limb leucovorin.
anomalies).
Ribavirin X Unknown Dose-dependent Reports of treatment Contra-indicated in early
risk of multiple during second half of pregnancy. No clear indications
defects pregnancy in 9 women in pregnancy.
(craniofacial, CNS, without incident. Contra-
skeletal, indicated in first trimester
anophthalmia) in because of consistent
rats, mice, and teratogenicity in animals.
hamsters starting at
doses below those
used in humans.
Rifabutin B Unknown Not teratogenic in No specific concerns for Treatment or prophylaxis of
rats or rabbits. pregnancy. MAC, active TB.
V-61
ATERNAL
RATIO)
RIF C Yes (0.12- Teratogenic in mice No clear teratogenicity in Active TB.
0.33) (cleft palate), rats humans. Vitamin K
(spina bifida) but recommended at birth to
not in rabbits. prevent haemorrhagic
disease of the newborn.
Streptomycin D Unknown No teratogenicity in Possible increased risk of Alternate therapy for active TB.
mice, rats, or deafness and VIII nerve
guinea pigs. damage; no evidence of
other defects.
Sulfadiazine B Yes (0.7-0.9) Sulfonamides No clear teratogenicity in Secondary prophylaxis of TE.
teratogenic in some humans. Potential for
animal studies. increased jaundice,
kernicterus if used near
delivery.
TDF B 0.17 in No evidence of birth No experience with Not recommended. Report
monkeys defects in rats, human use. exposures during pregnancy to
rabbits, or monkeys ARV Registry, (910) 256-0238.
at high doses.
Decreased foetal
weights and
increased bone
porosity were seen in
monkeys with long-
term exposure in
utero to doses 25x
usual human dose.
Chronic
administration in
immature animals of
multiple species at 6-
50x human doses
have led to dose-
specific bone
changes ranging
from decreased
mineral density to
severe osteomalacia
and fractures.
TMP-SMX C Yes (~1.0) Teratogenic in rats Possible increase in Treatment and prophylaxis of
and mice (cleft congenital cardiac defects, PCP.
palate). facial clefts with first
trimester use. Potential
for increased jaundice,
kernicterus if used near
delivery.
Trimetrexate D Yes Teratogenic in rats, Similar drugs, Use in pregnancy should be
rabbits (visceral, methotrexate and avoided if possible, may be used
ocular, skeletal, aminopterin, are for PCP if refractory/intolerant to
cardiovascular, abortifacient and TMP-SMX and pentamidine.
CNS defects) at low associated with
doses. embryopathy including
“clover-leaf” skull, limb
defects, developmental
delay sometimes with
neural tube defects.
Frequency may increase
with increasing maternal
dose.
V-62
ATERNAL
RATIO)
Valacyclovir B Yes Not teratogenic in Experience with Alternate agent for HSV,
mice, rats, or valacyclovir in pregnancy varicella infections in pregnancy.
rabbits. limited. Prodrug of
acyclovir, which is
considered safe for use in
pregnancy.
Voriconazole D Unknown Embryotoxic in rats No experience with Not recommended.
and rabbits. human use.
Teratogenic in rats
(cleft palate,
hydronephrosis,
ossification
defects).
V-63
APPENDIX B: TREATMENT OF AIDS-ASSOCIATED OIS IN ADULTS
OPPORTUNISTIC PREFERRED THERAPY AND ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
INFECTIONS DURATION
Pneumocystis Acute Therapy: For Severe PCP: Indications for Corticosteroids:
jiroveci Pneumonia
(PCP) • TMP-SMX: [15-20mg TMP + 75- Pentamidine, 4mg/kg IV q.d infused over at PaO2 <70mmHg @ room air; or
100mg SMX]/kg/day IV given least 60 minutes, some experts reduce dose to
Alveolar-arterial O2 gradient >35mmHg
q6h or q8h; or 3mg/kg IV q.d because of toxicities
Prednisone doses (beginning as early as
• Same daily dose of TMP/SMX po For Mild to Moderate PCP:
possible and within 72 hours of PCP
in 3 divided doses; or
• Dapsone, 100mg po q.d + TMP, therapy):
• TMP-SMX, DS 2 tablets t.i.d 15mg/kg/day po (3 divided doses); or
40mg b.i.d days 1-5, 40mg q.d days 6-10,
Total duration = 21 days • Primaquine, 15-30mg (base) po q.d + then 20mg q.d days 11-21
clindamycin, 600-900mg IV q6h to q8h or IV methylprednisolone can be given as
Chronic Maintenance Therapy: clindamycin, 300-450mg po q6h to q8h; or 75% of prednisone dose
(Secondary prophylaxis) • Atovaquone, 750mg po b.i.d with food; or Chronic maintenance therapy (secondary
First choice: • Trimetrexate, 45mg/m2 or 1.2mg/kg IV q.d prophylaxis) should be discontinued if
with leucovorin, 20mg/m2 or 0.5mg/kg IV CD4+ T cell count increases in response to
• TMP-SMX, 1 DS tablet po q.d; or HAART from <200 to >200 cells/mm3 for
or po q6h (leucovorin must be continued
• TMP-SMX, 1 SS tablet po q.d for 3 days after the last trimetrexate dose); >3 months
addition of dapsone or SMX or sulfadiazine
Alternatives: may improve efficacy
• Dapsone, 50mg po b.i.d or 100mg
po q.d; or
• Dapsone, 50mg po q.d +
pyrimethamine, 50mg po q.w +
leucovorin, 25mg po q.w; or
• Dapsone, 200mg po +
pyrimethamine 75mg po +
leucovorin 25mg po q.w;
aerosolised pentamidine, 300mg
every month via Respirgard II™
nebuliser†; or
• Atovaquone, 1,500mg po q.d: or
TMP-SMX, 1 DS po t.i.w
†
The Respirgard II™ nebuliser is manufactured by Marquest, Englewood, Colorado, USA.
V-64
INFECTIONS DURATION
T. gondii Acute Therapy: • Pyrimethamine (leucovorin)* + Adjunctive corticosteroids (e.g.
Encephalitis Pyrimethamine 200mg po x1, then clindamycin, 600mg IV or po q6h; or dexamethasone) should be given when
50mg (<60kg) to 75mg (>60kg) po clinically indicated for treatment of mass
q.d + sulfadiazine 1,000 (<60kg) to • TMP-SMX (5mg/kg TMP + 25mg/kg effect due to focal lesions or associated
1,500mg (>60kg) po q6h SMX) IV or po b.i.d; or oedema and discontinued as soon as
+ Leucovorin 10-20mg po q.d (can • Atovaquone, 1,500mg po b.i.d with meals clinically feasible
increase up to 50mg or higher) (or nutritional supplement) + Anticonvulsants should be administered to
Total duration for acute therapy = at pyrimethamine (leucovorin)*; or patients with a history of seizures
least 6 weeks • Atovaquone, 1,500mg po b.i.d with meals Secondary Prophylaxis May Be
Chronic Maintenance Therapy: (or nutritional supplement) + sulfadiazine, Discontinued If:
1,000–1,500mg po q6h; or
(Secondary Prophylaxis) Free of TE signs and symptoms; and
• Atovaquone, 1,500mg po b.i.d with meals; sustained CD4+ T cell count of >200
First choice: or cells/mm3 for >6 months of HAART
• Sulfadiazine, 500-1,000mg po 4x • Pyrimethamine (leucovorin)* +
q.d + pyrimethamine, 25-50mg po azithromycin, 900-1,200mg po q.d
q.d + leucovorin, 10-25mg po q.d
For Severely Ill Patients Who Cannot Take
Second choice: Oral Meds:
• Clindamycin, 300-450mg po q6- TMP-SMX IV + pyrimethamine po
8h + pyrimethamine, 25-50mg po
q.d + leucovorin, 10-25 po q.d; or For other regimens with limited experience, see
text.
• Atovaquone, 750mg po q6-12h
with or without pyrimethamine,
25mg po q.d + leucovorin, 10mg
po q.d
• Continue with 50% of acute dose
for patients on pyrimethamine +
sulfadiazine or clindamycin or
those receiving TMP-SMX; or
• [Pyrimethamine, 50mg q.d +
leucovorin, 15mg q.d +
sulfadiazine, 1g q12h] given t.i.w;
or
• Full dose of alternative regimens
continued indefinitely
V-65
OPPORTUNISTIC PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
INFECTIONS
Cryptosporidosis Symptomatic treatment of diarrhoea Nitazoxanide, 500mg po b.i.d Supportive care including hydration,
nutritional support
Effective HAART (to increase CD4+ T cell count to Paromomycin, 25-35mg/kg po in 2-
>100 cells/mm3) can result in complete, sustained 4 divided doses
clinical, microbiological, and histologic resolution
of HIV-associated cryptosporidiosis
Microsporidiosis Initiate or optimise HAART with immune Disseminated Disease: Fluid support in patients with diarrhoea
reconstitution to CD4+ T cell count >100 cells/mm3 resulting in severe dehydration
Itraconazole, 400mg po q.d +
For Disseminated (Not Ocular) and Intestinal albendazole for disseminated Nutritional supplement for patients with
Infection Due to Microsporidia Other Than E. disease due to Trachipleistophora severe malnutrition and wasting
bienuesi:: or Brachiola
Treatment for ocular infection should be
• Albendazole, 400mg po b.i.d, continue until continued indefinitely; with immune
CD4+ T cell count is >200 cells/mm3 reconstitution, it is possible that this
treatment can be discontinued
For Ocular Infection:
Chronic maintenance therapy may be
• Fumidil B®, 3mg/mL in saline (final conc. = discontinued if patients:
fumagillin, 70 µg/mL eye drops continued
indefinitely (not available in U.S.) + • Remain asymptomatic with regards to
albendazole, 400mg po b.i.d for management signs and symptoms of
of systemic infection microsporidiosis;
• Have sustained CD4+ T cell count of
For Gastrointestinal Infections Due to E. >200 cells/mm3 for ≥6 months on
bienuesi: HAART
• Fumagillin, 60mg po q.d (not available in U.S.)
V-66
INFECTIONS DURATION
M. tuberculosis (TB) For Drug-Sensitive TB: Treatment for Drug Resistant TB: Treatment by DOT is strongly
recommended for all HIV
Initial Phase (8 Weeks): Resistant to INH:
patients
• INH, 5mg/kg (max 300mg) • discontinue INH (and streptomycin, if used) Rifabutin has less drug
po q.d + RIF, 10mg/kg (max
• Rifamycin, PZA, and EMB x 6 months; or interaction potential and can be
600mg) po q.d; or
• Rifamycin + EMB x 12 months (preferably with used in place of RIF
• Rifabutin, 300mg po q.d (or PZA during at least first 2 months) Rifapentine given q.w can result
dose adjusted based on
Resistant to Rifamycin: in development of resistance, it
concomitant meds∋) + PZA is NOT RECOMMENDED in
(dose based on wt%) po q.d + • INH + PZA + EMB + a fluorquinolone (e.g. HIV patients
EMB (EMB) (dose based on levofloxacin 500mg q.d) for 2 months, followed by
wt%) po q.d 10-16 additional months with INH + EMB + b.i.w intermittent regimen
fluoroquinolone containing rifamycin may lead
Continuation Phase (18 Weeks): to rifamycin resistance,
MDR-TB (e.g. Both INH- and Rifamycin-Resistant):
• INH, 5mg/kg (max 300mg) particularly in advanced HIV
po q.d + RIF, 10mg/kg • Therapy should be individualised based on patients with CD4+ T cell
(max 600mg) or rifabutin, resistance pattern and with close consultation with counts of <100 cells/mm3; in
300mg po q.d]; or experienced specialist this situation, therapy must be
TB Treatment in Patients with Liver Disease: given as q.d or t.i.w
• INH, 15mg/kg (max
900mg) po b.i.w or t.i.w + If AST >3x Normal Prior to Treatment Initiation: Paradoxical reactions that are
RIF, 10mg/kg (max 600mg) not severe may be treated with
• Standard therapy with frequent monitoring; or
or rifabutin, 300mg po or NSAIDs without change in TB
• Rifamycin + EMB + PZA x 6 months or HIV medications
t.i.w]
• INH + rifamycin + EMB x 2 months, then INH +
In patients with delayed clinical rifamycin x 7 months
or microbiological response to
initial therapy (e.g. sputum
culture (+) after 2 months or if For Patients with Severe Liver Disease:
cavitary pulmonary lesions are
• Rifamycin + EMB x 12 months (preferably with
present), total duration up to 9
another agent such as fluoroquinolone for first 2
months
months)
•
V-67
INFECTIONS DURATION
MAC At Least 2 Drugs as Initial Alternative to Clarithromycin: NSAIDs may be used for
Therapy: patients who experience
Azithromycin, 500-600mg po q.d
moderate to severe symptoms
Clarithromycin, 500mg po b.i.d
Alternative Third or Fourth Drug for Patients with More due to HAART-associated IRS
+ EMB, 15mg/kg po q.d
Severe Symptoms or Disseminated Disease:
If symptoms persist, short term
Consider adding third drug for
Ciprofloxacin, 500-750mg po b.i.d; or (4-8 weeks of systemic
patients with advanced
corticosteroid (20-40mg of
immunosuppression (CD4+ T Levofloxacin, 500mg po q.d; or prednisone)) can be used.
cell count of <50 cells/mm3),
high mycobacterial loads, or in Amikacin, 10-15mg/kg IV q.d Maintenance therapy can be
the absence of effective discontinued in patients who:
HAART:
• completed >12 months
Rifabutin, 300mg po q.d (dosage therapy, and
may be adjusted based on drug-
drug interactions) • remain asymptomatic, and
Duration (Chronic Maintenance • have sustained (>6 months)

Therapy): Lifelong therapy CD4+ T cell counts of >100
unless in patients with sustained cells/mm3
immune recovery on HAART.
Chronic Maintenance Therapy:
(Secondary Prophylaxis)
First choice:
• Clarithromycin, 500mg po
b.i.d + EMB, 15mg/kg body
weight po q.d; with or
without rifabutin, 300mg po
q.d
Second choice:
• Azithromycin, 500mg po q.d
+ EMB 15mg mg/kg body
weight po q.d; with or
without rifabtuin, 300mg po
q.d
V-68
OIS PREFERRED THERAPY AND ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
DURATION
Bacterial Empiric Therapy (Targeting towards For High-Level Penicillin Resistant Isolates (MIC Patients with CD4+ T cell counts of >200
Pneumonia Streptococcus pneumoniae and ≥4.0µg/mL): cells/mm3 should receive a single dose of
Haemophilus Influenzae): 23-valent polysaccharide pneumococcal
• Consider adding vancomycin or a fluoroquinolone vaccine (if not received in the past 5
• Extended spectrum cephalosporin years)
Empiric Therapy in Patients with Severe
(such as cefotaxime or
Immunodeficiency (CD4+ T cell counts of <100 Yearly influenza vaccine may be useful in
ceftriaxone); or
cell/mm3), a Known History of Prior Pseudomonas preventing pneumococcal superinfection
• Fluoroquinolone with enhanced Infection, Bronchiectasis, or Relative or Absolute after influenza respiratory infection
activity against pneumococcus Neutropaenia):
(e.g. gatifloxacin, levofloxacin, or Antibiotic prophylaxis may be considered
• Broaden empiric coverage to include antimicrobials in patients with frequent recurrences;
moxifloxacin)
with activities against P. aseruginosa and other caution should be taken for the risks of
Empiric Therapy in Patients with gram-negative bacilli (e.g. ceftazidime, cefepime, development of drug resistance and drug
Severe Illness: piperacillin-tazobactam, a carbepenem, or high-dose toxicities
ciprofloxacin or levofloxacin)
• Extended-spectrum cephalosporin
+ a macrolide • If ceftazidime or ciprofloxacin is used, the addition
of another antibacterial with optimal coverage for
gram-positive infection is recommended
Salmonellosis Salmonella Gastroenteritis: • TMP-SMX po or IV Treatment is recommended in HIV
• Ciprofloxacin, 500–750mg po patients due to high risk of bacteraemia
• Third generation cephalosporin such as ceftriaxone in this population
b.i.d (or 400mg IV b.i.d) (IV) or cefotaxime (IV)
Duration: Newer fluoroquinolones (e.g.
• Mild gastroenteritis without levofloxacin, gatifloxacin, or
bacteraemia: 7-14 days moxifloxacin) may also be effective
• Advanced HIV (CD4+ T cell
count of <200 cells/mm3) and/or
bacteraemia: at least 4-6 weeks
Chronic Suppressive Therapy:
For patients who relapse after
cessation of therapy: to be given
for several months or until
HAART-induced immune
reconstitution
For patients with Salmonella
bacteraemia: ciprofloxacin,
500mg po b.i.d
V-69
OIS PREFERRED THERAPY AND ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
DURATION
C. jejuni For Mild Disease: There is an increasing rate of quinolone
Infections May withhold therapy unless resistance
symptoms persist for >several days Antimicrobial therapy should be modified
Optimal therapy is not well-defined; based on susceptibility reports
options include: Role of aminoglycoside is unclear
• Ciprofloxacin, 500mg po b.i.d; or
• Azithromycin, 500mg po q.d
*consider addition of an
aminoglycoside in bacteraemic
patients
Duration:
• Mild to moderate disease: 7 days
• Bacteraemia: at least 2 weeks
Shigellosis Fluoroquinolone IV or po x 3-7 days • TMP-SMX DS 1 tab po b.i.d x 3-7 days; or Therapy is indicated both to shorten the
duration of illness and to prevent spread
Duration for bacteraemia: 14 days • Azithromycin, 500mg po on day 1, then 250mg po of infection
q.d x 4 days
Shigella infections acquired outside of
Duration for bacteraemia: 14 days U.S. have high rates of TMP-SMX
resistance
Bartonella Non-CNS Infections: • Azithromycin, 600mg po q.d
Infections
• Erythromycin, 500mg po q.i.d (or • Clarithromycin, 500mg po b.i.d
IV at same dose if unable to take
po); or • Fluoroquinolones have variable activity in case
reports and in vitro; may be considered as
• Doxycycline, 100mg po or IV alternative
q12h
CNS Infections:
• Doxycycline, 100mg po or IV
q12h
Duration:
At least 3 months
Life-long therapy for patients with
relapse
V-70
OIs PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
T. pallidum Early Stage (Primary, Secondary, and Early Early Stage (Primary, Secondary, Desensitisation to penicillin may be a better
Infection Latent Syphilis): and Early Latent Syphilis): treatment option than ceftriaxone in penicillin-allergic
(Syphilis) with close clinical monitoring patients with neurosyphilis
• Benzathine penicillin, G 2.4 MIU IM x 1
• Doxycycline, 100mg po b.i.d x 14 Combination of procaine penicillin +
Late-Latent Disease (>1 Year or of Unknown probenecid is not recommended for patients
days; or
Duration, without CNS Involvement): with history of sulfa allergy as these patients
• Ceftriaxone, 1g IM or IV q.d x 8-10 may be at risk of hypersensitivity reactions
• Benzathine penicillin, G 2.4 MIU IM q.w x 3
days; or to probenecid
Late-Stage (Aortitis and Gummata):
• Azithromycin, 2g po x 1 dose
• Infectious diseases consultation
Late-Latent Disease (without CNS
Neurosyphilis (CNS Involvement including Otic Involvement):
and Ocular Disease):
• Doxycycline, 100mg po b.i.d x 28
• Aqueous crystalline penicillin G, 3-4 MIU IV days
q4h or total dose by continuous IV infusion x
Neurosyphilis:
10-14 days +/- benzathine penicillin G, 2.4
MIU IM q.w x 3 after completion of IV therapy • Procaine penicillin, 2.4 MIU IM q.d
+ probenecid, 500mg po q.i.d x 10-
14 days +/- benzathine penicillin, G
2.4 MIU IM q.w x 3 after
completion of above; or
• For penicillin allergic patients:
Ceftriaxone, 2g IM or IV q.d x 10-
14 days
Candidiasis Oropharyngeal Candidiasis: Fluconazole-Refractory Suppressive Therapy – Generally Not
(Mucosal) Oropharyngeal Candidiasis: Recommended Unless Patients Have
Initial Episodes (7-14-Day Treatment):
Frequent or Severe Recurrences
• Itraconazole oral solution, >200mg
• Fluconazole, 100mg po q.d; or
po q.d; or • Oropharyngeal Candidiasis:
• Itraconazole oral solution, 200mg po q.d; or
• Amphotericin B suspension, fluconazole or itraconazole oral solution
• Clotrimazole troches, 10mg po 5x daily ; or 100mg/mL (not available in U.S.) – may be considered.
1 mL po q.i.d; or
• Nystatin suspension, 4-6mL q.i.d or 1-2 • Vulvovaginal Candidiasis: daily
flavoured pastilles q4-5d • Amphotericin B deoxycholate, topical azole for recurrent cases
0.3mg/kg IV q.d; or
Oesophageal Candidiasis (14-21 Days): • Oesophageal Candidiasis: fluconazole,
• Caspofungin, 50mg q.d 100-200mg q.d.
Fluconazole, 100mg (up to 400mg) po or IV q.d; or
• Voriconazole, 200mg po b.i.d
Itraconazole oral solution, 200mg po q.d Chronic or prolonged use of azoles may
V-71
OIs PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ ISSUES
Vulvovaginitis: Fluconazole-Refractory Oesophageal promote development of resistance
Candidiasis:
• Topical azoles (clotrimazole, butoconazole,
miconazole, tionazole, or terconazole) x 3-7 • Caspofungin, 50mg q.d; or
days
• Voriconazole, 200mg po or IV b.i.d
• Topical nystatin x 14 days
• Amphotericin B, 0.3-0.7mg/kg IV
• Oral itraconazole, 200mg b.i.d x 1 day or q.d; or
200mg q.d x 3 days
• Amphotericin liposomal or lipid
• Oral fluconazole, 150mg x 1 dose complex, 3-5mg/kg IV q.d
C. glabrata and Other Non-albicans
Candida:
• Caspofungin; or
• Amphotericin B preparations
C. neoformans Acute Infection: Acute Infection (Alternative): Repeated lumbar puncture may be indicated
Meningitis as adjunctive therapy for patients with
• Amphotericin B deoxycholate, 0.7mg/kg IV • Amphotericin B, 0.7mg/kg/day IV x increased intracranial pressure
q.d + flucytosine, 25mg/kg po q.i.d x 2 weeks; 2 weeks; or
or Discontinuation of antifungal therapy can be
• Fluconazole, 400-800mg/day (po or considered in patients who remain
• Liposomalamphotericin B, 4mg/kg IV q.d + IV) for less severe disease asymptomatic, with CD4+ T cell counts of
flucytosine, 25mg/kg po q.i.d x 2 weeks >100–200 cells/mm3 for >6 months
• Fluconazole, 400-800mg/day (po or
Consolidation Therapy: IV) + flucytosine, 25mg/kg po q.i.d Some may consider performing a lumbar
for 4-6 weeks puncture before discontinuation of
• Fluconazole, 400mg po q.d x 8 weeks or until
CSF cultures are sterile Consolidation Therapy (Alternative): maintenance therapy
Chronic Maintenance Therapy: • Itraconazole, 200mg po b.i.d

(Secondary Prophylaxis) Maintenance Therapy (Alternative):
First choice: • Amphotericin B, 1mg/kg IV per
week for patients with multiple
• Fluconazole, 200mg po q.d; relapse on azole(s) or intolerant of
Second choice: azole(s); or
• Amphotericin B, 0.6-1.0mg/kg body weight IV • Itraconazole, 200mg po q.d for
q.w x 3; or patients intolerant of or failed
fluconazole
• Itraconazole, 200mg capsule po q.d
V-72
OIs PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ISSUES
H. capsulatum Severe Disseminated: Severe Disseminated: Acute pulmonary histoplasmosis in HIV-infected
Infections patients with CD4+ T cell counts of >500
Acute Phase (3–10 Days or Until Clinically Acute Phase (Alternative):
cells/mm3 may require no therapy
Improved):
Itraconazole, 400mg IV q.d
Some experts would consider discontinuation of
• Amphotericin B deoxycholate, 0.7mg/kg IV antifungal therapy in patients who:
Continuation Phase
q.d; or
Alternatives:
• are in remission
• Liposomal amphotericin B, 4mg/kg IV q.d
• Itraconazole oral
• have completed 1 year itraconazole
Continuation Phase (12 Weeks): solution
• have CD4+ T cell counts of >100 cells/mm3
• Itraconazole, 200mg cap po b.i.d • Fluconazole, 800mg q.d
Less Severe Disseminated: Mild Disseminated:
• Itraconazole, 200mg cap po t.i.d. x 3 days, • Fluconazole, 800mg po
then 200mg po b.i.d x 12 weeks q.d
Meningitis:
• Amphotericin B deoxycholate or liposomal x
12–16 weeks
Chronic Maintenance Therapy (Chronic
Suppression):
• Itraconazole, 200mg capsule po b.i.d
Chronic Maintenance Therapy

(Secondary prophylaxis)
First choice:
• Itraconazole capsule, 200 mg po b.i.d
Second choice:
• Amphotericin B, 1.0 mg/kg body weight IV
q.w; or
V-73
OIs PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ISSUES
Coccidiodomycosis Non-Meningeal Infection: Non-Meningeal Infection: Not enough data to recommend discontinuation of
chronic suppressive therapy at this point
Acute Phase (Diffuse Pulmonary or Disseminated Acute Phase (Diffuse
Disease): Pulmonary or Disseminated
Disease):
• Amphotericin B deoxycholate, 0.5–1.0mg/kg
IV q.d continue until clinical improvement, • Some experts add azole
usually 500–1,000mg total dose to amphotericin B
Acute Phase (Milder Disease): therapy
• Fluconazole, 400-800mg po q.d; or Meningeal Infections:
• Itraconazole, 200mg po b.i.d • Intrathecal amphoterin B

Meningeal Infections:
• Fluconazole, 400-800mg IV or po q.d
• Fluconazole, 400mg po q.d; or
• Itraconazole, 200mg po b.i.d

(Secondary prophylaxis)
First choice:
• Fluconazole, 400mg po q.d
Second choice:
• Amphotericin B, 1.0mg/kg body weight IV
q.w; or
Invasive Voriconazole, 400mg IV or po q12h x 2 days, • Amphotericin B Not enough data to recommend chronic
Aspergillosis then 200mg q12h deoxycholate, suppression or maintenance therapy
1mg/kg/day IV; or
Duration:
Based on clinical response • Lipid formulations of
amphotericin B,
5mg/kg/day IV
• Voriconazole +
caspofungin
V-74
OIS PREFERRED THERAPY AND ALTERNATIVE THERAPY OTHER OPTIONS/ISSUES
DURATION
CMV CMV Retinitis: CMV Retinitis: Choice of initial therapy for CMV retinitis should
Disease be individualised, based on location and severity of
For Immediate Sight-Threatening Lesions: • Valganciclovir, 900mg po b.i.d x 14-21 the lesion(s), level of immunosuppression, and
days, then 900mg po q.d; or other factors such as concomitant medications and
Ganciclovir intraocular implant +
valganciclovir, 900mg po q.d • Ganciclovir intraocular implant + ability to adhere to treatment
For Peripheral Lesions: valganciclovir, 900mg po q.d; or Initial therapy in patients with CMV retinitis,
• Ganciclovir, 5mg/kg IV q12h x 14-21 days, oesophagitis, colitis, and pneumonitis should
Valganciclovir, 900mg po b.i.d x 14-21 include optimisation of HAART
days, then 900mg po q.d then 5mg/kg IV q.d; or
• Ganciclovir, 5mg/kg IV q12h x 14-21 days, Some experts suggest delaying HAART in patients
Duration of Chronic Maintenance Therapy: with CMV neurological disease due to concerns of
then valganciclovir, 900mg po q.d; or
• Implant: replace q6-8m until immune worsening of condition as a result of immune
recovery on HAART • Foscarnet, 60mg/kg IV q8h or 90 mg/kg IV recovery inflammatory reaction
q12h x 14-21 days, then 90-120mg/kg IV
• Systemic therapy: continue for life or q24h; or Pre-emptive treatment of patients with CMV
until immune recovery on HAART viraemia without evidence of organ involvement is
• Cidofovir, 5mg/kg IV x 2 weeks, then generally not recommended
Chronic Maintenance Therapy: 5mg/kg q.o.w; each dose should be given
with IV saline hydration and oral Maintenance therapy for CMV retinitis can be
(Secondary Prophylaxis) safely discontinued in patients with inactive
probenecid; or
First choice: disease and sustained CD4+ T cell counts (>100-
• Repeated intravitreal injections with 150 cells/mm3 for >6 months); consultation with
• Ganciclovir, 5-6mg/kg body weight/day fomivirsen (for relapses only, not as initial ophthalmologist is advised
IV for 5-7 days q.w or 1,000mg po t.i.d; therapy)
or Patients with CMV retinitis who discontinued
maintenance therapy should undergo regular eye
• Foscarnet, 90-120mg/kg body weight IV examinations for early detection of relapse
q.d; or
IRU may develop in the setting of immune
• For retinitis, ganciclovir sustained- reconstitution. Treatment of IRU: periocular
release implant, q6-9m + ganciclovir, corticosteroid or short courses of systemic steroid
1.0-1.5g po t.i.d
Due to its poor oral bioavailability and with the
Second choice: availability of valganciclovir, oral ganciclovir
should no longer be used
• Cidofovir, 5mg/kg body weight IV q.o.w
with probenecid, 2g po 3 hours before
the dose followed by 1g po 2 hours after
the dose, and 1g po 8 hours after the
dose (total of 4g); or
• Fomivirsen, 1 vial (330 µg) injected into
V-75
DURATION
the vitreous, then repeated q2-4w; or
• Valganciclovir, 900mg po q.d
CMV Oesophagitis or Colitis:
• Ganciclovir IV or foscarnet IV x 21-28
days or until signs and symptoms have
resolved; oral valganciclovir may be
used if symptoms are not severe enough
to interfere with oral absorption
• Maintenance therapy is generally not
necessary, but should be considered
after relapses
CMV Pneumonitis:
Treatment should be considered in patients
with histologic evidence of CMV
pneumonitis and who do not respond to
treatment of other pathogens
The role of maintenance therapy is not yet
established.
CMV Neurological Disease:
• GCV IV + foscarnet IV; continue until
symptomatic improvement
• Maintenance therapy should be
continued for life
HSV Orolabial Lesions and Initial or Acyclovir-Resistant HSV: Chronic suppressive therapy with oral acyclovir,
Disease Recurrent Genital HSV: famciclovir, or valacyclovir may be indicated in
• Foscarnet, 120-200mg/kg/day IV in 2-3 patients with frequent or severe recurrences
• Famciclovir, 500mg po b.i.d; or divided doses until clinical response
• Valaciclovir, 1g po b.i.d; or • Cidofovir, 5mg/kg IV q.w until clinical
response
• Acyclovir, 400mg po t.i.d x 7 days
Alternative for Acyclovir-Resistant HSV
Moderate to Severe Mucocoetaneous Infections:
HSV Infections:
• Topical trifluridine
• Initial therapy acyclovir, 5mg/kg IV
V-76
DURATION
q8h • Topical cidofovir
• After lesions began to regress, change Note: Both of the above preparations are not
to famciclovir, 500mg po b.i.d or commercially available. Extemporaneous
valacyclovir, 1g po b.i.d or acyclovir, compounding of these topical products can be
400mg po t.i.d. Continue therapy until prepared using trifluridine ophthalmic solution
lesions have completely healed. and cidofovir for IV administration
HSV Keratitis:
• Trifluridine 1% ophthalmic solution,
one drop onto the cornea q2h, not to
exceed 9 drops per day for no longer
than 21 days
HSV Encephalitis:
• Acyclovir, 10mg/kg IV q8h x 14-21
days
VZV Primary VZV Infection (Chickenpox):
Disease
o Acyclovir, 10mg/kg IV q8h x 7-10
days
o Switch to oral therapy (acyclovir,
800mg po q.i.d; valacyclovir, 1g t.i.d;
or famciclovir, 500mg t.i.d) after
defervescent if there is no evidence of
visceral involvement
Local Dermatomal Herpes Zoster:
• Famciclovir, 500mg or valacyclovir, 1g
po t.i.d x 7-10 days
Extensive Coetaneous Lesion or Visceral
Involvement:
• Acyclovir, 10mg/kg IV q8h, continue
until coetaneous and visceral disease
clearly resolved
Progressive Outer Retinal Necrosis
(poRN):
• Acyclovir, IV 10mg/kg q8h + foscarnet,
60mg/kg IV q8h
V-77
HPV Treatment of Condyloma Acuminata (Genital Warts)
Patient-Applied Treatment: Provider-Applied Treatment: Intralesional interferon-alpha – generally not
recommended due to high cost, difficult
Podofilox 0.5% solution or 0.5% gel – apply to • Liquid nitrogen cryotherapy – apply until administration, and potential for systemic side
all lesions b.i.d x 3 consecutive days, repeat q.w each lesion is thoroughly frozen, repeat q1- effects
x up to 4 weeks; or 2w for up to 3-4x
The rate of recurrence of genital warts is high
Imiquimod 5% cream – apply to lesion at • Trichloroacetic acid or bicloroacetic acid despite treatment
bedtime and remove in the morning on 3 non- cauterisation – 80-95% aqueous solution,
consecutive nights q.w x up to 16 weeks apply to each lesion, repeat q.w x 3-6 weeks There are limited data on the responses to
treatment in the HIV-infected patients
• Surgical excision or laser surgery
• Cidofovir topical – not commercially
available
• Podophyllin resin 10-25% suspension in
tincture of benzoin – apply to area and wash
off in a few hours, repeat q.w x up to 3-6
weeks
• Intralesional interferon alpha is an option,
but is generally not recommended
Treatment of Cervical Intraepithelial Neoplasia (CIN) or
Anal Intraepithelial Neoplasia (AIN)
CIN 1: CIN 2 or 3: Low-dose intravaginal 5-fluorouracil (2g b.i.d
x 6 months) for CIN may reduce short-term
• Pap smears and/or colposcopy q4-6m • Cryotherapy risk for recurrence
CIN 2 or 3: • Laser therapy Efficacy of treatment of AIN 2 or 3 in
• LEEP • Cone biopsy preventing anal cancer is unknown
AIN: Insufficient data to recommend specific
treatment. Treatment decision based on size,
location of lesion, and grade of histology
V-78
OIS PREFERRED THERAPY AND DURATION ALTERNATIVE THERAPY OTHER OPTIONS/ISSUES
HCV Combination therapy: In patients where ribavirin is contra-indicated All patients should be counselled to avoid
Disease (e.g. unstable cardiopulmonary disease, pre- alcohol consumption due to increased risk of
[Peginterferon alfa-2b (1.5mcg/kg), sc q.w; or
existing anaemia, or haemoglobinopathy): fibrosis progression
peginterferon alfa-2a (180mcg), sc q.w]
o Peginterferon alfa-2b, 1.5 mcg/kg or Preliminary data suggest that responses to
+
HCV therapy correlates to CD4+ T cell count
o Peginterferon alfa-2a, 180 mcg sc q.w
Ribavirin, po (weight-based dosing: if <75mg,
• Some suggest treating HCV before CD4+
400mg in A.M. + 600mg in P.M.;. if >75kg,
T cell count drops <500 cells/mm3;
600mg b.i.d)
Duration: • Conversely, if patient has CD4+ T of
<500 cells/mm3, some suggest initiating
For genotype 1 ARV before treatment of HCV
• 48 weeks: for patients who demonstrate an
early virologic response (>2 log decrease in
HCV viral load at 12 weeks)
• 12 weeks: for patients who failed to achieve
early virologic response at 12 weeks -
therapy beyond 12 weeks is almost always
futile for achieving virologic cure
For genotype 2 or 3:
• 24 weeks: based on data in non-HIV-1
infected patients
• Some experts suggest 48 weeks
V-79
HBV Disease Due to the lack of controlled trial data on the 3TC-Naïve Patients Requiring All patients should be advised to avoid
use of antiviral agents against HBV in HAART: or limit alcohol consumption
HIV/HBV-co-infected patients, none of the
current therapy can be recommended as • 3TC, 150mg po b.i.d, should be Patients should receive 2 doses of
used as part of a HAART regimen hepatitis A vaccine, preferably before
preferred regimen
for a minimum of one year or 6 CD4+ T cell count drops to <200
In patients with HIV/HBV/HCV co-infection, months after seroconversion from cells/mm3
consideration for ARV therapy should be the HBeAg (+) to HbeAg (-) and anti-e
Interferon should not be used in
first priority. If ARV therapy is not required, positive;
patients with decompensated liver
then treatment for HCV should be considered
• Adefovir, 10 mg per day in disease
before HBV, as interferon treatment for HBV
addition to HAART for a
may also treat HBV infection Discontinuation of therapy for HBV
minimum of one year or 6 months
after seroconversion from HBeAg infection risks flare of liver disease in
(+) to HbeAg (-) and anti-e ≈15% of patients and lost of anti-HBV
positive; benefit
• Some experts advise adding HAART should always include HBV

adefovir, 10mg q.d or TDF, 300mg treatment to minimise immune
q.d to 3TC; or reconstitution flares
• Interferon alfa 2a or 2b, 5MU sc
q.d or 10MU sc t.i.w; may be
considered in patients who do not
require ARV therapy^ or PEG IFN,
180mcg sc q.w
Duration of Interferon Alfa Therapy:
HBeAg (+) patients: 16-24 weeks
HBeAg (-) patients: minimum of
12 months
3TC-naïve patients where HAART is
not indicated:
o Adefovir, 10mg po q.d or PEG
IFN, 180mcg sc q.w
Use for Treatment of Both HIV and
HBV Infection:
TDF, 300mg po q.d as part of a
HAART regimen +/- 3TC
V-80
Penicilliosis Acute Infection in Severely Ill Patients: HAART should be administered
according to standard of care in the
Amphotericin B, 0.6mg/kg/day IV x 2 weeks;
community
followed by itraconazole oral solution 400mg
q.d x 10 weeks
Chronic Suppressive Therapy:
Itraconazole, 200mg po q.d
Leishmaniasis Pentavalent antimony (or sodium • Amphotericin B deoxycholate, 0.5- Severely neutropaenic patients with
stibogluconate) = 20mg/kg IV or IM q.d x 3-4 1.0 mg/kg IV q.d (maximum of visceral leishmaniasis may benefit
weeks depending on initial response 50mg q.d) for total dose of 1.5- from short course of granulocyte
2.0gm; or macrophage colony stimulating factor
Secondary Prophylaxis:
• Amphotericin B lipid formulation, (GM-CSF), 5µg/kg/day sc x 5 days
Single dose of the initial therapy every 4 3-5mg/kg IV q.d x 10 days; there is Other Regimens (Generally Not
weeks, especially in patients with CD4+ T less experience with shorter Recommended):
cell counts of <200 cells/mm3 regimens (see text); or
• Miltefosine, 100mg/day for 30
• Pentamidine isethionate, 3-4mg/kg days. Schedule for secondary
IV t.i.w x 3-4 weeks followed by prophylaxis is unknown
monthly maintenance therapy
Secondary Prophylaxis:
Single dose of the initial therapy every
4 weeks, especially in patients with
CD4+ T cell counts <200 cells/mm3
Paracoccidioidomycosis Amphotericin B for severely ill • Ketoconazole, 200-400mg po q.d HAART should be initiated in
accordance with standards of care in
Itraconazole, 100-200mg po q.d for less ill • Sulfonamide the community.
Isospora belli Infection TMP, 160mg + SMX, 800mg po (or IV) q.i.d • Pyrimethamine, 50-75mg po q.d + Fluid management in patients with
x 10 days; or leucovorin, 5-10mg po q.d; or dehydration
TMP, 320mg + SMX, 1,600mg po (or IV) • Ciprofloxacin, 500mg po b.i.d Nutritional supplementation for
b.i.d x 10-14 days malnutrition and wasting
• Other fluoroquinolones
Secondary Prophylaxis: Immune reconstitution with HAART
Alternative Secondary Prophylaxis: may result in fewer relapses
In patients with CD4+ T cell counts of <200
Pyrimethamine, 25mg po q.d + Discontinuation of secondary
cells/mm3, TMP, 320mg + SMX, 1,600mg po
leucovorin prophylaxis may be considered in
q.d or t.i.w
patients with sustained CD4+ T cell
counts of >200 cells/mm3 for >3
months
V-81
Chagas Disease Benznidazol, 5-8 mg/kg/day in 2 divided Nifurtimox (currently not available),
(American doses x 30–60 days 10mg/kg/d
Trypanosomiasis)
Lifelong secondary prophylaxis probably
indicated
*Pyrimethamine and leucovorin doses are the same as in “preferred therapy” for toxoplasmosis.
%
See Table 6 for rifabutin doses based on concomitant ARV drug use.
%
PZA dose: <55kg = 1,000mg; 56-75mg = 1,500mg; >76 kg = 2,000mg.
&
EMB dose: <55kg = 800mg; 56-75kg = 1,200mg; >76kg = 1,600mg.
^In HIV-HBV-co-infected patients who do not need HIV therapy but who have HBeAg+ chronic hepatitis B and ALT >2x normal, some authorities would
recommend treating HBV with interferon-alfa provided there is no evidence of hepatic decompensation. This strategy spares the patient from developing HIV
and HBV resistance to 3TC therapy and from the toxicity of HAART.
=Available in the U.S. through the Centers for Disease Control and Prevention.
V-82
APPENDIX C: DOSAGE ADJUSTMENT IN RENAL INSUFFICIENCY
DRUGS NORMAL DOSE DOSAGE ADJUSTMENT IN RENAL INSUFFICIENCY
CREATININE DOSE
CLEARANCE
(ML/MIN)
Acyclovir IV dose for serious 25-50 10mg/kg q12h
HSV/VZV infections:
10-25 10mg/kg q24h
10mg/kg q8h
0-10 10mg/kg q48h
po dose for herpes
zoster: 800mg q4h 10-25 800mg q8h
(5x/day)
0-10 800mg q12h
Amikacin 10-15mg/kg/day IV Dosage adjustment based Dosage adjustment based on serum
on therapeutic drug levels
monitoring
Amphotericin B 0.5–1.0mg/kg/day IV No dosage adjustment necessary;
alternative amphotericin B
preparation or other antifungals
may be considered if renal
insufficiency occurs during therapy
Cidofovir 5mg/kg IV q.w x 2, If ↑ 0.3–0.4mg/dL 3mg/kg per dose
then every 2 weeks >baseline
d/c therapy
(with probenecid and
hydration) If ↑ >0.5mg/dL
>baseline or >3+
proteinuria
Ciprofloxacin 500mg po b.i.d 30–50 250mg q12h
5-29 250mg q18h (or 375mg q24h)
Patients on 250mg q24h (given after dialysis)
haemodialysis or
peritoneal dialysis
Clarithromycin 500mg po b.i.d <30 250mg b.i.d or 500mg q.d
EMB 15mg/kg q24h po 10-50 15mg/kg q24-36h
<10 15mg/kg q48h
Haemodialysis 15mg/kg t.i.w after haemodialysis
Fluconazole 200-800mg po or IV >50 Full dose
q.d
<50 50% of full dose
Haemodialysis Full dose after haemodialysis
Flucytosine 25mg/kg po q6h 20-40 25mg/kg q12h
10-20 25mg/kg q24h
Haemodialysis 25-50mg/kg q48-72h (after
haemodialysis)
Foscarnet 120-180mg/kg/ day Dosage adjustment according to calculated CrCl/kg; please
consult package labelling for dosing table
V-83
CREATININE DOSE
CLEARANCE
(ML/MIN)
Ganciclovir Induction Therapy: 50-69 2.5mg/kg q12h
5mg/kg IV q12h
25-49 2.5mg/kg q24h
Maintenance Therapy:
10-24 1.25mg/kg q24h
5mg/kg IV q24h
<10 or on Haemodialysis 1.25mg/kg t.i.w after
haemodialysis
50-69 2.5mg/kg q24h
25-49 1.25mg/kg q24h
10-24 0.625mg/kg q24h
<10 or on Haemodialysis 0.625mg/kg t.i.w after
haemodialysis
3TC For HIV/HBV-Co- 30-49 150mg q.d
Infected Patients:
15-29 150mg x 1, then 100mg q.d
150mg b.i.d
5-14 150mg x 1, then 50mg q.d
<5 50mg x 1, then 25mg q.d
Levofloxacin 500 mg po q.d 20-49 250mg q24h
10-19 250mg q48h
Haemodialysis or CAPD 250mg q48h
Aqueous Penicillin G Neurosyphilis or 10-50 2-3MU q4h
Ocular Syphilis: 3-
<10 1MU q4-6h
4MU IV q4h
Haemodialysis 1MU q4-6h
Ribavirin 1,000–1,200mg/day <50 Not recommended
(based on weight)
Rifabutin 300mg daily (or <30 50% of dose
adjustment based on
drug-drug interaction–
see Table 10)
Streptomycin 1g IM or IV q24h 10-50 1g q24-72h
<10 1g q72-96h
Haemodialysis Supplemental 500mg after
haemodialysis (unless 1g dose is
scheduled around the same time)
SMX-TMP 15–20 mg/kg/day (of 15–30 5mg/kg q6-8h x 48 hours,
TMP) IV or po in 3-4 then 3.5-5mg/kg q12h
<15
divided doses
Haemodialysis 7-10mg/kg/day in 1-2 divided doses
7-10mg/kg after haemodialysis
V-84
CREATININE DOSE
CLEARANCE
(ML/MIN)
TDF For HIV (in HBV 30-49 300mg q48h
Pts): 300mg po q.d
10-29 300mg b.i.w
ESRD or Haemodialysis 300mg q.w
Valacyclovir For Herpes Zoster: 1g 30-49 1g po q12h
po t.i.d
10-29 1g po q24h
<10 500mg po q24h
Haemodialysis 500mg po q24h, schedule timing of
dose after haemodialysis
Valganciclovir 900mg po b.i.d 40-59 Induction Maintenance
(induction)
25-39 450mg b.i.d 450mg q.d
900mg po q.d
10-25 450mg q.d 450mg q.o.d
(maintenance)
Haemodialysis 450mg q.o.d 450mg b.i.w
not recom- not recom-
mended mended
V-85
APPENDIX D: COMMON TOXICITIES OF SYSTEMIC AGENTS FOR TREATMENT OF OIS
DRUG CLASS DRUGS TOXICITIES
Antifungal Agents Amphotericin B Nephrotoxicity, infusion-related reactions, electrolyte imbalances,
anaemia, thrombophlebitis, nausea, vomiting
*Lipid formulation may have lower incidence of nephrotoxicity and
infusion-related reactions
Caspofungin Headache, thrombophlebitis, facial flushing, erythema, skin rash,
infusion-related reactions
Flucytosine Bone marrow suppression, diarrhoea, nausea, vomiting
Fluconazole Hepatotoxicity
Itraconazole Hepatotoxicity, congestive heart failure, oedema, hypokalaemia,
nausea, vomiting, diarrhoea, abdominal pain
Voriconazole Visual disturbances, photosensitivity, skin rash, hepatotoxicity,
peripheral oedema, headache, hallucination
Agents for Treating Atovaquone Diarrhoea, rash, nausea, vomiting, headache
PCP Clindamycin Diarrhoea, pseudomembranous colitis, rash
Dapsone Methemoglobinaemia and haemolytic anaemia (especially in patients
with G6PD deficiency), neutropaenia, rash, fever, hepatitis,
hyperkalaemia, peripheral neuropathy
Pentamidine Nephrotoxicity, infusion-related hypotension and/or arrhythmias,
pancreatitis, hypoglycaemia, diabetes mellitus, hepatitis, electrolyte
abnormalities
Primaquine Methemoglobinaemia and haemolytic anaemia (especially in patients
with G6PD deficiency), abdominal cramps, nausea, vomiting
TMP-SMX Rash, Stevens-Johnson syndrome, bone marrow suppression,
hepatotoxicity, increased serum creatinine, nausea, vomiting,
crystalluria
Trimetrexate Bone marrow suppression, stomatitis, fever, rash, hepatitis
Anti-Toxoplasmosis Pyrimethamine Neutropaenia, thrombocytopaenia, megaloblastic anaemia, rash
Agents (for Sulfadiazine Rash, Stevens-Johnson syndrome, bone marrow suppression,
atovaquone, crystalluria, renal insufficiency, nausea, vomiting
clindamycin, and
TMP-SMX, see
Agents for PCP)
Antimycobacterial Amikacin Nephrotoxicity, ototoxicity
Agents Azithromycin Hepatotoxicity, ototoxicity, skin rash, urticaria, pruritus, nausea,
vomiting, abdominal pain, diarrhoea
Clarithromycin Hepatotoxicity, ototoxicity, headache, nausea, vomiting, abdominal
cramps, diarrhoea, skin rash
Ciprofloxacin/ Nausea, vomiting, abdominal pain, diarrhoea, headache, dizziness,
Levofloxacin sleep disturbances, crystalluria, renal impairment, tendonitis,
photosensitivity, neurotoxicity (especially with high-dose or in
patients with renal dysfunction)
Cycloserine Neuropsychiatric toxicities (headache, somnolence, vertigo, tremor,
dysarthria, irritability, confusion, paranoia, psychosis, etc.)
EMB Optic neuritis, peripheral neuropathy, headache, nausea, vomiting,
anorexia, hepatotoxicity, hyperuricaemia
INH Hepatotoxicity, peripheral neuropathy, ataxia, optic neuritis
Pyrizinamide (PZA) Hepatotoxicity, hyperuricaemia, arthralgia
Rifabutin Hepatotoxicity, uveitis, neutropaenia, red-orange discolouration of
body fluids, skin rash
RIF Hepatotoxicity, red-orange discolouration of body fluids,
thrombocytopaenia, haemolytic anaemia, skin rash
Streptomycin Nephrotoxicity, ototoxicity (esp. vestibular toxicity)
V-86
DRUG CLASS DRUGS TOXICITIES
Drugs for Acyclovir Crystalluria, nausea, vomiting, neurotoxicity (high doses, especially
Treatment of Viral in patients with renal impairment–agitation, confusion, hallucination,
Infections seizure, coma), nephrotoxicity (particularly after rapid IV infusion),
thrombophlebitis at peripheral IV infusion site
Adefovir Increase serum creatinine, nausea, vomiting, asthaenia
Cidofovir Nephrotoxicity, proteinuria, ocular hypotony, anterior uveitis/iritis,
neutropaenia, metabolic acidosis, asthaenia
Side effects most likely related to co-administration of probenecid:
skin rash, nausea, vomiting, anorexia
Famciclovir Headache, nausea, vomiting, anorexia
Foscarnet Nephrotoxicity, electrolyte imbalances (hypocalcaemia,
hypomagnesaemia, hypophosphataemia, hyperphosphataemia,
hypokalaemia), penile ulceration, nausea, vomiting, anorexia,
headache, seizure
Ganciclovir Neutropaenia, thrombocytopaenia, anaemia, catheter-related
infections
Oral ganciclovir: nausea, vomiting
Interferon-alfa and Flu-like syndrome (fever, headache, fatigue, myalgia)
Peginterferon-alfa neuropsychiatric disorders (depression, suicidal ideation),
neutropaenia, thrombocytopaenia, thyroid dysfunction, injection site
reactions, alopecia, nausea, anorexia, diarrhoea, weight loss,
development or exacerbation of auto-immune disorders,
ophthalmologic disorders (e.g. retinal haemorrhage, retinal artery or
vein obstructions, cotton wool spots)
3TC Nausea, vomiting, pancreatitis in children
Ribavirin Haemolytic anaemia, leukopaenia, hyperbilirubinaemia, nausea,
vomiting, anorexia, dyspepsia, skin rash
Valacyclovir Nausea, vomiting, headache
At a very high dose of 8g/day: thrombotic thrombocytopaenic
purpura-haemolytic uremic syndrome reported in advanced HIV
patients and in transplant recipients
Valganciclovir Neutropaenia, thrombocytopaenia, anaemia, nausea
Anti-Parasitic Agent Albendazole Nausea, vomiting, hepatotoxicity, hypersensitivity, neutropaenia,
dizziness, headache
Benznidazol Peripheral neuropathy, bone marrow suppression, skin rash
Fumagillin Oral therapy: neutropaenia, thrombocytopaenia, vertigo, nausea,
(investigational) vomiting, diarrhoea, anorexia, abdominal cramps
Ocular therapy: minimal systemic effect or local effect
Pentavalent antimony Serum transaminase elevation, amylase, lipase elevations,
pancreatitis, thrombophlebitis, prolonged QT interval and T wave
inversion; rarely, arrhythmias
Treatment for Ceftriaxone Cholelithiasis, skin rash, bone marrow suppression, injection site
Syphilis reactions (IM administration)
Doxycycline Photosensitivity reaction, nausea, vomiting, oesophageal ulceration
Erythromycin Nausea, vomiting, abdominal pain, hepatotoxicity, cholestatic
jaundice, ototoxicity (hearing loss, tinnitus), skin rash; rarely, cardiac
arrhythmia
Penicillin G All Penicillin G Preparations: hypersensitivity reactions (immediate
or delayed reaction), bone marrow suppression, drug fever
Benzathine Penicillin G: injection site reactions–pain, erythema
Procaine Penicillin G: injection site reactions–pain, erythema
Aqueous Crystalline Penicillin G: thrombophlebitis, neurotoxicity at
high doses (esp. in patients with renal dysfunction)
V-87
APPENDIX E: SIGNIFICANT PHARMACOKINETIC DRUG-DRUG INTERACTIONS FOR DRUGS IN THE
TREATMENT OF OIS
This table provides pharmacokinetic drug-drug interaction data between drugs for treatment of OIs and
ARV agents. For interactions between drugs for OI treatment and other medications taken by individual
patients, consult with other drug information resources.
DRUGS INTERACTING WITH MECHANISM/EFFECTS RECOMMENDATIONS
Acyclovir Probenecid (with Probenecid may ↓ renal No dosage adjustment; monitor
cidofovir) clearance of acyclovir by for acyclovir toxicities
32% → ↑ acyclovir AUC
Atovaquone Rifabutin Atovaquone conc. ↓ by 34%; This combination should be
rifabutin conc. ↓ by 19% avoided
RIF Atovaquone conc. ↓ by 52%; This combination should be
RIF conc. ↑ by 37% avoided
Tetracycline Atovaquone conc. ↓ by 40% This combination should be
avoided; interaction study with
doxycycline not available
AZT AZT AUC ↑ by 31%, No dosage adjustment
possibly due to atovaquone recommended, monitor for
inhibition of AZT AZT toxicities
glucuronidation
Caspofungin EFV, NVP, NFV, RIF Possible ↓ caspofungin conc. Manufacturer recommended ↑
based on regression analyses maintenance dose to 70mg q.d
of patient pharmacokinetic if patient has suboptimal
data; no formal response to caspofungin if co-
pharmacokinetic study administered with the
available at this time interacting drugs
Cidofovir (+ Acyclovir, Probenecid may ↓ renal Given the infrequent dosing of
Probenecid) cephalosporins, clearance of these drugs → ↑ probenecid when used with
dapsone, plasma conc. cidofovir, no dosage adjustment
fluoroquinolones, is necessary for interacting
ganciclovir, drugs; monitor for dose-related
penicillins, toxicities
valacyclovir,
valganciclovir,
zalcitabine (ddC),
AZT
Ciprofloxacin Didanosine (ddI)- ↓ ciprofloxacin absorption Administer ddI-buffered
buffered formulations due to chelation with preparation at least 2 hours after
magnesium-aluminium buffer or 6 hours before ciprofloxacin
Cidofovir + Probenecid may reduce renal No dosage adjustment
probenecid clearance of ciprofloxacin → necessary; monitor for
↑ plasma conc. ciprofloxacin toxicities
Clarithromycin ATV ATV Cmin ↑ 91%; Due to concerns of QT
CYP 3A4 clarithromycin AUC ↑ 94% prolongation, ↓ clarithromycin
Inhibitor and dose by 50% or use alternative
Substrate agent
V-88
DLV DLV AUC ↑ by 44%; No dosage adjustment
clarithromycin AUC ↑ by recommended; may consider
100%; and 14-OH clarithromycin dose adjustment
clarithromycin AUC ↓ by in patients with renal
75% insufficiency; monitor for
clarithromycin toxicities; or
switch to azithromycin
EFV Clarithromycin AUC ↓ by Significance unknown, no
39%; 14-OH clarithromycin dosage adjustment
AUC ↑ 34% recommended; some suggest
switching to azithromycin
Itraconazole Possible bi-directional CYP Monitor for toxicities of both
3A4 inhibition and ↑ AUC of itraconazole and clarithromycin
both drugs
LPV/r (Kaletra®) ↑ clarithromycin AUC and ↓ No dosage change in patients
in 14-OH clarithromycin with normal renal function
AUC CrCl (ml/min)
clarithromycin
30-60 ↓dose by 50%
<30 ↓dose by 75%
Rifabutin Clarithromycin AUC ↓ by May need clarithromycin dose
44%; rifabutin AUC ↑ by 76- ↑ and ↓ rifabutin dose; may
99% result in ↑ rifabutin toxicities;
some suggest to use
azithromycin in place of
clarithromycin
RIF ↓ mean clarithromycin conc. This combination should be
by 87% avoided; consider switching to
azithromycin
RTV Clarithromycin AUC ↑ by No dosage change in patients
77% and ↓ in 14-OH with normal renal function
clarithromycin AUC CrCl (ml/min) clarithromycin
30-60 ↓dose by 50%
<30 ↓dose by 75%
Trimetrexate May ↑ trimetrexate AUC No formal study performed;
avoid concomitant use or
monitor for trimetrexate
toxicities
Dapsone RIF ↓ dapsone level by 7-10x and Reduced dapsone activities;
↓ dapsone t1/2 from 24 to 11 may consider increasing
hours dapsone dose or use alternative
agent
Doxycycline Atovaquone Tetracycline ↓ atovaquone Until doxycycline-atovaquone
conc. by 40%; effect of interaction data become
doxycycline on atovaquone available; avoid this
unknown combination if possible
ddI-buffered ↓ doxycycline absorption due Separate doxycycline with ddI
formulations to chelation with magnesium- by at least 2 hours or use ddI-
aluminium buffer enteric-coated capsule
V-89
RIF ↑ doxycycline clearance, ↓ Potential for ↓ doxycycline
t1/2 and AUC efficacy, monitor closely for
therapeutic failure
Erythromycin Itraconazole Potential for bi-directional Monitor for toxicities of both
inhibition of hepatic drugs
CYP 3A4 metabolism and ↑ serum
Inhibitor conc. of both
toxicities
Fluconazole Rifabutin Rifabutin AUC ↑ by 80%; no Monitor for rifabutin toxicity or
effect on fluconazole levels may consider dose reduce to
CYP 3A4 150mg q.d
Inhibitor RIF Fluconazole AUC ↓ by 23- May need to ↑ fluconazole dose
56%; no change in RIF conc.
toxicities
AZT Fluconazole ↓ Monitor for AZT toxicities
glucuronidation of AZT;
fluconazole 400mg/day
results in ↑ AZT AUC by
74%
Ganciclovir ddI-buffered ddI AUC ↑ by 78% with IV May consider reducing ddI
formulations (study ganciclovir and ↑ by 111% dose; monitor for ddI toxicities
with enteric-coated with po ganciclovir
ddI has not been done)
Cidofovir + Probenecid may ↓ ganciclovir Given the infrequent dosing of
probenecid clearance and ↑ ganciclovir probenecid when used with
conc. cidofovir, no dosage adjustment
is necessary; monitor for dose-
related toxicities
Itraconazole Clarithromycin Potential for bidirectional Monitor for toxicities of
inhibition of CYP3A4 clarithromycin; monitor
CYP 3A4 metabolism with ↑ AUC of itraconazole level and toxicities
Inhibitor and itraconazole and/or
Substrate interacting drug(s)
DLV Potential for bidirectional Monitor for toxicities of DLV;
inhibition of CYP3A4 monitor itraconazole level and
metabolism with ↑ AUC of toxicities
itraconazole and/or DLV
ddI-buffered May ↓ itraconazole oral Administer itraconazole at least
preparation absorption due to ↑ gastric 2-4 hours before ddI-buffered
pH from antacid in the ddI tablets; or use ddI enteric-
preparation coated capsule; or take
itraconazole with cola beverage
to ↓ gastric pH
V-90
EFV No interaction study reported; Monitor itraconazole level and
potential induction or adjust dose accordingly
inhibition of itraconazole
metabolism → ↑ or ↓ in
itraconazole AUC
Erythromycin Potential for bidirectional Monitor for toxicities of
inhibition of CYP3A4 erythromycin; monitor
metabolism with ↑ AUC of itraconazole level and toxicities
itraconazole and/or
erythromycin
NVP Potential for induction of Monitor itraconazole level and
itraconazole metabolism and adjust according; monitor
↓ in itraconazole conc. therapeutic efficacy
PIs other than RTV Potential for bidirectional Monitor for toxicities of PIs;
inhibition of CYP3A4 monitor itraconazole level and
metabolism with ↑ AUC of toxicities (esp. in patients with
itraconazole and/or PIs RTV-boosted PI regimens)
Rifabutin ↓ in itraconazole conc. by Avoid concomitant use if
70%; potential for inhibition possible; if the combination is
of rifabutin metabolism and ↑ to be used, monitor itraconazole
rifabutin conc. level and adjust dose
accordingly; monitor for
rifabutin toxicity
RIF Itraconazole AUC ↓ by 64%- Avoid concomitant use if
88%; no change in RIF conc. possible; if the combination is
to be used, monitor itraconazole
level and adjust dose
accordingly; monitor
therapeutic response
RTV Potential for significant ↑ in May require reduced
itraconazole conc. itraconazole dose; monitor
itraconazole level and toxicities
Trimetrexate Itraconazole may Monitor for trimetrexate
significantly ↑ trimetrexate toxicities
level due to inhibition of
CYP3A4 metabolism
Ketoconazole APV APV AUC ↑ by 31%; Monitor for toxicities of each
ketoconazole AUC ↑ 44% drug
CYP 3A4 DLV DLV Cmin ↑ by 50% Monitor for DLV toxicities
Substrate ddI-buffered May ↓ oral absorption of Space apart doses of
formulations ketonconazole due to ↑ ketoconazole and ddI by at least
gastric pH from antacid in the 2 hours or administer
ddI-preparation ketoconazole with cola
beverage to ↓ pH
IDV IDV AUC ↑ by 68%; o ↓ IDV dose to 600mg q8h
significant change in
ketocoazole conc.
V-91
LPV/r (Kaletra®) Ketoconazole AUC ↑ by 3x; ↓ ketoconazole dose and
no significant change in LPV monitor for toxicities
pharmacokinetics
NVP Ketoconazole AUC ↓ by Consider alternative antifungal
63%; NPV AUC ↑ by 15%- or monitor for ketoconazole
30% efficacy
Rifabutin Possible ↑ in rifabutin conc. Monitor for rifabutin toxicities
and ↓ in ketoconazole conc. and ketoconazole efficacy
RIF Ketoconazole levels ↓ by Avoid concomitant use if
50% possible; consider alternative
antifungal and/or
antimycobacterial agent(s)
RTV Ketoconazole AUC ↑ by 3.4x Ketoconazole dose >200mg q.d
not recommended; monitor for
ketoconazole toxicities
Trimetrexate Ketoconazole may Monitor for trimetrexate
significantly ↑ trimetrexate toxicities
level due to inhibition of
CYP3A4 metabolism
PZA AZT ↓ PZA conc. in one study Monitor therapeutic efficacy or
consider monitoring PZA level
Ribavirin ddI ↑ intracellular levels of ddA- ↑ ddI-associated mitochondrial
TP toxicities; avoid concomitant
use if possible; if used
together, monitor for toxicities
(lactic acidosis, pancreatitis,
peripheral neuropathy)
AZT ↓ intracellular activities of Potential for worsening of HIV
AZT against HIV in vitro suppression; monitoring HIV
viral load
Rifabutin APV Rifabutin AUC ↑ by 193%; ↓ rifabutin dose by 50% (to
no change in APV conc. 150mg q.d)
CYP 3A4 ATV Rifabutin AUC ↑ by 210%; ↓ rifabutin dose by 75% (to
Inducer and Cmin ↑ by 343%; minimal 150mg every other day or t.i.w)
Substrate change in ATV
pharmacokinetics
Atovaquone Atovaquone conc. ↓ by 34%; This combination should be
rifabutin conc. ↓ by 19% avoided
Clarithromycin Rifabutin AUC ↑ by 76% due Consider reducing rifabutin
to inhibition of hepatic dose, monitor for rifabutin
metabolism; clarithromycin toxicities, or switching
AUC may be reduced macrolide to azithromycin
DLV DLV AUC ↓ by 80%; This combination should be
rifabutin AUC ↑ by 100% avoided
ddI-buffered ↓ rifabutin oral absorption Space rifabutin and ddI-
formulation buffered formulation apart by at
least 2 hours or use enteric-
coated ddI-capsule
V-92
EFV Rifabutin AUC ↓ by 38%; no ↑ rifabutin dose to 450 q.d or
change in EFV conc. 600mg b.i.w or t.i.w; effect of
EFV + PI(s) on rifabutin conc.
has not been studied
Fluconazole Rifabutin AUC ↑ by 80% due Consider reducing rifabutin
to inhibition of hepatic dose or monitor for rifabutin
metabolism toxicities
Fosamprenavir No data of interactin between ↓ rifabutin dose by 50% (to
fosamprenavir and rifabutin; 150mg q.d); if used with
interaction between APV and RTV/fosamprenavir
rifabutin suggests inhibition combination, dose reduction to
of rifabutin metabolism 150mg q.o.d or t.i.w
Itraconazole Itraconazole conc. ↓ by 70%; Avoid concomitant use if
potential for inhibition of possible; if the combination is
rifabutin metabolism and ↑ to be used, monitor itraconazole
rifabutin conc. level and adjust dose
accordingly; monitor for
rifabutin toxicity
IDV Rifabutin AUC ↑ by 204%; ↓ rifabutin dose to 150mg q.d
IDV AUC ↓ by 32% and ↑ IDV dose to 1,000mg
q8h
Ketoconazole Possible ↑ in rifabutin conc. Monitor for rifabutin toxicities
and ↓ in ketoconazole conc. and ketoconazole efficacy
LPV/r (Kaletra®) Rifabutin AUC ↑ by 303%; ↓ rifabutin dose to 150mg every
25-O-des-acetyl rifabutin other day or t.i.w
AUC ↑ by 47.5x
NFV Rifabutin AUC ↑ by 207%; ↓ rifabutin dose to 150mg q.d
insignificant ∆ in NFV conc.
RTV Rifabutin AUC ↑ by 430%; ↓ rifabutin dose to 150mg every
no change in RTV conc. other day or t.i.w
SQV SQV AUC ↓ by 43%; no This combination should be
change in rifabutin conc. avoided; may consider adding
RTV to SQV and monitor SQV
conc.
Voriconazole Voriconazole AUC ↓ by This combination should be
79%; rifabutin AUC ↑ by 3x avoided
RIF APV APV AUC ↓ by 82%, Cmin This combination should be
↓ by 92%; no change in RIF avoided; effect of RIF on RTV
Potent CYP3A4 conc. + APV has not been studied
inducer ATV Pharmacokinetic study not This combination should be
available; expect RIF to ↓ avoided
ATV concentrations
substantially (up to 90%↓), as
seen with other PIs
Atovaquone Atovaquone conc. ↓ by 52%; This combination should be
RIF conc. ↑ by 37% avoided
V-93
Clarithromycin ↓ mean clarithromycin conc. This combination should be
by 87% avoided; consider switching
clarithromycin to azithromycin
Dapsone Dapsone half-life ↓ from 24 Monitor for dapsone efficacy;
to 11 hours; dapsone conc. ↓ consider alternative therapy
by 7-10x
DLV DLV AUC ↓ by 95%, no This combination should be
change in RIF conc. avoided
EFV EFV AUC ↓ by 22%; no No dosage adjustment or ↑
change in RIF conc. EFV dose to 800mg q.d
Fluconazole Fluconazole AUC ↓ by 23%- May need to ↑ fluconazole dose
56%; no change in RIF conc.
Fosamprenavir No study done with This combination should be
fosamprenavir to date; APV avoided
AUC ↓ by 82%, Cmin ↓ by
92%
IDV IDV AUC ↓ by 89%; RIF This combination should be
conc. slightly ↑ avoided
Itraconazole Itraconazole AUC ↓ by 64- Avoid concomitant use if
88%; no change in RIF conc. possible; if the combination is
to be used, monitor itraconazole
level and adjust dose
accordingly; monitor
therapeutic response
Ketoconazole Ketoconazole levels ↓ by Avoid concomitant use if
50% possible; consider alternative
antifungal and/or
antimycobacterial agent(s)
LPV/r (Kaletra®) LPV AUC ↓ by 75% and This combination should be
Cmin ↓ by 99%; RIF AUC avoided
may be increased
NFV NFV AUC ↓ 82%; no change This combination should be
in RIF conc. avoided
NVP NVP AUC ↓ by 37%; no This combination should be
change in RIF conc. used with caution; monitor
ARV response
RTV RTV AUC ↓ by 35%; no Monitor for ARV activity of
change in RIF conc. RTV
SQV SQV AUC ↓ by 84%; no This combination should be
change in RIF conc. avoided; potential for use in the
presence of RTV, consider
monitoring SQV concentration
Trimetrexate May ↑ trimetrexate Monitor for trimetrexate
metabolism and ↓ efficacy
trimetrexate conc.
Voriconazole Voriconazole AUC ↓ by 96% This combination should be
avoided
V-94
AZT RIF ↑ AZT glucuronidation Monitor for AZT efficacy
→ ↓ AZT AUC by 47%
TDF Acyclovir, cidofovir, Potential for compete active Monitor for toxicities of these
ganciclovir, tubular secretion of these drugs and TDF
valacyclovir, drugs
valganciclovir
ATV ATV Cmin ↓ by 40%; Co-administer with RTV at a
mechanism unknown dose of RTV 100mg q.d + ATV
300mg q.d
ddI (buffered and ↑ ddI AUC by 44%-60%; no Monitor for ddI-associated
enteric-coated change in TDF AUC toxicities; discontinue ddI if
preparations) serious toxicity occurs; some
suggest reduction of ddI dose
(e.g. from 400mg to 250mg in
patients >60kg)
Trimetrexate CYP 3A4 inhibitors May ↑ trimetrexate Monitor for trimetrexate
e.g. clarithromycin, concentration toxicities
CYP 3A4 DLV, fluconazole,
Substrate itraconazole,
ketoconazole,
voriconazole, PIs
CYP 3A4 inducers May ↓ trimetrexate Monitor for trimetrexate
e.g. EFV, NVP, concentration efficacy
rifabutin, RIF
Valganciclovir Cidofovir + Probenecid may ↓ ganciclovir Given the infrequent dosing of
probenecid renal clearance and ↑ probenecid when used with
ganciclovir conc. cidofovir, no dosage adjustment
is necessary; monitor for dose-
related toxicities
ddI-buffered Oral ganciclovir ↑ ddI AUC Monitor for ddI toxicities; study
formulation by 111% with valganciclovir and ddI
enteric-coated formulation has
not been done
Voriconazole DLV, EFV Potential bi-directional No formal interaction studies;
inhibition of metabolism → ↑ monitor for toxicities
CYP 2C9, 2C19, conc. of both drugs
and 3A4 NVP, EFV Potential induction of No formal interaction studies;
Substrate and voriconazole metabolism → monitor for therapeutic failure
Inhibitor ↓ voriconazole conc. of voriconazole
PIs (except IDV) Potential bi-directional No formal interaction studies
inhibition of metabolism → ↑ except for IDV; monitor for
conc. of both drugs; IDV + toxicities
voriconazole → no
significant interaction
Rifabutin Voriconazole AUC ↓ by This combination should be
79%; rifabutin AUC ↑ by 3- avoided
fold
RIF Voriconazole AUC ↓ by 96% This combination should be
avoided
V-95
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V-97
VI. RECOMMENDATIONS FOR ADULT AND PAEDIATRIC
OPPORTUNISTIC INFECTION (OI) PROPHYLAXIS1
TABLE OF CONTENTS
INTRODUCTION ........................................................................................................................................................ VI-1
PROPHYLAXIS TO PREVENT FIRST EPISODE OF OPPORTUNISTIC DISEASE IN ADULTS AND ADOLESCENTS
WITH HIV INFECTION ............................................................................................................................VI-2
Strongly Recommended as Standard of Care ..........................................................................................VI-2
Generally Recommended as Standard of Care.........................................................................................VI-3
Evidence for Efficacy but Not Routinely Indicated..............................................................................................VI-4
PROPHYLAXIS TO PREVENT RECURRENCE OF OPPORTUNISTIC DISEASE (AFTER CHEMOTHERAPY FOR
ACUTE DISEASE) IN ADULTS AND ADOLESCENTS WITH HIV INFECTION .................................................. VI-6
Recommended Only if Subsequent Episodes Are Frequent or Severe ............................................................ VI-7
RECOMMENDATIONS FOR USE OF SPECIFIC VACCINES IN INDIVIDUALS WITH HIV INFECTION .................. VI-9
PROPHYLAXIS TO PREVENT FIRST EPISODE OF OPPORTUNISTIC DISEASE IN INFANTS AND CHILDREN WITH
HIV INFECTION ...............................................................................................................................................VI-14
Strongly Recommended as Standard of Care..................................................................................................VI-14
Generally Recommended as Standard of Care.......................................................................................VI-15
Not Recommended for Most Children; Indicated for Use Only in Unusual
Circumstances....................................................................................................................................................... VI-16
PROPHYLAXIS TO PREVENT RECURRENCE OF OPPORTUNISTIC DISEASE (AFTER CHEMOTHERAPY FOR
ACUTE DISEASE) IN INFANTS AND CHILDREN WITH HIV INFECTION ......................................................VI-17
Recommended for Life as Standard of Care ...................................................................................................VI-17
Recommended for Standard of Care Only if Subsequent Episodes Are
Frequent or Severe.....................................................................................................................................VI-18
CRITERIA FOR STARTING, DISCONTINUING, AND RESTARTING OI PROPHYLAXIS FOR ADULTS WITH HIV
INFECTION ........................................................................................................................................................................VI-19
RECOMMENDATIONS TO HELP PATIENTS AVOID EXPOSURE TO OR INFECTION
WITH OPPORTUNISTIC PATHOGENS ............................................................................................................. VI-21
Sexual Exposures .............................................................................................................................................VI-21
Injection Drug Use Exposures ...............................................................................................................VI-21
Environmental and Occupational Exposures...................................................................................................VI-21
TABLES
Table 1: Age-Specific CD4+ T Cell Counts Indicating Severe Immunosuppression in HIV Infection ..VI-9
Table 2: Recommended Immunisation Schedule for HIV-Infected Children................................................VI-11
1
This chapter has been adapted from the 2001 United States Public Health Service/Infectious Disease Society of
America’s Guidelines for Prevention of Opportunistic Infections in Persons Infected with HIV (2001). Accessible
online at http://www.aidsinfo.nih.gov/guidelines/op_infections/OI_112801.html
VI-i
VI. RECOMMENDATIONS FOR ADULT AND PAEDIATRIC OPPORTUNISTIC
INFECTION (OI) PROPHYLAXIS
INTRODUCTION
HAART has reduced the incidence of OIs, substantially extended life, and should be considered for all
HIV-infected persons who qualify for such therapy. Some patients, however, are not ready or able to take
HAART, and others have tried HAART regimens but the therapy has failed. Such patients can still
benefit from prophylaxis against OIs. Prophylaxis against specific OIs also continues to provide survival
benefits among persons who are receiving HAART.
Since HAART was introduced, it has become increasingly clear that chemoprophylaxis for OIs need not
necessarily be life-long because HAART can restore immune function. The period of susceptibility to
opportunistic processes continues to be accurately indicated by the CD4+ T cell count for patients
receiving HAART. A strategy of stopping primary or secondary prophylaxis for certain patients whose
immunity has improved as a consequence of HAART is supported by clinical trials and observational
data. Stopping prophylactic regimens can simplify treatment, reduce toxicity and drug interactions, lower
the cost of care, and potentially facilitate adherence to HAART regimens. Specific recommendations
regarding the discontinuation of prophylaxis depend on factors such as the duration of a patient’s CD4+ T
cell count increase, and, in the case of secondary prophylaxis, the duration of treatment of the disease’s
initial episode.
Although considerable data exist regarding the discontinuation of primary and secondary OI prophylaxis,
essentially no data are available regarding restarting prophylaxis when the CD4+ T cell count decreases
again to levels at which the patient is likely to again be at risk for an OI. For primary prophylaxis,
whether to use the same threshold at which prophylaxis was stopped (derived from data in studies
addressing prophylaxis discontinuation) or to use the threshold below which initial prophylaxis is
recommended, is unknown. In the following guidelines, therefore, in some cases ranges are provided for
restarting primary or secondary prophylaxis. For prophylaxis against Pneumocystis jiroveci pneumonia
(PCP), the suggested threshold for restarting both primary and secondary prophylaxis is 200 cells/mm3.
For each of the nineteen diseases covered in these guidelines, specific recommendations address: a)
prevention of exposure to the opportunistic pathogen; b) prevention of the first episode of disease; and c)
prevention of disease recurrence. Recommendations for the prevention of OIs are presented separately
for adults and children.
VI-1
PROPHYLAXIS TO PREVENT FIRST EPISODE OF OPPORTUNISTIC DISEASE IN ADULTS AND
ADOLESCENTS WITH HIV INFECTION
PREVENTIVE REGIMENS
PATHOGEN INDICATION FIRST CHOICE ALTERNATIVES
Strongly Recommended as Standard of Care
Pneumocystis jiroveci CD4+ T cell count Trimethoprim- Dapsone, 50mg po b.i.d or
(PCP) formerly <200/mm3 or sulfamethoxazole (TMP- 100mg po q.d; dapsone,
known as oropharyngeal candidiasis SMX), 1 double-strength 50mg po q.d plus
Pneumocystis carinii)1 (DS) tablet po q.d pyrimethamine, 50mg po
q.w plus leucovorin 25mg
TMP-SMX, 1 single-
po q.w
strength (SS) tablet po q.d
Dapsone, 200mg po plus
pyrimethamine, 75mg po
plus leucovorin, 25mg po
q.w
Aerosolised pentamidine,
300mg q.m via Respirgard
II(TM) nebuliser
Atovaquone, 1,500mg po
q.d
TMPSMX, 1 DS po t.i.w
Mycobacterium tuberculosis (TB)
Isoniazid (INH)- Tuberculin skin test (TST) INH, 300mg po plus Rifampin (RIF), 600mg po
sensitive2 reaction of ≥5 mm or prior pyridoxine, 50mg po q.d q.d x 4 months or rifabutin,
positive TST result x 9 months or INH, 300mg po q.d x 4 months
without treatment or 900mg po plus
Pyrazinamide (PZA), 15-
contact with case of active pyridoxine, 100mg po
20mg/kg po q.d x 2 months
TB regardless of TST b.i.w x 9 months
plus either RIF, 600mg po
result q.d x 2 months or rifabutin,
300mg po q.d x 2 months
INH resistant Same as above; high RIF, 600mg po or PZA 15-20mg/kg po q.d
probability of exposure to rifabutin, 300mg po q.d x plus either RIF, 600mg po
INH-resistant TB 4 months or rifabutin, 300mg po q.d
x 2 months
Multi-drug (INH Same as above; high Choice of drugs requires
and RIF) resistant probability of exposure to consultation with public
multi-drug resistant TB health authorities.
Depends on susceptibility
of isolation from source
patient
VI-2
PREVENTIVE REGIMENS
Toxoplasma gondii3 IgG antibody to TMP-SMX, 1 DS po q.d TMP-SMX, 1 SS po q.d
Toxoplasma and CD4+ T dapsone, 50mg po q.d plus
cell count of <100/mm3 pyrimethamine, 50mg po
q.w plus leucovorin, 25mg
po q.w
plus leucovorin, 25mg po q
w
Atovaquone, 1500mg po
q.d with or without
q.d plus leucovorin, 10mg
po q.d
Mycobacterium avium CD4+ T cell count of Azithromycin, 1,200mg Rifabutin, 300mg po q.d;
Complex (MAC)4 <50/mm3 po q.w or clarithromycin4, azithromycin, 1,200mg po
500mg po b.i.d q.w plus rifabutin, 300mg
po q.d
Varicella zoster Virus Significant exposure to Varicella zoster immune
(VZV) chickenpox or shingles for globulin (VZIG), 5 vials
patients who have no (1.25 mL each) IM,
history of either condition administered ≤96 hours
or, if available, negative after exposure, ideally
antibody to VZV within 48 hours
Generally Recommended as Standard of Care
Streptococcus CD4+ T cell count 23-valent polysaccharide None
pneumoniae5 >200/mm3 vaccine, 0.5mL IM
Hepatitis B Virus All susceptible (anti-HBc- HBV vaccine: 3 doses None

(HBV)6, 7 negative) patients
Influenza Virus6,8 All patients (annually, Inactivated trivalent Oseltamivir, 75mg po q.d
before influenza season) influenza virus vaccine: (influenza A or B)
1 annual dose (0.5mL)
Rimantadine, 100mg po
IM
b.i.d, or amantadine,
100mg po b.i.d (influenza
A only)
Hepatitis A Virus All susceptible (anti- HAV vaccine: 2 doses None
(HAV)7 HAV-negative) patients
at increased risk for HAV
infection (e.g. illicit drug
users, men who have sex
with men (MSM),
VI-3
PREVENTIVE REGIMENS
haemophiliacs) or with
chronic liver disease,
including chronic HBV
or hepatitis C
Evidence for Efficacy but Not Routinely Indicated
Invasive Bacterial Neutropaenia Granulocyte-colony- None
Infections stimulating factor (G-
CSF), 5-10 µg/kg SC q.d
x 2-4 weeks or
granulocyte-macrophage
colony-stimulating factor
(GM-CSF), 250 µg/m2
SC IV x 2-4 weeks
Cryptococcus CD4+ T cell count of Fluconazole, 100-200mg Itraconazole capsule,
neoformans <50/mm3 po q.d 200mg po q.d
Histoplasma CD4+ T cell count of Itraconazole capsule, None
capsulatum9 <100/mm3, endemic 200mg po q.d
geographic area
Cytomegalovirus CD4+ T cell count of Oral ganciclovir, 1g po None
(CMV)10 <50/mm3 and CMV t.i.d
antibody positivity
NOTES: The Respirgard IITM nebuliser is manufactured by Marquest, Englewood, Colorado, USA.
1
Prophylaxis should also be considered for persons with a CD4+ T cell percentage of <14%, for persons with a
history of an AIDS-defining illness, and possibly for those with CD4+ T cell counts of >200 but <250 cells/mm3.
TMP-SMX also reduces the frequency of toxoplasmosis and some bacterial infections. Patients receiving dapsone
should be tested for glucose-6 phosphate dehydrogenase deficiency. A dosage of 50mg q.d is probably less effective
than 100mg q.d. The efficacy of parenteral pentamidine (e.g. 4mg /kg/month) is uncertain. Fansidar® (sulfadoxine-
pyrimethamine) is rarely used due to severe hypersensitivity reactions. Patients who are being administered therapy
for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need additional
prophylaxis against PCP.
2
Directly observed therapy (DOT) is recommended for INH, e.g. 900mg b.i.w; INH regimens should include
pyridoxine to prevent peripheral neuropathy. If RIF or rifabutin is administered concurrently with protease
inhibitors (PIs) or non-nucleoside reverse transcriptase inhibitors (NNRTIs), careful consideration should be given
to potential pharmacokinetic interactions. There have been reports of fatal and severe liver injury associated with
the treatment of latent TB infection in HIV-uninfected persons treated with the two-month regimen of daily RIF and
PZA; therefore, it may be prudent to use regimens that do not contain PZA in HIV-infected persons whose
completion of treatment can be assured (Source: CDC. Update: fatal and severe liver injuries associated with
rifampin and pyrazinamide for latent tuberculosis infection and revisions in American Thoracic Society/CDC
recommendations, United States 2001. MMWR Weekly [serial on the Internet] 2001 Aug 31 [cited 2004]
50(34):[about 2p.]. Available from: <http://www.cdc.gov/mmwr>.). Exposure to multidrug-resistant TB might
require prophylaxis with two drugs; consult public health authorities. Possible regimens include PZA plus either
ethambutol (EMB) or a fluoroquinolone.
3
Protection against toxoplasmosis is provided by TMP-SMX, dapsone plus pyrimethamine, and possibly by
atovaquone. Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides
little, if any, protection.
VI-4
4
See Treatment Guidelines for discussion of drug interactions.
*During pregnancy, azithromycin is preferred over clarithromycin due to the teratogenicity in animals of
clarithromycin.
5
Vaccination may be offered to persons who have CD4+ T cell counts of <200 cells/mm3, although the efficacy is
likely to be diminished. Revaccination five years after the first dose, or sooner if the initial immunisation was given
when the CD4+ T cell count was <200 cells/mm3 and the CD4+ T cell count has increased to >200 cells/mm3 on
HAART, is considered optional. Some authorities are concerned that immunisations might stimulate the replication
of HIV.
6
Although data demonstrating the clinical benefit of these vaccines in HIV-infected persons are not available, it is
logical to assume that those patients who develop antibody responses will derive some protection. Some authorities
are concerned that immunisations might stimulate HIV replication, although for influenza vaccination, a large
observational study of HIV-infected persons in clinical care showed no adverse effect of this vaccine, including
multiple doses, on patient survival (Ward J, personal communication). Also, this concern may be less relevant in the
setting of HAART. However, due to the theoretical concern that increases in HIV plasma RNA following
vaccination during pregnancy might increase the risk of perinatal transmission of HIV, providers may wish to defer
vaccination for such patients until after HAART is initiated.
7
HBV vaccine has been recommended for all children and adolescents and for all adults with risk factors for HBV.
For persons requiring vaccination against both HAV and HBV, a combination vaccine is now available.
8
Oseltamivir is appropriate during outbreaks of either influenza A or influenza B. Rimantadine or amantadine is
appropriate during outbreaks of influenza A (although neither rimantadine nor amantadine is recommended during
pregnancy). Dosage reduction for antiviral chemoprophylaxis against influenza might be indicated for decreased
renal or hepatic function and for persons with seizure disorders. Physicians should consult the drug package inserts
for more specific information about adverse effects and dosage adjustments.
9
In a few unusual occupational or other circumstances, prophylaxis should be considered; consult a specialist.
10
Acyclovir is not protective against CMV. Valacyclovir is not recommended because of an unexplained trend
toward increased mortality observed in persons with AIDS who were being administered this drug for prevention of
CMV disease.
VI-5
PROPHYLAXIS TO PREVENT RECURRENCE OF OPPORTUNISTIC DISEASE (AFTER
CHEMOTHERAPY FOR ACUTE DISEASE) IN ADULTS AND ADOLESCENTS WITH HIV INFECTION
PREVENTIVE REGIMENS
Pneumocystis jiroveci Prior episode of TMP-SMX, 1 DS po q.d Dapsone, 50mg po b.i.d or
(PCP) (formerly P. jiroveci 100mg po q.d
TMP-SMX 1 SS po q.d
known as pneumonia (PCP)
Dapsone, 50mg po q.d plus
Pneumocystis carinii)
pyrimethamine, 50mg po q.w
plus leucovorin, 25mg po q.w
pyrimethamine, 75mg po plus
leucovorin, 25mg po q.w
Aerosolised pentamidine,
300mg q.m via Respirgard
IITM nebuliser
Atovaquone, 1,500mg po q.d
TMPSMX, 1 DS po t.i.w
1
T. gondii Prior toxoplasmic Sulfadiazine, 500- Clindamycin, 300-450mg po
encephalitis 1,000mg po q.i.d plus q6-8h plus pyrimethamine, 25-
pyrimethamine, 25-50mg 50mg po q.d plus leucovorin,
po q.d plus leucovorin, 10-25mg po q.d
10-25mg po q.d
Atovaquone, 750mg po q6-
12h with or without
pyrimethamine, 25mg po q.d
plus leucovorin, 10mg po q.d
MAC2 Documented Clarithromycin2, 500mg Azithromycin, 500mg po q.d
disseminated po b.i.d plus ethambutol plus EMB, 15mg/kg po q.d;
disease (EMB), 15mg/kg po q.d; with or without rifabutin,
with or without rifabutin, 300mg po q.d
300mg po q.d
VI-6
PREVENTIVE REGIMENS
Cytomegalovirus Prior end-organ Ganciclovir, 5-6mg Cidofovir, 5mg/kg IV q.o.w
(CMV) disease /kg/day IV 5-7 with probenecid 2g po 3 hours
days/week or 1,000mg before the dose followed by 1g
po t.i.d po 2 hours after the dose, and
1g po 8 hours after the dose
Foscarnet, 90-120mg/kg
(total of 4g).
IV q.d
Fomivirsen 1 vial (330µg)
(For retinitis) ganciclovir
injected into the vitreous, then
sustained-release implant
repeated q2-4w
q6-9m plus ganciclovir,
1.0-1.5g po t.i.d Valganciclovir, 900mg po q.d
C. neoformans Documented Fluconazole, 200mg po Amphotericin B, 0.6-1.0mg/kg

disease q.d (AI) IV q.w.-t.i.w
Itraconazole, 200mg capsule
po q.d
H. capsulatum Documented Itraconazole capsule, Amphotericin B, 1.0mg /kg IV
disease 200mg po b.i.d (AI) q.w (AI)
Coccidioides immitis Documented Fluconazole, 400mg po Amphotericin B, 1.0mg/kg IV
disease q.d (AII) q.w
Itraconazole, 200mg capsule
po b.i.d
Salmonella Species, Bacteraemia Ciprofloxacin, 500mg po Antibiotic chemoprophylaxis
(non-typhi)3 b.i.d for several months with another active agent
Recommended Only if Subsequent Episodes Are Frequent or Severe
Herpes simplex Frequent/severe Acyclovir, 200mg po Valacyclovir, 500mg po b.i.d
Virus (HSV) recurrences t.i.d or 400mg po b.i.d
Famciclovir, 250mg po
b.i.d
Candida Frequent/severe Fluconazole, 100-200mg Itraconazole solution, 200mg
(oropharyngeal or recurrences po q.d po q.d
vaginal)
Candida Frequent/severe Fluconazole, 100-200mg Itraconazole solution, 200mg

(oesophageal) recurrences po q.d po q.d
VI-7
1
Pyrimethamine-sulfadiazine confers protection against PCP as well as toxoplasmosis; clindamycin-
pyrimethamine does not offer protection against PCP.
2
Many multiple-drug regimens are poorly tolerated. Drug interactions (e.g. those seen with clarithromycin and
rifabutin) can be problematic; rifabutin has been associated with uveitis, especially when administered at daily doses of
>300mg or concurrently with fluconazole or clarithromycin. During pregnancy, azithromycin is recommended instead
of clarithromycin because clarithromycin is teratogenic in animals.
3
Efficacy for eradication of Salmonella has been demonstrated only for ciprofloxacin.
VI-8
RECOMMENDATIONS FOR USE OF SPECIFIC VACCINES IN INDIVIDUALS WITH HIV INFECTION
The vaccination of HIV-infected individuals is complicated by the fact that the immune response to
vaccines may be inadequate. Furthermore, there is a risk that some live vaccines may themselves cause
progressive infection. The degree of immunodeficiency induced by HIV varies from insignificant to
profound, and this range should be taken into account when considering a schedule of vaccination, as
should the risk of acquisition of the infection one is trying to prevent. Although it may be logical to give
higher or more frequent doses of vaccines to these patients, in most cases, there are insufficient data to
advocate such measures. Children with perinatally-acquired HIV differ substantially from adults, as
immunisation and first-exposure to vaccine antigens occurs after HIV infection in these patients. For
adults, most vaccines are inducing a secondary immune response. HIV-infected individuals of any age
who are well-controlled on HAART (undetected or low viral loads with good preservation of CD4+ T cell
counts) are likely to respond well to vaccines.
Diphtheria-Pertussis-Tetanus (DPT) Vaccines: Use the standard schedule.
Haemophilus influenzae Type B (Hib) Vaccine: Use the standard schedule.
Poliomyelitis Vaccines: Due to the theoretical risk of the oral polio vaccine (OPV)'s neurotropic effect
on immunocompromised persons, the inactivated polio vaccine (IPV) is preferred for all HIV-positive
individuals and their household contacts. OPV has been given to HIV-positive children without adverse
effects, but faecal excretion may be prolonged. If OPV is given, family or household contacts should take
extra care with handwashing after changing the nappies of a vaccinated child or providing toilet care.
Measles-Mumps-Rubella (MMR) Vaccine: Unless they are severely immunosuppressed, MMR should
be routinely administered to HIV-infected children at age twelve months. Table 1 shows age-specific
definitions of severe immunosuppression. Measles may cause severe disease in HIV-infected children;
severely immunocompromised children who are exposed to measles should therefore be given normal
immunoglobulin (in a dose of 0.5 mL/kg), regardless of their vaccination status.
Table 1: Age-Specific CD4+ T Cell Counts Indicating Severe Immunosuppression in HIV Infection†
Age <12 Months 1-5 Years >6 Years
CD4+ T Cell Count <750 <500 <200
(0.75X109/1) (0-50X109/1) (0.20X109/1)
Pneumococcal Vaccine: Pneumococcal disease, both respiratory and invasive, is a frequent cause of
morbidity in HIV-infected children and adults. Pneumococcal polysaccharide vaccine is recommended
for all HIV-infected patients age two years or older, although there is limited evidence of efficacy in this
group.
VZV Vaccine: VZV vaccine should be given only to asymptomatic, non-immunosuppressed children.
Eligible children should receive two doses of vaccine with at least a three-month interval between doses.
The first dose may be given as early as age twelve months. Varicella zoster immunoglobulin (ZIG or
VZIG) should be offered to HIV-positive individuals who have been infected with clinical chickenpox or
who can be shown to be non-immune following exposure to chickenpox or shingles. ZIG should be given
within seventy-two hours of exposure but may still have some protective effects if administered up to
seven days later.
Influenza Vaccine: Because of potential morbidity from influenza, annual vaccination is advisable in
†
Australian Government, Dept. of Health and Ageing. The Australian Immunisation Handbook. 7th ed. 2000.
Available at <http://immunise.health.gov.au/handbook.htm>. Last accessed 2004.
VI-9
symptomatic HIV-infected adults and children because benefit is likely to exceed risk.
BCG Vaccine: BCG must not be given to HIV-infected children or adults due to the risk of disseminated
BCG infection. Hence, BCG should not be administered to infants born to HIV-infected mothers shortly
after birth. BCG can be administered once HIV infection has been ruled out in the infant.
HBV Vaccine: Recombinant HBV vaccines are safe to use, but the immunological response may be
poor. HIV-positive individuals may have to receive twice the normal dosage (e.g. double the normal
volume of vaccine on three occasions or a standard dose of the increased strength dialysis formulation of
vaccine on three occasions). A patient’s antibody level should be measured at the completion of the
vaccination schedule. The indications for the use of HBV vaccine are the same as for non-HIV infected
individuals. A proportion of HIV-positive MSM may already have been exposed to HBV.
HAV Vaccine: The use of HAV vaccine in HIV-infected individuals has not been evaluated, but there is
no reason to believe that the vaccine would pose a risk. It should be given if indicated.
Vaccinations for Travel: Live attenuated typhoid or yellow fever vaccines should not be given to HIV-
infected individuals. Meningococcal, typhoid, and rabies vaccines are safe and can be used for the usual
indications.
VI-10
Table 2: Recommended Immunisation Schedule for HIV-Infected Childrena
Vaccine Age
1 2 4 6 12 mos. 15 mos. 18 mos. 24 mos. 4-6 yrs. 11-12 yrs. 14-16

Birth mo. mos. mos. mos. yrs.
ª Recommendations for these vaccines are the same as those for immunocompetent children. ª
Hepatitis B1 Hep B #1
Hep B #2 Hep B #3 Hep B
Diphtheria and tetanus

toxoids, pertussis2
DTP or DTP or DTP or DTaP DTP or Td

DTaP DTaP DTaP DTaP
Haemophilus influenzae
type b3 Hib Hib Hib Hib*
Inactivated polio4 IPV IPV IPV IPV
Hepatitis A5 Hep A in selected areas
ª Recommendations for these vaccines differ from those for immunocompetent children. ª
Pneumococcus6 PCV PCV PCV PCV
PCV PPV23 PPV23
(age 5-7
yrs)
Do not give to severely
MMR7 immunosuppressed (Category 3) children. MMR MMR
MMR
Give only to asymptomatic non-
Varicella8 immunosuppressed (Category 1) children. Var Var Var
Contra-indicated in all other HIV-infected
children.
Influenza9 A dose is recommended every year.
VI-11
*Fourth dose of Hib is not mandatory.
These Caribbean guidelines for immunisation in HIV-infected and -exposed infants and children primarily reflect the immunisation schedule in the United States,
with some modifications made to reflect the WHO/PAHO/CAREC Expanded Programme on Immunisations (EPI) schedule. This document can therefore be
reasonably construed to represent the maximum standard of care. Licensed combination vaccines may be used whenever any components of the combination are
indicated and the vaccine’s other components are not contra-indicated. Providers should consult the manufacturer’s package inserts for detailed
recommendations.
1
In countries that use the pentavalent-combination vaccine (DPT/Hep B/Hib), four doses of HBV vaccine are administered (along with the DPT and Hib doses). Infants born to
hepatitis B surface antigen (HBsAg)-negative mothers should receive the first dose of HBV vaccine soon after birth and before hospital discharge but no later than age two
months. Only monovalent HBV can be used for the birth dose. The second dose should be administered at least one month after the first dose, except for combination vaccines
that cannot be administered before age six weeks. The third dose should be administered at least four months after the first dose and at least two months after the second dose, but
not before age six months. Infants born to HBsAg-positive mothers should receive HBV vaccine and 0.5 mL hepatitis B immune globulin (HBIG) within twelve hours of birth at
separate sites. The second dose is recommended at age one to two months and the third dose at age six months. These infants should be tested for HBsAg and antibody to HBsAg
(anti-HBs) at age nine to fifteen months. Infants born to mothers whose HBsAg status is unknown should receive the HBV vaccine within twelve hours of birth. Maternal blood
should be drawn at delivery to determine the mother’s HBsAg status; if the HBsAg test is positive, the infant should receive HBIG as soon as possible (no later than age one
week). All children and adolescents (through age eighteen years) who have not been immunised against HBV should begin the series during any visit. Providers should make
special efforts to immunise children who were born in or whose parents were born in areas of the Caribbean where HBV infection is moderately or highly endemic.
2
The fourth dose of diphtheria and tetanus toxoids and whole-cell or acellular pertussis vaccine (DTP or DTaP) may be administered as early as age twelve months, provided
that six months have elapsed since the third dose and the child is unlikely to return at age fifteen to eighteen months. Tetanus and diphtheria toxoids (Td) is recommended at
age eleven to twelve years if at least five years have elapsed since the last dose of DTP, DTaP, or Td. Subsequent routine Td boosters are recommended every ten years.
3
Many countries use the pentavalent-combination vaccine (DPT/HepB/Hib).
4
If available, all infants and children should get IPV. All children should receive four doses of IPV at age two months, age four months, between ages six and eighteen
months, and between ages four and six years. In areas where IPV is not available, WHO/UNICEF recommend OPV for children with asymptomatic HIV infection. Due to
the theoretical risk of OPV's neurotropic effect on immunocompromised persons, IPV is preferred for all HIV-positive individuals and their household
contacts. OPV has been given to HIV-positive children without adverse effects, but faecal excretion may be prolonged. If OPV is given, family or household
contacts should take extra care with handwashing after changing the nappies of a vaccinated child or after providing toilet care.
5
HAV vaccine is recommended for certain high-risk groups such as those with HBV or hepatitis C infection. Information is available from local public health authorities.
6
The heptavalent pneumococcal conjugate vaccine (PCV) is recommended for all children age two to fifty-nine months with HIV. Children age two years and older should also
receive the 23-valent pneumococcal polysaccharide vaccine; a single revaccination with the 23-valent vaccine should be offered to children after age three to five years.
7
MMR should not be administered to severely immunocompromised (Category 3) children. HIV-infected children without severe immunosuppression would routinely receive
their first dose of MMR as soon as possible after reaching their first birthday. Consideration should be given to administering the second dose of MMR as soon as one month
(e.g. a minimum of twenty-eight days) after the first dose rather then waiting until school entry. An alternative immunisation schedule per WHO recommendation is to give
standard measles vaccine at age six months with a second dose as soon after age nine months as possible. Measles may cause severe disease in HIV-infected children.
Severely immunocompromised children who are exposed to measles should therefore be given normal immunoglobulin (in a dose of 0.5 mL/kg), regardless of
their vaccination status.
8
VZV vaccine should be given only to asymptomatic, non-immunosuppressed children. Eligible children should receive two doses of vaccine with at least a three-month interval
between doses. The first dose may be given as early as age twelve months. ZIG should be offered to HIV-positive individuals who have been infected with clinical
VI-12
chickenpox or who can be shown to be non-immune following exposure to chickenpox or shingles. ZIG should be given within seventy-two hours of exposure
but may still have some protective effects if administered up to seven days later.
9
Inactivated split influenza virus vaccine should be administered to all HIV-infected children age six months each year. For children age six months to less than nine years who are
receiving influenza vaccine for the first time, two doses given one month apart are recommended.
.
VI-13
PROPHYLAXIS TO PREVENT FIRST EPISODE OF OPPORTUNISTIC DISEASE IN INFANTS AND
CHILDREN WITH HIV INFECTION
PREVENTIVE REGIMENS
Strongly Recommended as Standard of Care

Pneumocystis HIV-infected or HIV- TMP-SMX, Dapsone (children aged >1
jiroveci (PCP) indeterminate, infants aged 150/750mg/m2/d in 2 month), 2mg/kg (max 100mg)
(formerly 1-12 months divided doses po t.i.w on po q.d or 4g/kg (max 200mg) po
known as consecutive days q.w
HIV-infected children
Pneumocystis
aged 1-5 years with CD4+ Acceptable alternative On aerosolised pentamidine
carinii)1
T cell count <500/mm3 or dosage schedules: (children aged ≥5 years.),
CD4+ T cell percentage 300mg q.m via Respirgard II™
Single dose po t.i.w on
<15% nebuliser atovaquone (children
consecutive days
HIV-infected children aged 1-3 months and >24
2 divided doses po q.d; 2 months, 30mg/kg po q.d;
aged 6-12 years with
divided doses on alternate children aged 4-24 months,
CD4+ T cell count
days 45mg/kg po q.d)
<200/mm3, or CD4+ T cell
percentage <15%
Mycobacterium tuberculosis2
INH-sensitive TST reaction of ≥5mm or INH, 10-15mg/kg (max RIF, 10-20mg/kg (max 600mg)
prior positive TST result 300mg) po q.d x 9 po q.d x 4-6 months
without treatment months
Contact with any case of 20-30mg/kg (max
active TB regardless of 900mg) po b.i.w x 9
TST result months
INH resistant Same as above; high RIF, 10-20mg/kg (max Uncertain
probability of exposure to 600mg) po q.d x 4-6
INH-resistant TB months
Multi-drug Same as above; high Choice of drugs requires
(INH and RIF) probability of exposure to consultation with public
resistant multidrug resistant TB health authorities and
depends on susceptibility
of isolation from source
patient.
Mycobacterium For children aged ≥6 years, Clarithromycin, 7.5mg/kg Azithromycin, 5mg/kg (max
avium CD4+ T cell counts of (max 500mg) po b.i.d 250mg) po q.d
Complex <50/mm3 Azithromycin, 20mg/kg Children aged ≥6 years,
(MAC)2 Aged 2-6 years, CD4+ T (max 1,200mg) po q.w rifabutin, 300mg po q.d
cell count <75/mm3
Aged 1-2 years, CD4+ T
cell count <500/mm3
Aged <1 year, CD4+ T cell
count <750/mm3
VI-14
PREVENTIVE REGIMENS
Varicella Significant exposure to VZIG, 1 vial None

zoster Virus varicella or shingles with (1.25mL)/10kg (max 5
(VZV)3 no history of chickenpox vials) IM, administered
or shingles ≤96 hours after exposure,
ideally within 48 hours
Vaccine- HIV exposure/infection Routine immunisations None
Preventable (see Table 3)
Pathogens4
Generally Recommended as Standard of Care
T. gondii5 IgG antibody to TMP-SMX, Dapsone (children aged ≥1
Toxoplasma and severe 150/750mg/m2/d in 2 month), 2mg/kg or 15mg/m2
immuno-suppression divided doses po q.d (max 25mg) po q.d plus
pyrimethamine, 1mg/kg po q.d
plus leucovorin, 5mg po every
3 days
Atovaquone, (aged 1-3 months
and >24 months, 30mg/kg po
q.d; aged 14-24 months
45mg/kg po q.d)
Varicella HIV-infected children VZV vaccine (See None

zoster Virus who are asymptomatic Vaccine-preventable
(VZV) and not pathogens section of this
immunosuppressed table)
Influenza All patients (annually Inactivated split trivalent Oseltamivir (during outbreaks
Virus before influenza season) influenza vaccine (See of influenza A or B) for
Vaccine-preventable children aged ≥13 years, 75mg
pathogens section of this po q.d
table)
Rimantadine or amantadine
(during outbreaks of influenza
A); aged 1-9 years, 5mg/kg in
2 divided doses (max 150mg
/day) po q.d; aged >10 years,
use adult doses
VI-15
PREVENTIVE REGIMENS
Not Recommended for Most Children; Indicated for Use Only in Unusual Circumstances
Invasive Hypogamma- IVIG, 400mg/kg q2-4w None

Bacterial globulinaemia (e.g. IgG
Infections6 <400mg/dL)
C. neoformans Severe Fluconazole, 3-6mg/kg Itraconazole, 2-5mg/kg po q12-
immunosuppression po q.d 24h
H. capsulatum Severe Itraconazole, 2-5mg/kg None

immunosuppression, po q12-24h
endemic geographic area
Cytomegalo- CMV antibody positivity Oral ganciclovir, None

virus (CMV)7 and severe 30mg/kg po t.i.d
immunosuppression
1
Daily TMP-SMX reduces the frequency of some bacterial infections. TMP-SMX, dapsone-pyrimethamine, and possibly
atovaquone (with or without pyrimethamine) appear to protect against toxoplasmosis, although data have not been
prospectively collected. When compared with weekly dapsone, daily dapsone is associated with lower incidence of PCP but
higher haematologic toxicity and mortality (Source: McIntosh K, Cooper E, Xu J, et al. Toxicity and efficacy of daily vs.
weekly dapsone for prevention of Pneumocystis jiroveci pneumonia in children infected with HIV. Ped Infect Dis J
1999;18:432-9). The efficacy of parenteral pentamidine (e.g. 4mg/kg every 2-4 weeks) is controversial. Patients receiving
therapy for toxoplasmosis with sulfadiazine-pyrimethamine are protected against PCP and do not need TMP-SMX.
2
Significant drug interactions can occur between rifamycins (RIF and rifabutin) and PIs and NNRTIs. Consult a specialist.
3
Children routinely being administered IVIG should receive VZIG if the last dose of IVIG was administered more than
twenty-one days before exposure.
4
HIV-infected and -exposed children should be immunised according to the childhood immunisation schedule in this section
(See Table 2), which has been adapted from the January-December 2001 schedule recommended for immunocompetent
children by the U.S. Advisory Committee on Immunisation Practices, the American Academy of Paediatrics, and the
American Academy of Family Physicians. This schedule differs from that for immunocompetent children in that both the
conjugate pneumococcal vaccine (PCV-7) and the pneumococcal polysaccharide vaccine (PPV-23) are recommended, and
vaccination against influenza should be offered. MMR should not be administered to severely immunocompromised
children. Vaccination against varicella is indicated only for asymptomatic non-immunosuppressed children. Once an HIV-
exposed child is determined not to be HIV-infected, the schedule for immunocompetent children applies.
5
Protection against toxoplasmosis is provided by the preferred anti-Pneumocystis regimens and possibly by atovaquone.
Atovaquone may be used with or without pyrimethamine. Pyrimethamine alone probably provides little, if any, protection.
6
Respiratory syncytial virus (RSV) IVIG (750mg/kg), not monoclonal RSV antibody, may be substituted for IVIG during the
RSV season to provide broad anti-infective protection, if this product is available.
7
Oral ganciclovir and perhaps valganciclovir result in reduced CMV shedding in CMV-infected children. Acyclovir is not
protective against CMV.
VI-16
PROPHYLAXIS TO PREVENT RECURRENCE OF OPPORTUNISTIC DISEASE (AFTER CHEMOTHERAPY
FOR ACUTE DISEASE) IN INFANTS AND CHILDREN WITH HIV INFECTION
PREVENTIVE REGIMENS
Recommended for Life as Standard of Care
Pneumocystis jiroveci Prior episode of TMP-SMX, Dapsone (children aged ≥1
(PCP) (formerly P. jiroveci 150/750mg/m2/day in 2 month), 2mg/kg (max
known as pneumonia (PCP) divided doses po t.i.w on 100mg) po q.d or 4mg/kg
Pneumocystis carinii) consecutive days (max 200mg) po q.w
Acceptable alternative Aerosolised pentamidine
schedules for same dosage: (children aged ≥5 years),
Single dose po t.i.w on 300mg q.m via Respirgard
consecutive days; 2 divided IITM nebuliser
doses po q.d; 2 divided doses
po; t.i.w on alternate days Atovaquone (aged 1-3
months and >24 months,
30mg/kg po q.d; aged 4-24
months, 45mg/kg po q.d)
T. gondii1 Prior toxoplasmic Sulfadiazine, 85-120mg/kg/d Clindamycin, 20-
encephalitis in 2-4 divided doses po q.d 30mg/kg/d in 4 divided
plus pyrimethamine, 1mg/kg doses po q.d plus
or 15mg/m2 (max 25mg) po pyrimethamine, 1mg/kg po
q.d plus leucovorin, 5mg po q.d plus leucovorin, 5mg
q3d po q3d
Mycobacterium Prior disease Clarithromycin, 7.5mg/kg Azithromycin, 5mg/kg (max
avium Complex (max 500mg) po b.i.d plus 250mg) po q.d plus EMB,
(MAC)2 EMB, 15mg/kg (max 900mg) 15mg/kg (max 900mg) po
po q.d; with or without q.d.; with or without
rifabutin, 5mg/kg (max rifabutin, 5mg/kg (max
300mg) po q.d 300mg) po q.d
C. neoformans Documented Fluconazole, 3-6mg/kg po q.d Amphotericin B, 0.5-
disease 1.0mg/kg IV q1-3w
Itraconazole, 2-5mg/kg po
q12-24h
H. capsulatum Documented Itraconazole, 2-5mg/kg po Amphotericin B, 1.0mg/kg
disease q12-48h IV q.w
Coccidioides immitis Documented Fluconazole, 6mg/kg po q.d Amphotericin B, 1.0mg/kg

disease IV q.w; itraconazole, 2-
5mg/kg po q12-48h
Cytomegalovirus Prior end-organ Ganciclovir, 5mg/kg IV q.d; or (For retinitis) Ganciclovir
(CMV) disease foscarnet, 90-120mg/kg IV q.d sustained-release implant q6-
9m plus ganciclovir,
30mg/kg po t.i.d
VI-17
PREVENTIVE REGIMENS
Salmonella Species Bacteraemia TMP-SMX, 150/750mg/m2 in Antibiotic
(non-typhi)3 2 divided doses po q.d for chemoprophylaxis with
several months another active agent
Recommended for Standard of Care Only if Subsequent Episodes Are Frequent or Severe
Invasive Bacterial >2 infections in 1 TMP-SMX 150/750mg/m2, in Antibiotic
Infections4 year period 2 divided doses po q.d; or chemoprophylaxis with
IVIG, 400mg/kg q2-4w another active agent
Herpes simplex Virus Frequent/severe Acyclovir, 80mg/kg/day in 3-4

(HSV) recurrences divided doses po q.d
Candida Frequent/severe Fluconazole, 3-6mg/kg po q.d

(oropharyngeal) recurrences
Candida Frequent/severe Fluconazole, 3-6mg/kg po q.d Itraconazole solution,

(oesophageal) recurrences 5mg/kg po q.d
1
Only pyrimethamine plus sulfadiazine confers protection against PCP as well as toxoplasmosis. Although the
clindamycin plus pyrimethamine regimen is recommended in adults, it has not been tested in children. However, these
drugs are safe and are used for other infections.
2
Significant drug interactions might occur between rifabutin and PIs and NNRTIs. Consult an expert.
3
The drug should be determined by susceptibilities of the organism isolated. Alternatives to TMP-SMX include
ampicillin, chloramphenicol, or ciprofloxacin. However, ciprofloxacin is not approved for use in persons aged less than
18 years; therefore, it should be used in children with caution and only if no alternatives exist.
4
Antimicrobial prophylaxis should be chosen based on the microorganism and antibiotic sensitivities. TMP-SMX, if
used, should be administered daily. Providers should be cautious about using antibiotics solely for this purpose because
of the potential for development of drug-resistant microorganisms. IVIG might not provide additional benefit to
children receiving daily TMP-SMX but may be considered for children who have recurrent bacterial infections despite
TMP-SMX prophylaxis. Choice of antibiotic prophylaxis vs. IVIG should also involve consideration of adherence, ease
of IV access, and cost. If IVIG is used, RSV IVIG (750mg/kg), not monoclonal RSV antibody, may be substituted for
IVIG during the RSV season to provide broad anti-infective protection, if this product is available.
VI-18
CRITERIA FOR STARTING, DISCONTINUING, AND RESTARTING OI PROPHYLAXIS FOR ADULTS WITH HIV INFECTION*
Criteria for Criteria for Criteria for Criteria for Criteria for Criteria for
Initiating Primary Discontinuing Restarting Initiating Discontinuing Restarting
Prophylaxis Primary Primary Secondary Secondary Secondary
Prophylaxis Prophylaxis Prophylaxis Prophylaxis Prophylaxis
Opportunistic Illness
PCP CD4+ T cell count of CD4+ T cell count CD4+ T cell Prior PCP CD4+ T cell count of CD4+ T cell
<200 cells/mm3 or if >200 cells/mm3 count of <200 >200 cells/mm3 for ≥3 count of <200
oropharyngeal for ≥3 months cells/mm3 months cells/mm3
candidiasis
Toxoplasmosis IgG antibody to CD4+ T cell count CD4+ T cell Prior toxoplasmic CD4+ T cell count of CD4+ T cell
toxoplasma and of >200 cells/mm3 count of <100- encephalitis >200 cells/mm3 count of <200
CD4+ T cell count of for ≥3 months 200 cells/mm3 sustained (e.g. ≥6 cells/mm3
<100 cells/mm3 months) and
Completed initial
therapy and
Asymptomatic for
toxoplasmosis
Disseminated CD4+ T cell count of CD4+ T cell count CD4+ T cell Documented CD4+ T cell count of CD4+ T cell
MAC <50 cells/mm3 of >100 cells/mm3 count of <50- disseminated >100 cells/mm3 count of <100
for ≥3 months 100 cells/mm3 disease sustained (e.g. ≥6 cells/mm3
months) and
Completed 12 months of
MAC therapy and
Asymptomatic for
MAC
VI-19
Cryptococcosis None Not applicable Not applicable Documented CD4+ T cell count of CD4+ T cell
disease >100-200 cells/mm3 count of <100-
sustained (e.g. ≥6 200 cells/mm3
months) and
Completed initial
therapy and
Asymptomatic for
cryptococcosis
Histoplasmosis None Not applicable Not applicable Documented No criteria Not applicable
disease recommended for
stopping
Coccidioido- None Not applicable Not applicable Documented No criteria Not applicable
mycosis disease recommended for
stopping
CMV retinitis None Not applicable Not applicable Documented end- CD4+ T cell count of CD4+ T cell
organ disease >100-150 cells/mm3 count of <100-
sustained (e.g. ≥6 150 cells/mm3
months) and
No evidence of active
disease
Regular ophthalmic
examination
VI-20
RECOMMENDATIONS TO HELP PATIENTS AVOID EXPOSURE TO OR INFECTION WITH
OPPORTUNISTIC PATHOGENS
SEXUAL EXPOSURES
√ Patients should use a latex condom during every act of sexual intercourse to reduce the risk for acquiring
CMV, HSV, and human papillomavirus (HPV), as well as other sexually transmitted pathogens. Condom
use also will, theoretically, reduce the risk for acquiring human herpes virus-8 (HHV-8), as well as super-
infection with another HIV strain. Condom use will also reduce the risk of transmission of HIV and other
sexually transmitted pathogens to others. Data regarding the use and efficacy of female condoms are
incomplete, but these devices should be considered as a risk-reduction strategy.
√ Patients should avoid sexual practices that might result in oral exposure to faeces (e.g. oral-anal contact) to
reduce the risk for intestinal infections (e.g. cryptosporidiosis, shigellosis, campylobacteriosis, amebiasis,
giardiasis, and HAV). Latex condom use alone may not reduce the risk of acquiring these faecal-orally
transmitted pathogens, especially those which have low infectious doses. Persons wishing to reduce their
risk of exposure might consider using dental dams or similar barrier methods for oral-anal and oral-genital
contact, changing condoms after anal intercourse, and wearing latex gloves during digital-anal contact.
Frequently washing hands and genitals with warm soapy water during and after activities that may bring
these body parts in contact with faeces may further reduce risk of illness.
√ HBV immunisation is recommended for all susceptible (anti-HBc-negative) HIV-infected patients.
√ HAV immunisation is recommended for all susceptible MSM, as well as others with indications for HAV
vaccine.
INJECTION DRUG USE EXPOSURES
√ Injection drug use is a complex behaviour that puts HIV-infected persons at risk for HBV and hepatitis
C virus infection; additional, possibly drug-resistant strains of HIV; and other blood-borne pathogens.
Providers should assess the individual’s readiness to change this practice, and encourage efforts to provide
education and support directed at recovery. Patients should be counselled to stop using injection drugs
and to enter and complete substance-abuse treatment including relapse prevention programmes.
√ If they are continuing to inject drugs, patients should be advised:
√ to never reuse or share syringes, needles, water, or drug preparation equipment; if, nonetheless,
injection equipment that has been used by other persons is shared, to first clean the equipment with
bleach and water;3
√ to use only sterile syringes obtained from a reliable source (e.g. pharmacies or syringe exchange
programmes);
√ to use sterile (e.g. boiled) water to prepare drugs; if this is not possible, to use clean water from a
reliable source (e.g. fresh tap water); to use a new or disinfected container (“cooker”) and a new filter
(“cotton”) to prepare drugs;
√ to clean the injection site with a new alcohol swab before injection; and
√ to safely dispose of syringes after one use.
√ All susceptible injection drug users should be immunised against HBV and HAV.
ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES
√ Certain activities or types of employment might increase the risk for exposure to TB. These include
3
US Public Health Service. HIV prevention bulletin: medical advice for persons who inject illicit drugs. 8 May 1997.
Available from: http://www.cdc.gov/hiv/pubs/guidelines.htm. Last accessed 2004.
VI-21
volunteer work or employment in healthcare facilities, correctional institutions, and homeless shelters, as
well as other settings identified as high-risk by local health authorities. Decisions about whether to
continue with such activities should be made in conjunction with the healthcare provider and should be
based on such factors as the patient’s specific duties in the workplace, the prevalence of TB in the
community, and the degree to which precautions designed to prevent the transmission of TB are taken in
the workplace. These decisions will affect the frequency with which the patient should be screened for TB.
√ Childcare providers and parents of children in childcare are at increased risk for acquiring CMV infection,
cryptosporidiosis, and other infections (e.g. HAV and giardiasis) from children. The risk for acquiring
infection can be diminished by good hygienic practices, such as handwashing after faecal contact (e.g.
during nappy-changing) and after contact with urine or saliva. All children in childcare facilities also are at
increased risk for acquiring these same infections; parents and other caretakers of HIV-infected children
should be advised of this risk.
√ Occupations involving contact with animals (e.g. veterinary work and employment in pet stores, farms, or
slaughterhouses) might pose a risk for cryptosporidiosis, toxoplasmosis, salmonellosis, campylobacteriosis, or
Bartonella infection. However, the available data are insufficient to justify a recommendation against work in
such settings.
√ Contact with young farm animals, especially animals with diarrhoea, should be avoided to reduce the risk for
cryptosporidiosis.
√ Handwashing after gardening or other contact with soil might reduce the risk for cryptosporidiosis and
toxoplasmosis.
√ In areas endemic for histoplasmosis, patients should avoid activities known to be associated with increased
risk (e.g. creating dust when working with surface soil; cleaning chicken coops that are heavily contaminated
with compost droppings; disturbing soil beneath bird-roosting sites; cleaning, remodelling, or demolishing old
buildings; and cave exploring).
√ In areas endemic for coccidioidomycosis, when possible, patients should avoid activities associated with
increased risk, including those involving extensive exposure to disturbed native soil (e.g. at building
excavation sites or during dust storms).
VI-22
VII: ANTIRETROVIRAL THERAPY IN PREGNANT WOMEN AND
PREVENTION OF MOTHER-TO-CHILD TRANSMISSION (PMTCT) OF
HIV
TABLE OF CONTENTS
INTRODUCTION AND BACKGROUND .................................................................................................... VII-1
GENERAL RECOMMENDATIONS REGARDING THE ANTENATAL CARE OF PREGNANT WOMEN
WITH HIV INFECTION .................................................................................................................... VII-1
POTENTIAL FOR THE DEVELOPMENT OF NEVIRAPINE (NVP) RESISTANCE FOLLOWING THE
ADMINISTRATION OF SINGLE DOSE NEVIRAPINE (SD NVP) AND OTHER NVP-BASED
PMTCT REGIMENS ........................................................................................................................ VII-2
PMTCT ANTIRETROVIRAL THERAPY RECOMMENDATIONS: SPECIFIC SCENARIOS ..................... VII-5
Scenario A: Non-Pregnant Woman Who Needs ART for Her Own Health .................................. VII-5
Scenario B: Woman Who Is Already Receiving ART at the Time She Becomes Pregnant .......... VII-5
Scenario C: Pregnant Woman, Not on HAART, Who Now Requires HAART for Her
Own Health .................................................................................................................................. VII-6
Scenario D: Pregnant Woman Who Does Not Require HAART for Her Own Health .................. VII-6
Scenario E: HIV-Infected Woman without Prenatal Care Who Presents in Labour ...................... VII-8
Scenario F: Infants Born to Women Who Received No Antiretroviral Therapy for PMTCT Either
Prepartum or During Labour ........................................................................................................ VII-9
GENERAL RECOMMENDATIONS FOR MANAGEMENT OF THE HIV-INFECTED MOTHER DURING
LABOUR AND DELIVERY ................................................................................................................ VII-9
RECOMMENDATIONS REGARDING BREASTFEEDING AND POSTPARTUM MANAGEMENT OF THE
MOTHER ......................................................................................................................................... VII-9
EFFICACY OF PMTCT INTERVENTIONS: SUMMARY OF THE EVIDENCE ....................................... VII-10
RISKS OF ART IN PREGNANCY .......................................................................................................... VII-10
Risks to the Mother’s Health......................................................................................................... VII-11
Infant Health Considerations......................................................................................................... VII-13
APPENDIX A: SUMMARY OF SELECTED CLINICAL TRIALS OF PROPHYLACTIC ARV REGIMENS FOR

PMTCT.......................................................................................................................................... VII-15
APPENDIX B: ANTIRETROVIRAL DRUG PHARMACOKINETIC AND TOXICITY DATA IN HUMAN
PREGNANCY AND RECOMMENDATIONS FOR USE FOR TREATMENT OF PREGNANT WOMEN
WITH HIV INFECTION .................................................................................................................... VII-20
APPENDIX C: DOSING OF ARVS IN PMTCT REGIMENS .................................................................... VII-26
VII-i
VII. ANTIRETROVIRAL THERAPY IN PREGNANT WOMEN AND PREVENTION
OF MOTHER-TO-CHILD TRANSMISSION (PMTCT) OF HIV
INTRODUCTION AND BACKGROUND

Mother-to-child transmission (MTCT) of HIV can occur during pregnancy, during delivery, or
postpartum via breastfeeding. Without treatment, MTCT occurs in 15% to 30% of pregnancies in non-
breastfeeding HIV-infected women. In breastfeeding populations, the rate is as high as 30% to 45%.
Several clinical trials have clearly established that interventions exist for the HIV-infected pregnant
woman that can dramatically reduce the rate of HIV transmission to her infant. Combination antiretroviral
therapy (ART) and avoidance of breastfeeding can reduce this rate to 2% or less. Even where alternatives
to breastfeeding are unavailable or unacceptable, appropriate ART can significantly reduce the risk of
MTCT. Elective caesarean section has also been demonstrated to reduce the risk of vertical transmission
in women receiving ART monotherapy or no ART during pregnancy. However, in most resource-limited
settings, Caesarean section is not commonly available and is often unsafe, reducing the relevance of this
intervention in PMTCT efforts.
The potential benefits of ART in reducing MTCT should be balanced against the risks to both the mother
and the infant posed by ART. Fortunately, these risks appear to be low and are generally strongly
outweighed by the benefits of ART.
These guidelines present specific recommendations for PMTCT in various clinical scenarios, followed by
a discussion of the evidence from clinical trials that form the basis of these recommendations.
GENERAL RECOMMENDATIONS REGARDING THE ANTENATAL CARE OF PREGNANT WOMEN

WITH HIV INFECTION
Identification of HIV-infected women prior to or during pregnancy is essential in order to properly
administer PMTCT and optimal therapy for the infected mother. Voluntary HIV counselling and testing
(VCT) is therefore recommended for all pregnant women. Strict confidentiality must be maintained at all
levels.
Ideally, HIV-infected pregnant women should be enrolled in high-risk clinics to ensure appropriate
routine obstetric care along with antiretroviral (ARV) prophylaxis and on-going counselling. The
importance of adherence and of maintaining all medical appointments should be emphasised. Where
possible, any potential barriers to adherence should be addressed prior to initiation of ARV prophylaxis.
Standard antenatal investigations should be performed on all pregnant women, including haemoglobin,
blood typing, haemoglobin electrophoresis (or sickle test if this is unavailable), syphilis serology, and
hepatitis B screening. Counselling on healthy nutrition should be offered, as well as referral to a
nutritionist if necessary. Counselling regarding the risks of breastfeeding and investigation into the
possibility of formula-feeding should begin in the antenatal period.
Mothers who receive ART for PMTCT should be taught how to self-medicate during labour to ensure
prompt compliance at the onset of labour, and the ARV(s) that will be taken during labour should be
dispensed by thirty-six weeks gestation.
VII-1
POTENTIAL FOR THE DEVELOPMENT OF NEVIRAPINE (NVP) RESISTANCE FOLLOWING THE
ADMINISTRATION OF SINGLE DOSE NEVIRAPINE (SD NVP) AND OTHER NVP-BASED PMTCT
REGIMENS
Background
Several clinical trials have documented detectable resistance to NVP* following delivery in a significant
portion of women who received SD NVP during labour. The frequency with which resistance is detected
appears to depend upon several variables, including the subtype (clade) of HIV-1 involved; the mother’s
clinical status at the time she receives SD NVP; the time at which resistance testing is performed after
delivery; and the sensitivity of the resistance assay used. Studies involving clade B virus, the
predominant clade of HIV-1 in the Caribbean, have documented detectable NVP resistance following
delivery in 15 to 40% of women who received SD NVP (with or without other ARVs) during labour.
The degree to which viral resistance induced by single-dose nevirapine (SD NVP) is associated with
diminished clinical response to subsequent NNRTI-based highly active antiretroviral therapy (HAART)
in women has not been clearly established. Follow-up of women enrolled in one trial from Thailand
revealed a diminished virologic response at six months to NVP-based HAART in women who had
previously received SD NVP (median time from SD NVP exposure to initiation of HAART was 6
months), though the immunologic response (rise in CD4+ T cell count) was equally robust in these
women as it was in women who had not previously received SD NVP (see Scenario D for additional
details). However, data from a study in Botswana indicate that a diminished virologic response may be
confined to women who initiate HAART therapy within 6 months of SD NVP exposure: those who
started HAART more than 6 months after SD NVP exposure had a virologic response to HAART that
was similar to that seen in women who lacked prior SD NVP exposure (Lockman, IDSA, 2005).
Additional research is ongoing that will hopefully clarify the impact of specific viral mutations on future
maternal treatment outcomes.
The development of resistance to NVP in these trials results from the extraordinarily long half-life of this
agent: NVP persists at detectable levels in the bloodstream of pregnant women for up to three weeks
following the administration of a single dose. The prolonged exposure of HIV to NVP in this fashion
exerts selective pressure on HIV that favours the development of resistance to NVP. Strategies that may
reduce or eliminate the risk of inducing resistance are being investigated in clinical trials, and preliminary
results have already been reported from some studies.
Possible Strategies to Reduce the Risk of NVP Resistance Associated with PMTCT Regimens: firm data
are lacking to strongly endorse or refute any of the following strategies; however, until further clinical
data become available to clarify their relative advantages and disadvantages, the following options are
presented for consideration. These strategies should be discussed by national and regional policymakers
and, where appropriate, options reviewed with the patients themselves.
1. Administer a “tail” of two NRTIs for a period of time following the administration of SD
NVP. If the mother begins taking two NRTIs (e.g., AZT and 3TC) immediately after the
administration of SD NVP and continues taking the NRTIs for a defined period of time, during
that time period the HIV in her serum will be exposed to three ARVs rather than just NVP, which
should discourage the emergence of NVP resistance. Indeed, several small clinical trials of this
strategy have documented some (but not complete) success in preventing the development of
NVP resistance following SD NVP. However, the ideal length of administration of the 2 NRTI
tail has not been determined, and may vary between different women because the half-life of
NVP varies across individual patients. Administration of a tail that is too short risks promotion of
NVP resistance, while administration of too long a tail (theoretically) risks promotion of
*
Unfortunately, resistance to NVP usually indicates resistance to efavirenz and delavirdine as well, due to
the high degree of cross-resistance in the NNRTI class.
VII-2
resistance to one or both of the NRTIs used in the tail. The studies that have shown decreased
NVP resistance have used a 3 to 7 days tail of AZT/3TC. In the TOPS study, for example, the
rate of NVP resistance was 60% without the tail versus 12% with a 4 day tail of AZT/3TC versus
10% with a 7 day tail of AZT/3TC. The optimal duration of the tail and the optimal components
are not known; studies are ongoing to define this. Because there are no data on the safety and
efficacy of a prolonged tail (more than 1 week) after SD NVP, if a tail is used a duration of 7 days
might be chosen based on the available studies.
2. Administer HAART to all HIV-infected pregnant women for PMTCT, regardless of clinical
status. It is important to note that this strategy does not necessarily solve the problem. First, the
choice of drug regimen is complicated because the risk of symptomatic NVP-related hepatic
toxicity, which can be life-threatening, is markedly increased in women with CD4 counts greater
than 250 cells/mm3 at the time of therapy initiation. Thus, NVP-based HAART would not be an
optimal choice for use in such women, and if prescribed the woman would need close monitoring
for liver toxicity. Additionally, if NVP-based HAART is prescribed for a pregnant woman who
does not herself have clinical indications for starting antiretroviral therapy, then HAART should
be discontinued following delivery. When the HAART regimen is stopped, serum levels of the
NRTIs (e.g., AZT and 3TC) in her HAART regimen will drop much more rapidly than that of
NVP, resulting in the same problem of prolonged HIV exposure to just NVP. Indeed, NVP
resistance has been documented in a cohort of pregnant women in Mozambique in whom this
strategy was employed. If, however, a PI-based HAART regimen is prescribed instead, the risks
of NVP toxicity and inducing NVP resistance are avoided altogether.
3. Administer short-course AZT boosted by SD NVP, but omit the maternal dose of SD NVP.
Omitting the maternal dose of SD NVP avoids any risk of inducing maternal NVP resistance.
The obvious drawback of this approach is that it might compromise the effectiveness of this
intervention in reducing the risk of HIV transmission to the infant. However, results from the
Mashi trial, conducted in a non-breastfeeding population in Botswana, found that omission of the
maternal dose of SD NVP did not result in an increased risk of HIV transmission to the infant, so
long as the rest of the regimen (AZT to mother and infant, plus SD NVP to infant) was
administered appropriately. Validation from other clinical trials is needed before this approach
can be universally endorsed, but clinicians may nevertheless want to consider this option. If this
option is chosen, AZT should be initiated at 34 weeks gestation, as in the Mashi trial, and
administered to the infant for 4 weeks postpartum.
4. Use PMTCT regimens that do not contain NVP, such as AZT monotherapy, AZT/3TC
combination therapy, or PI-based HAART. Resistance to AZT requires prolonged duration of
exposure, and multiple mutations must develop before resistance is observed; thus resistance to
AZT following AZT single drug prophylaxis is much less frequent than that observed with NVP
or 3TC, for which a single mutation induces resistance. However, AZT monotherapy for PMTCT
is not as effective as AZT boosted by SD NVP. AZT/3TC combination therapy is similarly less
effective than AZT boosted by SD NVP, and risks the promotion of 3TC resistance (which was
documented in six of 50 women [12%] who received AZT/3TC prepartum, intrapartum, and
postpartum in the PETRA trial). PI-based HAART, if administered appropriately, constitutes a
very potent PMTCT regimen with very little risk of generating resistance, but is generally more
expensive and less convenient than other PMTCT regimens. Additionally, appropriate dosing of
many PI drugs in pregnancy needs to be defined: SQV boosted with low dose RTV will achieve
adequate levels in pregnant women; NFV given twice daily may achieve adequate levels but there
is significant variability of levels between women; and LPV/RTV may require an increased
dosage in the third trimester due to low levels observed in the third trimester in one study.
5. Reserve the use of SD NVP PMTCT regimens for women with relatively high CD4 counts
and low HIV viral loads. Studies of SD NVP for PMTCT suggest that the presence of a high
VII-3
HIV viral load and/or low CD4 count in the mother at the time of SD NVP administration
elevates her risk of developing resistance to NVP. Limiting the administration of SD NVP to
women with relatively low HIV viral loads and high CD4 counts would likely reduce the overall
risk of promoting NVP resistance, but the degree of risk reduction that could be anticipated with
this approach remains unclear. Certainly, all efforts should be made to start HIV-infected women
who require therapy for their own health (as indicated by clinical symptoms, low CD4 count,
and/or high HIV viral load) on HAART. These women are at highest risk of both disease
progression and transmission of HIV to their infants, and HAART will significantly reduce the
risk of each of these events. Additionally, such women are at greatest risk for development of
NVP resistance following administration of SD NVP; if HAART is started instead and continued
postpartum, this risk is avoided.
Implications for Women Initiating HAART who received SD NVP or 3TC in the Past:
Based on current information, prior administration of SD NVP-containing prophylaxis for PMTCT should
not preclude the use of these agents as part of a HAART regimen initiated for treatment of HIV disease in
women. It may be prudent to consider prescribing protease inhibitor (PI)-based HAART for women with
prior exposure to SD NVP, particularly if there has been a recent exposure to NVP (e.g., initiation of
therapy within 6 months of SD NVP exposure). However, if a PI-based HAART regimen is inconvenient
or not readily available, an NNRTI-based regimen should be initiated. Similarly, women who received
3TC in the past as part of a non-HAART PMTCT regimen (e.g. AZT/3TC) are at some risk for having
developed 3TC resistance, but this should not necessarily preclude the use of 3TC in subsequent HAART
regimens.
VII-4
PMTCT ANTIRETROVIRAL THERAPY RECOMMENDATIONS: SPECIFIC SCENARIOS
The following sections outline ART options for different clinical scenarios. Please refer to Appendix C
for details regarding the exact dosing options for the ARVs described. Please also refer to the section
immediately preceding this one for a discussion of options to reduce the risk of promoting NVP
resistance in women who receive a NVP-based PMTCT regimen.
SCENARIO A: NON-PREGNANT WOMAN WHO NEEDS ANTIRETROVIRAL THERAPY FOR

HER OWN HEALTH
Treatment recommendations generally follow those described in Chapter IV: Recommendations for
Antiretroviral Therapy for Adults and Adolescents with HIV Infection. However, the design of the
HAART regimen for women with the potential to become pregnant must involve a consideration of the
possibility that the ARVs may be received early in the first trimester, before the recognition of pregnancy
and during the primary period of foetal organ development. Efavirenz (EFV) should therefore be avoided
in such women due to its potential for teratogenicity. Women who are receiving HAART and do not wish
to become pregnant should have effective and appropriate contraceptive methods available to them in
order to reduce the likelihood of unintended pregnancy. In those women for whom effective
contraception can be assured, EFV could be considered for inclusion in the HAART regimen, with careful
counselling of the woman regarding the potential for congenital abnormalities should she become
pregnant while receiving EFV.
SCENARIO B: WOMAN WHO IS ALREADY RECEIVING ANTIRETROVIRAL THERAPY AT

THE TIME SHE BECOMES PREGNANT
Mother
Generally, she should continue her HAART regimen. Adding or substituting AZT for another
NRTI in her regimen (e.g. for stavudine (d4T)) should be considered given the proven efficacy of AZT in
reducing the risk of MTCT. If a woman is receiving EFV-containing HAART and becomes
pregnant, and this is recognized during the first trimester, EFV should be discontinued and
replaced by another drug. In this scenario NVP could be substituted for EFV even in women with CD4
counts greater than 250 cells/mm3 because symptomatic NVP-associated hepatotoxicity has been
primarily observed in antiretroviral-naïve patients initiating NVP-based HAART. If NVP is substituted
for EFV, close monitoring for hepatotoxicity is recommended. Alternatively, a protease inhibitor could
be substituted for EFV. If the woman is already in the second or third trimester when pregnancy is
recognized, EFV could be continued, given that the high risk exposure has already occurred; the exposure
and risk should be discussed with the patient, and adequate contraception should be ensured for the
postpartum period. Suspension of HAART during the first trimester to avoid potential teratogenicity is
not recommended; some patients who discontinue HAART experience a dramatic rise in HIV viraemia,
and in a pregnant woman, this may elevate the risk of in utero HIV transmission. The HAART regimen
should be continued intrapartum and postpartum.
Infant
Options include:
SD NVP; or
AZT for one week;* or
SD NVP plus AZT for one week.*
*
Consider an extended course (four to six weeks) of AZT therapy for the infant if the mother received less than four
weeks of prepartum ART.
VII-5
SCENARIO C: PREGNANT WOMAN NOT ON HAART WHO NOW REQUIRES HAART FOR
HER OWN HEALTH (e.g. a woman who was diagnosed with HIV infection and AIDS at the same time
as her pregnancy was diagnosed; or a woman who deteriorated clinically after she became pregnant and
is now at a stage where HAART is indicated for her own health)
Mother
Treatment should generally be initiated as soon as possible. Delaying the initiation of therapy until after
the first trimester minimises the risk of teratogenicity, but treatment should not be delayed if the mother is
seriously ill. Unless specifically contra-indicated, the HAART regimen should consist of AZT plus 3TC
plus NVP.
AZT is favoured because of its proven efficacy in preventing MTCT, but if the mother cannot take this
agent (e.g. severe anaemia or other toxicities), d4T or another NRTI can be substituted.
NVP should be reasonably safe in this scenario. If the mother requires HAART for her own health, her
CD4+ T cell count is very likely less than 250 cells/mm3, and her risk of severe hepatotoxicity is low.
However, if NVP is contra-indicated (e.g. history of past NVP toxicity or resistance to NVP strongly
suspected), substitution of a PI or ritonavir-boosted PI (PI/r) is reasonable. EFV can be used instead of
NVP in the third trimester, but only if effective postpartum contraception can be guaranteed.
The HAART regimen should be continued intrapartum and postpartum.
Infant
Options include:
SD NVP; or
SCENARIO D: PREGNANT WOMAN WHO DOES NOT REQUIRE HAART FOR HER OWN
HEALTH
Though she does not require ART for her own health, ART in some form is indicated to reduce the risk of
MTCT. Several options exist, but two are generally favoured:
Option 1: AZT Boosted by SD NVP
This regimen is now favoured by the World Health Organisation (WHO) and the Thai Ministry of Health
based on results of the PHPT-2 trial, because it was associated with an MTCT rate of just 2% in a non-
breastfeeding population – a rate similar to transmission rates seen in mothers who receive HAART
during pregnancy. Mothers who take this regimen are at risk for developing NVP resistance,† which
could compromise their response to future NNRTI-based HAART regimens. However, the WHO
endorses this as a preferred PMTCT regimen for resource-constrained settings because it offers a potent,
simple, and relatively inexpensive intervention, and data regarding the true clinical impact of prior SD
NVP-exposure on the response to future NNRTI-based regimens is lacking. Furthermore, the risk of
NVP resistance is greatest among women with higher viral loads and lower CD4+ T cell counts who
would likely require HAART for their own health; the risk of NVP resistance is lower in women who do
not require antiretroviral therapy for their own health.
†
Several clinical trials have documented detectable resistance to NVP following delivery in a portion of women who
received SD NVP during labour. For example, using a conventional genotypic resistance assay, NVP resistance
could be detected following delivery in approximately 20% of women who received SD NVP in the PHPT-2 trial.
VII-6
Mother
AZT starting at twenty-eight weeks gestational age (or as soon as possible thereafter) plus AZT during
labour plus SD NVP during labour.
Infant
SD NVP (within seventy-two hours of birth) plus AZT for one week.*
Option 2: HAART
Treating the mother with HAART is attractive because it offers effective reduction of the risk of MTCT
(with HAART the risk is estimated to be 1% to 2% in women who do not breastfeed), while minimising
the risk that she may develop resistance to any ARVs, thereby preserving her future options for HAART.
Drawbacks chiefly include the expense and the risks of adverse effects both for the mother and for the
infant. Additionally, the design of the HAART regimen for a relatively healthy pregnant woman is
complicated by four factors: 1) the risk of severe NVP toxicity in pregnant women with CD4+ T cell
counts of >250 cells/mm3 is high; 2) EFV should not be used in the first or second trimesters; 3) PI-based
HAART may not be easily obtainable; and 4) data on the pharmacokinetics of PIs in pregnancy are
limited [the greatest experience is with nelfinavir (NFV) (1,250mg twice daily) or saquinavir (SQV) with
low-dose ritonavir (RTV)-boosting [e.g. 800mg SQV/100mg RTV twice daily]).
Mother
Unless specifically contra-indicated, the HAART regimen should consist of AZT plus 3TC plus (PI or
NVP). If NVP is chosen, the woman should have close monitoring for liver toxicity during the first 12
weeks of therapy.
AZT is favoured due to its proven efficacy in preventing MTCT, but if the mother cannot take this agent
(e.g. severe anaemia or other toxicities), d4T or another NRTI can be substituted.
The risk of severe NVP toxicity in pregnant women with CD4+ T cell counts of >250 cells/mm3 is high;
hence a PI-based regimen is preferred for these women.
The HAART regimen should be continued intrapartum.
The HAART regimen should be discontinued after delivery if the mother does not require continued
therapy for her own health.
Infant
Options include:
SD NVP; or
Other Options (these represent valid options that have also been demonstrated to significantly reduce the
risk of HIV transmission to the infant)
1. AZT Monotherapy: The PACTG 076 protocol of oral AZT started in the second trimester, intravenous
(IV) AZT during labour, and six weeks of AZT for the infant following delivery was associated with a
66% reduction in the rate of HIV transmission in a non-breastfeeding population. Simpler AZT regimens
(e.g. oral AZT prepartum, oral AZT in labour, and one to six weeks of AZT for the infant following
delivery) have been associated with a roughly 50% reduction in the rate of HIV transmission.
2. SD NVP. SD NVP administered to the mother during labour and another dose administered to the
infant following delivery has been associated with an approximately 42% reduction in the rate of HIV
*
Consider extended course (four to six weeks) of AZT therapy for the infant if the mother received less than four
VII-7
transmission, even in breastfeeding women. The risk of NVP resistance is greatest among women with
higher viral loads and lower CD4+ T cell counts; that is, women who would likely require HAART for
their own health. Thus, the risk of development of NVP resistance would be less among women who do
not require HAART for their own health.
3. AZT plus 3TC Dual Therapy. The PETRA trial, conducted among a population of breastfeeding
women in South Africa, found that AZT/3TC administered antepartum, orally intrapartum, and
postpartum to the infant reduced the rate of transmission to approximately 6% at six weeks postpartum.
The potential for developing resistance to 3TC remains a concern with this regimen. Additionally, the
efficacy of this regimen was significantly diminished at age eighteen months with breastfeeding.
4. AZT plus 3TC Boosted by SD NVP. This regimen, combined with SD NVP and one week of AZT for
the infant following delivery, was associated with an HIV transmission rate of approximately 5% in a
mixed breast- and bottle-feeding population in Côte d’Ivoire. This regimen may be inadvisable given that
it does not appear to offer more efficacy than the AZT monotherapy boosted by SD NVP regimen
described above, and has the additional drawback of potentially promoting the development of resistance
to 3TC in the mother’s strain of HIV.
SCENARIO E: HIV-INFECTED WOMAN WITHOUT PRENATAL CARE WHO PRESENTS IN

LABOUR
Because much of the transmission of HIV is thought to occur around the time of delivery, intervention at
this stage with ART can still substantially reduce the risk of the infant becoming infected. Two options
exist, based on results of the HIVNET 012 trial and the PETRA trial.
Option 1: HIVNET 012 Regimen

Mother
SD NVP in labour.
Infant
SD NVP at forty-eight to seventy-two hours postpartum.
Two doses of NVP are recommended for the infant (one at birth and the second at seventy-two hours) if
the mother delivered before or within two hours of receiving the intrapartum NVP dose.
For women who received a single dose of NVP in false labour, a repeat NVP dose during established
labour should not be given as the risk of NVP resistance is higher following two NVP doses. In such
instances, the infant should receive NVP as soon as possible after birth plus one week of AZT, as per
recommendation for Situation F.
Option 2: PETRA Regimen

In the PETRA trial, conducted among a population of breastfeeding women in sub-Saharan Africa, this
regimen was associated with an HIV transmission rate of 8.9% at six to eight weeks postpartum,
significantly less than the transmission rate of 15.3% seen in the placebo arm. However, the efficacy of
this regimen was diminished in breastfeeding women, and was no longer statistically significant at age
eighteen months.
Mother
AZT/3TC dual therapy in labour (plus AZT/3TC for one week postpartum if breastfeeding).
Infant
AZT/3TC dual therapy for one week.
VII-8
SCENARIO F: INFANTS BORN TO WOMEN WHO RECEIVED NO ANTIRETROVIRAL
THERAPY FOR PMTCT EITHER PREPARTUM OR DURING LABOUR
The NVAZ study documented that AZT plus SD NVP administered to the infant is more effective than
NVP alone in this setting. If the infant does not present for medical care until more than two days
following the delivery (as might happen if the birth occurred outside of a medical facility), the efficacy of
this intervention is doubtful.
Infant
SD NVP at birth (or as soon as possible following birth) plus one week of AZT.
GENERAL RECOMMENDATIONS FOR MANAGEMENT OF THE HIV-INFECTED MOTHER DURING

LABOUR AND DELIVERY
During labour, universal precautions should be followed. Gowns, gloves, boots, and protective eyewear
should be worn during the delivery of all patients. Additional strategies to reduce the risk of MTCT as
well as the risk of HIV exposure to personnel assisting with the delivery include:
¾ Avoiding unnecessary invasive procedures
¾ Avoiding episiotomy unless otherwise indicated
¾ Avoiding artificial rupturing of the membranes
¾ Avoiding prolonged rupture of membranes, as rupture of membranes for more than four hours is
associated with an increased risk of HIV transmission to the infant
¾ Avoiding the use of straight suture needles if possible, to reduce the risk of needle stick injury
¾ Clamping and cutting the umbilical cord immediately after delivery, and, if possible, avoiding the
use of a scalpel to cut the umbilical cord
¾ Exercising special care in handling the placenta
¾ Handling the infant with gloves until bathing, and bathing the infant as soon as possible with soap
and water
¾ Cleaning the infant’s eyes with sterile swabs
¾ Performing routine post-delivery care, including the weighing and measuring of the infant
¾ Ensuring that the infant receives antiretroviral prophylaxis as outlined above
¾ Ensuring the examination of the infant by a paediatrician as soon as possible.
RECOMMENDATIONS REGARDING BREASTFEEDING AND POSTPARTUM MANAGEMENT OF THE

MOTHER
Breastfeeding women with indications for HAART for their own health should receive and continue
HAART during and after lactation. Thus, if the mother was already on HAART at the time she became
pregnant, or if she initiated HAART during pregnancy for her own health needs, then HAART should be
continued.
If she initiated HAART during pregnancy solely for the purposes of PMTCT, her need for continued
HAART following delivery should be carefully assessed and discontinuation of HAART should be
considered if she does not require therapy for her own health. If an antiretroviral PMTCT regimen was
administered during her pregnancy consisting of just one or two ARVs, these agents should be
VII-9
discontinued after delivery, as the risk of development of resistance is higher with use of non-suppressive
mono- or dual-therapy regimens.
Where feasible and where acceptable alternatives exist, efforts should be made to discourage HIV-
infected mothers from breastfeeding in order to interrupt this potential route of HIV transmission to the
infant. However, for many women in resource-limited countries, breastmilk alternatives are not
acceptable, feasible, affordable, sustainable, or safe. If an infant is breastfed, exclusive breastfeeding is
recommended, with weaning as soon as feasible (e.g. at age three to six months). Exclusive breastfeeding
means giving the infant only breastmilk and no water, other liquids, or solid foods except prescribed
medicines. While the use of expressed and heat-treated breastmilk has been suggested, data are limited
on the efficacy of heat treatment in reducing HIV in breastmilk as well as on the effect of such heat
treatment on constituents of breastmilk (including immune components) that are important for the infant’s
health. Therefore, the use of heat-treated breastmilk cannot be generally recommended at this time,
although further research on this approach is warranted.
EFFICACY OF PMTCT INTERVENTIONS: SUMMARY OF THE EVIDENCE

Appendix A summarises in tabular form the clinical trials that have established the efficacy of ART in
reducing the risk of MTCT. Data from these studies suggest that several options exist for the pregnant
HIV-infected mother.
Clinical trials have been performed in both breastfeeding and non-breastfeeding populations. The risk of
breast milk transmission is higher in women with symptomatic HIV disease or those who become newly
infected with HIV while breastfeeding, and may vary by pattern (exclusive versus mixed) and duration of
breastfeeding. Some data suggest the risk of breast milk transmission may be highest during the first six
months of life, but the risk of transmission continues for the duration of breastfeeding.
It is recognised that avoidance of all breastfeeding is the most reliable way to prevent postnatal
transmission of HIV. Therefore, when replacement feeding is acceptable, feasible, affordable,
sustainable, and safe, avoidance of all breastfeeding by HIV-infected women is recommended. In all
other settings, exclusive breastfeeding is recommended during the first months of life, because clinical
trial data from South Africa suggest that exclusive breastfeeding is associated with a lower risk of HIV
transmission than mixed feeding.
The efficacy and safety of maternal or infant ART in preventing postnatal breast milk HIV transmission is
not yet known. Several international clinical trials are evaluating a variety of approaches to preventing
breast milk transmission, including administration of one or more ARVs to the infant and/or HAART to
the mother during the breastfeeding period. Approaches have included the administration of ARVs
(NVP, 3TC, or AZT) to the infant for six weeks to six months while breastfeeding, or administration of
HAART to the mother during lactation; however, the efficacy and safety of such approaches have not
been defined.
RISKS OF ANTIRETROVIRAL THERAPY IN PREGNANCY

Fortunately, the risks associated with ART in pregnancy are generally far outweighed by the potential
benefit in interrupting transmission of HIV to the infant and in potentially preserving the mother’s health.
However, certain risks should be considered, and the pregnancy should be carefully managed to minimise
these risks.
VII-10
RISKS TO THE MOTHER’S HEALTH
Certain toxicities related to ARVs may occur more frequently in pregnant women and deserve special
consideration.
NVP Toxicity
Toxicities commonly associated with NVP include liver and skin toxicity, which typically develop within
the first eighteen weeks of therapy.
Signs and symptoms of liver toxicity include nausea, jaundice, abdominal pain, hepatic tenderness,
hepatomegaly, fatigue, and malaise; elevated transaminases are typically seen on laboratory testing.
Hepatic toxicity occurs more frequently in women than in men, and the degree of risk for hepatic toxicity
varies with CD4+ T cell count; women with CD4+ T cell counts of greater than 250 cells/mm3 have a
significantly increased risk of symptomatic hepatic toxicity.
Skin toxicity is most commonly a mild, self-limited rash that does not warrant discontinuation of NVP.
However, though rare, severe skin toxicity can occur, including potentially fatal Stevens-Johnson
syndrome. The rash may also be more frequent in women with higher CD4+ T cell counts.
Although deaths due to hepatic failure and Stevens-Johnson syndrome have been reported in HIV-
infected pregnant women receiving NVP as part of a combination ARV regimen, it is unknown if
pregnancy increases the risk of hepatotoxicity or rash in women receiving NVP or other ARVs. Patients
with symptomatic hepatitis or who have asymptomatic but severe transaminase elevations and those with
severe rashes should discontinue NVP and not receive NVP therapy in the future. Pregnant women who
take NVP-containing combination ART warrant monitoring for signs and symptoms of liver or skin
toxicity, especially in the first eighteen weeks of therapy. If resources permit, this monitoring should
optimally include serum transaminases levels at baseline, every two weeks for the first month, monthly
through four months, and every one to three months thereafter.
NVP toxicity has not been described in pregnant women who use only a single dose of the agent in labour
to reduce the risk of vertical transmission to their infants.
NRTI-Induced Mitochondrial Toxicity
NRTI-containing HAART regimens may induce mitochondrial toxicity via an interaction with DNA
polymerase gamma, a key mitochondrial enzyme whose function is critical to normal cellular oxidative
phosphorylation. This toxicity is thought to be responsible for several toxicities associated with HAART,
including lactic acidosis, pancreatitis, steatohepatitis, cardiomyopathy, and possibly peripheral
neuropathy. The risk of severe mitochondrial toxicity appears to be highest with the dideoxynucleosides
d4T, didanosine (ddI), and zalcitabine (ddC). Several cases of fatal lactic acidosis have been documented
in pregnant women on HAART whose regimens included both d4T and ddI; for this reason, the use of
these two agents together in pregnant women is strongly discouraged.
The clinical presentation of NRTI-induced mitochondrial toxicity may mimic other potentially severe
complications of pregnancy, such as acute steatohepatitis or the HELLP* syndrome. It is not known if
pregnant women on NRTI-containing HAART regimens are at an elevated risk for developing this
potentially fatal complication as compared with non-pregnant women on similar HAART regimens.
While screening lactate levels are not recommended, clinicians should consider the diagnosis of
mitochondrial toxicity in pregnant women receiving NRTI drugs who develop compatible signs and
symptoms such as fatigue, abdominal pain, nausea, malaise, respiratory distress, or evidence of hepatic
dysfunction. In such cases, appropriate evaluations, such as serum lactate, serum bicarbonate and anion
gap, and serum transaminases should be performed, and ART should be suspended if clinical and
laboratory manifestations of lactic acidosis syndrome occur. More information on lactic
*
Haemolysis, elevated liver enzymes, low platelets
VII-11
acidosis/hyperlactataemia can be found at the end of Chapter IV: Recommendations for Antiretroviral
Therapy for Adults and Adolescents with HIV Infection.
Other Potential Maternal Complications of ART
While some studies have suggested that combination ART during pregnancy may increase the risk of
preterm delivery or low birth weight infants, other studies have failed to detect such an association. PIs
have been associated with insulin resistance and may increase the risk of gestational diabetes. There is no
clear evidence that pregnancy accelerates the course of HIV infection or increases the risk of virologic
failure.
Preservation of the Mother’s ART Options
Several studies have confirmed the efficacy of short-term ART involving only one or two ARVs in
significantly reducing the risk of vertical HIV transmission. The relative simplicity and low cost of these
PMTCT strategies make them attractive options in resource-limited settings. However, administration of
ART that does not fully suppress HIV replication promotes the development of drug resistance.
Therefore, the use of just one or two ARVs in pregnancy can induce ARV resistance that could
compromise the efficacy of future HAART regimens for the mother (as well as for the infant, should the
infant become infected despite the PMTCT intervention). Drugs that lose efficacy following the
development of a single resistance mutation, such as 3TC or NVP, are especially vulnerable to this
complication. It is not clear at this time just how serious a problem this poses, making it difficult to
establish firm recommendations. However, a brief review of the relevant data is warranted.
Resistance to AZT
Resistance to AZT typically develops only after several months of partially-suppressive ART. Clinical
data document a low prevalence of AZT resistance following short-course AZT regimens, hence it is not
likely that short-term administration of this agent for PMTCT will compromise the efficacy of this agent
in future HAART regimens for the mother.
Resistance to 3TC
Resistance to 3TC can develop rapidly even when combined with AZT, because a single mutation in the
HIV genome can result in high-level resistance to this agent. The ANRS 075 study, a cohort study in
France involving the use of AZT with 3TC added after thirty-two weeks gestation, reported an overall
resistance rate of 39% to 3TC six weeks following delivery, although the risk of developing resistance
depended heavily on the length of exposure to the regimen. No 3TC resistance was reported with the use
of this regimen for less than one month, whereas one to two months of prophylaxis was associated with a
20% risk of 3TC resistance, and over two months of prophylaxis was associated with a 50% risk of 3TC
resistance. However, in the PETRA trial, 12% of women who received a regimen of oral AZT plus 3TC
(starting at thirty-six weeks antepartum and continued intrapartum and postpartum for one week)
developed resistance to 3TC.
Resistance to NVP
Low levels of HIV (approximately 1 in 1,000 viral particles) with mutations associated with NVP
resistance are present in treatment-naïve individuals. Following administration of SD NVP, there is a
rapid selection of resistant virus due to the long half-life of the drug: detectable NVP levels can persist
for three weeks or longer following a single dose. Unfortunately, cross-resistance with other agents in the
NNRTI class, such as EFV, is very common.
The HIVNET 012 trial involved SD NVP administered to the mother during labour and another dose to
the infant after delivery. 25% of NVP-exposed women had evidence of NVP resistance at six weeks
postpartum, as did 46% of the infants who became infected with HIV.
Follow-up analysis of women who had developed NVP resistance in the HIVNET 012 trial found that
resistance was no longer detectable by conventional resistance assays one year following delivery
(conventional assays require 15% to 20% or more of viral quasispecies to contain the mutation to be
VII-12
detectable). However, this apparent ‘fading’ of resistance over time may be misleading. Research has
suggested that resistant strains of HIV remain ‘archived’ in the body at levels undetectable by
conventional resistance assays, even after the ARV that induced the resistance is withdrawn. The
resistant strain may subsequently re-emerge under selective drug pressure when a HAART regimen
containing that ARV is initiated at a later date, potentially resulting in treatment failure.
The PHPT-2 trial included both AZT and NVP in its PMTCT regimen. AZT was administered to the
mother starting at twenty-eight weeks gestation and orally during labour, and one week of AZT was given
to the infant following delivery (four to six weeks if the mother received less than four weeks of AZT).
SD NVP was also administered to the mother during labour and to the infant following delivery. NVP
resistance was detected ten to fourteen days after SD NVP exposure in 20% of ninety randomly selected
trial participants, and was more likely to develop in women with higher HIV viral loads and lower CD4+
T cell counts.
A preliminary assessment of response to NNRTI-based therapy in women who required initiation of
HAART at some time after delivery was performed as a follow-up study of the PHPT-2 trial. Women
who required HAART after completion of the study received a NVP-based HAART regimen (primarily
d4T/3TC/NVP). A preliminary analysis compared the virologic outcome after three and six months of
NVP-based HAART among women who had received SD NVP as part of their PMTCT regimen versus a
small group of women who did not receive SD NVP. No significant differences in clinical response (as
demonstrated by weight gain following initiation of therapy), immunologic response at three and six
months following initiation of therapy (both groups with an increase of about 100 cells at six months), or
in virologic response to <400 copies/mL were seen between women who received or did not receive SD
NVP. However, women who received SD NVP and who had genotypic resistance to NVP detected at
two weeks postpartum were less likely to achieve an HIV viral load <50 copies/mL after six months of
therapy than women who had not received SD NVP (38% versus 68%, respectively). The rate of
virologic suppression to <50 copies/mL in women who had received SD NVP but did not have virus with
detectable genotypic NVP resistance was intermediate between the two groups (52%).
In a preliminary report on a study from Botswana in which women received short course AZT with or
without SD NVP, virologic response (defined as the likelihood of viral load suppression to less than 400
or less than 40 copies/mL) to subsequent NVP-based HAART varied by the time of initiation of HAART
after SD NVP exposure. Women who initiated HAART less than 6 months following SD NVP exposure
had a poorer virologic response than women without prior SD NVP exposure; however, women who
initiated HAART more than 6 months following SD NVP exposure experienced a virologic response that
was similar to the response seen in women without prior SD NVP exposure.
Hence, it is difficult to draw definitive conclusions regarding the relevance of resistance incurred by
antiretroviral PMTCT regimens that do not fully suppress HIV replication. It is clear that such regimens
can and often do lead to the selection of HIV resistance mutations, but the clinical impact of this
resistance on future therapeutic options for the mother awaits further clarification. Strategies that can be
considered to reduce the risk of promoting resistance in the mother are outlined above in the section
entitled “POTENTIAL FOR THE DEVELOPMENT OF NEVIRAPINE (NVP) RESISTANCE FOLLOWING THE
ADMINISTRATION OF SINGLE DOSE NEVIRAPINE (SD NVP) AND OTHER NVP-BASED PMTCT
REGIMENS.”
INFANT HEALTH CONSIDERATIONS

Teratogenicity of ARVs
Limited evidence exists regarding the potential teratogenicity and carcinogenicity of ARVs; the data
available are summarised in Appendix B. Most agents are classified by the U.S. Food and Drug
Administration (FDA) as Class B or C. EFV is now classified as Class D and is specifically contra-
VII-13
indicated in pregnancy, due to the occurrence of severe central nervous system (CNS) congenital
abnormalities in three of twenty infants born to monkeys who received EFV during pregnancy, and four
cases of neural tube defects in human newborns whose mothers were exposed to EFV during the first
trimester of pregnancy, as identified in retrospective case reports in the Antiretroviral Pregnancy Registry.
The Antiretroviral Pregnancy Registry is an international registry that is designed to evaluate any major
teratogenic effect of in utero ARV exposure. Information is obtained from the healthcare provider or
from pregnant women receiving ARVs in an entirely voluntary and confidential manner, with follow-up
for pregnancy outcomes.* The Registry has accumulated a significant amount of follow-up data on
infants exposed to ARVs in utero; fortunately, data collected to date fail to demonstrate an association
between ART in general and an increased risk of birth defects. Furthermore, no increased risk of birth
defects could be demonstrated in association with exposure to AZT, 3TC, d4T, NVP, or NFV--agents that
have been most frequently included in maternal ARV regimens. However, the database is not extensive
enough and the follow-up not long enough to rule out the possibility of an association between ARV
exposure in utero and rare birth defects. Given that most MTCT occurs at or around the time of delivery,
it is reasonable to defer maternal ART used solely for prevention of MTCT until after the first trimester of
pregnancy, which is the maximal period of organogenesis. However, for pregnant women who are severely
ill and require HAART for their own health, the benefit of early therapy clearly outweighs any potential foetal
risks, and therapy should be initiated as soon as possible in these cases.
Mitochondrial Toxicity
Since some ARVs are associated with mitochondrial dysfunction in HIV-infected persons receiving
chronic therapy, there have been concerns that in utero exposure to such drugs might result in
mitochondrial dysfunction in exposed infants. The data on this are mixed. In a French cohort of
approximately 2,600 uninfected infants with in utero exposure to ARVs, the incidence of mitochondrial
dysfunction, predominantly consisting of neurologic symptoms and, in some cases, lactic acidosis, was
0.25%; there were two deaths, for a mortality rate of 0.07%. However, a review of data from more than
16,000 HIV-uninfected children with and without in utero ARV exposure from several U.S. databases
identified no deaths similar to those reported from France, nor any cases with clinical findings suggestive
of mitochondrial dysfunction. Additionally, review of data from over 2,400 uninfected infants followed
in the European Collaborative Study found no association of perinatal ARV exposure with any clinical
findings suggestive of mitochondrial dysfunction. Thus, there are conflicting data regarding whether
mitochondrial dysfunction is associated with perinatal ARV exposure. If such disorders occur, they
appear to be rare and should be compared against the clear benefit of ARV prophylaxis in reducing
transmission of a fatal infection by 50% or more. However, long-term follow-up is recommended for any
child with in utero exposure to ARVs, and mitochondrial dysfunction should be considered in uninfected
children with perinatal ARV exposure who present with severe, persistent clinical findings of unknown
aetiology, particularly neurologic findings.
Risk of Preterm Birth
As reviewed above, evidence is mixed regarding a possible association between ART and preterm
delivery. If an association does exist, the risk appears to be very small and outweighed by the potential
benefits of ART.
*
The international telephone number of the Antiretroviral Pregnancy Registry is (910) 256-0238; its website is
http://www.APRegistry.com.
VII-14
APPENDIX A: SUMMARY OF SELECTED CLINICAL TRIALS OF PROPHYLACTIC ARV REGIMENS FOR PMTCT*
Study Drugs Antenatal/ Postpartum Median Mode of Infant Vertical Transmission Rate (VTR)
Intrapartum Maternal Feeding and Efficacy
(location)
CD4+ T Cell
Count by
Arm at
Enrollment
PACTG 076/ANRS ZDV vs. placebo Long (from 14 Long (6 weeks) 538, 560 Formula-feeding VTR 7.6% in intervention arm vs.
024 Trial weeks), IV (infant only) 22.6% in placebo arm at 18 months
intrapartum (68% efficacy)
USA; France
Bangkok CDC ZDV vs. placebo Short (from 36 None 411, 427 Formula-feeding VTR 9.4% in intervention arm vs.
Short-Course ZDV weeks), oral 18.9% in placebo at 6 months (50.1%
Trial intrapartum efficacy)
Thailand
Thai Perinatal HIV ZDV different Long (from 28 Long (for 6 350, 380 Formula-feeding Short-short arm was stopped.
Prevention Trial regimens, no weeks), short weeks), short (for
VTR 6.5% in long-long arm vs. 4.7% in
placebo (from 36 weeks) 3 days) (infant
Thailand long-short arm and 8.6% in the short-
only)
long arm at 6 months (statistical
equivalence)
In utero transmission significantly
higher with short compared to long
maternal therapy regimens (5.1% vs.
1.6%)
Côte d’Ivoire CDC ZDV vs. placebo Short (from 36 None 528, 548 Breastfeeding VTR 15.7% in intervention arm vs.
Short-Course ZDV weeks) 24.9% in placebo at 3 months (37%
Trial efficacy)
Côte d’Ivoire
*
Adapted from: World Health Organization. Antiretroviral drugs for treating pregnant women and prevention HIV infection in infants: guidelines on care,
treatment and support for women living with HIV/AIDS and their children in resource-constrained settings. Geneva, 2004.
VII-15
(location)
CD4+ T Cell
Count by
Arm at
Enrollment
DITRAME/ANRS ZDV vs. placebo Short (from 36 Short (1 week) 535, 568 Breastfeeding VTR 18.0% in ZDV arm, 27.5% in
049a Trial weeks) (mother only) placebo at 6 months (38% efficacy);
21.5% vs. 30.6% (30% efficacy) at 15
Côte d’Ivoire;
months; 22.5% vs. 30.2% (26%
Burkina Faso
efficacy) in pooled analysis with other
Côte d’Ivoire trial at 24 months
PETRA Trial ZDV + 3TC in 3 Short (from 36 Short (7 days) 435, 475 Breastfeeding VTR 5.7% at 6-8 weeks for
regimens vs. weeks) (mother and antenatal/intrapartum/neonatal ZDV +
South Africa;
placebo infant) 3TC, 8.9% for intrapartum/neonatal
Tanzania; and
ZDV + 3TC, 14.2% for intrapartum
Uganda
ZDV + 3TC only, and 15.3% for
placebo (efficacy compared to placebo,
63%, 42%, and 0%, respectively)
VTR 14.9% at 18 months for
antenatal/intrapartum/neonatal ZDV +
3TC, 18.1% for intrapartum/neonatal
ZDV + 3TC, 20.0% for intrapartum
ZDV + 3TC only and 22.2% for placebo
(efficacy compared to placebo, 34%,
18%, and 0%, respectively)
French ZDV + Open label, non- ZDV (from 14 3TC and ZDV 426 Formula-feeding VTR 1.6%; 5x lower than in historical
3TC/ANRS 075 randomised ZDV weeks) with for 6 weeks controls receiving ZDV only
Trial + 3TC 3TC added at 32 (infant only)
France weeks
Thai ZDV + 3TC Open label, non- Short (from 34 Long (ZDV, 4 274 Formula-feeding VTR 2.8% at 18 months
Trial randomised ZDV weeks) weeks) (infant
+ 3TC only)
Thailand
VII-16
(location)
CD4+ T Cell
Count by
Arm at
Enrollment
PACTG 316 Trial NVP vs. placebo Non-study ART SD 2mg/kg 423, 441 Formula-feeding 77% women received combination ARV
in women antenatal. within 72 hours during pregnancy
(USA; Europe;
already receiving of birth plus non-
Brazil; Bahamas) Intrapartum: SD Trial stopped early due to very low VTR
ZDV or ZDV study ART
NVP 200mg in both arms
plus other ART including 6
plus ZDV
weeks ZDV VTR 1.4% in intervention arm vs. 1.6%
continuous
(infant only) in placebo arm
infusion IV
HIVNET 012 Trial NVP vs. ZDV No antenatal SD NVP 2mg/kg 426, 461 Breastfeeding Placebo arm was stopped
ART within 72 hours
Uganda VTR 13.1% in NVP arm vs. 25.1% in
of birth vs. short
Intrapartum: SD ZDV arm (47% efficacy) at 14-16 weeks
ZDV (7 days)
NVP 200mg vs.
(infant only) VTR 15.7% in NVP arm vs. 25.8% in
oral ZDV
ZDV arm (41% efficacy) at 18 months
SAINT Trial NVP vs. ZDV + No antenatal SD NVP within 384, 404 Breastfeeding VTR 12.3% in NVP arm vs. 9.3% in
3TC ART 48 hours of birth (42%) and ZDV + 3TC arm at 8 weeks (not
South Africa
(infant only) vs. formula-feeding significantly different)
Intrapartum: SD
short ZDV +
NVP 200mg vs.
3TC (7 days)
ZDV + 3TC
(mother and
infant)
DITRAME Open label, ZDV ZDV from 36 SD NVP, plus 370 Breastfeeding VTR 6.4% at 6 weeks
Plus/ANRS 1201.0 boosted by SD weeks, NVP one one week ZDV (50%) and
Trial NVP dose at onset of (infant only) formula-feeding
labour
Abidjan, Côte
d’Ivoire
VII-17
(location)
CD4+ T Cell
Count by
Arm at
Enrollment
DITRAME Open label, ZDV ZDV + 3TC SD NVP, plus 439 Breastfeeding VTR 4.6% at 6 weeks
Plus/ANRS 1201.1 + 3TC boosted from 32 weeks one week ZDV and formula-
Trial by SD NVP (stopped at day (infant only) feeding
3 postpartum),
Abidjan, Côte
SD NVP at
d’Ivoire
onset of labour
Thai Perinatal HIV ZDV alone vs. ZDV from 28 One week ZDV Formula-feeding ZDV alone arm was stopped due to
Prevention Trial-2 ZDV plus weeks and with or without higher transmission rate than
mother/infant intrapartum SD NVP (infant maternal/infant NVP arm (VTR 6.3%
Thailand
NVP vs. ZDV only) vs. 1.1%)
Intrapartum:
plus mother NVP
ZDV alone or Final result comparing two NVP arms:
plus SD NVP at VTR not significantly different when
onset of labour infant received vs. did not receive SD
NVP (2.0% vs. 2.8%).
SIMBA Trial NVP vs. 3TC ZDV + ddI from ZDV + ddI for 1 423, 432 Breastfeeding VTR 7.8% at 6 months (no difference
postnatally in 36 weeks and week (mother (median between the two arms).
Rwanda; Uganda
neonates given only), SD NVP duration 3.4
Transmission rate between 4 days and 6
exposed intrapartum then b.i.d vs. months,
months of age: 2.4% (1.0% between 1
antenatally and 1 3TC b.i.d while interquartile
and 6 months)
week postpartum breastfeeding range: 2.9–5.1
to ZDV + ddI (infant only) months)
NVAZ Trial (late Neonatal NVP None SD NVP right Not reported Breastfeeding Overall VTR at 6-8 weeks 15.3% in
presenters–no vs. NVP + ZDV (latecomers) after birth; ZDV NVP + ZDV arm and 20.9% with NVP
maternal SD NVP) b.i.d for 1 week only. VTR at 6-8 weeks in infants who
(infant only) were negative at birth 7.7% and 12.1%,
Malawi
respectively (36% efficacy)
VII-18
(location)
CD4+ T Cell
Count by
Arm at
Enrollment
NVAZ Trial (early Neonatal NVP SD NVP SD NVP right Not reported Breastfeeding Overall VTR at 6-8 weeks 16.3% in
presenters–mothers vs. NVP + ZDV intrapartum after birth; ZDV NVP + ZDV arm and 14.1% with NVP
got SD NVP) b.i.d for 1 week only. VTR at 6-8 weeks in infants who
(infant only) were negative at birth 6.9% and 6.5%
Malawi (JAMA)
respectively (no efficacy)
VII-19
APPENDIX B: ANTIRETROVIRAL DRUG PHARMACOKINETIC AND TOXICITY DATA IN HUMAN PREGNANCY AND RECOMMENDATIONS FOR USE FOR
TREATMENT OF PREGNANT WOMEN WITH HIV INFECTION #
ARV DRUG FDA PHARMACOKINETICS IN CONCERNS IN PREGNANCY RATIONALE FOR
PREGNANCY PREGNANCY RECOMMENDED USE FOR
CLASS√ TREATMENT OF HIV-INFECTED
WOMEN DURING PREGNANCY
NRTI/NtRTIs See text for discussion of potential maternal and infant mitochondrial
toxicity.
RECOMMENDED AGENTS
Zidovudine* (AZT, ZDV) C Pharmacokinetics not significantly No evidence of human Preferred NRTI for use in
altered in pregnancy; no change in teratogenicity. Well-tolerated, combination ARV regimens in
dose indicated. short-term safety demonstrated for pregnancy based on efficacy
mother and infant. studies and extensive experience;
should be included in treatment
regimen unless significant
toxicity or d4T use.
Lamivudine* (3TC) C Pharmacokinetics not significantly No evidence of human Because of extensive experience
altered in pregnancy; no change in teratogenicity. Well-tolerated, with 3TC in pregnancy in
dose indicated. short-term safety demonstrated for combination with AZT, 3TC plus
mother and infant. AZT is the recommended dual
NRTI backbone for treatment of
pregnant women.
ALTERNATE AGENTS
Didanosine (ddI) B Pharmacokinetics not significantly Cases of lactic acidosis, some fatal, Alternate NRTI for dual
altered in pregnancy; no change in have been reported in pregnant nucleoside backbone of
dose indicated. women receiving ddI and d4T combination regimens. ddI
together. should be used with d4T only if
no other alternatives are
available.
Emtricitabine (FTC) B No studies in human pregnancy. No studies in human pregnancy. Alternate NRTI for dual
nucleoside backbone of
combination regimens.
VII-20
Stavudine (d4T) C Pharmacokinetics not significantly No evidence human teratogenicity. Alternate NRTI for dual
altered in pregnancy; no change in Cases of lactic acidosis, some fatal, nucleoside backbone of
dose indicated. have been reported in pregnant combination regimens. d4T
women receiving ddI and d4T should be used with ddI only if no
together. other alternatives are available.
Do not use with AZT due to
potential for antagonism.
Abacavir* (ABC) C Phase I/II study in progress. Hypersensitivity reactions occur in Alternate NRTI for dual
~5-8% of non-pregnant persons, a nucleoside backbone of
much smaller percentage is fatal and combination regimens. See
usually associated with re-challenge; footnote regarding use in triple
rate in pregnancy unknown. Patient NRTI regimen.**
should be educated regarding
symptoms of hypersensitivity
reaction.
INSUFFICIENT DATA TO RECOMMEND USE

Tenofovir (TDF) B No studies in human pregnancy. Studies in monkeys show decreased Due to lack of data on use in
Phase I study in late pregnancy in foetal growth and reduction in foetal human pregnancy and concern
progress. bone porosity within 2 months of regarding potential foetal bone
starting maternal therapy. Clinical effects, TDF should be used as a
studies in humans (particularly component of a maternal
children) show bone combination regimen only after
demineralisation with chronic use; careful consideration of
clinical significance unknown. alternatives.
NOT RECOMMENDED
Zalcitabine (ddC) C No studies in human pregnancy. Rodent studies indicate potential for Given lack of data and concerns
teratogenicity and developmental regarding teratogenicity in
toxicity. animals, not recommended for
use in human pregnancy unless
alternatives not available.
VII-21
NNRTIs
RECOMMENDED AGENTS
Nevirapine (NVP) C Pharmacokinetics not significantly No evidence human teratogenicity. NVP should be used with caution
altered in pregnancy; no change in Increased risk of symptomatic, often in pregnant women with CD4+ T
dose indicated. rash-associated, and potentially fatal cell counts of >250/mm3 who are
liver toxicity among women with starting combination therapy for
CD4+ T cell counts of >250/mm3 preventing perinatal transmission
when first initiating therapy; unclear but do not require therapy for
if pregnancy increases risk. own health; if used, monitor
closely for liver toxicity in first
18 weeks of therapy. Women
who enter pregnancy on NVP
regimens and are tolerating well
may continue therapy, regardless
of CD4+ T cell count.
NOT RECOMMENDED
D No studies in human pregnancy. Significant malformations Use of EFV should be avoided in
Efavirenz (EFV)
(anencephaly, anophthalmia, cleft the first trimester, and women of
palate) were observed in 3 (15%) of childbearing potential must be
20 infants born to cynomolgus counselled regarding risks and
monkeys receiving EFV during the avoidance of pregnancy. Because
first trimester at a dose giving of the known failure rates of
plasma levels comparable to contraception, alternate regimens
systemic human therapeutic should be strongly considered in
exposure; 4 case reports of neural women of childbearing potential.
tube defects in humans after first Use after the second trimester of
trimester exposure; relative risk pregnancy can be considered if
unclear. other alternatives not available
and if adequate contraception can
be assured postpartum.
C No studies in human pregnancy. Rodent studies indicate potential for Given lack of data and concerns
Delavirdine (DLV)
carcinogenicity and teratogenicity. regarding teratogenicity in
animals, not recommended for
use in human pregnancy unless
alternatives not available.
VII-22
PIs Hyperglycaemia, new onset or exacerbation of diabetes mellitus, and
diabetic ketoacidosis reported with PI use; unclear if pregnancy increases
risk. Conflicting data regarding preterm delivery in women receiving
PIs; see text.
RECOMMENDED AGENTS
B Adequate drug levels are achieved No evidence of human Given pharmacokinetic data and
Nelfinavir (NFV) extensive experience with use in
in pregnant women with NFV teratogenicity. Well-tolerated,
1,250mg b.i.d. short-term safety demonstrated for pregnancy compared to other PIs,
mother and infant. NFV dosing at preferred PI for combination
750mg t.i.d produced variable and regimens in pregnant women,
generally low levels in pregnant particularly if HAART is being
women. given solely for perinatal
prophylaxis. In clinical trials of
initial therapy in non-pregnant
adults, NFV-based regimens had a
lower rate of viral response
compared to LPV/r- or EFV-based
regimens, but similar viral response
compared to ATV- or NVP-based
regimens.
B Adequate drug levels are achieved Well-tolerated, short-term safety Given pharmacokinetic data and
Saquinavir (SQV)-soft gel
in pregnant women with SQV- demonstrated for mother and infant. moderate experience with use in
capsule [SGC]
SGC 800mg boosted with RTV Inadequate drug levels observed in pregnancy, RTV-boosted SQV-
(Fortovase®)/ritonavir 100mg b.i.d. Recommended adult pregnant women when SQV-SGC SGC can be considered a
dosing of SQV-SGC 1,000mg plus given alone at 1,200 mg t.i.d. preferred PI for combination
RTV 100mg may be used. No regimens in pregnancy.
pharmacokinetic data on SQV-
hard gel capsule [HGC]/ritonavir
in pregnancy, but better GI
tolerance in non-pregnant adults.
ALTERNATE AGENTS
C Two studies involving 18 women Theoretical concern regarding Alternate PI to consider if unable
Indinavir (IDV)
receiving IDV t.i.d showed increased indirect bilirubin levels, to use NFV or SQV-SGC/r, but
markedly lower serum drug levels which may exacerbate physiologic would need to give IDV as RTV-
during pregnancy compared to hyperbilirubinaemia in the neonate, boosted regimen to achieve
those postpartum, although HIV but minimal placental passage. Use adequate levels during pregnancy.
viral suppression was seen. of IDV during pregnancy without Optimal dosing for RTV-boosted
RTV-boosting not recommended. IDV in pregnancy is not known.
VII-23
C Phase I/II safety and Limited experience in human Preliminary studies suggest
Lopinavir/Ritonavir (LPV/r)
pharmacokinetic study in progress pregnancy. increased dose may be required
using LPV 400mg and RTV during pregnancy, though specific
100mg b.i.d. dosing recommendations not
established. If used during
pregnancy, monitor response to
therapy closely. If expected
virologic result not observed,
consider increasing dose in
consultation with a specialist with
expertise in HIV in pregnancy.
B Phase I/II study in pregnancy Minimal experience in human Given low levels in pregnant
Ritonavir (RTV)
showed lower serum drug levels pregnancy. women when used alone,
during pregnancy compared to recommended for use in
postpartum. combination with second PI as
low-dose RTV “boost” to
increase levels of second PI.

C No studies in human pregnancy. Oral solution contra-indicated in Data are insufficient regarding
Amprenavir (APV)
pregnant women because of high safety and pharmacokinetics in
levels of propylene glycol, which pregnancy to recommend use of
may not be adequately metabolised capsules during pregnancy. Oral
during pregnancy. solution contra-indicated.
C No studies in human pregnancy. No experience in human pregnancy. Data are insufficient regarding
Fosamprenavir (f-APV)
safety and pharmacokinetics in
pregnancy to recommend use
during pregnancy.
B No studies in human pregnancy. Theoretical concern re: increased Data are insufficient regarding
Atazanavir (ATV)
indirect bilirubin levels, which may safety and pharmacokinetics in
exacerbate physiologic pregnancy to recommend use
hyperbilirubinaemia in the neonate, during pregnancy.
although transplacental passage of
other PI’s has been low.
C No studies in human pregnancy No experience in human pregnancy Data are insufficient regarding
Tipranavir
the safety and pharmacokinetics
in pregnant to recommend use
during pregnancy.
VII-24
Fusion Inhibitors

B No studies in human pregnancy. No experience in human pregnancy. Data are insufficient regarding
Enfurvirtide
safety and pharmacokinetics in
pregnancy to recommend use
during pregnancy.
#
This table represents information abstracted from Safety and Toxicity of Individual Antiretroviral Agents in Pregnancy - February 24th, 2005, a supplement to
the United States Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health
and Interventions to Reduce Perinatal HIV-1 Transmission in the United States - February 24th, 2005 (both documents available at
http://www.aidsinfo.nih.gov/guidelines/default_db2.asp?id=66). The reader is encouraged to consult these documents for a more detailed discussion of the safety
and toxicity of individual ARVs in pregnancy.
√
FDA Pregnancy Categories:
A: Adequate and well-controlled studies of pregnant women fail to demonstrate a risk to the foetus during the first trimester of pregnancy (and there is no
evidence of risk during later trimesters).
B: Animal reproduction studies fail to demonstrate a risk to the foetus and adequate and well-controlled studies of pregnant women have not been conducted.
C: Safety in human pregnancy has not been determined, animal studies are either positive for foetal risk or have not been conducted, and the drug should not be
used unless the potential benefit outweighs the potential risk to the foetus.
D: Positive evidence of human foetal risk based on adverse reaction data from investigational or marketing experiences, but the potential benefits from the use of
the drug in pregnant women may be acceptable despite its potential risks.
X: Studies in animals or reports of adverse reactions have indicated that the risk associated with the use of the drug for pregnant women clearly outweighs any
possible benefit.
*AZT and 3TC are included as a fixed-dose combination in Combivir®, and AZT, 3TC, and ABC are included as a fixed-dose combination in Trizivir®.
**
Triple NRTI regimens including ABC have been less potent virologically compared to PI-based HAART regimens. These regimens should be used only when
an NNRTI or PI-based HAART regimen cannot be used (e.g. due to significant drug interactions). A study evaluating use of AZT/3TC/ABC among pregnant
women with HIV RNA <55,000 copies/mL as a class-sparing regimen is in development.
VII-25
APPENDIX C: DOSING OF ARVS IN PMTCT REGIMENS
Recommendations regarding the dosing of ARVs in PMTCT regimens are complicated by 1) the fact that a
variety of dosing schedules have been used in clinical trials; and 2) head-to-head comparative data are
lacking to establish which dosing schedule is most effective. Hence, where different dosing options exist, it
is reasonable to use clinical judgment to decide which option would be the most effective for a given patient
and to consider factors such as cost, convenience, and regional availability of the relevant formulations.
RECOMMENDED ARV DOSING OPTIONS (see text for a discussion of which ARV(s) should be used
in various clinical scenarios)
Maternal Prepartum ARV Dosing
Dosing of ARVs in pregnancy does not differ from that recommended for non-pregnant women, with the
following caveats:
Though the PACTG 076 trial involved maternal AZT dosing of 100mg five times daily, the
generally accepted dosing of AZT in pregnancy (before onset of labour) is 300mg twice daily (as
it is for non-pregnant women).
SQV should be administered with low-dose RTV-boosting (either SQV-SGC, 800mg + RTV,
100mg [each agent twice daily] or SQV-SGC, 1,000mg + RTV, 100mg [each agent twice
daily]).
NFV dosed at 1,250mg b.i.d. results in adequate drug levels in pregnant women and is generally
well tolerated at this dose. NFV dosing at 750mg t.i.d results in variable and generally low
levels in pregnant women. RTV-boosting is not recommended with NFV.
Limited data exist on the use of other PIs in pregnancy. IDV by itself results in low plasma
levels in pregnant women, hence RTV-boosting is indicated, but clinical trial data in pregnancy
are lacking to define the optimal dose.
Maternal ARV Dosing in Labour
a. AZT: either administer 300mg orally every three hours, or administer a 600mg oral loading
dose at the onset of labour, followed by 300mg orally every three hours.
b. NVP: 200mg orally given once at the onset of labour.
c. 3TC: 150mg orally twice daily.
d. HAART: continue prepartum regimen through labour.
ARV Dosing for the Infant Following Delivery
a. AZT: 2mg/kg orally four times daily OR 4mg/kg orally twice daily. There have been no
comparative studies of these alternative regimens. The 2mg/kg four times a day regimen was
used in PACTG 076 and in the Thailand PHPT-1 and PHPT-2 studies, whereas the 4mg/kg twice-
daily regimen has been used in most PMTCT studies in Africa. The twice-daily regimen offers
the potential benefit of increased adherence since it is given less frequently, although the four
times a day regimen is used in more developed country settings.
b. NVP: 2mg/kg orally given once. Generally, this dose is administered at forty-eight to seventy-two
hours, with two caveats:
if the infant will be leaving the hospital prior to forty-eight to seventy-two hours, the dose of
NVP can be administered as early as twenty-four hours;
if the mother did NOT receive her intrapartum dose of NVP, or received it less than two
hours prior to delivery, the dose of NVP should be administered to the infant as soon as
possible after birth. Some clinicians would recommend repeating the infant dose (2mg/kg)
at forty-eight to seventy-two hours as well in this scenario.
VII-26
c. 3TC: 2mg/kg orally twice daily.
VII-27
VIII. CARE OF CHILDREN BORN TO HIV-INFECTED MOTHERS
TABLE OF CONTENTS
INTRODUCTION .....................................................................................................................................................VIII-1
RECOMMENDATIONS FOR MANAGEMENT OF MOTHERS WITH HIV INFECTION
DURING LABOUR AND DELIVERY ........................................................................................................................VIII-1
RECOMMENDATIONS REGARDING BREASTFEEDING .........................................................................................VIII-2
RECOMMENDATIONS FOR MANAGEMENT OF INFANTS BORN TO MOTHERS WITH HIV INFECTION .............VIII-3
ARV Prophylaxis...........................................................................................................................................VIII-3
Diagnosis of HIV Infection in Infants ...........................................................................................................VIII-3
Prophylaxis against Pneumocystis jiroveci (Formerly Pneumocystis carinii) Pneumonia (PCP) .................VIII-4
Immunisations ...............................................................................................................................................VIII-4
Growth and Nutrition.....................................................................................................................................VIII-5
Follow-Up Care .............................................................................................................................................VIII-5
REFERENCES .........................................................................................................................................................VIII-12
APPENDIX A: WHO CLINICAL CASE DEFINITION FOR PAEDIATRIC AIDS..........................................................VIII-7

APPENDIX B: WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN CHILDREN ..................................VIII-8
APPENDIX C: 1994 CDC REVISED HUMAN IMMUNODEFICIENCY VIRUS PAEDIATRIC
CLASSIFICATION SYSTEM: CLINICAL CATEGORIES ...........................................................................................VIII-9
APPENDIX D: INTERVENTIONS TO REDUCE THE RISK OF MTCT: SUMMARY OF THE EVIDENCE........................VIII-11
VIII-i
VIII: CARE OF CHILDREN BORN TO HIV-INFECTED MOTHERS
INTRODUCTION
The great dichotomy between the various Caribbean countries in their economic development and
healthcare resources, as well as the region’s varied religious and cultural beliefs, impact greatly on the
implementation of prevention of mother-to-child transmission (PMTCT) programmes and on the
subsequent care available to HIV-exposed infants. While these guidelines represent the ideal,
modifications will need to be made to meet each country’s resources. As such, the advent of funding
from international agencies, such as The Clinton Foundation and The Global Fund to Fight AIDS,
Tuberculosis and Malaria, should encourage the improvement of facilities to meet the challenges of the
HIV/AIDS epidemic in the Caribbean. Many Caribbean nations have already commenced national
PMTCT programmes, and preliminary results suggest an excellent uptake of interventions and outcomes.1
RECOMMENDATIONS FOR MANAGEMENT OF MOTHERS WITH HIV INFECTION DURING

LABOUR AND DELIVERY
The following specific interventions are recommended to reduce the risk of MTCT as well as the risk of
HIV exposure to personnel assisting with the delivery:
o Universal precautions should be followed (e.g. gowns, gloves, boots, and protective eyewear should
be worn during the deliveries of all patients).
o Unnecessary invasive procedures should be avoided.
o Episiotomies should be avoided unless clearly indicated.
o Artificial rupturing of the membranes should be avoided.
o Prolonged rupturing of membranes should be avoided, since rupture of membranes for more than
four hours is associated with an increased risk of HIV transmission to the infant.
o The use of straight suture needles should be avoided, if possible, to reduce the risk of needle-stick
injury.
o Umbilical cords should be clamped and cut immediately after delivery, and, if possible, the use of a
scalpel to cut umbilical cords should be avoided.
o Special care in handling placentas should be exercised.
o Infants should be handled with gloves until bathing, and infants should be bathed as soon as
possible with soap and water.
o Infants’ eyes should be cleaned with sterile swabs.
o Routine post-delivery care should be performed, including weighing and measuring of infants.
o Infants should receive antiretroviral (ARV) prophylaxis as outlined below.
o Examinations of infants by a paediatrician should be performed as soon as possible.
Specific recommendations regarding the administration of antiretroviral therapy (ART) to mothers to
reduce the risk of HIV transmission to infants are reviewed in Chapter VII: Antiretroviral Therapy in
Pregnant Women and Prevention of Mother-to-Child Transmission of HIV. Evidence from clinical trials
that forms the basis of these recommendations is summarised in Appendix D of this chapter.
VIII-1
RECOMMENDATIONS REGARDING BREASTFEEDING
The following specific interventions are recommended to minimise the risk of HIV transmission via
breastfeeding:
o Mothers should be counselled about the risks of HIV transmission via breastfeeding and the
benefits associated with breastmilk substitutes.
o Mothers should be counselled regarding the increased risk of HIV transmission if breastfeeding and
breastmilk substitutes are combined.
o Replacement feeding should be provided to infants of HIV-infected mothers who cannot afford
breastmilk substitutes and choose not to breastfeed. Infants require about 150mL of milk/kg per
day.
o A source of potable water should be ensured.
o Mothers should be provided with a supply of breastmilk substitutes on their last antenatal visit or
prior to discharge from the hospital.
o Infants should be referred to a nutritional clinic for follow-up of growth.
o Mothers should be taught hygienic preparation of replacement feeds prior to and after delivery.
o Mothers should be taught how to cup-feed their infants.
o If mothers choose to breastfeed, they should be taught good breastfeeding techniques to help
prevent and treat breast problems that can increase the risk of HIV transmission.
Breastfeeding women with indications for antiretroviral therapy for their own health should receive and
continue standard HAART during and after lactation. Thus, if the mother was already on HAART at the
time she became pregnant, or if she initiated HAART during pregnancy for her own health needs, then
HAART should be continued.
Where feasible and acceptable alternatives exist, efforts should be made to discourage HIV-infected
mothers from breastfeeding in order to interrupt this potential route of HIV transmission to infants.
However, for many women in resource-limited countries, breastmilk alternatives are not acceptable,
feasible, affordable, sustainable, and safe. If an infant is breastfed, exclusive breastfeeding is
recommended, with weaning as soon as possible (e.g. at age three to six months). Exclusive
breastfeeding means giving infants only breastmilk and no water, other liquids, or solid foods except
prescribed medicines. While the use of expressed and heat-treated breastmilk has been suggested, data
are limited on the efficacy of heat treatment in reducing HIV in breastmilk and on the effect of such heat
treatment on constituents of breastmilk (including immune constituents) that are important for the infant’s
health. Therefore, the use of heat-treated breastmilk cannot be generally recommended at this time,
although further research on this approach is warranted.
In developing countries in which clean water and formula-feeding knowledge are limited, the balance of
risks (infectious diseases and malnutrition) and benefits (health and survival benefits to infants and
contraceptive, economic, and social benefits to mothers) could be shifted.2 Thus, in 1987 and 1992,
WHO’s Global Programme on AIDS recommended that in regions where infectious diseases and
malnutrition are the primary causes of infant mortality, women should breastfeed irrespective of their
HIV status.3
VIII-2
RECOMMENDATIONS FOR MANAGEMENT OF INFANTS BORN TO MOTHERS WITH HIV
INFECTION
ARV PROPHYLAXIS
Infants should be administered antiretroviral prophylaxis to reduce the risk of MTCT. Typical options
include:
o single-dose (SD) nevirapine (NVP); or
o zidovudine (AZT) for one week;* or
o SD NVP plus AZT for one week.*
The exact ARV prophylaxis regimen and timing of administration depends in part on what therapy (if
any) mothers received during antenatal care and during labour and delivery. These regimens are
summarised in Chapter VII: Antiretroviral Therapy in Pregnant Women and Prevention of Mother-to-
Child Transmission of HIV.
DIAGNOSIS OF HIV INFECTION IN INFANTS
HIV DNA PCR (polymerase chain reaction) should be performed at age six to eight weeks followed by
serial DNA PCRs. Two consecutive positive DNA PCRs are considered diagnostic of HIV infection.
If this is not available, then all children should have HIV ELISA done at age eighteen months. Prior to
diagnosis, all children are to be monitored clinically for any signs or symptoms of HIV infection.
The early diagnosis of HIV infection in infants is challenging in resource-constrained countries, both
from a diagnostic and therapeutic perspective. Tests for antibodies to HIV do not establish the presence
of HIV infection in infants due to the transfer of maternal antibodies; therefore, a virologic test is
required. PCR-based techniques that directly detect the existence of HIV in the plasma allow diagnosis
by age one month. Approximately 30% of infants with HIV infection will have a positive DNA PCR
result from samples obtained before age forty-eight hours, 93% are detectable by age two weeks, and
almost all are positive by age one month. A single DNA PCR has a sensitivity of 95% and a specificity
of 97% on samples collected after age one month.
Serial qualitative DNA PCR is currently the accepted standard for diagnosis of HIV infection. Two
positive assays drawn at separate time points are considered diagnostic of infection.4 Assays that detect
HIV RNA in plasma appear to be as sensitive as HIV DNA PCR, with sensitivities of 90% to 100% by
age two to three months. Specificity is also comparable. Some clinicians choose to use an HIV RNA
assay as the confirmatory test for infants testing HIV DNA PCR-positive. HIV culture can also be used
for diagnosis but is more complex and expensive to perform, and definitive results are not available for
four weeks. The use of p24 antigen testing alone is not recommended because of the high frequency of
false-positive assays.5
Although breastfeeding is discouraged in HIV-exposed infants in the Caribbean, if mothers still choose to
breastfeed, it should be noted that the risk of HIV infection continues throughout the entire duration of
breastfeeding. Therefore, a negative virologic test in early infancy does not negate the possibility of
infection occurring subsequently if breastfeeding continues.
Ideally, prenatal HIV testing would identify infants born to infected mothers, and DNA PCR of these
infants would identify those who are HIV-infected in early infancy. However, within the developing
world, such as the Caribbean, tests that directly measure the presence of HIV itself (e.g. p24 antigen, or
DNA or RNA PCR testing) are expensive and inaccessible to many. When early diagnosis is not
possible, clinical parameters are used to assess the possibility of HIV infection. The most common signs
*
Consider an extended course (four to six weeks) of AZT therapy for the infant if the mother received less than four
VIII-3
of HIV infection in infants include failure to thrive, hepatosplenomegaly, and diffuse adenopathy. HIV-
infected children may also present with frequent or chronic diarrhoea, frequent minor bacterial infections
such as otitis media and sinusitis, refractory thrush, and severe refractory non-infectious skin
manifestations.
The WHO has formulated both a case definition and a staging system for AIDS, given the challenges in
resource-poor settings regarding diagnosing HIV infection in children prior to age eighteen months (see
Appendix A and Appendix B).6 The WHO recognises that the current staging system for HIV infection in
children has its limitations, and is currently revising its staging system, since many of the clinical
symptoms in the paediatric stages are not specific for HIV infection and may overlap those seen in
children without HIV infection in resource-limited settings.7 The U.S. Centers for Disease Control and
Prevention (CDC) has also developed a surveillance definition for AIDS without laboratory evidence of
HIV infection, as summarised in Appendix C.8 Despite the possible overlap with other infections, until a
definitive diagnosis can be made, the use of these clinical classifications can be useful in helping to define
the parameters for initiation of HAART.
PROPHYLAXIS AGAINST PNEUMOCYSTIS JIROVECI (FORMERLY PNEUMOCYSTIS
CARINII) PNEUMONIA (PCP)
The majority of paediatric PCP cases occur during the first year of life and may occur before HIV
infection is documented or a decline in the CD4+ T cell count is observed. PCP prophylaxis is therefore
recommended for all HIV-infected infants as well as for those whose HIV status is indeterminate.9
Prophylaxis is initiated at age four to six weeks, following the completion of AZT prophylaxis, and
continued until it is established that the child is not HIV-infected.
Trimethoprim-sulfamethoxazole (TMP-SMX; co-trimoxazole) is the agent of choice. Several dosing
options can be recommended:
• TMP-SMX, 5mg/kg/day of the TMP component administered orally in divided doses twice daily
and administered seven days per week;
• TMP-SMX, 5mg/kg/day of the TMP component administered orally divided twice daily and
administered three times per week on alternate days (e.g. Monday-Wednesday-Friday);
• TMP-SMX, 5mg/kg/day of the TMP component administered orally in divided doses twice daily
and administered three times per week on consecutive days (e.g. Monday-Tuesday-
Wednesday);
• TMP-SMX, 5mg/kg/day of the TMP component administered orally as a single daily dose and
administered three times per week on consecutive days (e.g. Monday-Tuesday-Wednesday).
No data from randomised clinical trials exist to guide the clinician in deciding between daily versus
thrice-weekly dosing of TMP-SMX. Theoretically, daily dosing has the added advantage of offering the
infant more protection against other pathogens such as T. gondii and some bacterial infections. However,
daily TMP-SMX dosing may result in a higher incidence of bone marrow toxicity than thrice-weekly
dosing. United States treatment guidelines endorse the thrice-weekly regimen as the preferred dosing
schedule, whereas the WHO generally recommends daily dosing. Current practices in the Caribbean vary
as well: the Bahamas uses thrice-weekly dosing, whereas Jamaica reports excellent outcomes using daily
dosing (personal communications, P. McNeil and C. Christie).
If TMP-SMX is not tolerated, children age one month or older can be given dapsone, dosed at 2mg/kg
(max 100mg) by mouth daily or 4g/kg (max 200mg) by mouth weekly.
IMMUNISATIONS
Immunisations for children who are HIV-infected (or HIV-exposed with unknown status) differ from
those who are not immunocompromised. The section entitled Recommendations for Use of Specific
VIII-4
Vaccines in HIV-Infected Individuals in Chapter VI: Recommendations for Adult and Paediatric
Opportunistic Infections Prophylaxis summarises the vaccination schedule for HIV-infected and HIV–
exposed infants. Live vaccines are generally contra-indicated with the following exceptions: the measles,
mumps and rubella (MMR) vaccine is recommended if the child is not severely immunocompromised; the
varicella (VZV) vaccine should be considered if the CD4+ T cell percentage is >25%;10 and the oral polio
vaccine (OPV) may be used for asymptomatic children if the inactivated polio vaccine (IPV) is not
available.
GROWTH AND NUTRITION
Growth failure is a prominent feature of HIV infection; hence, nutritional assessment is important both as
a diagnostic marker (when HIV status is unknown) and to maximise growth in infected children.11
FOLLOW-UP CARE
Close monitoring of HIV-exposed and -infected infants is critical.
Prior to Discharge from Hospital
o Infants should be reviewed prior to discharge by a paediatrician or the most senior available
clinician.
o Infants should be docketed and clinic follow-up ensured.
o Mothers should be taught how to administer ARV prophylaxis to their infants.
o Any issues that may prevent adherence to ARVs or to prophylactic medications should be
investigated and addressed.
o A supply of replacement feeds should be provided to mothers and a date for an appointment with
the nutritionist established.
Follow-Up in One to Two Weeks
o Routine physical examination of infants should be performed, including growth parameters.
o Adherence to ARV prophylaxis should be ensured.
o Any evidence of side effects of ARV prophylaxis should be monitored.
o Mothers should be advised to continue formula feeds and ensure hygienic preparation of same.
o Any concerns of the parents should be accessed and addressed.
Follow-Up at Six Weeks to Two Months
o Routine physical examination of infants should be performed.
o Growth and development should be assessed.
o ARV prophylaxis should be discontinued.
o TMP-SMX prophylaxis should be commenced, using one of the dosing options outlined on page
VIII-5. TMP-SMX prophylaxis should be continued until it is established that the child is HIV-
negative.
o Iron and vitamin supplementation should also be commenced.
o Blood samples for HIV DNA PCR testing should be drawn.
o Blood samples for other tests should be drawn, e.g. CBC and differential, TORCH screen, VDRL,
and Hepatitis BsAg and HTLV-1 serology, as appropriate.
o Vaccination with pentavalent (DPT, Hib, and Hepatitis B (HBV)) and polio should be started. IPV
is preferred, but if IPV is not available, OPV may be administered to asymptomatic infants.
VIII-5
o Continuation of formula feeds should be advised.
o Any medical problems should be treated.
Follow-Up at Four Months
o Second dose of vaccinations should be given.
o Blood sample for second HIV DNA PCR testing should be drawn.
o TMP-SMX prophylaxis should be continued.
o Iron and vitamin supplementation should be continued.
o Continuation of formula feeds should be advised.
Follow-Up beyond Four Months
Ideally, HIV-exposed children should be followed up by a comprehensive team of paediatricians, nurses,
and nutritionists. The routine follow-up schedule is similar to that of children who are not exposed to
HIV. Subsequent to the four-month visit, patients should be seen again at age six months, then at three-
month intervals or more frequently if indicated.
At Each Visit:
o Appropriate diet should be ensured.
o Adequate vaccination coverage should be ensured.
o TMP-SMX prophylaxis should be continued.
o Iron and vitamin supplementation should be continued.
o Any evidence of HIV or opportunistic infections (OIs) should be monitored.
Baseline follow-up physical examinations include temperature; measurement of weight, height, and head
circumference (monitor on growth charts); and examination for thrush, adenopathy, skin eruptions, ear,
nose, and throat infections, chest infections, abdominal organ enlargement, and neurological and
developmental abnormalities.
VIII-6
APPENDIX A: WHO CLINICAL CASE DEFINITION FOR PAEDIATRIC AIDS
The presence of any two major and any two minor signs from those listed below, in the absence of other
known causes of immunodeficiency:
Major Signs
√ weight loss or abnormally slow growth
√ chronic diarrhoea for more than one month
√ prolonged or intermittent fever for more than one month
Minor Signs
√ generalised lymph node enlargement
√ oropharyngeal candidiasis (oral thrush)
√ recurrent common infections
√ persistent cough
√ generalised dermatitis
√ confirmed maternal HIV infection
VIII-7
APPENDIX B: WHO STAGING SYSTEM FOR HIV INFECTION AND DISEASE IN CHILDREN
Clinical Stage I:
o Asymptomatic
o Generalised lymphadenopathy
Clinical Stage II:
o Chronic diarrhoea for more than thirty days’ duration in absence of known aetiology
o Severe persistent or recurrent candidiasis outside the neonatal period
o Weight loss or failure to thrive in the absence of known aetiology
o Persistent fever for more than thirty days’ duration in the absence of known aetiology
o Recurrent severe bacterial infections other than septicaemia or meningitis (e.g. osteomyelitis,
bacterial (non-TB) pneumonia, abscesses)
Clinical Stage III:
o AIDS-defining opportunistic infections
o Severe failure to thrive in the absence of known aetiology
o Progressive encephalopathy
o Malignancy
o Recurrent septicaemia or meningitis
VIII-8
APPENDIX C: 1994 CDC REVISED HUMAN IMMUNODEFICIENCY VIRUS PAEDIATRIC
CLASSIFICATION SYSTEM: CLINICAL CATEGORIES
CATEGORY N: Not Symptomatic

Children who have no signs or symptoms considered to be the result of HIV infection or who have only
one of the conditions listed in Category A.
CATEGORY A: Mildly Symptomatic

Children with 2 or more of the following conditions but none of the conditions listed in Categories B and
C:
• Lymphadenopathy (>0.5cm at >2 sites; bilateral = 1 site)
• Hepatomegaly
• Splenomegaly
• Dermatitis
• Parotitis
• Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
CATEGORY B: Moderately Symptomatic

Children who have symptomatic conditions, other than those listed for Category A or Category C, which
are attributed to HIV infection. Examples of conditions in clinical Category B include, but are not limited
to, the following:
• Anaemia (<8gm/dL), neutropaenia (<1,000/mm3), or thrombocytopaenia (<100,000/mm3)
persisting >30 days
• Bacterial meningitis, pneumonia, or sepsis (single episode)
• Candidiasis, oropharyngeal (e.g. thrush) persisting for >2 months in children age >6 months
• Cardiomyopathy
• Cytomegalovirus (CMV) infection with onset before age 1 month
• Diarrhoea, recurrent or chronic
• Hepatitis
• Herpes simplex virus (HSV) stomatitis, recurrent (e.g. >2 episodes within 1 year)
• HSV bronchitis, pneumonitis, or oesophagitis with onset before age 1 month
• Herpes zoster (e.g. shingles) involving at least 2 distinct episodes or more than 1 dermatome
• Leiomyosarcoma
• Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
• Nephropathy
• Nocardiosis
• Fever lasting >1 month
• Toxoplasmosis with onset before age 1 month
• Varicella, disseminated (e.g. complicated chickenpox)
VIII-9
CATEGORY C: Severely Symptomatic
• Serious bacterial infections, multiple or recurrent (e.g. any combination of at least 2 culture-
confirmed infections within a 2-year period), of the following types: septicaemia,
pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity
(excluding otitis media, superficial skin or mucosal abscesses, and indwelling catheter-related
infections)
• Candidiasis, oesophageal or pulmonary (bronchi, trachea, lungs)
• Coccidioidomycosis, disseminated (at site other than or in addition to lungs or cervical or
hilar lymph nodes)
• Cryptosporidiosis or isosporiasis with diarrhoea persisting >1 month
• CMV disease with onset of symptoms at age >1 month (at a site other than liver, spleen, or
lymph nodes)
• Encephalopathy (at least 1 of the following progressive findings present for at least 2 months
in the absence of a concurrent illness other than HIV infection that could explain the
findings): a) failure to attain or loss of developmental milestones or loss of intellectual
ability, verified by standard developmental scale or neuropsychological tests; b) impaired
brain growth or acquired microcephaly demonstrated by head circumference measurements
or brain atrophy demonstrated by CT or MRI (serial imaging is required for children age <2
years); c) acquired symmetric motor deficit manifested by 2 or more of the following:
paresis, pathologic reflexes, ataxia, or gait disturbance; d) HSV infection causing a
mucocoetaneous ulcer that persists for >1 month; or e) bronchitis, pneumonitis, or
oesophagitis for any duration affecting a child age >1 month
• Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical or hilar
lymph nodes)
• Kaposi's sarcoma (KS)
• Lymphoma, primary, in brain
• Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell lymphoma of
B-cell or unknown immunologic phenotype
• Mycobacterium tuberculosis, disseminated or extrapulmonary Mycobacterium, other species
or unidentified species, disseminated (at a site other than or in addition to lungs, skin, or
cervical or hilar lymph nodes)
• Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site other than
or in addition to lungs, skin, or cervical or hilar lymph nodes)
• Pneumocystis carinii pneumonia (PCP)
• Progressive multifocal leukoencephalopathy (PML)
• Salmonella (nontyphoid) septicaemia, recurrent
• Toxoplasmosis of the brain with onset at age >1 month
• Wasting syndrome in the absence of a concurrent illness other than HIV infection that could
explain the following findings: a) persistent weight loss >10% of baseline; OR b) downward
crossing of at least 2 of the following percentile lines on the weight-for-age chart (e.g. 95th,
75th, 50th, 25th, 5th) in a child age >1 year; OR c) <5th percentile on weight-for-height chart on
2 consecutive measurements, >30 days apart PLUS a) chronic diarrhoea (e.g. at least 2 loose
stools/day for >30 days); OR b) documented fever (for >30 days, intermittent or constant)
VIII-10
APPENDIX D: INTERVENTIONS TO REDUCE THE RISK OF MOTHER TO CHILD TRANSMISSION:
SUMMARY OF THE EVIDENCE
HIV transmission from an HIV-infected mother to her infant occurs in 25% to 45% of cases without
intervention. Primary prevention of Mother-to-Child Transmission (pMTCT) strategies include
prevention of women becoming infected and counselling those who are HIV-positive on making informed
choices about their reproductive health. With antiretroviral prophylaxis and nutritional supplementation,
the risk of MTCT can be reduced to less than 5%.
In 1994, results of the Paediatric AIDS Clinical Trials Group study 076 (PACTG 076) showed a two-
thirds reduction in perinatal transmission from HIV-infected women who received a complex regimen of
AZT.12 In developing countries, simplified AZT regimens in Thailand and Côte d’Ivoire have
demonstrated transmission reductions of one-third in breastfeeding populations and one-half in non-
breastfeeding populations.13 A trial in Uganda (HIVNET 012) of single-dose nevirapine (SD NVP) given
to mother and neonate showed a reduction of approximately 50% in a breastfeeding population.14 More
recently, short-course therapy with AZT plus 3TC decreased the transmission rate to between 6% and
15% in a breastfeeding population, and to 3% if breastmilk substitutes were implemented.15 In the United
States, with the use of HAART, Caesarean delivery, and breastmilk substitution, transmission rates are
less than 2%,16 and similar successes have been reported in Europe.17 In various Caribbean islands,
PMTCT with AZT prophylaxis has reduced transmission rates from 27% to 44% to 5.5% to 9%.18 More
recently, a Thai trial using AZT initiated during the second trimester plus SD NVP during labour
followed by SD NVP plus one week of AZT for the infant resulted in a transmission rate of less than 2%
in a non-breastfeeding population.19
The frequency of breastmilk transmission during acute maternal infection is estimated to be at 29%, and
for women with established infection, the additional risk of transmission is estimated at 14%.20 In a
randomised clinical trial in Nairobi, the frequency of breastmilk transmission of HIV was 16.2%, and the
majority of infections occurred early during breastfeeding. The use of breastmilk substitutes prevented
44% of infant infections and was associated with significantly improved HIV-free survival, which is a
similar magnitude to the short-course regimens of AZT.21 A study on the influence of feeding patterns in
MTCT showed that at age three months, 18.8% of infants who were not breastfed were estimated to be
HIV-infected compared with 21.3% of those who were breastfed. The estimated proportion of infants
HIV-infected by three months was significantly lower for those who exclusively breastfed than in those
who received mixed feeding (14.6% versus 24.1%) and had a similar risk of transmission to no
breastfeeding.22
Additional information on the efficacy of interventions to reduce the risk of MTCT can be found in
Chapter VII: Antiretroviral Therapy in Pregnant Women and Prevention of Mother-to-Child
Transmission of HIV and in Appendix A of that chapter.
VIII-11
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St. John A et al., 2003 and Jack N et al., 2000 and Gomez MP et al., 1997.
19
Lallemant M, Jourdain G, et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent
mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004;351:217-28.
20
Dunn DT, Newell ML, et al. Risk of human immunodeficiency virus type I transmission through
breastfeeding. Lancet 1992;340:585-88.
21
Nduati R, John G, et al. Effect of breastfeeding and formula feeding on transmission of HIV-1: a
randomised clinical trial. JAMA 2000;283:1167-1174.
22
Coutsoudis A, et al. Influence of infant-feeding patterns on early mother-to-child transmission of HIV-1
in Durban, South Africa: a prospective cohort study. Lancet 1999;354:471-76.
VIII-13
IX: CARE OF THE CHILD WITH HIV INFECTION, INCLUDING
CONSIDERATIONS OF ANTIRETROVIRAL THERAPY
TABLE OF CONTENTS
BACKGROUND................................................................................................................................................IX-1
DIAGNOSIS AND CLASSIFICATION OF PAEDIATRIC HIV/AIDS..................................................................IX-1
OI PROPHYLAXIS AND IMMUNISATIONS......................................................................................................IX-1
Tuberculosis.............................................................................................................................................IX-1
INITIATION OF HAART IN PAEDIATRIC PATIENTS: GENERAL CONSIDERATIONS .................................IX-2
RECOMMENDATIONS FOR INITIATION OF HAART IN RESOURCE-CONSTRAINED
SETTINGS: WHO GUIDELINES ..............................................................................................................IX-3
RECOMMENDATIONS FOR INITIATION OF HAART IN RESOURCE-FULL
SETTINGS: NIH AND CDC GUIDELINES ...............................................................................................IX-6
PRACTICAL CONSIDERATIONS FOR THE CARIBBEAN .................................................................................IX-7
ADHERENCE...................................................................................................................................................IX-8
RECOMMENDED INITIAL PAEDIATRIC HAART REGIMENS ......................................................................IX-9
Special Considerations for Patients with TB .........................................................................................IX-12
Clinical Monitoring and Follow-Up ......................................................................................................IX-12
Treatment Toxicity.................................................................................................................................IX-12
Treatment Failure...................................................................................................................................IX-14
SECOND-LINE AND SALVAGE ANTIRETROVIRAL THERAPY ....................................................................IX-15
HIV Resistance to ARV Medications ....................................................................................................IX-16
Second-Line HAART Regimens ...........................................................................................................IX-16
Salvage Therapy.....................................................................................................................................IX-18
PAEDIATRIC ANTIRETROVIRAL THERAPY DRUG FORMULARY FOR THE CARIBBEAN ..........................IX-18
REFERENCES................................................................................................................................................IX-51
TABLES
Table 1: WHO Guidelines for the Initiation of HAART in Resource-Limited Settings........................................... IX-4
Table 1a: Recommendations for Initiating HAART in Infants and Children if CD4+ T Cell
Count Testing Is Available .............................................................................................................................. IX-4
Table 1b: Recommendations for Initiating HAART in Infants and Children if CD4+ T Cell
Count Testing Is Not Available......................................................................................................................... IX-4
Table 2: Indications for Initiation of HAART in HIV-Infected Children Age One Year or Younger
in Resource-Rich Settings................................................................................................................................. IX-6
Table 3: Indications for Initiation of HAART in HIV-Infected Children Age One Year or Older
in Resource-Rich Settings................................................................................................................................. IX-7
Table 4: Recommended Initial HAART Regimens for HIV-Infected Children ...................................................... IX-10
Recommended Drug Substitutions.................................................................................................................. IX-13
Table 6: Second-Line Regimen Recommendations for Treatment Failure........................................................... IX-17
Table 7: Paediatric ART Drug Formulary for the Caribbean.............................................................................. IX-18
Table 8: Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) – Part 1 ........................................................... IX-21
Table 9: Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) – Part 2 ........................................................... IX-24
Table 10: Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) ........................................................................ IX-29
Table 11: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) .............................................................. IX-33
Table 12: Protease Inhibitors (PIs) – Part 1........................................................................................................ IX-35
Table 13: Protease Inhibitors (PIs) – Part 2........................................................................................................ IX-40
Table 14: Protease Inhibitor (PI) Combinations – Part 3.................................................................................... IX-42
IX-i
Table 15: Fusion Inhibitors.................................................................................................................................. IX-45
Table 16: WHO Staging System for HIV Infection and Disease in Children.................................................... IX-47
Table 17: 1994 CDC Revised Human Immunodeficiency Virus Classification System:
Clinical Categories......................................................................................................................................... IX-48
Table 18: Human Immunodeficiency Virus: Paediatric Immune Category Classification System
Based on Age-Specific CD4+ T Cell Count and Percentage ......................................................................... IX-50
APPENDIX A: CONSIDERATIONS ON SPECIFIC DRUGS ................................................................................IX-19

APPENDIX B: CURRENTLY AVAILABLE ARVS FOR PAEDIATRIC USE ........................................................IX-21
APPENDIX C: CLASSIFICATION OF PAEDIATRIC HIV/AIDS .......................................................................IX-47
IX-ii
IX. CARE OF THE CHILD WITH HIV INFECTION, INCLUDING CONSIDERATIONS
OF ANTIRETROVIRAL THERAPY
BACKGROUND
HIV/AIDS is the first or second leading cause of death in Caribbean children age one to four years. In the
Caribbean, HIV is transmitted to infants in utero, during delivery, via breastfeeding, and due to sexual
abuse.
The Caribbean is extremely diverse with regard to expertise, healthcare facilities, laboratory diagnostic
capabilities, and treatment options for managing infants and children with HIV/AIDS. Recognising this
diversity, the recommendations in this chapter are drawn primarily from the World Health Organisation
(WHO), the U.S. National Institutes of Health (NIH), and the U.S. Centers for Disease Control and
Prevention (CDC). Wherever possible, HIV-infected infants and children should be managed by
clinicians experienced in the use and monitoring of antiretroviral therapy (ART) as well as in the
identification and treatment of opportunistic infections (OIs) in HIV-infected children.
With low-cost antiretroviral drugs (ARVs) now more available in the region, expertise in the
administration of Highly Active Antiretroviral Therapy (HAART) for Caribbean children is critical.
Numerous studies, including data from the Caribbean,1 have established the remarkable efficacy of
HAART in reducing HIV-associated morbidity and mortality in paediatric populations. It should be
remembered, however, that these medications are an essential but incomplete part of the healthcare
equation for the HIV patient. The commitment to treat is a life-long contract, encompassing the
development of a support system for the patient and family.
DIAGNOSIS AND CLASSIFICATION OF PAEDIATRIC HIV/AIDS

WHO and CDC HIV/AIDS classification systems for infants and children age thirteen or younger are
presented in Appendix C. WHO recognises that this staging system can overlap with several other
conditions in children seen in resource-poor settings, and this system is currently under revision.
Alternatively, CDC’s revised criteria may be used, which offers more specific clinical diagnostic
categories of A, B, and C for mild, moderate, and severe disease respectively and immunological criteria
of classes 1, 2, and 3 for mild, moderate, and severe immunosuppression respectively.
OI PROPHYLAXIS AND IMMUNISATIONS

The management of the HIV-exposed infant, including considerations of prophylaxis against
Pneumocystis jiroveci pneumonia (PCP), are summarised in Chapter VIII: Care of Children Born to
HIV-Infected Mothers. The diagnosis and management of OIs in HIV-infected children are detailed in
Chapter X: Diagnosis and Treatment of Opportunistic Infections (OIs) among HIV-Exposed and -
Infected Children, while paediatric OI prophylaxis recommendations are summarised in Chapter VI:
Recommendations for Adult and Paediatric Opportunistic Infections (OIs) Prophylaxis. Immunisation
recommendations are detailed in Chapter VI, Table 4.
Tuberculosis (TB)
TB deserves special mention for reasons related to epidemiology, diagnosis, and treatment. Alarming
increases in active TB in Caribbean children have been recently documented in Jamaica and Haiti. HIV
co-infection among paediatric TB cases has increased dramatically as well, with rates of 50% in some
IX-1
prospective studies.2 These children usually have close household exposures and/or contact to family
members with active (and often undiagnosed) TB.
Paediatric TB-HIV co-infection presents several diagnostic challenges. TB and HIV infection have the
same features of chronic cough, recurrent fever, growth failure, lymphadenopathy, and abnormal chest
radiographs. Children with HIV/AIDS are often anergic and may not respond to the Mantoux skin test.
Experience in the management of Jamaican children with TB-HIV co-infection has suggested that those
who were treated with TB medications alone typically improved initially, but subsequently deteriorated or
died, whereas those treated with anti-TB medications and HAART usually improved. Hence, treatment
with both HAART and anti-TB drugs generally leads to improved survival and the best long-term
outcomes in children with TB-HIV co-infection. However, the timing of HAART initiation as well as the
selection of the initial HAART regimen must be considered carefully and should be performed in
consultation with an expert in the management of both diseases.
INITIATION OF HAART IN PAEDIATRIC PATIENTS: GENERAL CONSIDERATIONS

HAART, defined as the combination of three or more antiretroviral agents taken concurrently to suppress
HIV replication, represents the current standard of care of antiretroviral therapy for children infected with
HIV. This strategy evolved from the recognition that treatment of chronic HIV infection with only one or
two ARV agents typically results in rapid treatment failure and the development of ARV resistance,
compromising future therapeutic options.
These recommendations provide general guidance rather than absolute recommendations for the
individual patient. As is true for adult antiretroviral therapy, many factors must be considered in deciding
whether to initiate HAART including:
• the potential benefits and risks of therapy;
• the ability of the caregiver and child to adhere to administration of the therapeutic regimen
(discussed in more detail below); and
• the risk of disease progression as suggested by the CD4+ T cell count and HIV viral load (if these
tests are available).
HIV infection generally progresses more rapidly in children than in adults. Without treatment, about 50%
of adults develop AIDS ten years post-infection, whereas approximately 50% of children will develop
AIDS three years post-infection, and 25% by twelve months without effective HAART. Infants are at
particular risk for rapid disease progression and are especially vulnerable to central nervous system (CNS)
complications. It is impossible to predict which infants will progress rapidly, hence many experts
recommend that all infants found to be HIV-infected before age one year be treated with HAART.
The laboratory diagnosis of HIV infection in infants age eighteen months or younger is difficult due to the
persistence of maternal antibodies against HIV. Virologic tests are therefore required to make the
definitive diagnosis of HIV infection in this age group, as reviewed in Chapter VIII.
The penetration of antiretroviral medications (ARVs) into human breastmilk in lactating women has not
been quantified for most of these agents. If an ARV is secreted into breastmilk, the quantity and
concentration may not be sufficient to achieve therapeutic levels in the infants. Therefore, ARVs should
be given in standard doses to infants who require it regardless of whether the mother is receiving
antiretroviral therapy.
Recommendations for initiation of HAART in Caribbean HIV-infected children are derived from WHO
guidelines for resource-constrained settings and from the NIH and CDC for more resource-rich regions.
IX-2
RECOMMENDATIONS FOR INITIATION OF HAART IN RESOURCE-CONSTRAINED SETTINGS:
WHO GUIDELINES
WHO recommendations for initiation of HAART depend on the child’s age and on the availability of
virologic and CD4+ T cell testing. Where CD4+ T cell assays are available, the use of the CD4+ T cell
percentage, rather than the absolute CD4+ T cell count, is recommended because the CD4+ T cell
percentage varies less with age. The total lymphocyte count (TLC) also correlates with the risk of
mortality in symptomatic HIV-infected children, and may be used instead of the CD4+ T cell count in
these patients where CD4+ T cell testing is unavailable.
Despite cost constraints, the WHO recommends the development of tests applicable to resource-limited
settings that would allow early diagnosis of HIV infection in infants. The availability of such tests is
critical to the development of improved recommendations for therapy initiation in infants age eighteen
months or younger.
The WHO guidelines for initiating HAART in resource-constrained settings are summarised in Table 1a
and Table 1b.
IX-3
Table 1: WHO Guidelines for Initiation of HAART in Resource-Limited Settings3
Table 1a: Recommendations for Initiating HAART in Infants and Children if CD4+ T Cell Count Testing Is Available
AGE HIV DIAGNOSTIC TESTING TREATMENT RECOMMENDATION
<18 months HIV virologic testing not available but WHO Paediatric Stages II and III disease and CD4+ T cell count <20%a
infant is HIV antibody-seropositive**
Positive HIV virologic testb WHO Paediatric Stage III (e.g. AIDS) irrespective of CD4+ T cell percentage
WHO Paediatric Stage II disease (with consideration of using CD4+ T cell count
of <20% to assist in decision-making)a,c
WHO Paediatric Stage I disease (e.g. asymptomatic) and CD4+ T cell count of
<20%a,d
>18 months HIV antibody-seropositive WHO Paediatric Stage III disease, irrespective of CD4+ T cell percentage
WHO Paediatric Stage II disease (with consideration for using CD4+ T cell count
of <15% to assist in decision-making)
WHO Paediatric Stage I disease and CD4+ T cell count of <15%
Table 1b: Recommendations for Initiating HAART in Infants and Children if CD4+ T Cell Count Testing Is Not Available
AGE HIV DIAGNOSTIC TESTING TREATMENT RECOMMENDATION
<18 months HIV virologic testing not available but Treatment not recommendedd,e
infant is HIV antibody-seropositive
Positive HIV virologic testb WHO Paediatric Stage III, irrespective of TLC
WHO Paediatric Stage II disease (with consideration for using the TLC of
<2,500/mm3 to assist in decision-making)f
>18 months HIV antibody-seropositive WHO Paediatric Stage III, irrespective of TLC*
WHO Paediatric Stage II disease (with consideration for using the TLC of
<1,500/mm3 to assist in decision-making)f
**HIV serologic testing must be repeated at age eighteen months to obtain definitive diagnosis of HIV infection.
a
A CD4+ T cell count of <20% corresponds to an absolute CD4+ T cell count of approximately <1,000/mm3 for children age twelve months or younger and
<750/mm3 for children age twelve to eighteen months; a CD4+ T cell count of <15% corresponds to <500/mm3 for children age one to five years and to
<200/mm3 for children age six years or younger.
b
HIV DNA PCR or HIV RNA amplification assays or immune complex disassociated p24 antigen assays.
c
A CD4+ T cell percentage is advisable to assist with determining the need for immediate therapy.
d
If a child is asymptomatic and treatment is being initiated on a basis of CD4+ T cell count criteria, consideration should be given to performing a confirmatory
CD4+ T cell assay if resources permit.
e
Many of the clinical symptoms in WHO Paediatric Stage II and III disease classifications are not specific for HIV infection and significantly overlap with those
seen in children without HIV infection in resource-limited settings; thus, in the absence of virological testing and CD4+ T cell count availability, symptomatic
IX-4
seropositive infants age eighteen months or younger should only be considered for HAART in exceptional circumstances (e.g. a child with a classic AIDS-
defining condition such as PCP or cryptococcal meningitis). If ARVs are given to a symptomatic HIV-positive infant in the absence of a definitive virological
diagnosis, HIV antibody testing should be repeated at age eighteen months to confirm infection status; HAART should only be continued in infants with
confirmed HIV infection.
f
A total lymphocyte count of <2,500/mm3 for children age eighteen months or younger or <1,500/mm3 for children age eighteen months or older can be
substituted for CD4+ T cell percentage when the latter is unavailable and HIV-related symptoms exist. Its utility in asymptomatic children is unknown. In the
absence of CD4+ T cell testing, therefore, asymptomatic HIV-infected children (WHO Paediatric Stage I) should not be treated because no other reliable marker
is currently available in severely resource-constrained settings.
IX-5
RECOMMENDATIONS FOR INITIATION OF HAART IN RESOURCE-FULL SETTINGS: NIH AND
CDC GUIDELINES
It is recommended that Caribbean settings with more resources use the NPHRC/HRSA/NIH guidelines
for deciding when to commence HAART in infants and children (Tables 2 and 3).4 It should be noted
that many clinicians would recommend treatment of all HIV-infected children age one year or younger,
regardless of clinical, immunological, or virologic status. Infancy represents a period when there is
usually a very high viral load with a high risk for rapid progression of HIV disease and the potential to
develop irreversible brain injury as a result of HIV encephalopathy.
Table 2: Indications for Initiation of HAART in HIV-Infected Children Age One Year or Younger in
Resource-Rich Settings
CLINICAL CD4+ CELL PLASMA HIV RNA

RECOMMENDATION
CATEGORY PERCENTAGE COPY NUMBER*
Symptomatic
<25%
(Clinical
OR (Immune category Any value Treat
category A, B,
2 or 3)
or C)
Asymptomatic
≥25% (Immune Consider
(Clinical AND Any value
category 1) Treatment**
category N)
* Plasma HIV RNA levels are higher in HIV-infected infants than in older infected children and adults, and may be
difficult to interpret in infants age twelve months or younger because overall HIV RNA levels are high and there is
overlap in HIV RNA levels between infants who have and those who do not have rapid disease progression.
**
Because HIV infection progresses more rapidly in infants than in older children or adults, some experts would treat
all HIV-infected infants age six months or younger or age twelve months or younger regardless of clinical,
immunologic, or virologic parameters.
Adapted from: NPHRC/HRSA/NIH. Guidelines for the use of antiretroviral agents in pediatric HIV
infection. 30 November 2004. Accessed 2004. Available at:
http://aidsinfo.nih.gov/guidelines/default_db2.asp?id=51.
IX-6
Table 3: Indications for Initiation of HAART in HIV-Infected Children Age One Year or Older in
Resource-Rich Settings
CLINICAL CD4+ CELL PLASMA HIV RNA
RECOMMENDATION
CATEGORY PERCENTAGE COPY NUMBER
AIDS
<15%
(Clinical OR Any value Treat
(Immune category 3)
category C)
Mild-Moderate
Symptoms 15-25%*
OR OR ≥100,000 copies/mL** Consider Treatment
(Clinical category (Immune Category 2)
A or B)
Many experts would

Asymptomatic defer therapy and
>25% (Immune
(Clinical category AND AND <100,000 copies/mL** closely monitor
Category 1)
N) clinical, immune and
viral parameters
*
Many experts would initiate therapy if CD4+ T cell percentage is between 15% to 20% and defer therapy with
increased monitoring frequency in children with CD4+ T cell percentage of 21% to 25%.
**
There is controversy among paediatric HIV experts regarding the plasma HIV RNA threshold warranting
consideration of therapy in children in the absence of clinical or immune abnormalities; some experts would
consider initiation of therapy in asymptomatic children if plasma HIV RNA levels are between 50,000 to 100,000
copies/mL.
Adapted from: NPHRC/HRSA/NIH. Guidelines for the use of antiretroviral agents in pediatric HIV
infection. 30 November 2004. Accessed 2004. Available at:
http://aidsinfo.nih.gov/guidelines/default_db2.asp?id=51.
PRACTICAL CONSIDERATIONS FOR THE CARIBBEAN

In practice, all confirmed HIV-infected children in the Caribbean should be treated, in decreasing order of
importance, for:
• TB;
• Severe failure to thrive;
• Encephalopathy;
• Meningitis or septicaemia;
• Hospitalisation for HIV-related illnesses;
• CDC Category C, then B, disease; and
• Any known HIV-infected child who is age one year or younger.
Additionally, efforts must be made to ensure ongoing adherence, access to medications, and care for those
children who merit HAART. HAART should generally be delayed if the patient is stable and there are
unresolved issues of non-adherence.
IX-7
ADHERENCE
The success or failure of antiretroviral therapy for children--as well as for adults--depends primarily on
the ability of the patient to take ARVs as prescribed. For this reason, intensive efforts should be made
prior to and following initiation of antiretroviral therapy to promote optimal adherence. These
interventions must necessarily involve the family and/or caregiver(s) of the child being treated. Practical
strategies to promote adherence include:
• Carefully assessing and preparing the family for adherence to medications and care, including
nursing, social, behavioural, and psychological assessments.
• Establishing trust and identification of mutually acceptable goals for care.
• Gathering information regarding the obtaining, storing, and administering of the child’s
medications.
• Determining who is responsible for administering medications and exactly how this is performed.
• Providing intensive family education and medication training before initiating treatment.
• Educating the family about the relationship between partial adherence and resistance.
• Educating the family that at the age of approximately three years, children can be successfully
trained to take pills without adverse experiences or behavioural problems.
o Training is best achieved by a neutral and non-authoritative individual who is not a
family member.
o Useful techniques for training a child to take pills include encouraging him/her to relax,
using increasing sizes of placebo pills, and encouraging swallowing with water or other
liquids.
• Facilitating encouragement with minimal extrinsic rewards.
• Not allowing the child to refuse medications once the child begins to take ARVs.
• Disallowing other activities until the ARVs are taken.
• Monitoring adherence at each visit, or between visits by phone.
• Providing ongoing support and encouragement.
• Considering a period of hospitalisation for virologic failure to assess adherence and to reinforce
that medication adherence is fundamental to successful HAART.
IX-8
RECOMMENDED INITIAL PAEDIATRIC HAART REGIMENS
The preferred paediatric initial regimens are summarised in Table 4. Three or more ARVs (generally two
NRTIs--the NRTI backbone--combined with either an NNRTI or a PI) should always be used in
conjunction to maximise the probability of sustained virologic suppression and to minimise the possibility
of the development of resistance. The use of zidovudine (AZT)/lamivudine (3TC)/abacavir (ABC) as a
first-line therapy is now considered a secondary alternative due to recent data from a clinical trial in HIV-
infected adults (ACTG 5095a) demonstrating a significantly higher failure rate in individuals receiving
this regimen than in individuals receiving similar efavirenz (EFV)-based regimens.
Preferred dual NRTI backbones include AZT plus 3TC; AZT plus didanosine (ddI); or stavudine (d4T)
plus 3TC. AZT penetrates the blood brain barrier and is therefore ideally suited for infancy given the risk
of HIV encephalopathy and developmental delay in this age group. d4T can be substituted for AZT if the
child is anaemic or experiences AZT-related toxicity. 3TC is generally preferred over ddI for pairing
with AZT and d4T because 3TC is highly potent, generally well-tolerated, and available in simple dosing
formulations. EFV is not recommended in children age three years or younger or weighing less than
twenty-five pounds due to the lack of dosing information and an appropriate formulation.
HAART regimens must be based on sound virologic and pharmacologic principles but must also be
acceptable to the individual patient. Thus, the design of the HAART regimen is influenced by
considerations of drug potency, side effect profiles, laboratory monitoring requirements, potential for
maintenance of future treatment options, anticipated patient adherence, co-existent conditions,
concomitant medications, availability, and cost. The potential for ARV resistance in infants infected
despite ARV PMTCT prophylaxis should also be considered in the design of the HAART regimen; this
issue is discussed in more detail in the section that immediately follows.
ARVs can be given to children in liquid formulations or in pills. Drug doses must be continually adjusted
as the child grows to avoid under-dosing, which could lead to the development of ARV resistance.
Regimens should consider the timing and interval between doses to maximise adherence. Combination
formulations of ARVs are not readily available for infants and children. Nevertheless, until appropriate
paediatric formulations can be made more widely available, splitting adult-dose solid formulation ARVs
may be the only way a severely ill child can receive appropriate ART when no alternatives are available.
Currently available paediatric dosages and formulations of ARVs are presented in Appendix B, as well as
significant adverse effects and toxicities associated with these ARVs.
Risk of ARV resistance in Infants Who Become Infected Despite PMTCT Prophylaxis
Infants who become infected with HIV despite antiretroviral PMTCT prophylaxis may be infected with
drug-resistant virus. This is most likely to occur with PMTCT regimens using ARVs for which a single
point mutation can confer drug resistance, such as NVP or 3TC; resistance is less likely to develop to
ARVs for which prolonged exposure and multiple mutations are associated with resistance, such as AZT.
Hence, infants who receive SD NVP (with or without other ARVs) and become infected with HIV despite
this intervention are at risk for harbouring a strain of HIV that is resistant to NVP (and by extension, to
other NNRTIs, since cross-resistance in the NNRTI class is very common). This phenomenon has been
documented in several clinical trials, with a range of 8 to 52% of NVP-exposed infants demonstrating
NVP resistance when tested within several weeks of birth. The risk appears to be elevated in infants
whose mothers also received SD NVP during labour. In theory, the development of NVP resistance in
this fashion could compromise the infant’s response to future NNRTI-based HAART regimens; clinical
trials are underway that will hopefully answer this important question. Until more data become available,
clinicians managing HIV-infected infants who were exposed to SD NVP may consider favouring PI-
based HAART regimens over NNRTI-based regimens. However, if a PI-based regimen is not readily
IX-9
available or is impractical for other reasons, NNRTI-based HAART can and should be used for these
infants.
Variable patterns of resistance to other ARVs such as AZT and 3TC in infants exposed to these agents
have also been documented. In PACTG 076, where mothers received AZT starting at 14-34 weeks
gestation and infants received 6 weeks of AZT, no AZT resistance was observed in infected infants;
however, in PACTG 185, where the PACTG 076 AZT regimen was given but the women were sicker at
entry, 30% of infected infants had AZT resistance. In a Thai study of short-course AZT, 20% of infants
infected despite prophylaxis had AZT-resistant virus. In a study in France in which 3TC was added to
AZT after 32 weeks gestation and the infants received 6 weeks of AZT/3TC, 3TC resistance was
observed in 2 of 5 infected infants (40%); AZT resistance was seen in 2/5 infected infants as well. In the
SAINT study, where AZT/3TC was administered during labour and post-partum, no AZT or 3TC
resistance was observed in infected infants. As is the case with NVP, the clinical implications remain
unclear; hence, exposure to PMTCT regimens that include AZT or 3TC should not preclude the inclusion
of these agents in future HAART regimens for HIV-infected infants.
IX-10
Table 4: Recommended Initial HAART Regimens for HIV-Infected Children5
Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)-Based Regimens
Strongly Recommended: Age >3 years: 2 NRTIsa + EFVb (with or without nelfinavir (NFV))
Age<3 years or who cannot swallow capsules: 2 NRTIsa + NVPb
Alternative 2 NRTIsa + NVPb (age >3 years)
Recommendation:
Protease Inhibitor (PI)-Based Regimens
Strongly Recommended: 2 NRTIsa + LPV (lopinavir)/r (Kaletra®) or NFV or ritonavir (RTV)
Alternative 2 NRTIsa + indinavir (IDV) or amprenavir (APV)c
Recommendation:
Triple Nucleoside Reverse Transcriptase Inhibitor (NRTI) Regimens
Strongly Recommended: None
Alternative AZT + 3TC + ABC
Recommendation:
Regimens Not Recommended
Monotherapyd
Certain 2 NRTIa combinations
2 NRTIsa + saquinavir (SQV) as sole PId
Insufficient Data to Recommend
2 NRTIsa + delavirdine (DLV)
Dual PIs with the exception of LPV/re
1 NRTI + 1 NNRTI + 1 PIf
Regimens that contain tenofovir (TDF), atazanavir (ATV), emtricitabine (FTC),
fos-amprenavir, or enfuvirtide
a
Dual NRTI combination recommendations:
• Strongly Recommended: AZT + ddI + 3TC; or d4T + 3TC
• Alternative Choices: ABC + AZT or 3TC; or ddI + 3TC
• Use in Special Circumstances: d4T + ddI; or zalcitabine (ddC) + AZT
• Insufficient Data: TDF- or FTC-containing regimens
• Not Recommended: ddC + ddI, d4T, or 3TC; or AZT + d4T
b
EFV is currently available only in capsule form, although a liquid formulation is currently under study to determine
appropriate dosage in HIV-infected children age three years or younger; NVP would be the preferred NNRTI for
children age three years or younger or who require a liquid formulation.
c
APV should not be administered to children age four years or younger due to the propylene glycol and vitamin E
content of the oral liquid preparation and lack of pharmacokinetic data in this age group.
d
Except for AZT chemoprophylaxis administered to HIV-exposed infants during the first six weeks of life to
prevent perinatal HIV transmission; if an infant is confirmed as HIV-infected while receiving AZT prophylaxis,
therapy should either be discontinued or changed to a combination ARV drug regimen.
e
With the exception of LPV/r, data on the pharmacokinetics and safety of dual PI combinations (e.g. low-dose RTV
pharmacologic boosting of SQV, IDV, APV, or NFV) are limited, use of dual PIs as a component of initial therapy
is not recommended, although such regimens may have utility as secondary treatment regimens for children who
have failed initial therapy. SQV soft and hard gel capsules require low-dose RTV-boosting to achieve adequate
levels in children, but pharmacokinetic data on appropriate dosing are not yet available.
f
With the exception of EFV + NFV + one or two NRTIs, which has been studied in HIV-infected children and
shown to have virologic and immunologic efficacy in a clinical trial.
IX-11
SPECIAL CONSIDERATIONS FOR PATIENTS WITH TB
Special considerations around antiretroviral therapy must be made for the child co-infected with HIV and
TB:
• Selection of the Initial HAART Regimen: NVP is generally avoided due to significant interactions
with rifamycin. If EFV- or PI-based regimens are not an option, administration of the triple-
NRTI regimen AZT plus 3TC plus ABC should be considered.
• Timing of HAART Initiation: The optimal time to initiate HAART in patients with TB is unclear
and should be considered on a case-by-case basis. Clinical experience in Jamaica suggests that
survival is improved in co-infected children who receive both HAART and TB treatment.
However, it may be advisable to delay the initiation of HAART for two to eight weeks following
the initiation of anti-TB medications in order to minimise pill burden, drug-drug interactions,
overlapping toxicities, and the risk of immune reconstitution syndrome (IRS).* Hence, deferral of
HAART initiation until after the induction phase of TB therapy may be advisable for those
children without clinical or immunological evidence of advanced HIV disease.
CLINICAL MONITORING AND FOLLOW-UP
The goals of therapy are to achieve and to maintain an undetectable HIV viral load. This prevents disease
progression, optimises recovery of the immune system, and prevents antiretroviral drug resistance. An
effective HAART regimen should generally result in an undetectable (e.g. less than 50 copies/mL) HIV
viral load within six months of therapy initiation. Suboptimal adherence is the most common reason for
failure of the initial HAART regimen. Adherence should therefore be monitored closely following
therapy initiation using pill counts, pharmacy prescription refill logs, and patient/caregiver self-reports.
Failure to achieve an undetectable viral load following initiation of HAART should prompt evaluation of
adherence and potential drug resistance. Common reasons for suboptimal adherence include drug side
effects, dosing difficulties, and inconvenience of administration.
If an undetectable HIV viral load is achieved, a significant rise in the CD4+ T cell count generally occurs,
signifying partial reconstitution of the immune system. However, the degree of rise of the CD4+ T cell
count can be quite variable, and some patients may not experience a significant rise in the CD4+ T cell
count despite a dramatic reduction in viraemia. The optimal management of patients with this discordant
response remains unclear, but should be based in part on consideration of clinical response to therapy.
Consultation with an expert in paediatric HIV management is also recommended.
Clinical markers that suggest a positive response to HAART include:
• reduced hospitalisations;
• increased appetite, weight, and height (in children with failure to thrive);
• improved brain growth, neurodevelopment, affect, and head circumference (in those with
developmental delay and/or encephalopathy); and
• reduced morbidity with reduced OIs and minor co-morbid illnesses (e.g. papular prurigo,
otitis media, oral thrush, upper respiratory tract infections).
TREATMENT TOXICITY
While adverse effects from HAART are common, they can usually be managed symptomatically while
continuing the HAART regimen without interruption, as most adverse effects associated with ARVs
resolve within one to three months of therapy initiation. If the adverse effect is severe enough to require
modification of the regimen, substitution of the offending drug with another ARV is a reasonable option
*
See the introduction to Chapter V: Recommendations for the Treatment of Opportunistic Infections among Adults
and Adolescents for a review of the pathophysiology and clinical presentation of IRS.
IX-12
if it can be reasonably deduced which agent is responsible for the side effect in question. Table 5 presents
options for drug substitution in the event of selected common adverse reactions. Consultation with an
expert HIV clinician is strongly recommended when a regimen change is necessary.
Recommended Drug Substitutions6
REGIMEN TOXICITY DRUG SUBSTITUTION
d4T/3TC/NVP • d4T-related neuropathy or pancreatitis Switch d4T Æ AZT
• d4T-related lipoatrophy
• NVP-related severe hepatotoxicity Switch d4T Æ ABC†
• NVP-related severe rash (but not life- Switch NVP Æ EFV‡
threatening)
• NVP-related life-threatening rash (e.g. Switch NVP Æ EFV
Stevens-Johnson syndrome)
Switch NVP Æ PI§
AZT/3TC/NVP • AZT-related persistent GI intolerance Switch AZT Æ d4T
or severe haematological toxicity
• NVP-related severe hepatotoxicity
• NVP-related severe rash (but not life- Switch NVP Æ EFV
threatening)
• NVP-related life-threatening rash (e.g. Switch NVP Æ EFV
Stevens-Johnson syndrome)
Switch NVP Æ PI
d4T/3TC/EFV • d4T-related neuropathy or pancreatitis Switch d4T Æ AZT
• d4T-related lipoatrophy
• EFV-related persistent CNS toxicity Switch d4T Æ ABC
Switch EFV Æ NVP
AZT/3TC/EFV • AZT-related persistent GI intolerance Switch AZT Æ d4T
or severe haematological toxicity
• EFV-related persistent CNS toxicity
Switch EFV Æ NVP
Occasionally, severe HAART-related toxicity requires discontinuation of all ARV agents. In such
circumstances, it is best to discontinue all medications simultaneously, because continuation of therapy
with only one or two ARV agents is associated with the development of drug resistance.** HAART
should be withheld until the patient recovers, at which time re-initiation of therapy with a different
regimen can be considered in consultation with an HIV expert.
†Switching off d4T appears to reduce, and in some cases reverse, lipoatrophy, though very slowly. TDF and ABC
represent the best alternatives to d4T in this setting, but their availability in the Caribbean is limited, and TDF
cannot be recommended for paediatric use given insufficient data. ddI and AZT are reasonable alternatives where
ABC is not available.
‡
Except in pregnancy. If the child is a teenager of child-bearing age who is pregnant or at risk for becoming
pregnant, substitute a PI (preferred) or ABC.
§
Recommended PIs include LPV/r or NFV or SQV/r.
**
If the HAART regimen being discontinued contains an NNRTI (e.g. NVP or EFV), some expert clinicians would
recommend discontinuing the NNRTI three to seven days prior to discontinuing the NRTIs, owing to the prolonged
plasma half-life of NNRTIs.
IX-13
TREATMENT FAILURE
Treatment failure refers to the absence of a sustained favourable response to HAART. Treatment failure
can be suspected on the basis of clinical grounds, but confirmation of failure with laboratory testing is
strongly recommended before changing a patient’s HAART regimen. Consultation with an expert HIV
clinician is also highly recommended if treatment failure is suspected on the basis of clinical,
immunologic, or virologic criteria. Efforts should be made to confirm suspected treatment failure as
rapidly as possible to prevent HIV disease progression and the development of further resistance to ARV
agents. Laboratory testing can be useful both to establish treatment failure and in guiding second-line
treatment options.
In the event of treatment failure, re-assessment of adherence is indicated. After adherence issues have
been adequately addressed, a change in the HAART regimen to second-line therapy is usually warranted,
as detailed later in this section.
Treatment Failure: Virologic Definition
With successful initial HAART, the HIV viral load is expected to decline by at least tenfold (one log10)
every two to eight weeks, and should be below the limit of detection of most viral load assays within
approximately six months of HAART initiation. Treatment failure can be defined by the absence of such
a decline in HIV viral load following initiation of therapy (failure to suppress), or by virologic
suppression to below the lower limit of detection followed by a subsequent sustained rise in HIV viraemia
(virologic breakthrough). These concepts are represented graphically in Chapter IV, Figures 3 and 4. If
HIV viral load testing confirms treatment failure, consideration of second-line therapy in consultation
with an HIV expert is recommended. Efforts should be made to change the HAART regimen as soon as
possible to discourage the development of drug resistance and to preserve effective treatment options.
Where viral load testing is not available, treatment failure can be made on the basis of immunologic or
clinical criteria, as described below.
Treatment Failure: Immunologic Definition
Because of age-related declines in absolute CD4+ T cell counts until age six years when near-adult levels
are reached, it is difficult to use such counts for assessing therapy failure in younger children. However,
for children age six years or older, similar CD4+ T cell count criteria to those used for adults are
appropriate. CD4+ T cell percentage varies less with age and is therefore more appropriate than the
absolute CD4+ T cell count for gauging treatment response in younger children. Where resources permit,
confirmatory repeat CD4+ T cell testing or viral load testing is warranted for the asymptomatic child
suspected of failure based on immunologic criteria alone. No data exist regarding the use of the total
lymphocyte count (TLC) for the evaluation of response to HAART in children.
U.S. Pediatric Guidelines7 suggest the following criteria for immunologic failure:
• Change in CDC immunologic classification (see Appendix C for immunologic classification
schemes);*** or
• For children with CD4+ T cell percentages of <15% (e.g. those in immune category 3), a
persistent decline of >5% in CD4+ T cell percentage (e.g. from 15% to 10%); or
• A rapid and substantial decrease in absolute CD4+ T cell count (e.g. >30% decline in less than six
months).
***Minimal changes in CD4+ T cell percentile that may result in change in immunologic category (e.g. from 26% to
24%, or 16% to 14%) may not be as concerning as a rapid substantial change in CD4+ T cell percentile within the
same immunologic category (e.g. a drop from 35% to 25%).
IX-14
WHO criteria8 for treatment failure in children include:
• Return of CD4+ T cell percentage (or for children age six years or older, of absolute CD4+ T cell
count) to pre-therapy baseline or below, in absence of other concurrent infection explaining
transient CD4+ T cell decrease; or
• >50% fall from peak level on therapy of CD4+ T cell percentage (or for children age six years or
older, of absolute CD4+ T cell count) in absence of other concurrent infection explaining
transient CD4+ T cell decrease.
Treatment Failure: Clinical Definition
Treatment failure should be suspected if progression of HIV disease continues following HAART
initiation or if no clinical improvement occurs in three months following therapy initiation. Clinicians
must be careful to distinguish suspected HIV disease progression from IRS, which can also manifest with
fevers, night sweats, and fatigue, but does not signify treatment failure. IRS typically resolves within a
couple of months following initiation of HAART, whereas a new OI generally will not. Further
discussion of IRS can be found in the introduction to Chapter V: Recommendations for the Treatment of
Opportunistic Infections among Adults and Adolescents.
In children, important clinical signs of treatment failure include:
• lack of growth, or falling off of growth in children with an initial growth response;
• loss of neurodevelopmental milestones or development of encephalopathy;
• occurrence of new OIs or of a malignancy signifying clinical disease progression;††† and
• recurrence of minor and major OIs that may be refractory to therapy, e.g. oral candidiasis.
Management of Suspected Treatment Failure
It should not be concluded on the basis of clinical criteria alone that a HAART regimen is failing until the
child in question has had a reasonable treatment trial (e.g. receiving the regimen for at least twenty-four
weeks). The HAART regimen should not be changed unless ongoing poor adherence has been ruled out
for failure. Laboratory testing at six months, especially viral load testing, is strongly recommended if
treatment failure is still suspected six months following the initiation of HAART. The viral load results
should be confirmed, if possible, to ensure that the suggested change is needed. Laboratory results should
be reviewed with an expert HIV clinician to guide management decisions. If treatment failure is
confirmed, a change in HAART to a second-line regimen is generally recommended, although if a
regimen has brought the viral load to low or nearly undetectable levels, intensification of the current
regimen with the addition of another drug may be a reasonable alternative strategy.
Where reasonable options for second-line HAART regimens are lacking, it may be more advantageous to
continue the initial HAART regimen despite a suboptimal response rather than change regimens.
However, it should be recognised that this approach risks the ongoing development of ARV drug
resistance, which can further compromise future treatment options.
SECOND-LINE AND SALVAGE ANTIRETROVIRAL THERAPY

Treatment failure of the initial HAART regimen is a common, though not inevitable, event. When initial
treatment fails, a second-line regimen is generally implemented. Salvage therapy refers to treatment
regimens designed for patients who have failed two or more ARV regimens. In general, each successive
HAART regimen is less likely than the previous regimen to achieve durable virologic and immunologic
†††Thismust be distinguished from IRS, which can occur in the first three months following HAART initiation and
does not signify treatment failure.
IX-15
success. Hence, treatment regimens must be selected carefully to maximise a patient’s likelihood of a
robust and durable response to HAART.
HIV RESISTANCE TO ARV MEDICATIONS
Treatment failure often (though not always) occurs because a patient’s strain of HIV has developed
resistance to one or more of his or her ARVs. The development of resistance by HIV is similar to the way
in which bacteria or mycobacteria (e.g. TB) develop resistance to antibiotics: insufficiently potent drug
therapy selects for mutant strains that are resistant to the medications administered to the patient. These
mutant strains then replace the wild-type strain due to their selective replication advantage in the face of
drug pressure, leading to treatment failure. Resistance to ARVs most commonly develops in the setting
of suboptimal adherence, but can occur even in patients who maintain very high levels of adherence to
their medications. For example, a patient with poorly-controlled diarrhoea may not fully absorb his or her
medications, leading to subtherapeutic drug levels in the blood, which could lead to the development of
resistance.
Cross-resistance between ARV drugs within drug classes is common; for example, a strain of HIV that is
resistant to NVP is very likely to be highly resistant to EFV as well, and vice versa. Considerations of
potential cross-resistance must therefore be incorporated into the design of second-line and salvage
treatment regimens.
Laboratory assays have been developed to estimate the patterns of resistance that have developed in a
given patient’s strain of HIV. Though imperfect, these assays have demonstrated clinical efficacy in
aiding the design of second-line treatment regimens following treatment failure. Unfortunately, these
assays are very expensive and not widely available in the Caribbean. However, where available, a
resistance assay can provide valuable information for patients experiencing treatment failure.
Even in the absence of resistance testing, knowledge of the patterns of resistance and cross-resistance that
commonly develop in patients failing specific regimens allows for reasonably accurate empiric decision-
making in designing a second-line regimen. Empirically designed algorithms have been incorporated into
the design of second-line treatment regimens (see Table 6).
A more detailed discussion of ARV resistance and resistance assays can be found in Appendix F of
Chapter IV.
SECOND-LINE HAART REGIMENS
Second-line HAART regimens are indicated for patients who are forced to discontinue their initial
treatment regimen as a consequence of treatment failure or severe toxicity. Consultation with an expert
HIV clinician is highly recommended when designing a second-line regimen. If the initial regimen was
discontinued due to toxicity without evidence of treatment failure, then the second-line regimen should
involve substitution of the drug most likely to be responsible for the toxicity, as outlined in Table 5. For
example, if a child develops a severe skin rash after starting an initial regimen of d4T plus 3TC plus NVP,
a second-line regimen can be constructed using the same nucleoside backbone but with a different third
agent, because it can be reasonably assumed that the NVP was responsible for the skin reaction.9
If the initial HAART regimen was discontinued due to treatment failure, however, it is likely that drug
resistance to one or more ARV agents in the initial regimen has developed. The next HAART regimen
must be constructed carefully to account for this potential resistance. Where available, ARV resistance
testing is strongly recommended to help guide the design of the second-line regimen. If a resistance-
testing assay is not available, empiric reasoning regarding the likelihood of resistance to agents in the
initial regimen, as well as considerations of cross-resistance, can be used to design a second-line regimen
with the highest likelihood of efficacy. Because the exact nature and extent of resistance is difficult to
estimate empirically, these guidelines suggest trying to replace as many of the agents in the initial
regimen as possible.
IX-16
Resistance to 3TC and to NNRTIs commonly develops in patients who fail initial treatment regimens
containing these agents. Hence, second-line regimens for patients who initiated an NNRTI-based
regimen generally involve replacement of the NNRTI with a PI.* Conversely, initial PI-based regimens
should generally be replaced with NNRTI-based regimens.
Most initial HAART regimens will also contain either AZT or d4T. Unfortunately, AZT and d4T share
similar resistance patterns, and a high degree of cross-resistance between these two drugs limits the utility
of replacing one of them with the other. Hence, for patients failing AZT- or d4T-containing HAART
regimens, the best second-line options include a nucleoside backbone of ddI plus ABC. Unfortunately,
ABC is not universally available in the Caribbean. Fortunately, AZT and d4T will often retain at least
partial efficacy in a second-line regimen, because typically HIV must develop multiple resistance
mutations before achieving full resistance to either of these agents. Hence, where ABC is not available,
AZT or d4T may be used in second-line regimens. The use of TDF cannot be recommended due to
insufficient data regarding its use in paediatric patients.
Table 6: Second-Line Regimen Recommendations for Treatment Failure
FAILED FIRST-LINE SECOND-LINE REGIMEN COMMENTS
REGIMEN OPTIONS†
d4T + 3TC + EFV ABC + ddI + PI/r§ • ABC not widely available; beware of
or or ABC hypersensitivity
d4T + 3TC + NVP AZT + ddI + PI/r • Potency questionable due to cross-
or resistance between d4T and AZT
Substitute NFV for PI/r in • PI/r favoured over NFV due to higher
above options potency
AZT + 3TC + EFV ABC + ddI + PI/r • ABC not widely available; beware of
or or ABC hypersensitivity
AZT + 3TC + NVP AZT + ddI + PI/r • Potency questionable
or • Higher pill burden and risk of toxicity
ABC + ddI + AZT + PI/r • PI/r favoured over NFV due to higher
or potency
Substitute NFV for PI/r in
above options
AZT + 3TC + ABC ABC + ddI + (EFV or NVP) • Potency questionable; ABC may still
or retain some activity
ABC + ddI + PI/r • PI/r favoured over NFV due to higher
or potency
ABC + ddI + NFV • d4T + ddI combination not generally
or recommended due to excess toxicity
Substitute d4T for ABC in
above options
*
LPV/r is the preferred PI in this circumstance given its high potency and established paediatric dosing and
formulation. The use of PIs other than LPV/r and NFV is more problematic in children because of a lack of suitable
paediatric drug formulations for IDV and SQV and a lack of appropriate dosing information for RTV-boosted PIs
other than LPV/r. However, SQV/r maybe considered as an alternative in children who weigh 25kg or more, and
can therefore receive the adult dosage.
† 3TC may be added to any of the above regimens. Some expert clinicians suggest continuing 3TC therapy even for
patients in whom 3TC resistance is likely, due to reduced replicative capacity (viral fitness) induced by the signature
3TC resistance mutation.
§ PI/r = RTV-boosted PI (LPV/r or, for children >25 kg, SQV/r)
IX-17
2 NRTIs + (PI or PI/r) 2 different NRTIs + (EFV or • See patterns above for NRTI selection
NVP) • Because PI resistance develops
or relatively slowly, an PI/r–based
2 different NRTIs + PI/r second-line therapy may be effective
even for patients who failed initial PI-
based therapy
SALVAGE THERAPY
Following failure of two or more ARV regimens, durable virologic suppression is unlikely. However,
prevention of further immunologic deterioration is possible even in the absence of full virologic
suppression. Studies in adults have demonstrated that highly treatment-experienced patients, including
those with demonstrably high levels of ARV resistance, generally fare better clinically if they remain on
HAART than if they discontinue antiretroviral therapy altogether. Hence, while full virologic
suppression may not be a realistic goal for highly treatment-experienced patients, attempts should be
made to construct a regimen that will still maintain some efficacy and hopefully prevent or slow further
progression of HIV disease. The design of salvage therapy regimens is exceedingly complex and should
be performed in consultation with an expert HIV clinician.
PAEDIATRIC ANTIRETROVIRAL THERAPY DRUG FORMULARY FOR THE CARIBBEAN

Based on the recommendations outlined above, nine ARV single drugs and two combination preparations
are recommended for consideration for the Paediatric ART Drug Formulary for the Caribbean (Table 7).
Table 7: Paediatric ART Drug Formulary for the Caribbean
DRUG CLASS GENERIC NAME TRADE NAME ABBREVIATION
Nucleoside Reverse Zidovudine Retrovir®* AZT or ZDV
Transcriptase Lamivudine Epivir®** 3TC
Inhibitor (NRTI) Stavudine Zerit® d4T
Didanosine Videx®, Videx® EC ddI
Abacavir Ziagen® ABC
Non-Nucleoside Nevirapine Viramune® NVP
Reverse Efavirenz Sustiva®; Stocrin® EFV or EFZ
Transcriptase
Inhibitor (NNRTI)
Protease Inhibitor Nelfinavir Viracept® NFV
(PI) Lopinavir/ritonavir Kaletra® LPV/r
*Also available as Combivir® (ZDV/3TC)
**Also available as Trizivir® (ZDV/3TC/ABC)
IX-18
APPENDIX A: CONSIDERATIONS ON SPECIFIC DRUGS
TASTE: There are no good-tasting ARV drugs; RTV and RTV-containing formulations are the worst.
NFV tablets dissolve easily in water for ease of administration. The paediatric formulation of NFV is a
non-palatable powder.
DOSING: Regimes should be simple, i.e. once or twice-daily. When initiating treatment with NVP, it is
administered once daily for two weeks, and if no reaction occurs, then it should be stepped up to twice
daily. Discontinue NVP if there is a grade 2 rise in AST and/or ALT.
COMBINATIONS: AZT plus d4T in any combination is not recommended due to antagonism of these
drugs in vivo. Dual or monotherapy with just one or two ARVs is also discouraged. HAART is
recommended for all infants, children, and adolescents who are treated with ARV agents, because
HAART affords the best opportunity to preserve immune function and delay disease progression.
Considerations related to the choice of initial HAART regimens should include an understanding of
barriers to adherence, including the complexity of schedules and food requirements for different
regimens, as well as palatability problems and potential limitations in subsequent treatment options
should resistance develop.
MONITORING AND FOLLOW-UP: It is recommended that all children be seen on a monthly basis,
both to monitor for general well-being and toxicity and to encourage adherence. Blood work, including
CBC with differential, LFTs, creatinine, and amylase, should be performed one month after initiating
treatment and then at three monthly intervals (beginning at three months after commencing treatment).
CD4+ T cell counts (percent and absolute) and viral load should be done at three-month intervals, if
accessible and available.
TOXICITY: In general, (see toxicity table in Appendix B), grade 1 and 2 anomalies are monitored, while
grade 3 and 4 toxicities are indications to discontinue the responsible ARV. In some situations, this may
mean discontinuing all ARVs until resolution of the abnormality. The most common toxicity is usually
AZT-induced anaemia or neutropaenia. In rare cases, there is a rapid drop in haemoglobin, which may be
life-threatening, within the first two to four weeks after starting AZT. NRTIs, particularly d4T, ddI, and
(to a lesser extent) AZT and 3TC, may cause mitochondrial toxicity. This should be considered
especially in a patient presenting with multi-organ dysfunction and/or CNS signs. Elevated ALT or rash
(particularly Stevens-Johnson syndrome) is of particular concern in relation to NVP.
TREATMENT FAILURE: The most common cause of treatment failure is nonadherence (poor
compliance) with the treatment regime; every effort should be made to confirm that medications are being
taken as prescribed prior to any change of therapy for failure. Directly observed therapy (DOT) is
strongly recommended as an interventional strategy to facilitate success.
Since a significant proportion of the children may be orphans and cared for by grandparents or elderly
guardians, attention should also be paid to the health and well-being of the guardian with particular
reference to their eyesight.
SPECIAL PROBLEMS OF CHILDHOOD

GROWTH AND DEVELOPMENT are of paramount importance to the paediatric patient. Even though
the child who is nonadherent may have normal growth and development, the failure of these parameters is
usually indicative of poor virologic control. The Growth Chart and noting of the Tanner Score are
important tools in the care of the paediatric patient.
DISCLOSURE is also an important aspect of care because as children approach adolescence, they
participate more in their own care. Their understanding of their condition can make all the difference
IX-19
between treatment success and failure. It also makes them aware of their parents’ diagnoses and
subsequent needs to be handled with appropriate sensitivity.
The issue of disclosure is also important in the emerging sexuality of the paediatric patient to control the
spread of infection.
Although awareness of HIV has resulted in drastic improvements in care, STIGMA and SEVERE
POVERTY remain major causes of poor adherence. Many patients refuse to be seen at clinics and will
not allow healthcare workers to visit their homes. Most liquid ARVs require refrigeration, and this can
pose problems since many families do not own refrigerators and some may not want other household
members to know that their child is on medication. The healthcare team must be aware of such issues and
be willing to devise innovative approaches to the delivery of care to achieve success.
PROGNOSIS
Children treated optimally with HAART, OI prophylaxis, nutritional, and other supportive therapy can
grow up to lead normal adult lives. In developed countries, such children are now growing up to consider
university educations, buying a house, marrying, and even having children. The long-term prognoses of
paediatric HIV/AIDS can therefore be excellent.
IX-20
APPENDIX B: CURRENTLY AVAILABLE ARVS FOR PAEDIATRIC USE§§§
Table 8: Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) (Part 1 of 2 tables on NsRTIs)*
PART 1 OF 2 ABACAVIR DIDANOSINE
SHORT FORM ABC ddI, ddI EC
TRADE NAME Ziagen®, Trizivir® (GW) Videx®, Videx EC® (BMS)
PAEDIATRIC DOSE* Paediatric (age >90 days): 8mg/kg/dose po b.i.d1 Paediatric1 (age >90 days): 120mg/m2/dose po b.i.d
Do not exceed the Neonate (age 30-90 days) (investigational): 8mg/kg/dose po b.i.d1 Range: 90-150mg/m2/dose po b.i.d (higher doses if risk of CNS
recommended adult disease, especially in young children with developmental delay).
dose. Paediatric Enteric-Coated Capsules: 240mg/m2/dose po q.d12
Neonate (age <90 days):1 50mg/m2/dose po b.i.d
ADOLESCENT & 300mg po b.i.d <60kg: 125mg b.i.d1,2 EC: 250mg q.d or 125mg b.i.d2
ADULT DOSE >60kg: 200mg b.i.d1,2 EC: 400mg q.d or 200mg b.i.d2
Use 2 buffered tablets/dose
CANADIAN 300mg tablet 25mg, 50mg, 100mg, 150mg chewable-buffered tablets, room temp,
AVAILABLE room temperature, prescription vial Rx vial (60/bottle)
FORMS6 & 20mg/mL solution 240mL 125mg, 200mg, 250mg, 400mg enteric-coated beadlets capsules (EC)
STORAGE sorbitol, banana-strawberry flavoured (contains no antacid component) (30/bottle)
room temperature, Rx bottle Oral solution 10mg/mL (4g/400mL). Add 200mL water. Shake
Trizivir® film-coated tablet (ABC, 300mg + 3TC, 150mg + AZT, well, then add 200mL antacid (also available as 2g/200mL).
100mg) Oral solution 20mg/mL (clinical investigative drug) - 4g/200mL.
Loosen powder in bottle. Add 100mL antacid and shake gently for 1
minute. Add 100mL antacid and shake gently for 1 more minute.11
30 days, refrigerated, shake well, glass bottle
Antacid = Mylanta Double Strength, Maalox TC, or Maalox Plus ES
(cherry-flavoured, saccharin)5 (other antacids in product monograph)
§§§
All pharmaceutical charts in Appendix IX-B were graciously authored and contributed by Natalie Dayneka, B.Sc.Phm., PharmD, Clinical
Specialist, Children’s Hospital of Eastern Ontario, Ontario, Canada.
IX-21
MAIN PRECAUTION Potentially fatal hypersensitivity ± rash (3.7% of children and adults) Pancreatitis (less common in paediatrics)1, peripheral neuropathy
usually within first 6 weeks (1-2 weeks most common).3 Signs include:
flu-like symptoms, fever, shortness of breath, maculopapular or urticarial
rash, fatigue, nausea and vomiting, diarrhoea, and abdominal pain. Do
not restart: life-threatening hypotension and death can occur in hours.
TOXICITY More Common: Nausea, vomiting, fever, rash (maculopapular or Paediatric ADR Rates5:
urticarial)3, anorexia, diarrhoea
More Common1: Diarrhoea 81%, abdominal 35%, nausea and
1
Less Common (more severe): Potentially fatal hypersensitivity vomiting 58%, chills/fever 82%
reaction, ↑ CPK, ↑ Cr, lymphopaenia
Less Common (more severe):1 Peripheral neuropathy (dose
Rare:1 Pancreatitis, ↑ LFTs, ↑ glucose, ↑ TRIG related),
ADRs for NRTI Class:2 Lactic acidosis and severe hepatomegaly with ↑↓ electrolytes, ↑ uric acid
hepatic steatosis - rare, but may be fatal; discontinue all NRTIs if ↑↑
LFTs Rare:1 Pancreatitis 7% (dose-related, less common in paediatrics,
can be fatal, ↑ with d4T), ↑ LFTs 38%, retinal depigmentation
Sorbitol: abdominal pain, diarrhoea
ADRs for NRTI Class:2 Lactic acidosis and severe hepatomegaly
with hepatic steatosis - rare but may be fatal; discontinue all NRTIs if
↑↑ LFTs.
MONITORING (blood ALT, amylase, TRIG,8,9 CHOL,8,9 glucose,8,9 lactate, Cr, CBC with Diff, ALT, amylase, electrolytes, uric acid, lactate, TRIG,8,9 CHOL,8,9
tests) creatine phosphokinase (CPK) glucose,8,9 aluminium (only with oral liquid)
DRUG • Avoid co-administration with other drugs known to cause

INTERACTIONS peripheral neuropathy (d4T, ddC) or pancreatitis (d4T, ddC, 3TC,
RTV)2
• Take 2 hours BEFORE ddI: dapsone, azole antifungals, H2
blockers, fluoroquinolones, ganciclovir, TFV (↓ dose), RTV, (all
drugs altered by antacid of buffered tablets)
• Take 1 hour BEFORE ddI: tetracyclines, iron salts, NFV
MARKET STATUS6+ Marketed (tablets/liquid) Marketed (tablets/EC tablets), SAP – Sunnybrook (oral solution)
DOSE IN ORGAN ↓ dose in hepatic dysfunction ↓ dose if CrCl <60mL/min

FAILURE HD: Drug removed (supplement dose not required)
Liver disease: ↓ dose
IX-22
CSF/PLASMA 27-33%7 Adult 21%7, child mean 46%7

BIOAVAILABILITY F = 0.832 F = 0.3-0.42
HALF-LIFE t1/2C = 12-26h2, t1/2 = 1.5h2 t1/2c = >20h2, t1/2 = 1.5h2
MEALS May take with or without food Adults: Do not give with food;
Children: May take with food10
SPECIAL • Watch for rash Buffered Tablets:

INSTRUCTIONS • Manufacturer provides hypersensitivity warning card for patient • 2 tablets/dose (do not swallow whole)
• Chew tablets; crush or add 2 tablets to >30mL cold water for 10
minutes, then stir, may then add <30mL clear apple juice (stable
for 1 hour at room temperature once mixed)5
• Do not give with other fruit juices, acidic drinks, or feeds
• Adults: Do not give with >60mL milk
• Adults: Give at least 30 minutes before meal or 2 hours after2,5
• Children: May take with milk or food (one published study)10
• Separate from other medications by >2 hours
Enteric-Coated Capsules:
• Swallow whole
Note: *Do not exceed the recommended adult dose. Some information in this chart may be at variance with the product monograph. Please consult current
recommendations before using this chart.
+
Market status does not imply approval for paediatric use.
IX-23
Table 9: Nucleoside Reverse Transcriptase Inhibitors (NsRTIs) (Part 2 of 2 tables on NsRTIs)*
PART 2 OF 2 LAMIVUDINE STAVUDINE ZALCITABINE ZIDOVUDINE
SHORT FORM 3TC d4T ddC ZDV, AZT
TRADE NAME 3TC®, Heptovir® (GW) Zerit® (BMS) Hivid® (Roche) Retrovir®, Combivir®, Trizivir®
(Epivir® US) (GW)
PAEDIATRIC Paediatric:1 4mg/kg/dose po b.i.d Paediatric:1 1mg/kg/dose po b.i.d Paediatric:1 0.01mg/kg/dose Paediatric1:
DOSE* Neonate (<age 30 days):1 up to 30mg po b.i.d po q8h po: 180mg/m2/dose b.i.d
Do not exceed the 2mg/kg/dose po b.i.d Neonate (PACTG 332):1 160mg/m2/dose q8h
recommended adult Unknown Range: 90-180mg/m2/dose q6-
dose. 8h
Adult:1 For Zerit® extended-release IV: 120mg/m2/dose q6h or
(ER) 75 & 100mg capsules (not 20mg/m2/hour
available in Canada)
_________________________
>60kg: 100mg po q24h Perinatal Exposure: 8-12
<60kg: 75mg po q24h hours after birth for 6 weeks4
Neonate (term to age 90
days):1 2mg/kg/dose po q6h
1.5mg/kg/dose IV q6h
Premature (<35 weeks):1,4
2mg po q12h or
1.5mg/kg/dose IV q12h
<30 Weeks GA: ↑ q8h after 4
weeks
>30 Weeks GA: ↑ q8h after 2
weeks
ADOLESCENT & >50kg: 150mg po b.i.d or <60kg: 30mg po b.i.d1,2 0.75mg po t.i.d1,2 200mg t.i.d or 300mg b.i.d1,2
ADULT DOSE 300mg po q.d2 >60kg: 40mg po b.i.d1,2
IX-24
CANADIAN 1) 150mg white film-coated tablet 15mg, 20mg, 30mg, and 40mg 0.375mg and 0.75mg film- 1) 100mg capsule, Rx vial,
AVAILABLE capsules: Rx vial, room coated tablets
FORMS6 & (not scored – may cut in half) temperature room temperature
STORAGE 0.1mg/mL syrup, 30mL
Liquid: 1mg/mL fruit-flavoured (clinical investigative drug)
(60/bottle) (clinical investigational drug) room temperature, original 2) 10mg/mL syrup, 240mL
2g/200mL. Shake well, refrigerate, bottle (glass)
30-day expiry strawberry-flavoured, Rx bottle,
2) Oral solution: 10mg/mL
240mL strawberry-banana (20%
sucrose) Rx bottle, room room temperature
temperature
3) 10mg/mL injection--20mL
3) 300mg tablet (30/bottle) vial
4) Combivir® film-coated tablet IV: Over 1 hour NS or D5W
(3TC, 150mg + AZT, 100mg)
<4mg/mL, 8-hour expiry at
5) Trizivir® film-coated tablet
(ABC, 300mg + 3TC, 150mg +
room temperature, 24-hour
ZDV, 100mg)
For Hepatitis B: Heptovir®, expiry in refrigerator
100mg tablet (60/bottle) (not
scored - may cut in half) 4) Combivir® film-coated tablet
5mg/mL strawberry-banana (no (3TC, 150mg + AZT, 100mg)
alcohol) 5) Trizivir® film-coated tablet
(ABC, 300mg + 3TC, 150mg +
AZT, 100mg)
MAIN Pancreatitis Peripheral neuropathy, pancreatitis Peripheral neuropathy, Myelosuppression, severe

PRECAUTION pancreatitis anaemia
IX-25
TOXICITY More Common:1 HA, fatigue, More Common:1 Headache, GI More Common:1 Headache, More Common:1
nausea, diarrhoea, rash, abdominal disturbances, rash GI disturbances, malaise Haematologic toxicity (↓ WBC,
pain Less Common (more severe):1 ↓ Hgb, ↓ PLT), headache,
Less Common (more severe):1 nausea and vomiting
Less Common (more severe):1 Peripheral neuropathy (7-21%),5 • Peripheral neuropathy (↑ rate
Pancreatitis 14% (seen in pancreatitis in children) Less Common (more severe):1
paediatric advanced HIV on • Pancreatitis, hepatic toxicity, Myopathy, myositis, liver
multiple medications),5 Rare:1 ↑ LFTs oral ulcers, oesophageal toxicity
paresthaesia/peripheral neuropathy ulcers, rashes, ↓ platelets, ↓
15%,5 ↓ WBC (neutrophils), ↑ ADRs for NRTI Class:2 Lactic WBC, ↓ Hgb Bone Marrow Suppression:5
LFTs acidosis and severe hepatomegaly (Neutropaenia ± anaemia)
with hepatic steatosis - rare but may ADRs for NRTI Class:2
ADRs for NRTI Class:2 Lactic be fatal. Discontinue all NRTIs if Lactic acidosis and severe ↓ WBC: Mean onset 6 -8 weeks
acidosis and severe hepatomegaly ↑↑ LFTs hepatomegaly with hepatic Tx: G-CSF
with hepatic steatosis - rare but steatosis - rare but may be fatal.
may be fatal. Discontinue all d4T ↑ risk of lactic acidosis Discontinue all NRTIs if ↑↑ ↓ Hgb: Dose-related--mean
NRTIs if ↑↑ LFTs compared to other NRTIs2 LFTs onset 4-6 weeks, as early as 2
(discontinue stat if lactate weeks Tx: EPO
>10mmol/L, interrupt NRTI therapy
if 5–10mmol/L) ADRs for NRTI Class:2
Lactic acidosis and severe
hepatomegaly with hepatic
steatosis - rare but may be fatal.
Discontinue all NRTIs if ↑↑
LFTs
MONITORING CBC, ALT, amylase, lactate, ALT, amylase, TRIG,8,9 CHOL,8,9 CBC, ALT, amylase, TRIG,8,9 CBC (retic count, MCV), ALT,
(blood tests) TRIG,8,9 CHOL,8,9 glucose8,9 glucose8,9 CHOL,8,9 glucose8,9 amylase, lactate, TRIG,8,9
CHOL,8,9 glucose8,9
DRUG • TMP-SMX may ↑ 3TC levels (↓ • INH, metronidazole, dapsone, • Ampho B, gentamicin, • -Acyclovir, ganciclovir,
INTERACTIONS renal tubular secretion) phenytoin, pentamidine, (avoid foscarnet (↓ renal interferon α, β, and β1A
(significance???) co-administration with drugs that elimination) (bone marrow suppression)
• 3TC may prevent AZT ↑ risk of peripheral neuropathy) • ddI (avoid co-administration • RIF, rifabutin (↓ AZT)
resistance1 • ddI (avoid co-administration with with drugs that ↑ risk of
drugs that ↑ risk of pancreatitis, peripheral neuropathy) • Clarithromycin (4 hours
peripheral neuropathy, ↑ LFTs )5 • Pentamidine (↑ pancreatitis) apart) (↓ AZT absorption)
• AZT (↓ effect)1 • Antacids (↓ absorption) • Fluconazole (74% ↑ AZT),
IX-26
methadone, atovaquone,
valproic acid, phenytoin,
probenecid (inhibit
glucuronidation)
• d4T (↓ effect)1
MARKET STATUS6+ Marketed (tablets, liquid) Liquid and extended-release Syrup not marketed 300mg tablet not marketed in
capsules not marketed in Canada Canada
DOSE IN ORGAN ↓ dose if CrCl mL/min2: ↓ 30–40mg dose if CrCl mL/min2: ↓ frequency if CrCl mL/min2: ↓ dose if CrCl <30mL/min:2
FAILURE
30-49: 150mg po q24h 26-50: 15-20mg q12h 10-40: q12h HD: 100mg po t.i.d
15-29: 150mg x 1, 100mg po q24h 10-25: 15-20mg q24h <10: q24h Hgb <80 g/L: ↓ dose 30%
5-14: 150mg x 1, 50mg po q24h HD: Dose for CrCl 10-25mL/min Liver Disease: Caution Liver disease: ↓ dose
and give after dialysis
<5 & HD: 50mg x 1, 25mg po
q24h
CSF/PLASMA 6-31%7 Child 59%7 9-37% (mean 20%)7 Child 68%7

BIOAVAILABILITY F = 0.862 F = 0.862 F = 0.852 F = 0.62, t1/2c = 7h2
HALF-LIFE t1/2c = 18–22h2, t1/2 = 5–7h2 t1/2c = 7.5h2, t1/2 = 1h2 t1/2 = 1.2h2 t1/2 adult = 1.1h2, t1/2 neonate= 3.1h4
t1/2 prem (26-33 wk) = 7.2h4
MEALS Take with or without food Take with or without food Take with or without food2 Take with or without food1,2
SPECIAL • If 3TC upsets the stomach, take • If d4T upsets the stomach, take • If ddC upsets the stomach, • Manufacturer recommends
INSTRUCTIONS with food with food take with food 30 minutes before meals or 1
• May cut tablet in half • May open capsule and give in hour after, but OK to take
small portion of food or 5-10mL with food
• May crush tablet cool tap water • If AZT upsets the stomach,
take with food
• May open capsule and give
in small portion of food or 5-
10mL cool tap water
IX-27
Note:
*Do not exceed the recommended adult dose. Some information in this chart may be at variance with the product monograph. Please consult current
+
References:
1
US DHHS. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 30 Nov 2004 revision. Last accessed 30 Nov 2004. Available at:
<http://AIDSinfo.nih.gov>.
2
US DHHS. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. 29 Oct 2004 revision. Last accessed 29 Oct 2004. Available
at: <http://AIDSinfo.nih.gov>.
3
US DHHS. Supplement I: pediatric antiretroviral drug information in Guidelines for the use of antiretroviral agents in pediatric HIV infection. 30 Nov 2004
revision. Last accessed 30 Nov 2004. Available at: <http://AIDSinfo.nih.gov>.
4
US DHHS. Public health service task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and
interventions to reduce perinatal HIV-1 transmission in the United States. 17 Dec 2004 revision. Last accessed 17 Dec 2004. Available at:
5
Compendium of Pharmaceuticals and Specialties. Ottawa:Canadian Pharmacists Association; 2004.
6
Drug Product Database [database on the Internet]. Ottawa:Health Canada. c2004 [cited 21 Jan 2005]. Available at: http://www.hc-sc.gc.ca/hpb/drugs-dpd>.
7
Facts and Comparisons, Nov 2004.
8
Qaqish RB, Fisher E, Rublein J, Wohl DA. HIV-associated lipodystrophy syndrome. Pharmacotherapy 2000;20(1):13-22.
9
Leonard EG, McComsey GA. Metabolic complications of antiretroviral therapy in children. Ped Inf Dis J 2003;(22):77-84
10
Stevens RC et al. and the Pediatric AIDS Clinical Trials Group Protocol 144 Study Team. Effect of food and pharmacokinetic variability on didanosine
systemic exposure in HIV-infected children. AIDS Res & Hum Retrovir 2000;16(5):415-21.
11
Bristol-Myers Squibb personal communication, 25 Jan 2001.
12
King JR, et al. Single-dose pharmacokinetics of enteric-coated didanosine in HIV-infected children. Antiviral Ther 2002;(7):267-270.
IX-28
Table 10: Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)*
PART 1 OF 1 TENOFOVIR disoproxil fumarate
SHORT FORM TDF, TFV
TRADE NAME Viread® (Gilead)
PAEDIATRIC DOSE* Paediatric:

Do not exceed the recommended Study Gilead 926: 175mg/m2/dose po q.d7
adult dose. Study Gilead 927: Given po q.d7
10-<20kg: 75mg
20-<35kg: 150mg
35-<50kg: 225mg
>50kg: 300mg
ADOLESCENT & ADULT 300mg po q.d2

DOSE
CANADIAN AVAILABLE 300mg almond-shaped, light-blue film-coated tablet (30/vial with desiccant) original bottle
FORMS4 & STORAGE room temperature (not scored - may cut in quarters or half) (Note: Tenofovir DF 300mg = tenofovir D 245mg)
MAIN PRECAUTION Lactic acidosis and severe hepatomegaly
TOXICITY Most Common:1,2 Nausea, diarrhoea, vomiting, flatulence, asthaenia

Rare (animal data only):1 Reduced bone density and osteomalacia; renal toxicity (↑ BU, ↑ Cr, ↓ PO4, glycosuria, proteinuria,
phosphaturia, calcuria)
ADRs for NtRTI Class:2 Lactic acidosis and severe hepatomegaly - rare, but may be fatal; discontinue all NRTIs and NtRTIs if ↑↑ LFTs
MONITORING (blood tests) ALT, amylase, TRIG5, CHOL5, glucose5, BU, Cr, serum calcium, serum phosphate, urine analysis (glucose, protein, phosphate, calcium),
serum lactate, bone density (annual)
DRUG INTERACTIONS ↑ ddI AUC 44%,6 ↑ddI EC AUC 48%,6 ↓ ATV

LPV/RTV: ↑ TFV AUC 34% (no dose adjustment required)
MARKET STATUS4+ Tablet marketed
IX-29
PART 1 OF 1 TENOFOVIR disoproxil fumarate
DOSE IN ORGAN FAILURE ↓ dose if CrCl mL/min2:

30-49: 300mg po q48h
10-29: 300mg po b.i.w
ESRD and HD: 300mg po q.w
CSF/PLASMA CSF <1% serum concentration (monkey data)8

BIOAVAILABILITY HALF- F = 0.25 (fasting)2 F = 0.39 (high-fat meal)2
LIFE t1/2C = >60h,2 t1/2 = 17h2
MEALS Take with food
SPECIAL INSTRUCTIONS • Bitter taste

• Tablets may be split or chewed
• May dissolve in water, grape juice, or grapefruit juice. Once dissolved, take immediately n
• May take on an empty stomach but bioavailability increases when taken with high-fat meal1,2
• Give TDF 2 hours before or 1 hour after ddI.
• TDF is primarily excreted unchanged (70-80%) by the kidneys via glomerular filtration and active tubular secretion
Note:
+
References:
1
2
3
4
Drug Product Database [database on the Internet]. Ottawa, Canada:Health Canada. c2004 [cited 21 Jan 2005]. Available at: http://www.hc-
sc.gc.ca/hpb/drugs-dpd>.
5
6
Gildead Sciences. Viread® (tenofovir). Product monograph, October 2003. Last accessed 2004. Available at <http://www.gilead.com/pdf/viread_pi.pdf>.
7
Written Communication, Tenofovir DF (Viread®) in HIV-Infected Pediatric Patients, Gilead Sciences, Inc. 27 May 2003.
8
Verbal Communication, Gilead Sciences, Inc., 19 Aug 2003.
IX-30
Table 11: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
PART 1 OF 1 DELAVIRDINE EFAVIRENZ NEVIRAPINE
SHORT FORM DLV EFV NVP
TRADE NAME Rescriptor® (Agouron) Sustiva® (DUP) Viramune® (BOE)
PAEDIATRIC Unknown Paediatric (>age 3 years):1 Give q.d. Paediatric Starting Dose:1
DOSE* 10-<15kg: 200mg
15-<20kg: 250mg 120mg/m2/dose po q.d for 14 days, then
Do not exceed the 120mg/m2/dose po b.i.d if no rash or ADR
recommended adult 20-<25kg: 300mg
dose. 25-<32.5kg: 350mg Range (if no rash or ADR): 120-200mg/m2/dose
32.5-<40kg: 400mg po b.i.d OR
>40kg: 600mg
<Age 8 Years: 7mg/kg/dose po b.i.d
>Age 8 Years: 4mg/kg/dose po b.i.d
Neonate (<age 2 months) (PACTG 365):1
5mg/kg/dose or 120mg/m2/dose po q.d for 14
days, THEN 120mg/m2/dose po b.i.d for 14 days,
THEN 200mg/m2/dose po b.i.d
Newborn Prophylaxis:4 Mother, 200mg po x 1
at onset of labour; baby 2mg/kg/dose po x 1 at
48-72 hours (if mother given dose <1 hour before
delivery, baby requires 2 doses (1 stat and 2 at
48-72 hours)
ADOLESCENT & 400mg po t.i.d 600mg po q.d (qhs) (may give 300mg po b.i.d to 200mg po q.d for 14 days then if no rash, 200mg
ADULT DOSE 600mg po b.i.d1 (investigational) decrease dizziness) po b.i.d
CANADIAN 100mg white, film-coated, capsule-shaped tablet 50mg, 100mg, and 200mg capsules; Rx vial, 200mg scored tablet (60/bottle), (may cut in
AVAILABLE Room temperature, Rx vial room temperature half), room temperature, Rx vial
FORMS6 & Oral liquid (clinical investigative drug) 10mg/mL syrup (240mL bottle), sweet-flavoured
STORAGE (clinical investigative drug), room temperature,
shake well, original bottle (but CHEO uses glass
bottle)
IX-31
MAIN Rash Rash Rash, hepatitis

PRECAUTION
TOXICITY More Common:1 Headache, fatigue, vomiting, More Common:1,3 Skin rash: More Common:1 Skin rash (can be severe and
rash • maculopapular and pruritic (<40% incidence life-threatening, including Stevens-Johnson
Dermatologic:5 Rash may develop 1-3 weeks in children compared to 27% in adults) syndrome, toxic epidermal necrolysis), fever,
after starting DLV; resolves 3-14 days without • usual onset first 2 weeks of therapy headache, diarrhoea, nausea, ↑ LFTs
changing dose. Stevens-Johnson syndrome • usually do not need to discontinue EFV Less Common:1 Hepatitis (most cases of severe
reported. Discontinue DLV if rash plus fever, • CNS (somnolence, insomnia, abnormal and life-threatening skin reactions and/or serious
blistering, oral lesions, conjunctivitis, swelling, dreams, confusion, abnormal thinking, hepatitis/hepatic failure have occurred within the
muscle or joint pain. agitation, impaired concentration, amnesia, first 6-8 weeks of starting NVP5)
ADRs for NNRTI Class:1 Rash - (can be depersonalisation, hallucinations, euphoria) Rash:5 Maculopapular, erythematous ± itching
severe. Potentially fatal cases of Stevens- (50% adults compared to 14% children) 16%, severe or life-threatening rash 6.6%
Johnson syndrome have been reported). • ↑ LFTs Discontinue immediately and do not restart
Teragenic in primates: after:5 ↑ LFTs with rechallenge, clinical hepatitis,
1) do not use in pregnancy severe rash, hypersensitivity (rash +
2) caution in females with child-bearing potential fever/arthralgias + organ dysfunction including
ADRs for NNRTI class:1 Rash - (can be severe. eosinophilia, granulocytopaenia)
Potentially fatal cases of Stevens-Johnson ADRs for NNRTI Class:1 Rash - (can be
syndrome have been reported). severe. Potentially fatal cases of Stevens-
Johnson syndrome have been reported).
MONITORING CBC, (frequent ANC if also on NFV), ALT, CBC, ALT, TRIG,5,9 CHOL5,9 CBC, ALT, electrolytes, glucose, Cr [Monitor
(blood tests) CPK, amylase, Cr, TRIG,5,9 CHOL5,9 closely (b.i.w.) first 12 weeks of therapy],
TRIG,5,9 CHOL5,9
DRUG Inhibits CYP3A Mixed inducer/inhibitor of P450 CYP 3A4 Auto-induction occurs in 2-4 weeks (1.5-2xs ↑
INTERACTIONS 1,5 2 in clearance1)
DLV ↑ concentration of: SQV, RTV, IDV, Do not use with: Midazolam, triazolam, ergot
NFV, APV, LPV/RTV, clarithromycin, alkaloids, cisapride, St. John’s wort,10 Induces P450 CYP 3A and CYP 2B (may need
voriconazole voriconazole to ↑ dose of other drugs metabolised by P450
enzymes in the liver)
↑ concentration of DLV: ketoconazole, Use with caution: Warfarin, ethinyl estradiol
fluoxetine, clarithromycin, voriconazole (use additional method of birth control) Do not use with:2 Ketaconazole, RIF, St. John’s
wort10
Do not use with:2,5 EFV ↑ concentration of:1,2 RTV and EFV(↑
20%), NFV (↑ 20%) ↑ concentration of:1 SQV, IDV, LPV/r, ATV
• (↑ concentration of DLV) alprazolam,
IX-32
midazolam, triazolam, ergot alkaloids, EFV ↓ concentration of:1,2 Clarithromycin (use Caution with1: Clarithromycin, fluconazole (↑
simvastatin, lovastatin, H-2 blockers, proton azithromycin), SQV (↓ 50%), IDV (↓ 31%), LFTs), rifabutin, oral contraceptives (use
pump inhibitors, cisapride NFV, APV (36%), ATV (74%) additional methods), digoxin, triazolam,
midazolam, warfarin, phenytoin, prednisone (↑
• (↓ concentration of DLV) RIF, rifabutin, ↓ concentration of EFV:1,2 RIF, rifabutin, severity of rash during first 6 weeks of starting
phenytoin, carbamazepine, phenobarb, St. phenobarb, phenytoin, St. John’s wort10 NVP5)
John’s wort10
MARKET STATUS6+ Marketed Marketed CLINICAL INVESTIGATIVE DRUG: liquid
DOSE IN ORGAN Caution with hepatic impairment Caution with hepatic impairment Avoid with hepatic impairment
FAILURE
CSF/PLASMA 0.4%7 0.26-1.19% (av. 0.69%)7 0.45%7

BIOAVAILABILITY F = 0.852 F = unknown2 F = >0.92
HALF-LIFE t1/2 = 5.8h2 t1/2 = 40-55h2 t1/2 = 25-30h2
MEALS May take with or without food May take with or without food but do not take Take on an empty stomach or with food
with high fat meal (50% ↓ EFV)
SPECIAL • Check all medications for drug interaction • Peppery taste • Do not ↑ dose if rash appears within first 14
INSTRUCTIONS days
• May dissolve 100mg tablet in 25mL water.2 • May open capsule and add to food or liquid
Take immediately. • If discontinued for >7 days, restart at q.d5
• Grape jelly can be used to mask taste • Discontinue immediately and contact doctor
• If achlorhydria, take with acidic beverage if: Rash with fever, blistering, oral lesions,
(orange or cranberry juice) • Give at bedtime during first 2-4 weeks of
therapy to ↓ CNS effects conjunctivitis, swelling, muscle or joint aches,
• Take 1 hour before or after ddI or antacid2 or general malaise
• When mixed with applesauce, causes burning • Contact doctor if: any signs of liver injury
sensation in mouth (nausea, vomiting, tiredness, loss of appetite,
• 200mg capsule may be mixed in 5mL or jaundice)
OraSweet® immediately prior to NG tube • May crush tablets, mix in water and give
administration11 orally or by G-tube
• May give at same time as ddI1
IX-33
+
References:
1
2
3
4
5
6
7
8
9
Leonard EG, McComsey GA. Metabolic complications of antiretroviral therapy in children. Ped Inf Dis J 2003;(22):77-84.
10
Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St. John's wort. Lancet 2000;355:547-8 [letter].
11
Written communication, DuPont, 27 Mar 2001.
IX-34
Table 12: Protease Inhibitors (PIs) (Part 1 of 3 tables on PIs)*
PART 1 OF 3 AMPRENAVIR INDINAVIR
SHORT FORM APV IDV
TRADE NAME Agenerase® (GW) Crixivan® (Merck)
PAEDIATRIC DOSE* Paediatric (>age 3 years and <50kg):1 Paediatric:1

Do not exceed the Solution: 22.5mg/kg/dose po b.i.d or 17mg/kg/dose po t.i.d 500mg/m2/dose po q8h
recommended adult dose. Capsules: 20mg/kg/dose po b.i.d or 15mg/kg/dose po t.i.d Range: 300-500mg/m2/dose po q8h
Note:
• Do not use in neonates, children <age 4 years, pregnant women1 Neonate:
(vitamin E & propylene glycol toxicity) Do not give to neonates due to risk of hyperbilirubinaemia1
• Capsules and solution are difficult doses
ADOLESCENT & >50kg: 1,200mg po b.i.d1,2 (8 x 150mg capsules) 800mg po q8h2

ADULT DOSE 1,400mg po b.i.d (oral solution)
Combination Therapy2:
Combination Therapy: APV 600mg + RTV 100mg po b.i.d IDV 800mg + RTV 100 or 200mg po b.i.d
APV 1,200mg + RTV 200mg po q.d
IDV 1,000mg po t.i.d + EFV 600mg po q.d
CANADIAN 50mg and 150mg soft gelatin capsule 200 and 400mg capsule (powder) room temperature,
AVAILABLE FORMS6 (vitamin E 109IU and propylene glycol 57mg per 150mg capsule),
& STORAGE room temperature, original bottle Capsules OK for 7 days in Rx vial,19 dispense in original bottle
Oral solution 15mg/mL vitamin E 46IU/mL, propylene glycol 10mg/mL glass bottle, refrigerate, 14 days (complex compounding
550mg/mL, PEG400 170mg/mL, tutti-frutti-flavoured, saccharin, room formulation20)
temperature, original bottle
MAIN PRECAUTIONS Drug interactions, vitamin E and propylene glycol toxicity Drug interactions, nephrolithiasis, hyperbilirubinaemia
TOXICITY More Common:1 Vomiting, nausea, diarrhoea, perioral parethesias, More Common:1 Nausea, abdominal pain, headache, metallic taste,
rash dizziness, asymptomatic hyperbilirubinaemia (10%) (associated with
higher doses)
Less Common (more severe):1 Life-threatening rash, including
Stevens-Johnson syndrome (1%) Less Common (more severe):1 Nephrolithiasis (29% in paediatrics
vs. 9.8% in adults),5 ↑ chronic liver disease, precipitated IDV
Rare1: New onset and exacerbation of pre-existing diabetes mellitus, (crystalluria)15
haemolytic anaemia, ↑ LFTs
IX-35
Class ADR PIs:2 Hyperglycaemia/diabetes mellitus, ketoacidosis, fat Rare:1 Haemolytic anaemia
redistribution and lipid abnormalities, hyperlipidaemia, bleeding-
haemophilia1,2,9 Class ADR PIs:2 Hyperglycaemia/diabetes mellitus, ketoacidosis,
fat redistribution and lipid abnormalities, hyperlipidaemia, bleeding-
Vitamin E Toxicity:1 Creatinuria, ↓ PLT aggregation, ↓ wound healing, haemophilia1,2,9
hepatomegaly, ↑ PT, ↑ vitamin K deficiency coagulopathy
Propylene Glycol Toxicity:1 ↑ osmolarity, lactic acidosis, seizures,
respiratory depression
MONITORING (blood CBC, PT, ALT, glucose,8,14 TRIG,8,14 CHOL,8,14 lactate CBC, ALT, glucose,8,14 TRIG,8,14 CHOL,8,14 urinalysis, bilirubin,
tests) BUN, Cr
DRUG CHECK EACH NEW DRUG Cytochrome P450 3A4 Inhibitor MANY:2 CHECK EACH NEW DRUG
INTERACTIONS (RTV > IDV= NFV = APV> SQV)3
Inhibits CYP3A4 (P450) (RTV > IDV= NFV = APV > SQV)3
Do not use:2 Cisapride, ergot alkaloids, midazolam, RIF, triazolam, Ca
channel blocker bepridil, simvastatin, lovastatin, BCP Do not use: Cisapride, ergot alkaloids, triazolam, midazolam,
simvastatin, lovastatin, rifampin, ATV (↑ hyperbilirubinaemia)
↓ concentration of APV:2 NVP, EFV, St. John’s wort12, ketoconazole,
phenytoin, phenobarb, carbamazepine ↑ concentration of IDV: Ketoconazole, itraconazole, RTV, SQV,
NFV
↑ concentration of:2 Rifabutin (193%), sildenafil (Viagara®),
ketoconazole ↑ concentration: Rifabutin (use ½ dose)
Not recommended with:2 Cisapride, amiodarone, lidocaine, warfarin, ↓ concentration of IDV: St. John’s wort12, phenytoin, phenobarb,
tricyclic antidepressants, quinidine, oral contraceptives (use additional carbamazepine, grapefruit juice, NVP, EFV
methods), disulfiram, or metronidazole (propylene glycol is metabolised OK with:2 Acetaminophen, fluconazole, dimenhydrinate,
by alcohol and aldehyde dehydrogenase) azithromycin, clarithromycin, EMB, desloratadine (Aerius®),
OK with:2 Acetaminophen, fluconazole, dimenhydrinate, azithromycin, loratidine (Claritin®), fexofenadine (Allegra®), cetirizine (Reactine®),
clarithromycin, EMB, desloratadine (Aerius®), loratadine (Claritin®), lorazepam, temazepam, BCP
fexofenadine (Allegra®), cetirizine (Reactine®), lorazepam, temazepam
MARKET STATUS6+ 50mg and 150mg capsules; 15mg/mL (240mL bottle) 200mg and 400mg capsule
DOSE IN ORGAN Oral solution contra-indicated in liver and renal dysfunction Mild to moderate cirrhosis: 600mg po q8h2
FAILURE
Liver dysfunction: 300-450mg po b.i.d (see Child-Pugh Score) 2
IX-36
CSF/PLASMA 0.45-1.3%13 1.7-16%16-17

BIOAVAILABILITY F =unknown2 Fliq < Fcaps F = 0.652
HALF-LIFE t1/2 = 7.1-10.6h2 t1/2 = 1.5-2h2
MEALS May take with or without food (not with high fat meal as ↓ 21% AUC1) Give on empty stomach or may give with milk, juice, or light snack
SPECIAL • As APV is a sulfonamide, potential for cross sensitivity with • Give 1 hour before or 2 hours after a meal (can give with light
INSTRUCTIONS sulfonamide allergies1 snack)
• Liquid in capsule is unpalatable • May give with a meal if given with RTV
• Do not use in children <age 4 years (vitamin E and propylene glycol • Very unpalatable, tastes bitter
toxicity), pregnant women, patients with hepatic or renal failure, and
patients treated with disulfiram or metronidazole • Can open capsule and mix with water
• Do not take vitamin E supplement (daily recommendation for • Drink lots of water
children only 10IU/day and adults 30IU/day)
• Adults should drink 48oz of water (1.5L) per day
• Do not use in neonates1 (propylene glycol t1/2 neonate = 16.9 hours,
t1/2 adult = 5 hours) • Adults should drink so much water that they need to urinate at
least once during the night
• Oral solution does not equal capsule (bioavailability of solution 14%
< capsule) • Give 1 hour before or after ddI2
• Give 1 hour before or after ddI or antacid1
+
IX-37
Table 13: Protease Inhibitors (PIs) (Part 2 of 3 tables on PIs)*
PART 2 OF 3 NELFINAVIR RITONAVIR SAQUINAVIR SGC (SOFT-GEL CAPSULE)
SHORT FORM NFV RTV SQV
TRADE NAME Viracept® (Agouron) Norvir® (Abbott) sgc-Fortovase®, hgc-Invirase® (Roche)
PAEDIATRIC Paediatric1: 400mg/m2/dose po b.i.d1 Paediatric Investigational:

DOSE* Investigational (>age 6 years)1 (8 months to 16 Range: 350-400mg/m2/dose po b.i.d1 Protocol Dose1: 50mg/kg/dose SGC po q8h
Do not exceed the years):18 50-55mg/kg/dose po b.i.d Initial: ↑ dose over 5 days USING po b.i.d:1 Protocol Dose1: 33mg/kg/dose SGC po q8h plus
recommended adult 20-30mg/kg/dose po t.i.d 250mg/m2/dose x 2/7 (or ↑ dose by 100mg NFV
dose. Routine: 30-45mg/kg/dose capsule), then 300mg/m2/dose x 2/7, then
multiples of 50mg for powder 350mg/m2/dose 1/7, then 400mg/m2/dose po b.i.d
Neonate (<age 6 weeks) PACTG 353:1 Neonatal (<12 hours postbirth) PACTG 354:1
Protocol Dose: 40mg/kg/dose po b.i.d Protocol Dose: 350mg/m2/dose po b.i.d x 4
weeks
ADOLESCENT & 1,250mg po b.i.d1,2 600mg po b.i.d1,2 1,200mg sgc po t.i.d2 (no initial titration is
ADULT DOSE (5 x 250mg or 2 x 625mg tablets) To ↓ nausea, ↑ dose over 5 days:1 300mg po necessary)
or 750mg po t.i.d1,2 b.i.d x 2/7, 400mg po b.i.d x 2/7, 500mg po b.i.d With RTV (preferred regimen):2
Investigational: 1, 500mg po b.i.d1 x 1/7, then 600mg po b.i.d SQV sgc, 1,000mg + RTV, 100mg po b.i.d or
Pharmacokinetic booster for other PI:2 100- SQV sgc, 400mg + RTV, 400mg po b.i.d
400mg/day divided in 1 to 2 doses
CANADIAN 250mg and 625mg tablets (not scored - may cut 100mg soft-elastic capsule (120/bottle). 200mg sgc (preferred product)
AVAILABLE in half)21 Refrigerate until dispensed, then 30 days at room refrigerate until dispensed, then 3 months room
FORMS6 & room temperature, Rx vial temperature, original bottle temperature, Rx vial
STORAGE 200mg/5mL level scoop 80mg/mL peppermint/caramel-flavoured 200mg hgc (hard-gel capsule)
50mg in 1g powder (240mL), room temperature, original bottle Rx vial, room temperature
144g, room temp, original bottle Contains saccharin and possibly lecithin5 (peanut
allergy???) and coconut oil5
MAIN Diarrhoea Drug interactions, nausea and vomiting Drug interactions

PRECAUTION
TOXICITY Most Common:1,2 Diarrhoea (20%) More Common: Nausea, vomiting, diarrhoea, More Common:1 Diarrhoea, abdominal
headache, abdominal pain, anorexia discomfort, headache, nausea, paresthaesias, skin
IX-38
Less Common:1 Asthaenia, abdominal pain, Less Common:1 Paresthaesias rash

rash, and exacerbation of chronic liver disease (circumoral/extremities), ↑ LFTs, taste Less Common:1 ↑ chronic liver disease, ↑ LFTs2
perversion2
ADRs for PI Class:2: Hyperglycaemia/diabetes ADRs for PI Class:2 Hyperglycaemia/diabetes
mellitus, fat redistribution and lipid Rare:1 Pancreatitis, ↑ CHOL, ↑ TRIG, hepatitis mellitus, ketoacidosis, fat redistribution and lipid
abnormalities, hyperlipidaemia, bleeding- ADRs for PI Class:2 Hyperglycaemia/diabetes abnormalities, hyperlipidaemia, bleeding-
haemophilia1,2,9 mellitus, ketoacidosis, fat redistribution and lipid haemophilia1,2,9
abnormalities, hyperlipidaemia, bleeding-
haemophilia1,2,9
MONITORING CBC, ALT, glucose,8,14 TRIG,8,14 CHOL8,14 ALT, amylase, glucose,8,14 TRIG,8,14 CHOL8,14 CBC, ALT, glucose,8,14 TRIG,8,14 CHOL8,14
(blood tests)
DRUG MANY:2 CHECK EACH NEW DRUG MANY:2 CHECK EACH NEW DRUG MANY:2 CHECK EACH NEW DRUG
INTERACTIONS Inhibits CYP3A > CYP2D6 > CYP2C9 > Inhibits CYP 3A4 (RTV > IDV = NFV = APV
Inhibits CYP3A4 (P450) (RTV > IDV = NFV =
APV > SQV)3 CYPC19 (RTV > IDV= NFV = APV > SQV)3 > SQV) 3
Do not use with:1,2,10 Cisapride, rifabutin (↑ Do not use with:2 Simvastatin, lovastatin, RIF,
Do not use with:2 Cisapride, ergot alkaloids, uveitis, arthralgia, leukopaenia), RIF (↑ liver rifabutin, cisapride, midazolam, triazolam, ergot
simvastatin, lovastatin, rifampin, neuroleptics toxicity), meperidine, pimozide, desipramine, alkaloids, St. John’s wort,12 garlic supplements
(pimozide - Orap®), midazolam, triazolam, St. loratadine, fluoxetine, simvastatin, lovastatin,
John’s wort12, BCP (use additional methods) midazolam, triazolam, alprazolam, clorazepate, ↑ concentration of SQV: Cimetidine,
1 diazepam, estazolam, zolpidem, clozapine, erythromycin, RTV, IDV, NFV, ATV, DLV,
Adjust dose: SQV, RTV, IDV, DLV, NVP,
bupropion, ergot alkaloids, Ca channel blocker ketoconazole, grapefruit juice
voriconazole, rifabutin (½ dose rifabutin)
bepridil, amiodarone, BCP (↓ 40% AUC ethinyl
↓ concentration of NFV: Phenytoin, phenobarb, estradiol)5, flecanide, encainide, propafenone, ↓ concentration of SQV: NVP, phenytoin,
carbamazepine quinidine, St. John’s wort (↓ RTV)12, grapefruit phenobarb, carbamazepine, dexamethasone,
juice, voriconazole, fluticasone
OK with:2 Acetaminophen, fluconazole, ↑ concentration: Ca channel blockers,
Use with caution:1,2,10 Erythromycin, digoxin,
ketoconazole, dimenhydrinate, azithromycin, clindamycin, dapsone, quinidine
itraconazole, ketoconazole, SQV, IDV, NFV,
clarithromycin, EMB, desloratadine (Aerius®), warfarin, metronidazole, dexamethasone,
loratadine (Claritin®), fexofenadine (Allegra®), carbamazepine, phenobarb, phenytoin, ibuprofen OK with:2 Acetaminophen, fluconazole,
cetirizine (Reactine®), lorazepam, temazepam (Advil®) [predicted ↑ AUC ibuprofen (RTV dimenhydrinate, azithromycin, clarithromycin,
inhibits CYP2C9) or ↓ AUC (RTV induces EMB, desloratadine (Aerius®), loratidine
glucuronoysl transferase)] dextromethorphan (Claritin®), fexofenadine, (Allegra®), cetirizine
(DM) (metabolised by CYP2D6) (Reactine®), lorazepam, temazepam
OK with:2 Acetaminophen, fluconazole,
dimenhydrinate (use ¼ dose), azithromycin,
IX-39
clarithromycin (↓ dose in renal dysfunction),

EMB, desloratadine (Aerius®), loratadine
(Claritin®), fexofenadine (Allegra®), cetirizine
(Reactine®), lorazepam, temazepam
MARKET STATUS6+ Marketed Marketed Soft-gel capsule and hard-gel capsule marketed
DOSE IN ORGAN Caution: Decrease dose with hepatic Caution: Decrease dose with liver dysfunction Caution: Decrease dose with liver dysfunction
FAILURE dysfunction
CSF/PLASMA Brain penetration in rats13 Negligible (< 0.05mg/L13) Negligible13
KINETICS Clpaediatric 2-3x > Cladult Protein binding = 98-99% Protein binding = 98%
BIOAVAILABILITY F = 0.2-0.82 t1/2 = 3-5h2 Fhgc = 0.042
HALF-LIFE t1/2 = 3.5-5h2 t1/2 = 1-2h2
MEALS Give with meal Take with food Take with food
SPECIAL • Bitter if mixed with acidic food or juice • May develop resistance if only a few doses are • Give <2 hours after full meal or large snack to
INSTRUCTIONS • 250mg and 625mg tablets dissolve readily in missed increase absorption
water21 (½ tablet in 2mL, 1-2 tablets in 5mL • Liquid is unpalatable, bad aftertaste:1 • Unpalatable (very bitter)
minimum); can be added to milk or chocolate 1) Dull taste buds: give after Popsicle or frozen
milk • hgc-Invirase® contains powder in capsule that
juice can be opened and sprinkled on food or water,
• 250mg and 625mg tablets can be crushed and 2) Give with fat: ice cream, high-fat dairy but has unpalatable taste
added to pudding product
• Measure out powder and mix with water, milk, 3) Coat mouth: give after grape jelly, maple • Give with grapefruit if not on RTV
formula, pudding, ice cream, chocolate milk syrup, or peanut butter on toast • Wear sunscreen (photosensitivity <2%
• Mix well as drug will settle 4) Mix with: formula, milk, chocolate milk, ice patients)
• Powder has gritty and thick texture (G-tube cream, pudding, maple syrup, Tang®, Ensure® • sgc-Fortovase® contains liquid or gel in
blockage with powder or dissolved tablet) 5) Give strong flavour after dose: maple syrup, capsule
• Do not add water to bottle of oral powder–use cheese, strong-flavoured chewing gum
special scoop • Flush G-tube with milk or enteral feed
• Give 2 hours before or 1 hour after ddI1
• Tablet or powder may be mixed with food or • Give 2 hours before or after ddI2
liquid up to 6 hours before dose is taken1
IX-40
+
IX-41
Table 14: Protease Inhibitor (PIs)* Combinations (Part 3 of 3 tables on PIs)
PART 3 OF 3 LOPINAVIR PLUS RITONAVIR
SHORT FORM ABT-378/r; LPV/r; LPV/RTV
TRADE NAME Kaletra® (ABB)
PAEDIATRIC DOSE* Age 6 months to 12 years: 230/57.5mg/m2/dose po b.i.d1

Do not exceed the With concomitant therapy with EFV, NVP, or reduced LPV susceptibility:1
recommended adult dose. Age 6 months to 12 years: 300/75mg/m2/dose po b.i.d
ADOLESCENT & ADULT 400mg/100mg po b.i.d1,2

DOSE (3 capsules or 5mL po b.i.d)
With concomitant therapy with EFV or NVP:1,2
Maximum: 533/133mg po b.i.d
(4 capsules or 6.5mL po b.i.d)1,11
CANADIAN AVAILABLE 133.3mg LPV/33.3mg RTV orange soft gelatin capsules (180/bottle)
FORMS6 & STORAGE • Capsule contains propylene glycol11 and possibly lecithin5 (peanut allergy???) and coconut oil5
• Refrigerate until dispensed, then 6 weeks at room temperature,11 original bottle
Oral solution 80mg LPV/20mg RTV/mL (160mL/bottle) contains:
Alcohol 42.4% v/v11(alcohol sg 0.789), cotton candy-flavour, sugar, propylene glycol, and saccharin; refrigerate until
dispensed, then 6 weeks at room temperature11; original BTL
MAIN PRECAUTION Rash, drug interactions
TOXICITY More Common:1 Diarrhoea, headache, asthenia, nausea and vomiting, rash
Rare: Pancreatitis, hepatitis
Class ADR PIs:2 Hyperglycaemia/diabetes mellitus, ketoacidosis, fat redistribution and lipid abnormalities, hyperlipidaemia,
bleeding-haemophilia1,2,9
SEE ritonavir
MONITORING (blood CBC, PT, ALT, glucose,8,14 TRIG,8,14 CHOL,8,14 bilirubin, amylase
tests)
IX-42
PART 3 OF 3 LOPINAVIR PLUS RITONAVIR
DRUG INTERACTIONS MANY: CHECK EACH NEW DRUG: SEE ritonavir (RTV > IDV = NFV = APV > SQV)3
LPV is metabolised by CYP3A (RTV ↑ LPV concentration)
RTV concentration <7% of levels compared to RTV 600mg po b.i.d11
Do not use with: flecainide, propafenone, simvastatin, lovastatin, RIF, cisapride, proton pump inhibitors, neuroleptics
(pimozide - Orap®), midazolam, triazolam, ergot alkaloids, St. John’s wort12
↓ concentration of LPV:1 EPV, NVP, carbamazepine, phenytoin, phenobarbital, dexamethasone, inhaled or intranasal
fluticasone (Cushing’s syndrome and adrenal suppression) 11
↓ concentration of:1: BCP (use additional methods), atovaquone
↑ concentration of:1 rifabutin (75%), sildenafil (Viagara®), amiodarone, lidocaine, cyclosporine, tacrolimus, rapamycin,
calcium channel blockers, ketoconazole, itraconazole
• May need to ↑ dose of ABC, AZT (↑ glucuronidation)11
• Decrease dose with clarithromycin when CrCl <60mL/min11
OK with:2 acetaminophen, Septra®, dapsone, azithromycin, EMB, dimenhydrinate, desloratadine (Aerius®), loratadine
(Claritin®), fexofenadine (Allegra®), cetirizine (Reactine®), lorazepam, temazepam, fluconazole, d4T, 3TC11
MARKET STATUS6+ Marketed in Canada
DOSE IN ORGAN Caution: Decrease dose with liver dysfunction

FAILURE
CSF/PLASMA t1/2 = 5-6h2

BIOAVAILABILITY
HALF-LIFE
MEALS Take with food
SPECIAL • Capsule contains propylene glycol11 and possibly lecithin5 (peanut allergy???) and coconut oil5
INSTRUCTIONS • Oral solution contains alcohol 42.4% v/v11 (alcohol sg 0.789), cotton candy-flavouring, sugar, propylene glycol, and
saccharin
• Refrigerate oral solution and capsules until dispensed, then 6 weeks at room temperature11 in the original bottle
• Give with high-fat meal to enhance oral absorption
• Calculate dose of alcohol with liquid formulation
• See ritonavir special instructions
• Take ddI 1 hour before or 2 hours after Kaletra®
Note:
IX-43
+
Market status does not imply approval for paediatric use. Fosamprenavir f-APV(Telzir® Canada, Lexiva® USA GSK) 700mg tablet and Atazanazir (ATV)
(Reyataz® BMS) 150 and 200mg capsules marketed in Canada but do not have paediatric dosing guidelines yet.
References:
1
2
3
4
5
6
7
8
9
Health Canada. HIV Protease Inhibitors and Hemophilia Bulletin. Canadian ADR Newsletter 1997;7(1):2.
10
Abbott Laboratories. Norvir. ® Product Monograph. October 2003. Last accessed 14 Dec 2004. Available at <www.norvir.com>.
11
Abbott Laboratories. Kaletra.® Product Monograph January 2003. Last accessed 6 Jul 2004. Available at <http://www.rxabbott.com/PDF/kaletrapi.pdf>.
12
Piscitelli SC, Burstein AH, Chaitt D, et al. Indinavir concentrations and St John's wort. Lancet 2000;355:547-548.
13
Tseng A, Foisy M, Fletcher D, eds. Handbook of HIV Drug Therapy. 2002 ed. Tseng A, Foisy M, Fletcher D; Toronto, Canada: 2002.
14
Leonard EG, McComsey GA. Metabolic complications of antiretroviral therapy in children. Ped Inf Dis J 2003;(22):77-84.
15
Kline MW et al. Ped Res. Apr 1997;41(4 part 2):A124
16
Zhou XJ et al. [abstract 311]. 7th Conference on Retrovirus and Opportunistic Infections. 2000 Jan 30-Feb 2, San Francisco, California.
17
Stahle L, Martin C, Svensson JO, Sonnerborg A. Indinavir in cerebrospinal fluid of HIV-1-infected patients. Lancet 1997;350(9094):1823.
18
Floren LC, Wiznia A, Hayashi S, Jayewardene A, Stanley K, Johnson G, et al; Pediatric AIDS Clinical Trials Group 377 Protocol Team. Nelfinavir
pharmacokinetics in stable human immunodeficiency virus-positive children: Pediatric AIDS Clinical Trials Group Protocol 377. Pediatrics 2003;112(3 Pt
1):e220-7.
19
Verbal communication, Merck, 2 Mar 2000.
20
Hugen PW, Burger DM, ter Hofstede HJ, Koopmans PP, and Hekster YA. Development of an indinavir oral liquid for children. AJHP 2000;57(14):1332-9.
21
Verbal communication, Agouron, Pfizer Canada Inc., 8 Feb 2005.
IX-44
Table 15: Fusion Inhibitors*
PART 1 OF 1 ENFUVIRTIDE
SHORT FORM T-20
TRADE NAME Fuzeon® (Roche)
PAEDIATRIC DOSE* Paediatric (age 6-16 years):1

Do not exceed the recommended 2mg/kg/dose SC b.i.d to maximum of 90 (1mL) SC b.i.d
adult dose.
ADOLESCENT & ADULT 90mg (1mL) SC b.i.d

DOSE
CANADIAN AVAILABLE 90mg/mL: lyophilised powder for injection 108mg reconstituted with 1.1ml of sterile water for injection. Store powder at room
FORMS4 & STORAGE temperature (60/box).
MAIN PRECAUTION Hypersensitivity reaction
TOXICITY Most Common:1,2 98% of patients experience mild to moderate local injection site reactions including pain, discomfort, induration,
erythema (usually lasts 2-3 days), nodules, cysts, pruritis, and ecchymosis.
Less Common:1 Eosinophilia (11.2% vs. controls 2.4%),3 bacterial pneumonia (unclear association)
Rare (<1%):1 Hypersensitivity reactions (fever, nausea, vomiting, chills, rigors, hypotension, ↑ LFTs); immune-mediated reactions
(primary immune complex reaction, respiratory distress, glomerulonephritis, Guillain-Barré syndrome). Do not restart therapy.
MONITORING (blood tests) CBC, ALT, Cr
DRUG INTERACTIONS None reported1
MARKET STATUS4+ Marketed
DOSE IN ORGAN FAILURE No adjustment in renal failure required2
CSF/PLASMA t1/2 = 3.8h2

BIOAVAILABILITY HALF-
LIFE
IX-45
PART 1 OF 1 ENFUVIRTIDE
MEALS
SPECIAL INSTRUCTIONS Reconstitution: Slowly inject 1.1mL of sterile water for injection into the lyophilised powder, letting the drops gently slide down the side
of the vial. Gently tap vial for 10 seconds, then slowly roll the vial in the palm of your hands to dissolve the powder. DO NOT SHAKE.
May take up to 45 minutes to completely go into solution. (Do not shake or add water quickly as protein powder will foam and take up to
24 hours to settle.)
Reconstituted solution stable for 24 hours when refrigerated.
Administration using EMLA® (topical anaesthetic): Prepare both doses in the evening so the morning dose is ready to use. Let the prepared
dose warm up to room temperature before injecting. If required, apply EMLA® to injection site (takes 1 hour for full pain control). Wipe
off EMLA® (topical anaesthetic) and rub injection site with ice for several minutes. Use sterile technique, inject the drug SC at a 30o-40o
angle into upper arm, anterior thigh, or abdomen. Rotate injection sites.
If signs and symptoms of a hypersensitivity reaction occur, discontinue treatment and immediately seek medical attention. Do not restart
following a suspected hypersensitivity reaction.
Soreness at the injection site is common but rarely the reason for the patient to discontinue the drug: redness, pain, lymph node swelling,
mild itching, bruising, swelling, and tenderness may occur.
Note:
+Market status does not imply approval for paediatric use.
**Globally, dose use at >age 3 months.
References:
1
2
3
4Drug Product Database [database on the Internet]. Ottawa, Canada:Health Canada. c2004 [cited 21 Jan 2005]. Available at: http://www.hc-
IX-46
APPENDIX IX-C: CLASSIFICATION OF PAEDIATRIC HIV/AIDS
HIV/AIDS in infants and children age thirteen years or younger may be classified using WHO criteria
(Table 16). Alternately, the revised CDC criteria maybe used, which offers more specific clinical
diagnostic Categories of A, B, and C for mild, moderate, and severe disease, respectively (Table 17), as
well as immunological criteria of Class 1, 2, and 3 for mild, moderate, and severe immunosuppression,
respectively (Table 18).
Table 16: WHO Staging System for HIV Infection and Disease in Children
CLINICAL STAGE I
• Asymptomatic
CLINICAL STAGE II
• Unexplained chronic diarrhoea
• Severe persistent or recurrent candidiasis outside the neonatal period
• Weight loss or failure to thrive
• Persistent fever
• Recurrent severe bacterial infections
CLINICAL STAGE III

• AIDS-defining opportunistic infections (OIs)
• Severe failure to thrive (wasting in the absence of known aetiology)*
• Progressive encephalopathy
• Malignancy
• Recurrent septicaemia or meningitis
*Persistent weight loss of >10% of baseline or <5th percentile on weight-for-height chart on 2 consecutive
measurements >1 month apart in the absence of another aetiology or concurrent illness.
IX-47
Table 17: 1994 CDC Revised Human Immunodeficiency Virus Paediatric Classification System: Clinical
Categories
CATEGORY N: NOT SYMPTOMATIC

Children who have no signs or symptoms considered to be the result of HIV infection or who
have only one of the conditions listed in Category A.
CATEGORY A: MILDLY SYMPTOMATIC

Children with 2 or more of the following conditions but none of the conditions listed in
Categories B and C:
• Lymphadenopathy (>0.5cm at >2 sites; bilateral = 1 site)
• Hepatomegaly
• Splenomegaly
• Dermatitis
• Parotitis
• Recurrent or persistent upper respiratory infection, sinusitis, or otitis media
CATEGORY B: MODERATELY SYMPTOMATIC

Children who have symptomatic conditions, other than those listed for Category A or Category C,
which are attributed to HIV infection. Examples of conditions in clinical Category B include, but
are not limited to, the following:
• Anaemia (<8gm/dL), neutropaenia (<1,000/mm3), or thrombocytopaenia
(<100,000/mm3) persisting >30 days
• Bacterial meningitis, pneumonia, or sepsis (single episode)
• Candidiasis, oropharyngeal (e.g. thrush) persisting for >2 months in children age >6
months
• Cardiomyopathy
• Cytomegalovirus (CMV) infection with onset before age 1 month
• Diarrhoea, recurrent or chronic
• Hepatitis
• Herpes simplex virus (HSV) stomatitis, recurrent (e.g. >2 episodes within 1 year)
• HSV bronchitis, pneumonitis, or oesophagitis with onset before age 1 month
• Herpes zoster (e.g. shingles) involving at least 2 distinct episodes or more than 1
dermatome
• Leiomyosarcoma
• Lymphoid interstitial pneumonia (LIP) or pulmonary lymphoid hyperplasia complex
• Nephropathy
• Nocardiosis
• Fever lasting >1 month
• Toxoplasmosis with onset before age 1 month
• Varicella, disseminated (e.g. complicated chickenpox)
IX-48
CATEGORY C: SEVERELY SYMPTOMATIC
o Serious bacterial infections, multiple or recurrent (e.g. any combination of at least 2
culture-confirmed infections within a 2-year period), of the following types:
septicaemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal
organ or body cavity (excluding otitis media, superficial skin or mucosal abscesses,
and indwelling catheter-related infections)
o Candidiasis, oesophageal or pulmonary (bronchi, trachea, lungs)
o Coccidioidomycosis, disseminated (at site other than or in addition to lungs or
cervical or hilar lymph nodes)
o Cryptococcosis, extrapulmonary
o Cryptosporidiosis or isosporiasis with diarrhoea persisting >1 month
o CMV disease with onset of symptoms at age >1 month (at a site other than liver,
spleen, or lymph nodes)
o Encephalopathy (at least 1 of the following progressive findings present for at least 2
months in the absence of a concurrent illness other than HIV infection that could
explain the findings): a) failure to attain or loss of developmental milestones or loss
of intellectual ability, verified by standard developmental scale or
neuropsychological tests; b) impaired brain growth or acquired microcephaly
demonstrated by head circumference measurements or brain atrophy demonstrated by
CT or MRI (serial imaging is required for children age <2 years); c) acquired
symmetric motor deficit manifested by 2 or more of the following: paresis,
pathologic reflexes, ataxia, or gait disturbance; d) HSV infection causing a
mucocoetaneous ulcer that persists for >1 month; or e) bronchitis, pneumonitis, or
oesophagitis for any duration affecting a child age >1 month
o Histoplasmosis, disseminated (at a site other than or in addition to lungs or cervical
or hilar lymph nodes)
o Kaposi's sarcoma (KS)
o Lymphoma, primary, in brain
o Lymphoma, small, noncleaved cell (Burkitt's), or immunoblastic or large cell
lymphoma of B-cell or unknown immunologic phenotype
o Mycobacterium tuberculosis, disseminated or extrapulmonary Mycobacterium, other
species or unidentified species, disseminated (at a site other than or in addition to
lungs, skin, or cervical or hilar lymph nodes)
o Mycobacterium avium complex or Mycobacterium kansasii, disseminated (at site
other than or in addition to lungs, skin, or cervical or hilar lymph nodes)
o Pneumocystis carinii pneumonia (PCP)
o Progressive multifocal leukoencephalopathy (PML)
o Salmonella (nontyphoid) septicaemia, recurrent
o Toxoplasmosis of the brain with onset at age >1 month
o Wasting syndrome in the absence of a concurrent illness other than HIV infection
that could explain the following findings: a) persistent weight loss >10% of baseline;
OR b) downward crossing of at least 2 of the following percentile lines on the
weight-for-age chart (e.g. 95th, 75th, 50th, 25th, 5th) in a child age >1 year; OR c) <5th
percentile on weight-for-height chart on 2 consecutive measurements, >30 days apart
PLUS a) chronic diarrhoea (e.g. at least 2 loose stools/day for >30 days); OR b)
documented fever (for >30 days, intermittent or constant)
IX-49
Table 18: Human Immunodeficiency Virus: Paediatric Immune Category Classification System Based
on Age-Specific CD4+ T Cell Count and Percentage
IMMUNE DEGREE OF AGE <12 AGE 1-5 AGE 6-12

CATEGORY/CLASS IMMUNE MONTHS YEARS YEARS
SUPPRESSION
1 None, or mild 1,500 and >1,000 and >500 and

>25% >25% >25%
2 Moderate 750-1,499 or 500-999 or 15- 200–499 or

15-24% 24% 15-24%
3 Severe <750 or < 15% <500 or <15% <200 or

<15%
IX-50
REFERENCES
1
Evans-Gilbert T, Pierre R, et al. Antiretroviral drug therapy in HIV-infected Jamaican children. West
Indian Med J, 2004;53(5) 322-326.
2
Geoghagen M, Farr JA, et al. Tuberculosis and human immunodeficiency co-infections in Jamaican
infants and children. West Indian Med J, 2004;53:(5)339-345.
3
World Health Organisation. Revised WHO guidelines for scaling up antiretroviral therapy in resource-
limited settings. 2003 revision. Available at:
http://www.who.int/hiv/pub/prev_care/en/arvrevision2003en.pdf.
4
NPHRC/HRSA/NIH. Guidelines for the use of antiretroviral agents in pediatric HIV infection. 30
November 2004. Accessed 2004. Available at:
http://aidsinfo.nih.gov/guidelines/default_db2.asp?id=51 .
5
Ibid.
6
World Health Organisation. Table C: Major potential toxicities of first-line ARV regimens
recommended drug substitutions in Revised WHO guidelines for scaling up antiretroviral therapy in
resource-limited settings. 2004 revision. Available at:
<http://www.who.int/3by5/publications/documents/ arv_guidelines/en>.
7
NPHRC/HRSA/NIH, 2004.
8
World Health Organisation, 2003.
9
Steel-Duncan JC, Pierre R, et al. NVP-associated rash in a Jamaican child with HIV/AIDS. West Indian
Med J 2004;53(5):356–358.
IX-51
X: DIAGNOSIS AND TREATMENT OF OPPORTUNISTIC INFECTIONS
(OIs) AMONG HIV-EXPOSED AND -INFECTED CHILDREN∗
TABLE OF CONTENTS
INTRODUCTION .............................................................................................................................................. X-1
DISEASE-SPECIFIC RECOMMENDATIONS .................................................................................................... X-1
Pneumocystis jiroveci (Formerly carinii) Pneumonia (PCP)................................................................ X-1
Toxoplasmosis ...................................................................................................................................... X-3
Cryptosporidiosis/Microsporidiosis ...................................................................................................... X-5
Mycobacterium tuberculosis (TB) ........................................................................................................ X-6
Mycobacterium avium Complex (MAC) Disease ................................................................................. X-11
Serious and Recurrent Bacterial Infections........................................................................................... X-13
Syphilis ................................................................................................................................................. X-15
Candida Infections................................................................................................................................ X-17
Cryptococcosis...................................................................................................................................... X-19
Histoplasmosis ...................................................................................................................................... X-21
Coccidioidomycosis.............................................................................................................................. X-22
Cytomegalovirus (CMV) Disease......................................................................................................... X-23
Herpes Simplex Virus (HSV) Disease .................................................................................................. X-25
Varicella Zoster Virus (VZV) Disease.................................................................................................. X-27
Human Papillomavirus (HPV) Disease................................................................................................. X-29
Hepatitis B Virus (HBV) Disease ......................................................................................................... X-30
REFERENCES .................................................................................................................................................. X-47
APPENDIX A: RECOMMENDATIONS FOR TREATMENT OF OIS IN HIV-EXPOSED AND

-INFECTED CARIBBEAN INFANTS AND CHILDREN ....................................................................................... X-34
∗
This chapter has been adapted for use in the Caribbean from the 2004 U.S. Centers for Disease Control
(CDC)/National Institutes of Health (NIH)/Infectious Disease Society of America (IDSA) Guidelines for the
Treatment of Opportunistic Infections in HIV-Exposed and -Infected Children (CDC. Treating opportunistic
infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of
Health, and the Infectious Diseases Society of America. MMWR Weekly [serial on the Internet] 3 Dec
2004;53[RR14]:1-63.) Last accessed 2005. Available at: www.cdc.gov/mmwr).
X-i
X. DIAGNOSIS AND TREATMENT OF OPPORTUNISTIC INFECTIONS (OIs)
AMONG HIV-EXPOSED AND -INFECTED CHILDREN
INTRODUCTION
Opportunistic infections (OIs) remain a frequent cause of morbidity and mortality in HIV-infected
children in the Caribbean.1 The major conditions causing paediatric OIs include Pneumocystis jiroveci
(formerly Pneumocystis carinii) pneumonia (PCP), tuberculosis (TB), cytomegalovirus (CMV) infection,
gastroenteritis, persistent recurrent diarrhoea, and serious and recurrent bacterial infections causing
pneumonia and meningitis.
The management of OIs in children differs from that in adults in several key respects. OIs in children
usually reflect primary acquisition of the pathogen, whereas in adults, disease typically occurs as a
consequence of re-activation of a pathogen acquired prior to HIV infection. In children with perinatally-
acquired HIV infection, OIs are usually acquired in immature and already compromised immune systems.
Laboratory diagnosis of paediatric OIs is complicated by the relative difficulty of adequate specimen
collection in infants and children. Treatment recommendations must consider differences in paediatric
dosing, formulation, drug pharmacokinetics, administration, and toxicities. Finally, HIV-infected
pregnant women co-infected with opportunistic pathogens may be more likely to transmit these infections
to their infants than are women who are HIV-uninfected. As such, these guidelines also address
congenitally-acquired OIs that develop in HIV-uninfected infants born to HIV-infected mothers.
The Caribbean reflects a wide diversity of access to appropriate diagnostic and treatment options for
paediatric OIs. Although it currently may not be possible to implement specific testing and treatment
options in every setting, this document is written to present optimal tools for the future identification,
care, and treatment of OIs in HIV-exposed and -infected children. Caribbean nations presently obtain
funding for HIV/AIDS and OI care from various sources and are at varied stages of scaling up care and
treatment plans for paediatric OI management. Thusly, these guidelines must be interpreted,
implemented, and further adapted for use in light of available facilities in each Caribbean territory.
DISEASE-SPECIFIC RECOMMENDATIONS
PNEUMOCYSTIS JIROVECI (FORMERLY CARINII) PNEUMONIA (PCP)
Epidemiology
P. jiroveci, a fungus susceptible to antiprotozoal agents, causes Pneumocystis pneumonia (PCP). P.
carinii now refers to the organism that is found only in rats.
P. jiroveci is usually acquired in childhood; serum antibodies are found in more than 80% of children by
age two to four years. Most HIV-uninfected infants with P. jiroveci infection will have either mild
respiratory symptoms or remain completely asymptomatic.
PCP remains the most common AIDS-indicator disease in HIV-infected children. Its incidence varies
among countries and ranges from 5.4% in Jamaican children who are primarily on PCP prophylaxis2 to
23% in Puerto Rico3 and 37.5% of AIDS cases in children in Barbados.4
The highest incidence of PCP in HIV-infected children is in the first year of life, with cases peaking at
age three to six months. Mortality is high with PCP and is identified as the primary cause of death in up
to 70% of HIV-infected children in Barbados, as reported in the national surveillance system prior to the
availability of HAART therapy.5
X-1
Unlike in older children and adults, CD4+ T cell counts are not a good indicator of risk for PCP in infants
age one year or younger; many young infants with PCP have CD4+ T cell counts of >1,500 cells/mm3,
and counts can drop very rapidly shortly before PCP develops in infants.
Clinical features of PCP in HIV-infected children are similar to those in adults. Fever, tachypnea,
dyspnoea, and cough are seen most commonly, especially in the younger child. Onset can be abrupt or
may be insidious in the older child with non-specific symptoms such as mild cough, dyspnoea, poor
feeding, and weight loss. Almost all children will have tachypnea by the time pneumonitis is seen on
chest radiograph. Bibasilar rales with evidence of respiratory distress may be heard on physical
examination. Most children with PCP have significant hypoxia with low arterial oxygen pressure [pO2]
and an alveolar-arterial oxygen gradient [(A-a)DO2] of >30mmHg.
Chest radiographs most commonly show bilateral diffuse parenchymal infiltrates with “ground-glass” or
reticulogranular appearance, but they also may be normal or show only mild parenchymal infiltrates. The
earliest infiltrates are perihilar, progressing peripherally but sparing the apical portions of the lung until
last. Lobar, cavitary, nodular, or miliary lesions; pneumothorax; or pneumomediastinum are seen rarely.
Infants with dual infection with CMV and PCP may have more severe pneumonic disease, and they are
more likely to require assisted ventilation (in countries where available), receive corticosteroids, or die
than those with PCP alone.
Diagnosis
Definitive diagnosis of PCP requires demonstration of the organism in pulmonary tissues or fluids.
Diagnostic procedures are the same as those used for adults with suspected PCP, but some procedures
may be more difficult to perform in children. Induced sputum analysis, bronchoscopy with
bronchoalveolar lavage (BAL), fiberoptic bronchoscopy with transbronchial biopsy, and open-lung
biopsy are not uniformly available throughout the Caribbean. If possible, a specific diagnosis should be
sought rather than relying on presumptive diagnosis.
When an appropriate sample is available, three types of stains may be used to diagnose P. jiroveci
organisms in specimens. Gomori’s methenamine-silver stain stains the cyst wall brown or black.
Toluidine Blue stains the cyst wall blue or lavender and also stains fungal elements. Giemsa or Wright’s
stains stain the trophozoites and intracystic sporozoites pale blue with a punctate red nucleus. Unlike the
other stains, this does not stain the cyst wall.
Trimethoprim-sulfamethoxazole (TMP-SMX; co-trimoxazole) is the treatment of choice for PCP. For
severe disease requiring hospitalisation, TMP-SMX should initially be given intravenously. After the
acute pneumonitis has resolved, children with mild to moderate disease who do not have malabsorption or
diarrhoea may switch to oral treatment to complete a twenty-one-day course.
For patients intolerant of TMP-SMX or who demonstrate clinical treatment failure after five to seven days
of TMP-SMX therapy, the alternative treatment of choice is intravenous pentamidine isothionate.
Additional alternative treatments shown to be effective for mild to moderate PCP disease have limited
data in children but include clindamycin/primaquine, atovaquone suspension, and dapsone-TMP. There
is no evidence for synergistic or additive effects on efficacy of these agents; therefore, due to potential
increased toxicity, their combined use with TMP-SMX would not be recommended.
Based on studies in adults, a short course of corticosteroids may be indicated in cases of PCP of moderate
or great severity if started as early as possible and within seventy-two hours of diagnosis. Several small
studies have shown reduction in acute respiratory failure, decreased need for ventilation, and decrease in
mortality with early use of corticosteroids in HIV-infected children with PCP. Indications for
corticosteroid use include a pO2 value of <70mmHg or (A-a)DO2 of >35mmHg.
X-2
Adverse reactions to TMP-SMX reported in children include rash (including erythema multiforme and
rarely Stevens-Johnson syndrome); haematologic abnormalities such as neutropaenia, thrombocytopaenia,
megaloblastic or rarely aplastic anaemia; gastrointestinal complaints (generally mild); hepatitis; and renal
disorders such as interstitial nephritis. The overall frequency of adverse reactions appears to be lower in
HIV-infected children than in adults; only about 15% of children have significant adverse reactions to
TMP-SMX. For mild or moderate skin rash, TMP-SMX can be temporarily discontinued and restarted
once the rash has resolved. If an urticarial rash or Stevens-Johnson syndrome occurs, TMP-SMX should
be discontinued and not re-administered.
Serious adverse reactions to intravenous pentamidine have been reported in approximately 17% of
children. Use of intravenous pentamidine can cause renal toxicity but can be averted by adequate
hydration and careful monitoring of renal function and electrolytes. Severe hypotension (particularly if
infused rapidly), prolonged QT interval, and cardiac arrhythmias also can occur. Hypoglycaemia (usually
after five to seven days of therapy) or hyperglycaemia, hypercalcaemia, hyperkalaemia, pancreatitis, and
insulin-dependent diabetes mellitus have also been reported. A metallic or bitter taste may be
experienced.
Primaquine is contra-indicated in patients with glucose-6-dehydrogenase deficiency due to possibility of
inducing haemolytic anaemia. Primaquine, atovaquone, and dapsone may cause skin rashes, nausea, and
diarrhoea. Atovaquone and dapsone may also cause an increase in liver enzymes. The primary adverse
reaction to dapsone is reversible neutropaenia, although anaemia and thrombocytopaenia have been
observed.
In HIV-infected children, lifelong suppression is indicated following treatment for PCP to prevent
recurrence; details on secondary prophylaxis (maintenance therapy) are provided in Chapter VI.:
Recommendations for Adult and Paediatric Opportunistic Infections Prophylaxis. The safety of
discontinuation of secondary prophylaxis following immune reconstitution with HAART in children has
not been studied extensively.
TOXOPLASMOSIS
Epidemiology
The major mode of Toxoplasma gondii acquisition in infants and young children is congenital, occurring
almost exclusively among neonates born to women with primary toxoplasmosis during pregnancy.* In
1986, the seroprevalence of T. gondii was 57% in pregnant Jamaican women.6 Congenital infection in the
Caribbean has been associated with severe pathology, most often resulting in chorioretinitis.7
Older children, adolescents, and adults typically acquire T. gondii infection by eating poorly cooked meat
that contains parasitic cysts or by accidentally ingesting sporulated oocysts in soil or contaminated food
or water. Serosurveys performed in school-aged children from the Upper Leeward Islands (Saba, St.
Maarten, St. Eustatius, Netherland Antilles), Guadeloupe, and Jamaica have shown evidence of T. gondii
antibodies in 45.5% to 55% of children.8
AIDS-defining infection of the central nervous system (CNS) with T. gondii is uncommon in HIV-
infected children, being reported as an AIDS-indicator condition in less than 2% of paediatric AIDS cases
in Jamaica.9
*The incidence of T. gondii transmission from a mother with chronic T. gondii infection to her infant is uncommon
(<4%). A few cases have been reported of mother-to-infant T. gondii transmission from mothers with chronic T.
gondii infection who were also HIV-infected, presumably due to re-activation of chronic infection secondary to
severe immune suppression; however, this has not been documented in the Caribbean.
X-3
Most infants with congenital toxoplasmosis (70% to 90%) are asymptomatic at birth but are more likely
than symptomatic infants to develop late sequelae such as chorioretinitis, visual impairment, and
intellectual and/or neurologic impairment, months to years after infection. Predominantly neurologic
disease or generalised disease occurs in those infants who are symptomatic at birth. Symptoms may
include maculopapular rash, generalised lymphadenopathy, hepatosplenomegaly, jaundice, haematologic
abnormalities, and significant CNS disease including hydrocephalus, intracerebral calcification,
microcephaly, chorioretinitis, and seizures.
Similarly, toxoplasmosis acquired after birth is most often initially asymptomatic. When symptoms
ultimately develop, they are frequently nonspecific and may include malaise, fever, sore throat, myalgia,
lymphadenopathy (cervical), and/or a mononucleosis-like syndrome featuring a maculopapular rash and
hepatosplenomegaly. Toxoplasmosis may also present as ocular disease, pneumonitis, hepatitis, and
cardiomyopathy/myocarditis. T. gondii encephalitis should be considered in all HIV-infected children
with fever and new neurologic findings such as reduced alertness or seizures. Focal findings on
neurologic exam are typical.
Diagnosis
HIV-infected women may be at increased risk of transmitting Toxoplasma to their foetuses and serologic
testing for Toxoplasma should be performed on all HIV-infected pregnant women. All infants whose
mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital
toxoplasmosis by using an enzyme immuno-assay or an immunosorbent assay to detect the presence of
Toxoplasma-specific IgM, IgA, or IgE in neonatal serum within the first six months of life or persistence
of specific IgG antibody beyond age twelve months. IgA may be more sensitive for detection of
congenital infection than IgM or IgE. However, approximately 20% to 30% of infants with congenital
Toxoplasmosis will not be identified in the neonatal period with IgA or IgM assays.
If there is uncertainty regarding a possible diagnosis of congenital toxoplasmosis at the time of delivery,
an evaluation of the neonate should be undertaken and should include the following: ophthalmologic,
auditory, and neurologic examinations; lumbar puncture; and imaging of the head (either CT or MRI
scan) to determine whether hydrocephalus or calcifications are present.
A presumptive diagnosis of CNS toxoplasmosis is based on clinical symptoms, serologic evidence of
infection, and the presence of a space-occupying lesion on imaging studies of the brain. A negative
serology does not exclude that diagnosis. A CT scan of the brain may show multiple, bilateral, ring-
enhancing lesions in CNS toxoplasmosis, especially in the basal ganglia and cerebral corticomedullary
junction. MRIs are more sensitive and will confirm basal ganglia lesions in nearly all patients.
Definitive diagnosis of Toxoplasma encephalitis requires histologic or cytologic confirmation by brain
biopsy, which may demonstrate leptomeningeal inflammation, microglial nodules, gliosis, and
Toxoplasma cysts. Biopsy is usually reserved for patients with early neurologic deterioration despite
empiric treatment or for children who fail to respond to anti-Toxoplasma appropriate therapy.
If an HIV-infected woman has a symptomatic Toxoplasma infection during pregnancy, empiric therapy of
the newborn should be strongly considered, irrespective of whether the mother was treated during
pregnancy.
The preferred treatment for congenital toxoplasmosis is twelve months of pyrimethamine plus
sulfadiazine with supplementary leucovorin (folinic acid) to minimise pyrimethamine-associated
haematologic toxicity.
HIV-infected children with acquired CNS, ocular, or systemic toxoplasmosis should be treated with the
same combination for six weeks assuming clinical and radiological improvement. Clindamycin can be
X-4
used in patients who develop sulfonamide hypersensitivity. Longer courses of treatment may be required
in cases of extensive disease or poor response after six weeks of treatment.
Alternative regimens studied in adults but not in children include: TMP-SMX alone; atovaquone plus
pyrimethamine and leucovorin as above; atovaquone with sulfadiazine alone; and atovaquone as a single
agent in patients intolerant to both pyrimethamine and sulfadiazine.
Corticosteroids (e.g. dexamethasone or prednisone) have been used in children with CNS disease when
cerebrospinal fluid (CSF) protein is very elevated (e.g. >1,000 mg/dL) or with focal lesions with
significant mass effects. Because of the potential immunosuppressive effects of steroids, they should be
discontinued as soon as possible.
Pyrimethamine can be associated with rash (including rarely Stevens-Johnson syndrome) and nausea. Its
primary toxicity is reversible bone marrow suppression (neutropaenia, anaemia, and thrombocytopaenia).
A complete blood count should be performed at least weekly while the child is on daily pyrimethamine
and at least monthly while on less than daily dosing. Leucovorin (folinic acid) should always be
administered with pyrimethamine; increased doses of leucovorin may be required in the event of marrow
suppression. Because of the long half-life of pyrimethamine, leucovorin should be continued one week
after pyrimethamine has been discontinued.
Adverse effects of sulfadiazine include rash, fever, leukopaenia, hepatitis, gastrointestinal symptoms
(nausea, vomiting, diarrhoea), and crystalluria.
In HIV-infected children, lifelong suppression is indicated following treatment for toxoplasmosis to
prevent recurrence; details on secondary prophylaxis (maintenance therapy) are provided in Chapter VI.:
Recommendations for Adult and Paediatric Opportunistic Infections Prophylaxis.. The safety of
discontinuation of secondary prophylaxis following immune reconstitution with HAART in children has
not been studied extensively.
CRYPTOSPORIDIOSIS/MICROSPORIDIOSIS
Epidemiology
Cryptosporidium species, such as C. hominis, C. parvum, and C. meleagridis, are protozoal parasites that
mainly cause enteric illness in humans and animals. These parasites invade the gut mucosa, causing
severe profuse, nonbloody, watery diarrhoea leading to dehydration and malnutrition in
immunocompromised hosts. Diarrhoea is often more prolonged with cryptosporidiosis than with other
intestinal parasites.10
The parasite is transmitted by ingestion of oocysts excreted in the faeces of infected animals and humans.
Person-to-person transmission is common among young children, and foodborne spread can also occur.
Infection is endemic in Caribbean children and occurs most frequently in those age two years or
younger.11 Oocysts have been identified in up to 17% of Haitian children age two years or younger with
acute diarrhoea.12 Cryptosporidiosis has been reported in 4% to 8% of stool samples from children age
nine years or younger in Jamaica and Cuba, respectively.13
Microspora species are obligate, intracellular, spore-forming protozoa that in children primarily cause
moderate to severe diarrhoea. Enterocytozoon bieneusi and Encephalitozoon intestinalis are the most
common microsporidia that cause infection in patients with HIV infection. E. bieneusi is not associated
with disseminated disease.
Microspora parasites develop in enterocytes and are excreted with faeces, and like C. parvum, are
transmitted by the faecal-oral route, which can include ingestion of contaminated food or water.
X-5
Frequent, persistent, watery, and generally nonbloody diarrhoea is the most common manifestation of
both cryptosporidial and microsporidial infections, with abdominal cramps, fatigue, vomiting, anorexia,
and weight loss/poor weight gain. Fever and vomiting are also relatively common in children, mimicking
viral gastroenteritis.
In immunocompromised children, chronic severe diarrhoea can result in malnutrition, failure to thrive,
and significant intestinal fluid losses leading to severe dehydration and even death. Clinical history or
physical examination does not allow differentiation of Cryptosporidia from other pathogens.
Cryptosporidia can migrate into the bile duct and result in inflammation of the biliary epithelium,
acalculous cholecystitis, and sclerosing cholangitis. Symptoms include fever, right upper abdominal pain,
and elevated alkaline phosphatase. While infection is usually limited to the gastrointestinal tract,
pulmonary or disseminated infection can also (rarely) occur in immunocompromised children.
In addition to acute and chronic diarrhoea, Microsporidia species have been described in cases of
hepatitis, peritonitis, keratoconjunctivitis, myositis, cholangitis, sinusitis, and disseminated CNS disease.
Diagnosis
At least three stool samples should be submitted for oocyst evaluation by concentration using the sucrose
flotation or formalin-ethyl acetate method to concentrate the oocysts. A sample is then stained using a
modified Kinyoun acid-fast stain and examined for small (4-6µm in diameter) acid-fast positive oocysts.
Enzyme immuno-assays to detect antigens in stool samples are preferred to staining methods because of
enhanced sensitivity and specificity.
For diagnosis of Microsporidia infection, thin smears of unconcentrated stool-formalin suspension or
duodenal aspirates can be stained with modified trichrome stain. Microsporidia spores are stained pink to
red by the chemofluorescent agent Calcofluor White, are 1-3µm in size and ovoid, and contain a
distinctive equatorial-belt-like stripe. Urine sediment examination by light microscopy can be used to
identify microsporidia spores in disseminated disease with Encephalitozoonidae and Trachipleistophora.
Immune reconstitution (an increase in CD4+ T count to >100 cells/mm3) resulting from highly active
antiretroviral therapy (HAART) frequently results in clearance of Cryptosporidia. Effective HAART is
the treatment of choice for both of these infections. Supportive care with hydration, correction of
electrolyte abnormalities, and nutritional supplementation should be provided.
There is no consistently effective therapy for cryptosporidiosis, and the duration of treatment in HIV-
infected individuals is uncertain. Several agents have demonstrated some efficacy in decreasing the
severity of symptoms in children. Nitazoxanide is effective for treatment of paediatric diarrhoea caused
by Cryptosporidia and Giardia lamblia, and is available in a liquid formulation. Other potential
alternative treatments include paromomycin and azithromycin.
For treatment of Microsporidia infection, albendazole has been reported to decrease diarrhoea, sometimes
with eradication of the organism. It is most effective for cases due to E. intestinalis and other
Microsporidia species, but is not active against E. bienesi. Fumagillin is an antibiotic derived from the
fungus Aspergillus fumigatus that has been used to treat E. bieneusi microsporidiosis diarrhoea and
topically to treat microsporidial ocular infections.
MYCOBACTERIUM TUBERCULOSIS
Epidemiology
Tuberculosis (TB) is one of the leading causes of morbidity and mortality in HIV-infected individuals.14
The prevalence of HIV infection among patients with TB in Caribbean countries varies from 30% in
X-6
Jamaica to 40% in the Bahamas to 52.8% in Trinidad & Tobago.15 In 1999, the prevalence of TB in HIV-
infected individuals living in Haiti was 63.8%.
Data regarding the epidemiology of TB in HIV-infected children in the Caribbean are sparse. In Haiti,
where the reported prevalence of TB is reported to be 123 per 100,000 individuals, 38% of orphans with
no documentation of BCG vaccine had positive purified protein derivative (PPD) tests (38,202 per
100,000); there were ten active cases.16 Similarly, there were four paediatric cases of active TB with two
reported deaths in an orphanage in Jamaica, with concurrent outbreaks of scabies and varicella.17 In the
Dominican Republic between 1982 and 1986, rates of pulmonary TB were reported to be 46 per 100,000
children. The greatest mortality at that time was due to miliary and meningeal forms of TB and occurred
in infants age one year or younger.18 Seven and one-half percent (7.5%) of HIV-infected children
followed in Jamaica have been diagnosed with TB.19 In addition, TB was the presenting condition in
2.5% of HIV-infected children in Barbados.
Data from international sources suggest an increased risk of TB disease in HIV-infected children. In
Jamaica, there was a statistically significant increase in HIV and TB co-infections over a four-year period
in children attending the University Hospital of the West Indies.20 Morbidity and mortality were higher in
HIV-infected children who did not receive antiretroviral drugs (ARVs). A study of 204 children in the
Dominican Republic with TB showed no difference between HIV-infected and -uninfected children with
respect to clinical symptoms or anatomic sites of TB. HIV-infected children were less likely to have a
reactive PPD induration of >5mm and failed treatment significantly more frequently than HIV-uninfected
children.21 Additionally, there were more deaths among HIV-infected children than among HIV-
uninfected children, although whether this was attributable to TB could not be determined.
Extrapulmonary and miliary TB are more common in younger children (age four years or younger).
Younger children are also more likely to progress more rapidly from infection to active disease than older
children and adults, and may often not be recognised as having TB disease because they may have
negative skin tests and fewer symptoms of disease.
Congenital TB is rare but has been reported in children born to HIV-infected women with active TB. The
true incidence of congenital TB is not known, nor is it known whether this disease is more common in
children born to HIV-infected women with active TB as compared with children born to HIV-uninfected
women with active TB. Congenital TB can result from haematogenous dissemination of M. tuberculosis
following maternal mycobacteraemia, rupture of a placental tubercule into the foetal circulation, or
ingestion of infected amniotic fluid or maternal blood at delivery. The mother may not have symptoms of
TB disease, and subclinical maternal genital TB can also result in an infected neonate.
Children with TB disease are almost always infected by an adult in their daily environment, often a
household contact, and their infection represents primary infection rather than the re-activation disease
commonly seen in adults.22 Identification and treatment of the source case is particularly important and
all exposed children and other exposed members of the household should be evaluated because other
secondary TB cases and latent infections with M. tuberculosis are often found. Latent infections should
be treated to prevent progression to active disease. HIV counselling and testing should be offered to TB
contacts, because co-existing HIV infection, which increases the risk of TB disease, can reduce the
sensitivity of the tuberculin test.
The prevalence of multi-drug resistant TB (MDR-TB) in the Caribbean is not known. Drug resistant M.
tuberculosis is as transmissible as drug susceptible M. tuberculosis, and remains drug resistant in a new
host. Contacts to drug resistant TB should be treated under the assumption that any newly diagnosed
infections are similarly drug resistant.
Congenital TB often presents with early symptoms of poor feeding and failure to gain weight during the
first few weeks of life; upper respiratory symptoms and progressive hepatosplenomegaly may appear
X-7
somewhat later. Fever, progressive pneumonia, and meningitis may occur. Some infants may present
more acutely with progressive respiratory distress, apnoea, jaundice, and abdominal distension.
Children with pulmonary TB may have weight loss, fever, and failure to thrive, or they may have few or
no symptoms. TB in young children rarely manifests with the typical apical lung infiltrates and
cavitations seen in adults with TB. More commonly, pulmonary TB presents as a localised pulmonary
infiltrate with associated hilar lymphadenopathy–the primary complex. Multiple lobes are involved in up
to 25% of children. Concomitant atelectasis may be seen resulting from hilar adenopathy compressing
bronchi or from endobronchial granulomas.
Clinical presentation of TB disease in HIV-infected children is similar to that in HIV-uninfected children.
HIV-infected children are more likely to be younger, have failure to thrive, splenomegaly, hepatomegaly,
and generalised lymphadenopathy as compared with HIV-uninfected children with TB. Additionally,
HIV-infected children have longer hospital stays and greater mortality despite appropriate anti-TB
medications.23 Signs and symptoms may be consistent with acute pneumonia, and radiological evaluation
may show non-specific opacities without hilar adenopathy. Older HIV-infected children and adolescents
may have clinical presentations more similar to that seen in HIV-infected adults.
Commonly reported sites of extrapulmonary disease in children include lymph nodes, haematogenous
(miliary), CNS, bone, kidney, pericardium, peritoneum, and pleura.
Diagnosis
It is essential to have a high index of suspicion for TB disease in HIV-infected children. Diagnosis of TB
disease is difficult in children. M. tuberculosis can be detected in gastric aspirate samples from
approximately 50% of children without HIV infection who have TB disease. Other illnesses with similar
symptoms and radiographic abnormalities such as chronic lymphoid interstitial pneumonitis and
pulmonary bacterial infections further complicate the diagnosis of TB disease in the HIV-infected child.
Because of the difficulty in obtaining a definitive culture-proven diagnosis of TB disease in children,
often the diagnosis of TB disease involves linking the child to an adult with confirmed pulmonary TB
together with a positive tuberculin skin test (TST) and an abnormal radiograph or physical examination in
the child. However, a negative TST result cannot exclude TB disease in children, as approximately 10%
of children without HIV infection but with culture-positive TB disease do not react initially to a TST.
HIV infection further decreases TST reactivity.
Because children with HIV infection are considered at high risk for TB, annual Mantoux testing of this
population is recommended, beginning at age three to twelve months, using intradermally injected 5TU
PPD. Five millimetres (5mm) or more of induration is considered to be a positive (diagnostic) reaction in
children and adults with HIV infection. Although the BCG vaccine is routinely given in the majority of
Caribbean islands, the Mantoux skin test must still be read without regard to the BCG vaccination status.
Children age two years or younger or those who have HIV infection may be more likely to have a
negative skin test. Multiple puncture TB skin tests (e.g. tine) are not recommended.
A definitive diagnosis of TB disease requires isolation of M. tuberculosis from expectorated sputum;
BAL fluid; aspirated gastric fluid (obtained in the early morning after the child fasts overnight); biopsied
lung, peripheral lymph node, or other tissue (depending on location of disease); or mycobacterial blood
culture. In addition, availability of an isolate allows drug susceptibility testing to be performed.
Three consecutive morning gastric aspirates yield a positive culture of M. tuberculosis in up to 70% of
infants and 30% to 50% of children with clinical pulmonary TB. Gastric lavage samples, collected on
three consecutive mornings, have a higher yield on culture (50%) than a single sample collected by BAL
(10%). Nasopharyngeal aspiration and sputum induction are safe and effective in identifying M.
tuberculosis. The culture yield from other fluids and tissues from children with extrapulmonary TB is
less than 50% even with optimal samples.
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Antimycobacterial drug susceptibility testing should be performed on the initial M. tuberculosis isolate if
it is available and on subsequent isolates if treatment failure or relapse is suspected. Prior to obtaining
results of susceptibility testing, or if an organism from the child cannot be obtained, the antimycobacterial
drug susceptibility of the M. tuberculosis isolate from the adult source case can be used to define the
likely drug susceptibility of the child’s organism and used to design the empiric therapeutic regimen for
the child.
The principles for treatment of TB in the HIV-infected child are the same as for the HIV-uninfected child.
However, optimal therapy has not been defined, and modified treatment durations, schedules, and
medications are recommended for specific instances as described in this section.
Because of the high risk of dissemination in children age four years or younger, TB treatment should be
begun as soon as the diagnosis of TB is suspected. TB treatment should be initiated four to eight weeks
prior to initiating ART in the ARV-naïve child in order to improve adherence and better monitor and
reduce potential toxicities of TB treatment. For children already receiving ART who are diagnosed with
TB, the child’s ARV regimen should be reviewed and altered, if needed, to ensure optimal treatment for
both TB and HIV and to minimise potential toxicities and drug-drug interactions.
Directly observed therapy (DOT) is the mainstay of treatment for children and adolescents with TB. It
decreases rates of relapse, treatment failures, and drug resistance. For the first two months of treatment,
DOT should be given daily (induction phase); some experts feel that this can best be achieved by
hospitalisation. After this, DOT is usually given two to three times weekly (continuation phase). For
patients on rifampin (RIF)- or rifabutin-based regimens and who have severe immunosuppression, thrice-
weekly regimens are preferred due to concerns related to development of rifamycin resistance by M.
tuberculosis. However, data on the efficacy of thrice-weekly regimens in children are limited, and
healthcare providers may want to continue daily DOT.
Initial empiric treatment of active disease (induction phase) should generally consist of a four-drug
regimen (isoniazid (INH), RIF, pyrazinamide (PZA), and either ethambutol (EMB) or streptomycin) to
ensure efficacy against a potentially drug resistant organism. Ethionamide may be used as an alternative
to EMB in cases of TB meningitis as it has increased CNS penetration. If the organism is found to be
susceptible to INH, RIF, and PZA during the two-month period of induction therapy, EMB can be
discontinued and induction therapy completed using three drugs. INH and RIF should then be continued
daily or intermittently (two to three times weekly) to complete a minimum of nine months of therapy.
However, children with severe immunosuppression should receive either daily or thrice-weekly treatment
during the continuation phase, because TB treatment regimens with once- or twice-weekly dosing have
been associated with an increased rate of acquisition of rifamycin resistance in HIV-infected adults with
low CD4+ T cell counts (<100 cells/mm3).
The optimum duration of treatment for TB disease in HIV-infected children is controversial, though most
experts agree that for HIV-infected children with active pulmonary disease, the minimum recommended
duration of antituberculous drug treatment is nine months; for children with extrapulmonary disease
involving the bones or joints, CNS, or miliary disease, the minimum recommended duration of treatment
is twelve months. These recommendations assume that the organism is susceptible to the medications,
that adherence to the medications has been assured, and that the child has had a clinical and microbiologic
response to therapy.
Treatment of Drug Resistant TB
A minimum of three drugs should be given including at least two bactericidal drugs to which the isolate is
susceptible. Regimens may include three to six drugs with varying levels of activity.
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If the strain is resistant only to INH, INH should be discontinued and the patient treated with nine to
twelve months of a RIF- or rifabutin-containing regimen (e.g. RIF, PZA, and EMB; ethionamide or
streptomycin could be substituted for EMB if the M. tuberculosis isolate is sensitive to these agents).
If the strain is resistant only to RIF, there is an increased risk of relapse and treatment failure. RIF should
be discontinued, and a two-month induction phase of INH, PZA, EMB, and streptomycin given, followed
by an additional continuation phase of INH, PZA, and EMB to complete a minimum of a twelve-month
course of therapy, with the exact length of therapy based on clinical and radiologic improvement. In
older adolescents with RIF monoresistant strains, INH, EMB, and a fluoroquinolone such as levofloxacin
may be given, with PZA added for the first two months; an injectable agent (e.g. an aminoglycoside such
as streptomycin or amikacin) may also be included in the first two to three months for children with
severe disease.
When the strain is resistant to both INH and RIF (MDR-TB), therapeutic regimens must be individualised
based on the resistance pattern, relative activities of the drugs, extent of disease and any co-morbid
conditions. Therapy frequently requires twelve to twenty-four months. Consultation with an expert in the
management of paediatric TB is recommended.
INH may cause gastric upset during the initial weeks of treatment. Hepatotoxicity is the most common
adverse effect and includes subclinical hepatic enzyme elevation and clinical hepatitis that can rarely
progress to hepatic failure. When INH is given in a dosage exceeding 10mg/kg in combination with RIF,
the incidence of hepatic toxicity may be increased. Other toxicities reported with INH include peripheral
neuritis, mild CNS effects, and rare hypersensitivity reactions. Adverse effects typically resolve upon
discontinuation of the drug. Pyridoxine is recommended for children and adolescents on meat- and milk-
deficient diets and for children with nutritional deficiencies, including all symptomatic HIV-infected
children.
RIF is excreted in urine, tears, sweat, and other body fluids and colours them orange. The most common
adverse reaction to RIF therapy is gastrointestinal upset. Other reactions include skin rash, hepatitis, and
rarely, thrombocytopaenia and cholestatic jaundice. RIF induces hepatic cytochrome P450 enzymes and
can thus accelerate clearance of drugs metabolised by this pathway, such as protease inhibitors (PIs) and
non-nucleoside reverse transcriptase inhibitors (NNRTIs), potentially resulting in subtherapeutic levels of
these agents. As a result, concurrent administration of RIF and single PIs, with the exception of ritonavir
(RTV), is not recommended. Concomitant administration of RIF with efavirenz (EFV) is possible in the
older child. Regimens that include both RIF and nevirapine (NVP) should be used only when no other
options are available, because concomitant administration of these drugs results in a significant decrease
in plasma NVP levels.
PZA may cause hepatotoxicity, hyperuricaemia, arthralgias, skin rash, and gastrointestinal intolerance.
EMB may cause optic neuritis, with symptoms of blurry vision, central scotomata, and red-green colour
blindness, which is usually reversible and is rare at doses of 15mg/kg in children with normal renal
function. Children receiving EMB should have monthly monitoring of visual acuity and colour
discrimination if possible. Other toxicities include headache, nausea, peripheral neuropathy, rash, and
hyperuricaemia.
Unlike children without HIV infection, HIV-infected children on anti-TB medications and ART should
have liver enzymes obtained at baseline and monthly for the first few months of therapy. If symptoms of
drug toxicity develop, a physical examination and repeat liver enzyme measurement should be performed.
Mild elevations in serum transaminases (two to three times upper limit of normal) do not require
discontinuation of drugs if other findings are normal.
Adjunctive treatment with corticosteroids in children with TB is indicated for children with TB
meningitis, as dexamethasone has been shown to lower mortality and long-term neurologic impairment.
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Steroids may also be considered for children with pleural or pericardial effusions, severe miliary disease,
and significant endobronchial disease. Appropriate anti-TB therapy must be given concomitantly. Most
experts use 1mg to 2mg/kg/day of prednisone or its equivalent for six to eight weeks.
Monthly monitoring of clinical and bacteriologic response to therapy is important. For children with
pulmonary TB, chest radiographs should be obtained after two to three months of therapy to evaluate
response. Hilar adenopathy may persist for as long as two to three years despite successful anti-TB
therapy, and a normal radiograph is not required before discontinuation of therapy. Follow-up
radiographs after completion of therapy are not necessary unless clinical symptoms recur.
IRS (an increase in CD4+ T cell count to >100 cells/mm3) in patients receiving anti-TB therapy in the
setting of HAART has been reported in HIV-infected adults. It is not certain if this occurs in children.
New onset of systemic symptoms, especially high fever, expanding CNS lesions, and worsening
adenopathy, pulmonary infiltrates, or pleural effusions, have been reported in the setting of HAART up to
several months after starting TB therapy. Individuals with mild to moderate symptoms of IRS have been
treated symptomatically with nonsteroidal anti-inflammatory drugs (NSAIDs) while continuing anti-TB
therapy and HAART. If NSAIDs fail to result in clinical improvement, a short course (e.g. four weeks) of
systemic corticosteroid therapy while the child continues to receive HAART can be considered, though
data regarding this intervention are lacking.
Infection Control
In general, children with active TB are usually not infectious, as the concentration of TB bacilli in sputum
is usually sparse. This may not apply for children with HIV-TB co-infection. Children with HIV and TB
co-infection should be nursed in a room with air at negative pressure. Household family members and
close contacts who are visiting may be the adult source for TB and should also be evaluated.
Investigations should include a chest radiograph and Mantoux skin test. All children should be reported
to public health authorities if TB is suspected, enabling the appropriate community investigation and
intervention.
MYCOBACTERIUM AVIUM COMPLEX (MAC) DISEASE

Epidemiology
Mycobacterium avium complex (MAC) is caused primarily by the environmental nontuberculous
mycobacteria M. avium, M. intracellulare, and M. paratuberculosis. Respiratory and gastrointestinal
colonisation by inhalation or ingestion can subsequently lead to disseminated infection.
Although it has been reported as the second most frequent OI in HIV-infected children in the U.S., its
incidence in the Caribbean is uncertain, as it has only been reported in one child in Jamaica.24 Whether
this is due to decreased exposure to the organism or difficulties in diagnosis is unclear.
MAC can present as isolated lymphadenitis in HIV-infected children. Presentation with isolated MAC
pulmonary disease is a marker of high risk for dissemination. Disseminated infection with MAC in
paediatric HIV infection rarely occurs during the first year of life; its frequency increases with age and
declining CD4+ T cell count, and it is a frequent complication of advanced immunologic deterioration in
HIV-infected children. In children age two years or younger, disseminated MAC may occur at higher
CD4+ T cell counts than it does in older children or adults.
Recurrent fever, weight loss or failure to thrive, neutropaenia, night sweats, fatigue, chronic diarrhoea,
malabsorption, and persistent or recurrent abdominal pain are the symptoms most commonly associated
with disseminated MAC infection in children. Lymphadenopathy, hepatomegaly, and splenomegaly may
also be found. Laboratory abnormalities may include anaemia, leukopaenia, and thrombocytopaenia.
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Diagnosis
Procedures used to diagnose MAC in children are the same as those used in HIV-infected adults.
Definitive diagnosis is based on isolation of the organism from blood or biopsy specimens from normally
sterile sites, such as bone marrow, lymph node, or other tissues. Several mycobacterial blood cultures
over time may be required to yield a positive result. Culture is essential to differentiate nontuberculous
mycobacteria from M. tuberculosis as well as to determine which nontuberculous mycobacteria is the
cause of infection and the organism’s drug susceptibilities. Identification of MAC in stool or respiratory
tract secretions indicates colonisation but not necessarily invasive disease.
Combination therapy with a minimum of two drugs is recommended for treatment of MAC infections.
Monotherapy with a macrolide results in emergence of high-level drug resistance within weeks.
Initial empiric therapy consists of clarithromycin plus EMB. Azithromycin may be substituted in patients
with significant intolerance to clarithromycin or when drug interactions with clarithromycin are a
concern. Rifabutin may be added as a third drug to the clarithromycin/EMB regimen, particularly in
patients with more severe symptoms or disseminated disease.
Additional drugs can be considered depending on the severity of illness. In a patient with severe disease,
if rifabutin cannot be given, ciprofloxacin, levofloxacin, and/or amikacin or streptomycin can be used.
The most effective way to prevent disseminated MAC in HIV-infected children is to preserve immune
function through use of effective HAART. Additionally, improved immunologic status is important for
control of MAC disease in children with disseminated disease; HAART should therefore be initiated in
children with MAC disease who are ARV-naïve.
Most patients will show substantial clinical improvement in the first four to six weeks of therapy with
decreased fever and increased weight gain. Microbiologic response may take up to twelve weeks of
effective therapy and should be monitored by blood cultures every four weeks during initial therapy.
Major toxicities of clarithromycin and azithromycin include nausea, diarrhoea, and abdominal pain.
Uncommon toxicities include headache, leukopaenia, altered taste, and elevated transaminases.
Clarithromycin can inhibit hepatic metabolism of other drugs cleared by the liver, thus potential drug
interactions with concomitantly administered drugs need to be considered.
EMB may cause optic neuritis, with symptoms of blurry vision, central scotomata, and red-green colour
blindness, which is usually reversible and is rare at doses of 15mg/kg. Children receiving EMB should
have monthly monitoring of visual acuity and colour discrimination if possible. Other toxicities include
headache, nausea, peripheral neuropathy, rash, and hyperuricaemia.
Major toxicities of rifabutin include leukopaenia, gastrointestinal upset, polyarthralgias, rash, elevated
transaminases, and skin and secretion discoloration (pseudojaundice). Anterior uveitis has been reported
in adults and children receiving rifabutin as prophylaxis or as part of a combination regimen for
treatment, usually when given at higher doses.
Drug-drug interactions between rifabutin and ARVs can complicate the dosing of rifabutin. If added to
the clarithromycin/EMB regimen in a child whose HAART regimen includes RTV, indinavir (IDV),
nelfinavir (NFV), amprenavir (APV), or ritonavir-boosted saquinavir (SQV/r), the rifabutin dose must be
reduced by 50%. Conversely, the dose of rifabutin must be increased by 50% to 100% if co-administered
with EFV.
Adverse effects of quinolones include gastrointestinal upset, diarrhoea, rash, and headache. Cartilage
damage has been seen with use of the fluoroquinolone drugs in animals, and theoretically, these drugs
could have an effect on growing cartilage in children. Of the quinolone drugs, ciprofloxacin has had the
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greatest use in children, appears to be well-tolerated, and has not been associated with arthropathy in
clinical practice.
IRS (an increase in CD4+ T cell count to >100 cells/mm3) in patients receiving MAC therapy in the
setting of HAART has been reported in HIV-infected adults. New onset of systemic symptoms,
especially fever or abdominal pain, leukocytosis, and focal lymphadenitis (cervical, thoracic, or
abdominal) associated with pre-existing but relatively asymptomatic, often unrecognised, MAC infection
has been seen after starting HAART. Thus, before initiation of HAART in HIV-infected children with
very low CD4+ T cell counts, consideration should be given for an assessment for MAC and treatment if
MAC is identified. Children with moderate symptoms of IRS may be treated symptomatically with
NSAIDs or, if unresponsive to NSAIDs, a short course (e.g. four weeks) of systemic corticosteroid
therapy while continuing to receive HAART.
In HIV-infected children with MAC disease, following initial therapy, lifetime chronic suppressive
maintenance therapy for MAC (secondary prophylaxis) is required; detailed recommendations can be
found in the Chapter VI: Recommendations for Adult and Paediatric Opportunistic Infections
Prophylaxis. The safety of discontinuation of secondary prophylaxis following immunologic recovery
with HAART in children has not been studied extensively.
SERIOUS AND RECURRENT BACTERIAL INFECTIONS

Epidemiology
Serious and recurrent bacterial infections are a major cause of morbidity and mortality in HIV-infected
children worldwide. Immunologic defects in both cell-mediated (T cell) and humoral (B cell) immunity,
functional asplaenia, decrease in neutrophil number and function, and defects in complement components
all contribute to the increased susceptibility to bacterial agents in these children. In Jamaica, more than
16% of HIV-infected children presenting with CDC Category C disease and 35% presenting with CDC
Category B disease suffered from serious and recurrent bacterial meningitis, pneumonia, or sepsis.25
Chronic lung disease such as lymphoid interstitial pneumonitis, often seen in children with HIV infection,
may predispose to development of acute pneumonia. Acute pneumonia has been associated with
increased risk of long-term mortality in HIV-infected children, although multiple episodes of acute
pneumonia likely represent a marker of progressive disease and immunologic dysfunction rather than
being causally associated with increased long-term mortality. Serious and recurrent bacterial infections
such as pneumonia, meningitis, and sepsis associated with malnutrition were the most common causes of
mortality in HIV-infected children in Haiti and the Dominican Republic during the late 1980s and early
1990s.26
Streptococcus pneumoniae is the most prominent invasive bacterial pathogen in children with HIV
infection worldwide, accounting for more than 50% of bacterial blood-stream infections. In the mid-
1990s, HIV infection was the single most frequent condition predisposing patients to pneumococcal
infection in Trinidad.27 In Jamaica, children infected with HIV have a markedly increased risk for
invasive pneumococcal infection compared with uninfected children and have greater mortality.28
Approximately 30% of community-acquired sepsis in HIV-infected Jamaican children was due to this
organism.
The rate of antibiotic resistance to S. pneumoniae varies throughout the Caribbean. In 1997, the
prevalence of S. pneumoniae susceptibility to penicillin was almost 93% in the West Indies (including
both Jamaica and Trinidad).29 A later study in 1999 of invasive pneumococcal isolates in Jamaican
children suggested that penicillin resistance had increased (approximately 86% susceptible) with almost a
20% resistance to co-trimoxazole.30
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Haemophilus influenzae type B (Hib) was reported to be the most common cause of bacterial meningitis
in infants in Cuba, in children age five years or younger in the Dominican Republic (13 cases per
100,000), and in Jamaica (39 cases per 100,000) prior to the availability of the Hib vaccine.31 HIV-
infected children are at greater risk of overall invasive Hib disease and of developing bacteraemic
pneumonia than are uninfected children. Since 1998, when the Hib vaccine became available in Cuba, a
significant decrease in the number of cases of meningitis due to Hib was witnessed there. However, there
has also been an increase in the prevalence of mono- and multi-drug resistance in meningitis isolates
(including ampicillin, chloramphenicol, TMP-SMX, and tetracycline) from 1990 to 2000.32
While the frequency of gram-negative bacteraemia is lower than gram-positive bacteraemia in HIV-
infected children, gram-negative bacteraemia is more common in children with advanced HIV disease or
immunosuppression or those with central venous catheters. Gram-negative bacteria such as E. coli and
Klebsiella pneumoniae commonly cause urinary tract infections in Jamaican children with HIV
infection.33 However, in children age five years or younger, gram-negative bacteraemia is also seen in
children with milder levels of immune suppression.
The presence of a central venous catheter increases the risk of bacterial infections in HIV-infected
children, but the incidence is similar to that seen in children with cancer. S. aureus is the most commonly
isolated pathogen in catheter-associated bacteraemia in HIV-infected children; P. aeroginosa is also
common. Other organisms associated with catheter-associated bacteraemia include S. epidermidis,
Enterococcus, and Bacillus cereus.
HIV-infected children with invasive bacterial infections generally have a clinical presentation similar to
children without HIV infection. The classical signs, symptoms, and laboratory test abnormalities that
usually indicate invasive bacterial infection (fever, elevated white blood cell [WBC] count) are usually
present but may be lacking in immunocompromised HIV-infected children. Due to difficulties in
obtaining appropriate specimens, such as sputum, from young children, bacterial pneumonia is most often
a presumptive diagnosis in a child with fever, pulmonic symptoms, and an abnormal chest radiogram
unless there is an accompanying bacteraemia. One-third of HIV-infected children who develop acute
pneumonia have recurrent episodes.
Diagnosis
Attempted isolation of a pathogenic organism from normally sterile sites (blood, CSF, pleural fluid) is
strongly recommended. This is particularly important in the face of an increasing incidence of
antimicrobial resistance, including penicillin resistant S. pneumoniae and community-acquired methicillin
resistant S. aureus.
The diagnosis of pneumonia is typically made on the basis of clinical (e.g. fever, dyspnoea, tachypnea,
cough, rales) and radiographic findings, although it is difficult to differentiate viral from bacterial
pneumonia clinically. Culture of blood and pleural fluid, if present, should be done.
In bacteraemic children, a source for the bacteraemia should be sought. In addition to routine chest x-
rays, other diagnostic radiological evaluations may become necessary (CT chest, abdomen, ultrasound
studies) in HIV-infected children with compromised immune systems in order to identify less apparent
foci of infection such as bronchiectasis or internal organ abscesses. In children with central venous
catheters, both a peripheral and catheter blood culture should be obtained; if the catheter is removed, the
catheter tip should be sent for culture.
The local prevalence of resistance to common infectious agents when known (penicillin resistant S.
pneumoniae, methicillin resistant S. aureus), and the recent use of prophylactic or therapeutic antibiotics
need to be taken into consideration when initiating empiric therapy. Once the organism is identified,
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antibiotic susceptibility testing should be performed and therapy commenced based on the results of
susceptibility testing.
HIV-infected children whose immune systems are not seriously compromised (CDC Immune Class I) and
who are not neutropaenic can be expected to respond like HIV-uninfected children and should be treated
with the usual antimicrobial agents recommended for the most likely bacterial organisms. For example,
for HIV-infected children presenting with suspected bacteraemia, bacterial pneumonia, or meningitis,
empiric therapy with an extended-spectrum cephalosporin such as ceftriaxone, cefotaxime, or cefuroxime
would be reasonable until culture results are available.
Initial empiric therapy of HIV-infected children with suspected catheter sepsis should include coverage
for both gram-positive and enteric gram-negative organisms, such as ceftazidime, which has anti-
Pseudomonas activity, and vancomycin to cover methicillin resistant S. aureus. Severely immune
compromised HIV-infected children presenting with invasive or recurrent bacterial infections may require
expanded empiric antimicrobial treatment covering a broad range of resistant organisms (similar to that
chosen for suspected catheter sepsis) pending results of diagnostic evaluations and cultures.
HIV-infected children age five years or younger should receive Hib. New conjugate pneumococcal
vaccines with a serotype composition relevant to the Caribbean should be given as they become available.
Influenza vaccine should also be given yearly.
SYPHILIS
Epidemiology
T. pallidum can be transmitted from mother to child at any stage of pregnancy or during delivery.
Untreated or inadequately treated primary and secondary syphilis during pregnancy leads to congenital
infection in 60% to 100% of infants. Treatment of the mother for syphilis thirty days or more prior to
delivery is required for effective in utero treatment.
In Jamaica, the syphilis seroreactivity rate among pregnant women declined from 17% to 2% between
1990 and 2001. During that same time period, the prevalence of primary and secondary syphilis went
from 90 cases per 100,000 in 1987 to under 10 cases per 100,000 in 2001. During 2002-2003, 4% of 84
HIV-infected pregnant women in Kingston, Jamaica, had reactive VDRL.34
Cases of congenital syphilis in Jamaica have concomitantly decreased from sixty-eight to twenty-one
cases between 1994 and 2001.35 In Trinidad during 1985 to 1988, the annual average incidence of
congenital syphilis was 115 per 100,000 live births with a doubling of the incidence in the latter two years
of the study.36 In Haiti from 1985 to 1999, rates of congenital syphilis were 550 per 100,000 live births.
This very high rate decreased by 75% to 137 per 100,000 live births after decentralisation of their prenatal
screening program.37 There has been no published data relating the incidence of HIV co-infection and
congenital syphilis in the Caribbean.
Untreated early syphilis during pregnancy may lead to spontaneous abortion, stillbirth, hydrops fetalis,
preterm delivery, and perinatal death in up to 40% of pregnancies. At birth, approximately 60% of infants
with congenital syphilis are asymptomatic. If untreated, symptoms may occur within three weeks to six
months after birth, and may include hepatosplenomegaly, jaundice, mucocoetaneous lesions, skin rash,
nasal discharge, pseudoparalysis of an extremity, anaemia, thrombocytopaenia, and osteochondritis.
Late manifestations of congenital syphilis (after age two years) involve the CNS, bones, teeth, eyes, and
skin. Manifestations include mental retardation, interstitial keratitis, eighth cranial nerve deafness,
anterior bowing of the skins, frontal bossing, mulberry molars, Hutchinson teeth, saddle nose, rhaades,
and Clutton joints.
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HIV-infected children, adolescents, and adults with acquired early syphilis may be at increased risk of
neurologic complications and uveitis and have higher rates of treatment failure.
Diagnosis
The diagnosis of neonatal congenital syphilis depends on a combination of results from physical,
radiologic, serologic, and direct microscopic examinations. All infants born to women with reactive
nontreponemal and treponemal test results should be evaluated with a quantitative nontreponemal test
such as the VDRL slide test, rapid plasma reagin (RPR), and the automated reagin test. Testing should be
performed on neonatal serum due to the potential for maternal blood contamination of the umbilical cord
blood specimen. It is not necessary to perform specific treponemal tests, such as the fluorescent
treponemal antibody absorption (FTA-ABS) test and T. pallidum particle agglutination (TP-PA) test, for
evaluation of congenital syphilis in the neonate.
Darkfield microscopic examination or direct fluorescent antibody staining of lesions or body fluids should
be performed, although false-negative results are common. Definitive diagnosis of congenital syphilis
can be made if T. pallidum is detected in umbilical cord, placenta, nasal discharge, or skin lesion material.
Pathologic examination of the placenta and umbilical cord with specific fluoroscent antitreponemal
antibody staining, if available, is recommended.
Evaluation of suspected cases of congenital syphilis should include a physical examination, complete
blood count, differential and platelet count, and CSF analysis for VDRL, cell count, and protein. HIV-
infected infants may have increased cell counts and protein concentrations even in the absence of
neurosyphilis. Other tests should be performed as clinically indicated, such as long-bone radiographs,
chest radiograph, liver-function tests, cranial ultrasound, ophthalmologic examination, and auditory
brainstem response.
A presumptive case of syphilis is defined as an infant born to a mother with untreated or inadequately
treated syphilis at delivery, regardless of findings in the infant; or as any infant who has a reactive
treponemal test result and clinical signs or symptoms of congenital syphilis on physical exam or an
abnormal CSF finding without other cause or positive CSF VDRL.
For diagnosis of acquired syphilis, a reactive nontreponemal test must be confirmed by a specific
treponemal test such as FTA-ABS or TP-PA. These tests will remain positive for life, even with
successful treatment. The prozone phenomenon (a weakly reactive or falsely negative) reaction may
occur more frequently in HIV-infected individuals. Treponemal antibody titres do not correlate with
disease activity and should not be used to monitor treatment response. CSF evaluation should be
performed in HIV-infected adolescents with acquired syphilis who have neurologic or ocular symptoms
or signs (although some clinicians recommend a CSF examination for all HIV-infected patients).
Infants should be treated if mothers have untreated or inadequately treated syphilis (including treatment
with erythromycin or any other nonpenicillin regimen) or have no documentation of having received
treatment, received treatment for four weeks or less prior to delivery, been treated with penicillin but titres
did not decrease by four-fold, or have a four-fold or greater increase in nontreponemal antibody titre
suggesting relapse or re-infection.
Infants should be treated with aqueous crystalline penicillin G for a total of ten days regardless of
maternal history if: 1) there is an abnormal examination consistent with congenital syphilis; 2) positive
darkfield or fluorescent antibody test of body fluid(s); or 3) serum quantitative nontreponemal serologic
titre that is the same or four-fold greater than the maternal titre. An alternative to aqueous penicillin G is
procaine penicillin G intramuscularly for ten days. However, aqueous penicillin G is preferred because of
its higher penetration into the CSF.
Asymptomatic infants born to mothers who have had adequate treatment, response to therapy, and normal
physical examination and CSF findings, but who have a serum quantitative nontreponemal serologic titre
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that is the same or four-fold higher than maternal titre, may be treated with a single dose of benzathine
penicillin G intramuscularly, with careful clinical and serologic follow-up. However, some experts would
treat such infants with the standard ten days of aqueous penicillin because physical examination and
laboratory test results cannot definitively exclude congenital syphilis in all cases.
Acquired syphilis is treated with a single dose of benzathine penicillin G intramuscularly for early stage
disease (primary, secondary, early latent disease). For late latent disease, benzathine penicillin G should
be given intramuscularly once weekly for three doses. Alternative therapies such as doxycycline,
ceftriaxone, or azithromycin have not been evaluated in HIV-infected patients and should not be used as
first-line therapy. Neurosyphilis should be treated with aqueous penicillin G intravenously for ten to
fourteen days.
Infants with treated congenital syphilis should be examined at age one, two, three, six, and twelve
months, with serologic nontreponemal tests performed at three, six, and twelve months after conclusion of
treatment or until results become nonreactive. If the initial CSF examination was abnormal, repeat
lumbar puncture should be done every six months until results are normal. Nontreponemal antibody titres
should decline by age three months and be nonreactive by age six months if the infant was adequately
treated or not infected (e.g. passive antibody transfer from mother). Children with increasing titres or
persistently positive titres (even if low levels) at age six to twelve months should be evaluated and
considered for retreatment. Children with congenital syphilis who are also HIV-infected may take longer
to become nonreactive and may require retreatment.
Children and adolescents with acquired syphilis should have clinical and serologic response monitored at
three, six, nine, twelve, and twenty-four months after therapy. Nontreponemal test titres should decline
by at least four-fold by six to twelve months after successful therapy. If the initial CSF examination was
abnormal, repeat lumbar puncture should be done at three and six months after therapy and then every six
months until results are normal and the VDRL is negative.
CANDIDA INFECTIONS
Epidemiology
The most common fungal infections in HIV-infected children are due to Candida species. Oral thrush
and diaper dermatitis occur in 50% to 85% of HIV-infected children. Candida albicans is the most
common cause of mucosal and oesophageal candidiasis.
Oropharyngeal candidiasis is seen in 37% of HIV-infected children in Barbados, 13% of those in Jamaica,
and there was also a predominant finding in Dominican children.38 Candida oesophagitis is reported as
the AIDS-defining condition in approximately 2% of Jamaican children presenting with CDC Category C
disease.39
Disseminated candidiasis is infrequent in HIV-infected children, but Candida may disseminate from the
oesophagus particularly when co-infection with herpes simplex virus (HSV) or CMV is present.
Fungaemia occurs in up to 12% of HIV-infected children with chronically indwelling central venous
catheters for total parental nutrition or intravenous antibiotics. Approximately 50% of reported cases of
fungaemia in HIV-infected children are caused by non-albicans Candida species including C. tropicalis,
C. pseudotropicalis, C. parapsilosis, C. glabrata, C. krusei, and C. dubliniensis. A significant number of
children who develop fungaemia have received systemically absorbed oral antifungal azole compounds
(ketoconazole or fluconazole) for control of oral and oesophageal candidiasis.
Common complications of disseminated candidiasis include endophthalmitis, hepatosplaenic and renal
candidiasis, and osteomyelitis. Early detection and treatment of candidaemia may decrease mortality.
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Clinical manifestations of oropharyngeal candidiasis are variable and include pseudomembranous
(thrush), erythematous (atrophic), hyperplastic (hypertrophic), and angular cheilitis. Thrush is the most
classic form of oral candidiasis, commonly appearing as creamy white curdlike patches with inflamed
underlying mucosa that is exposed after removal of the exudate. It can be found on the oropharyngeal
mucosa, palate, and tonsils. Erythematous oropharyngeal candidiasis consists of flat erythematous lesions
on the mucosal surface. Hyperplastic candidiasis is made up of raised white plaques appearing on the
lower surface of the tongue, palate, and buccal mucosa and cannot be removed. Angular cheilitis occurs
as red, fissured lesions in the corners of the mouth.
Oesophageal candidiasis can present with odynophagia, dysphagia, or retrosternal pain, which can be
severe enough to cause dehydration and weight loss in children. Although common, evidence of
oropharyngeal candidiasis may be absent in children with oesophageal candidiasis. Unlike adults, a
significant number of children may present with nausea and vomiting.
New onset fever in an HIV-infected child with advanced disease and a central venous catheter is the most
common clinical manifestation of candidaemia. Renal candidiasis may present with candiduria and
ultrasonographically demonstrate renal parenchymal lesions without symptoms related to renal disease.
Systemic fungaemia may lead to endogenous endophthalmitis, and ocular examination by an
ophthalmologist may be warranted in children with candidaemia.
Diagnosis
Diagnosis of oral candidiasis can be made by a KOH preparation and culture with microscopic
demonstration of budding yeast cells in wet mounts or biopsy specimens. For recurrent or refractory
oropharyngeal candidiasis, cultures with in vitro susceptibility testing may be used to guide antifungal
treatment.
Oesophageal candidiasis has a classic cobblestoning appearance on barium swallow. With persistent
cases, unresponsive to usually effective therapy, one must consider HSV, CMV, MAC, and azole-
resistant Candida species. Diagnosis of candidaemia is best made with blood cultures. When fungaemia
is present, retinal exam for endophthalmitis, abdominal CT or ultrasound for hepatic or renal
involvement, and bone scans if osteomyelitis is clinically suspected may be appropriate.
Oropharyngeal candidiasis can be treated with fluconazole, clotrimazole troches, nystatin, or
amphotericin B suspension. Systemic therapy with ketoconazole or itraconazole is also effective for
initial treatment of oropharyngeal candidiasis. Fluconazole is available through National AIDS
Coordinators free of cost to all countries with an HIV seroprevalence of more than 1%.
Oesophageal disease should be treated systemically, and treatment with fluconazole or itraconazole
should be begun empirically in HIV-infected children with oropharyngeal candidiasis and oesophageal
symptoms. In most patients, symptoms should resolve within days of the start of effective therapy.
Itraconazole solution or low-dose intravenous amphotericin B may be used for patients with fluconazole-
refractory infections. Intravenous caspofungin, an echinocandin inhibitor of fungal (1,3)-beta-D-glucan
synthetase inhibitor, has been shown to be effective and comparable to amphotericin B and fluconazole
for treatment of oesophageal Candida infections and comparable to amphotericin B for treatment of
candidaemia in adults.
Central venous catheter candidaemia infection should be treated with intravenous amphotericin B.
Duration of therapy in treatment of fungaemia should be determined by presence of deep tissue foci,
patient clinical response, and presence of neutropaenia. Lipid formulations may be used in patients who
do not tolerate conventional amphotericin B or have severe renal disease. Patients at high risk for
morbidity and mortality should be treated for at least two to three weeks after the last positive blood
culture and until all signs and symptoms of infection have resolved. Flucytosine has been used in
combination with amphotericin B in some patients with CNS invasive candidiasis.
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Fluconazole has been used as an alternative to amphotericin B for treatment of invasive disease in stable
patients, such as those with uncomplicated candidaemia who have not recently received azole therapy.
However, fluconazole should not be initiated in the treatment of fungaemia without knowing the
speciation, because species such as C. krusei and C. glabrata are resistant to fluconazole.
The most frequent adverse effects of the azoles drugs are gastrointestinal, including nausea and vomiting,
most often reported with ketoconazole (10% to 40% of patients) and less commonly with the other azoles
(<5%). Skin rash and pruritus may be seen with all drugs; rare cases of Stevens-Johnson syndrome have
been reported with fluconazole therapy. All drugs are associated with asymptomatic increases in
transaminases, but rare cases of fatal hepatitis have been reported. Haematologic abnormalities have also
been reported, including haemolytic anaemia with ketoconazole, and thrombocytopaenia and leukopaenia
with itraconazole. Ketoconazole has been associated with endocrinologic abnormalities related to steroid
metabolism, including adrenal insufficiency and gynecomastia. Fluconazole has been associated with
alopaecia in scalp and pubic area.
CRYPTOCOCCOSIS
Epidemiology
Cryptococcosis is a fungal infection that is inhaled as spores into the lungs and spreads to the meninges
and viscera in HIV-infected hosts. It is primarily found in pigeon droppings. Cryptococcal infections
occur much less frequently in HIV-infected children than adults. Approximately 1% of children in
Jamaica have become infected.40
Meningoencephalitis is the most common initial manifestation of cryptococcosis, evolving over days to
weeks with fever, headache, and altered mental status. It can also present acutely, with nuchal rigidity,
seizures, and/or focal neurologic signs. CNS mass lesions (cryptococcomas) seen in adults have not been
reported in children.
Pulmonary cryptococcus without dissemination is unusual in children but may present as unexplained
recurrent fever, cough with scant sputum, intrathoracic lymphadenopathy, and focal or diffuse pulmonary
infiltrates. It may be asymptomatic with pulmonary nodules found on routine chest radiograph.
The skin may be secondarily involved in disseminated cryptococcosis. Lesions may be small, translucent,
umbilicated papules (indistinguishable from molluscum contagiosum), nodules, ulcers, or infiltrated
plaques resembling cellulitis.
Diagnosis
For diagnosis of suspected CNS disease, microscopic examination of CSF on India ink-stained wet
mounts should be performed. Cryptococcal antigen can be detected in CSF, serum, or BAL fluid by latex
agglutination test. However, CSF antigen detection may be negative in culture-positive cryptococcal
meningitis; high titres of antigen (prozone effect), low levels of antigen, or non-encapsulated strains may
contribute to this effect.
In HIV-infected children with CNS disease, the opening pressure is usually elevated and may be the only
abnormal finding. Head CT scans are usually nonspecific but may show signs of increased intracranial
pressure, hydrocephalus, or focal lesions, especially in the basal ganglia.
Fungal cultures from CSF, sputum, and blood may identify the organism. Diffuse pulmonary disease can
be diagnosed via BAL and direct examination of India ink-stained specimens, culture, and antigen
detection. Focal pulmonary and skin lesions may require biopsy with culture and staining.
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Without treatment, cryptococcosis is invariably fatal. Recommendation for the use of combination
therapy for severe cryptococcosis and cryptococcal meningitis are based on data from adult studies.
For children with severe disease that is isolated to the lungs, amphotericin B induction therapy, usually
combined with an initial two weeks of flucytosine, is recommended until symptoms are controlled.
Following treatment of acute pulmonary disease, maintenance therapy with fluconazole or itraconazole is
recommended.
For meningeal and extrameningeal cryptococcosis, initial therapy with the combination of amphotericin B
plus flucytosine, for a minimum of two weeks (induction therapy), is recommended. If flucytosine cannot
be used, amphotericin B alone can be given. Lipid formulations of amphotericin B have been used for
treatment of cryptococcal meningitis in adults, and may be particularly useful in patients with impaired
renal function, although the optimal dose in children has not been determined.
Fluconazole plus flucytosine has been shown to be superior to fluconazole alone and provides an
alternative option to amphotericin B for acute therapy of invasive disease, but there are little data on this
combination in children.
After successful two-week acute induction therapy, amphotericin B and flucytosine can be discontinued
in stable patients, and consolidation therapy with fluconazole given for a minimum of eight weeks or
until CSF cultures are stable should be commenced. Following induction and consolidation therapy,
maintenance suppressive therapy with lower-dose fluconazole should be instituted.
If fluconazole cannot be given, itraconazole is an alternative for consolidation, but may be less active than
fluconazole.
Oral acetazolamide should not be used for reduction of elevated intracranial pressure in cryptococcal
meningitis; it has been associated with an excess of severe acidosis, hypokalaemia, and other adverse
effects. Recommendations for the management of elevated intracranial pressure are the same as for
adults.
Cryptococcal antigen titres in CSF can be helpful in evaluating response to therapy or ongoing relapse;
however, changes in serum antigen titres do not correlate with clinical response. A rise in CSF antigen
titre of >1:8 during suppressive therapy is associated with treatment failure or pending relapse.
Amphotericin B is nephrotoxic. Permanent nephrotoxicity is related to cumulative doses. Intravenous
hydration is recommended prior to the amphotericin B infusion. Infusion-related fevers, chills, nausea,
and vomiting may occur, although they are less frequent in children than adults. Hepatic toxicity,
thrombophlebitis, and anaemia, and rarely neurotoxicity (manifested as confusion or delirium, hearing
loss, blurred vision, or seizures) may also occur. Liposomal preparations may cause acute, infusion-
related reactions in about 20% of patients, including chest pain, dyspnoea, and hypoxia; severe abdomen,
flank, or leg pain; and/or flushing and urticarial. Premedication with diphenhydramine can reduce the
incidence of these reactions.
Flucytosine has the potential for considerable toxicity especially affecting the bone marrow (anaemia,
leukopaenia, thrombocytopaenia), liver, gastrointestinal tract, kidney, and skin. Levels should be
monitored and doses adjusted to keep the level between 40 to 60µg/mL. The drug should be avoided in
children with severe renal impairment.
Fluconazole and the other azoles have relatively low rates of toxicity, but have significant drug
interactions that can limit their use. Because of their ability to inhibit the cytochrome P-450-dependent
hepatic enzymes, the potential for drug interactions, particularly with ARVs, should be carefully
evaluated prior to initiation of therapy. Skin rash and pruritis may be seen with all azole drugs, and rare
cases of Stevens-Johnson syndrome have been reported with fluconazole. Asymptomatic increases in
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transaminases can be seen and less frequently, hepatitis; rare cases of fatal hepatitis have been reported.
Thrombocytopaenia and leukopaenia have been reported with itraconazole.
Prevention of relapse after successful treatment requires lifelong suppressive treatment; details on
secondary prophylaxis (maintenance therapy) are provided in Chapter VI.: Recommendations for Adult
and Paediatric Opportunistic Infections Prophylaxis. Safety of discontinuation of secondary prophylaxis
following immune reconstitution with HAART in children has not been studied extensively.
HISTOPLASMOSIS
Epidemiology
Histoplasma capsulatum is endemic in the Caribbean, living in the soil in bird droppings and bat guano.
The incidence of disseminated histoplasmosis in HIV-infected paediatric patients in the Caribbean is
unknown. Only one case of disseminated histoplasmosis in an adolescent from Jamaica has been
described.41
The most common presenting symptom in HIV-infected children and adults with disseminated
histoplasmosis is prolonged fever. Children predominantly present with malaise and weight loss together
with nonproductive cough. Additionally, interstitial pneumonitis as seen in adults is rarely observed in
children, but a primary pulmonary focus frequently leads to widespread dissemination in HIV-infected
children.
The most frequent physical finding is hepatosplenomegaly. Coetaneous lesions that are erythematous and
nodular may occur. CNS involvement with meningitis and focal brain lesions is common in HIV-infected
adults and may be due to reactivated infection in the setting of very low CD4+ T cell numbers. Anaemia
and thrombocytopaenia are the most common haematologic abnormalities found, although pancytopaenia
has been reported. Elevated liver transaminases also occur.
Diagnosis
Culture of the organism is the definitive method of diagnosis but may require up to six weeks to grow.
Detection of H. capsulatum polysaccharide antigen by enzyme-linked immuno-assay (EIA), in urine,
BAL or CSF, and/or serum is a rapid, sensitive, and specific method for diagnosis; it can be detected prior
to culture positivity and, in acute histoplasmosis, is positive prior to antibody detection. EIA sensitivity is
greatest in patients with disseminated disease or acute pulmonary infection.
Diagnosis of CNS disease is difficult, particularly if the patient has isolated meningitis without
disseminated disease. The highest sensitivity is achieved by testing CSF for Histoplasma antigen and
antibody as well as culture.
Disseminated histoplasmosis is uniformly fatal without antifungal treatment. In HIV-infected children
with disseminated histoplasmosis, who require hospitalisation, or who are immunocompromised,
amphotericin B is recommended for four to six weeks, followed by itraconazole chronic suppressive
therapy. Some experts limit amphotericin B therapy to two to three weeks, followed by three to six
months of consolidation therapy with itraconazole after the patient is clinically stabilised and afebrile.
For children with confirmed H. capsulatum meningitis, amphotericin B therapy should be continued for
twelve to sixteen weeks, followed by chronic suppressive therapy (secondary prophylaxis) with
itraconazole. Liposomal amphotericin B is an alternative for patients who cannot tolerate conventional
amphotericin, and in one randomised trial, was associated with improved treatment response and survival
and less toxicity compared to conventional amphotericin B induction therapy.
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Mild disseminated histoplasmosis has been effectively treated by itraconazole given for three to twelve
months in a small number of non-immunocompromised children without HIV infection. High-dose
fluconazole is an alternative for patients with mild histoplasmosis who cannot take itraconazole, but is
less effective and the organism may develop drug resistance.
Amphotericin B is nephrotoxic. Permanent nephrotoxicity is related to cumulative dose. Intravenous
hydration is recommended prior to the amphotericin B infusion. Infusion-related fevers, chills, nausea,
and vomiting may occur, although they are less frequent in children than adults. Hepatic toxicity,
thrombophlebitis, and anaemia, and rarely neurotoxicity (manifested as confusion or delirium, hearing
loss, blurred vision, or seizures) may also occur. Liposomal preparations may cause acute, infusion-
related reactions in about 20% of patients including chest pain, dyspnoea, and hypoxia; severe abdomen,
flank, or leg pain; and/or flushing and urticarial. Premedication with diphenhydramine can reduce the
incidence of these reactions.
After successful treatment of acute disease, itraconazole chronic suppressive therapy (secondary
prophylaxis) should be instituted. Prevention of relapse after successful treatment requires lifelong
suppressive treatment; details on secondary prophylaxis (maintenance therapy) are provided in Chapter
VI.: Recommendations for Adult and Paediatric Opportunistic Infections Prophylaxis.
COCCIDIOIDOMYCOSIS
Epidemiology
Coccidioidomycosis is caused by Coccidioides immitis. There are no published reports of
coccidioidomycosis in children in Caribbean nations.
Primary infection of the newborn occurs rarely. However, infection of the genital tract of the mother can
result in placental involvement, coccidioidal endometritis, and aspiration of infected amniotic fluid by the
foetus. Both in utero and perinatal transmission of C. immitis have been reported.
Fever and dyspnea are common presenting symptoms in children, along with chills, weight loss,
lymphadenopathy, chest pain, and headache.
With pulmonary disease, chest radiographs exhibit bilateral, diffuse reticulonodular pulmonary infiltrates.
Some patients may develop persistent pulmonary nodules or thin-walled cavities. Diffuse pneumonia due
to C. immitis is usually accompanied by fungaemia, and patients should be evaluated for systemic disease
and extrapulmonary lesions (e.g. meningitis).
Disseminated disease with diffuse erythematous maculopapular rash, erythema multiforme, erythema
nodosum, and/or arthralgias may occur. Infection in bones and joints as well as CNS can also occur.
Diagnosis
Diagnosis can be made by direct examination and culture of respiratory secretions, CSF, or by biopsy of
suspicious pulmonary or coetaneous lesions to reveal characteristic double-contoured spherules with
endospores and without budding. Blood cultures may be positive less than 15% of the time in HIV-
associated coccidioidomycosis.
IgM antibody, detected by latex agglutination, enzyme immuno-assay, immunodiffusion, or tube
precipitin, appears early and is an indication of acute infection. IgG antibody gradually appears over the
first few months after primary infection and does not disappear in the presence of disseminated disease.
Titres of >1:16 are associated with disseminated disease (except in cases of isolated meningitis).
Serological tests such as complement fixation, tube precipitation, and immunodiffusion assays may have
reduced diagnostic utility in severely immunosuppressed HIV-infected patients.
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There is little experience treating coccidioidomycosis in HIV-infected children, and recommendations are
generally based on experience with adults.
Based on data from HIV-infected adults, for treatment of diffuse pulmonary or disseminated disease,
induction therapy with amphotericin B is recommended until clinical improvement is seen. Following
acute therapy, chronic suppressive therapy with fluconazole or itraconazole is recommended.
Treatment of disseminated nonmeningitic infection that is stable may include fluconazole or itraconazole.
CNS infections including meningitis should be treated with high-dose fluconazole since unlike
amphotericin B, it crosses the blood brain barrier well. For CNS infections unresponsive to fluconazole,
intravenous amphotericin B is used and augmented by intrathecal amphotericin B. Consultation with a
specialist is recommended when treating children with meningeal disease.
The most frequent adverse effects of fluconazole are gastrointestinal, including nausea and vomiting.
Skin rash and pruritis may be seen and rare cases of Stevens-Johnson syndrome have been reported with
fluconazole. Asymptomatic increases, and less frequently, hepatitis, in transaminases can be seen in 1%
to 13% of patients receiving azole drugs; rare cases of fatal hepatitis have been reported.
Surgical debridement or excision of localised, persistent, progressive, or resistant lesions in bone and lung
may be helpful. Lung cavities with recurrent bleeding and those >6cm in diameter are at greater risk of
rupture and require surgery.
As with other disseminated fungal infections, continued chronic suppressive therapy with fluconazole or
itraconazole is recommended following completion of initial therapy; details on secondary prophylaxis
(maintenance therapy) are provided in Chapter VI.: Recommendations for Adult and Paediatric
Opportunistic Infections Prophylaxis. The safety of discontinuation of secondary prophylaxis following
immune reconstitution with HAART in children has not been studied extensively.
CYTOMEGALOVIRUS (CMV)
Epidemiology
Infection with CMV is common and usually unapparent; acquisition of CMV may occur during infancy,
early childhood, or adolescence. Transmission can occur from an infected woman to her offspring;
horizontally by contact with virus-containing saliva, urine, or sexual fluid; or via transfusion of infected
blood or transplantation of infected organs.
Congenital (in utero) CMV infection occurs most commonly in infants born to women with primary
CMV infection during pregnancy. CMV can also be transmitted during the intrapartum or postpartum
periods from mother to infant. Up to 57% of infants whose mothers shed CMV at or around the time of
delivery become infected with CMV, and up to 53% of children who are breastfed with milk that contains
the infectious virus can become CMV-infected. However, symptomatic CMV disease in infants is much
less common when CMV is acquired intrapartum or through breastfeeding.
A seroprevalence study in Jamaican pregnant women from 1986 showed an overall prevalence rate of
CMV antibodies of 97%.42 The prevalence of CMV infection among HIV-infected pregnant women in
the Caribbean is unknown.
The rate of CMV antibody acquisition was 56% in Jamaican preschool-age children.43 It is unknown
whether antibody acquisition differs by HIV-infection status. In HIV-infected children in Barbados, 2.5%
of infected children had CMV disease as their presenting clinical condition, while CMV represented 2%
of CDC Category C disease in Jamaican children.44
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Approximately 10% of infants with in utero CMV infection are symptomatic at birth with congenital
CMV syndrome (CMV inclusion disease); mortality of children with symptomatic disease is as high as
30%. Newborns with symptomatic congenital CMV infection are generally small for gestational age, and
may have purpura/petechiae, jaundice, hepatosplenomegaly, chorioretinitis, microcephaly, intracranial
calcifications, and hearing impairment. Ninety percent (90%) of infants with symptomatic disease at birth
who survive have late complications, including significant hearing loss, mental retardation,
chorioretinitis, optic atrophy, seizures, or learning disabilities.
Although the majority of children with in utero CMV infection do not have symptoms at birth, 10% to
15% are at risk of developing later developmental abnormalities, sensorineural hearing loss,
chorioretinitis, or neurologic defects.
HIV-infected children with CMV co-infection may have accelerated progression of HIV disease
compared to those without CMV infection. CMV retinitis is the most frequent severe manifestation of
CMV disease in HIV-infected children. CMV retinitis in young HIV-infected children is frequently
asymptomatic. Older children with CMV retinitis present similarly to adults with floaters, loss of
peripheral vision, or reduction in central vision.
HIV-infected children with CD4+ T cell counts of <100 cells/mm3 are more likely to develop CMV
retinitis than those with higher CD4+ T cell counts, but CD4+ T cell count is less predictive of risk for
CMV disease in young infants, and systemic and localised CMV disease can also occur in HIV-infected
infants with higher age-adjusted CD4+ T cell counts.
End-organ CMV disease may occur in the lung, liver, gastrointestinal tract, pancreas, kidney, sinuses, and
CNS. In children with extra-ocular CMV disease, predominantly nonspecific symptoms such as fever,
poor weight gain, and loss of developmental milestones may occur. Gastrointestinal manifestations in
HIV-infected children include CMV colitis (the most common GI manifestation), oral and oesophageal
ulcers, hepatic involvement, ascending cholangiopathy, and gastritis.
The role of CMV in pulmonary disease in HIV-infected children is difficult to assess as it is often isolated
with other organisms, such as P. jiroveci. Histologic evidence of CMV disease is needed to determine if
active disease is present. CMV pneumonia is an interstitial process with gradual onset of shortness of
breath and dry, nonproductive cough.
CNS manifestations of CMV include subacute encephalopathy, myelitis, and polyradiculopathy
(primarily seen in adults but rarely reported in children). CSF findings are nonspecific, and may show a
polymorphonuclear predominance, elevated protein, and low glucose.
Diagnosis
CMV infection versus disease may be difficult to differentiate in HIV-infected children. In most
Caribbean countries, diagnosis in paediatric patients is primarily clinical and presumed when other
aetiologies have been ruled out. Due to transplacental transfer of antibody from mother to child, a
positive CMV antibody assay in an infant age twelve months or younger is indicative of maternal
infection but not necessarily infection of the infant. In an infant age twelve months or older, a positive
CMV antibody assay indicates prior infection with CMV but not necessarily active disease. At any age, a
positive CMV culture is indicative of infection, but again not necessarily of disease.
Oesophagitis due to CMV can be diagnosed based on characteristic shallow ulcerations at the distal
oesophagitis with histopathologic changes. Histopathology demonstrates characteristic “owl’s eye”
intranuclear and smaller intracytoplasmic inclusion bodies in biopsy specimens. Diagnosis of CMV
retinitis is based on clinical appearance, with white and yellow retinal infiltrates and associated retinal
haemorrhages.
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Most drugs for the treatment of CMV are not currently accessible or available in the Caribbean.
However, in countries where treatment is available, intravenous ganciclovir for two to three weeks should
be used in the treatment of newborns with severe or life- or sight-threatening congenital CMV disease.
The drug of choice for initial treatment of disseminated CMV disease, including CMV retinitis, in HIV-
infected children is intravenous ganciclovir followed by lifelong maintenance therapy. With long-term
therapy, the emergence of ganciclovir resistant CMV strains has occurred.
Foscarnet, given for fourteen to twenty-one days followed by lifelong maintenance therapy, is used as an
alternative in ganciclovir resistant CMV infections in HIV-infected children. Combination therapy with
ganciclovir and foscarnet may be helpful in patients failing monotherapy and may be used as initial
therapy in children with sight-threatening disease. Valganciclovir, a prodrug of ganciclovir, is one of the
first-line treatments for HIV-infected adults with CMV retinitis.
Prior to the availability of valganciclovir, oral ganciclovir (in combination with an intraocular ganciclovir
implant) had been used for maintenance treatment of CMV retinitis in older children. In children old
enough to receive adult dosage, valganciclovir would be the preferred drug over oral ganciclovir.
Intravitreous injections of ganciclovir, foscarnet, or cidofovir have been used for control of retinitis, but
require biweekly intraocular injections. Data are limited in children, and biweekly injections are
impractical for use in most children. Implantation of an intravitreous ganciclovir medication release
device in the posterior chamber of the eye has also been used in HIV-infected adults and adolescents.
Intraocular implants should not be used in children age three years or younger due to the small size of
young children’s eyes.
Complete blood counts, including platelet counts and liver enzyme counts, should be done twice weekly
to monitor for drug-induced effects. The major side effect of ganciclovir is myelosuppression (e.g.
anaemia, neutropaenia, thrombocytopaenia). Dose reduction or interruption may be necessary in up to
40% of patients due to dermatologic toxicity; granulocyte colony-stimulating factor (G-CSF) can be used
to ameliorate marrow suppression. Renal toxicity as seen by increased serum creatinine also may occur,
which may require ganciclovir dose modification. Other toxic reactions include CNS effects,
gastrointestinal dysfunction, thrombophlebitis, and elevated liver enzymes.
The main toxicity of foscarnet is decreased renal function; up to 30% of patients experience an increase in
serum creatinine levels. Renal toxicity, as well as foscarnet binding to divalent metal ions such as
calcium, leads to metabolic abnormalities in about one-third of patients, and serious electrolyte
imbalances (including abnormalities in calcium, phosphorus, magnesium, and potassium levels) and
secondary seizures or cardiac dysrhythmias can occur. Abnormal liver transaminases and CNS symptoms
can also occur. Valganciclovir causes myelosuppression.
In HIV-infected children with CMV disease, following initial induction therapy, lifetime chronic
suppressive maintenance therapy for CMV (secondary prophylaxis) is required; detailed
recommendations can be found in Chapter VI.: Recommendations for Adult and Paediatric
Opportunistic Infections Prophylaxis. The safety of discontinuation of secondary prophylaxis following
immune reconstitution with HAART in children has not been studied extensively.
HERPES SIMPLEX VIRUS (HSV) DISEASE

Epidemiology
Neonatal transmission of HSV occurs primarily through exposure of the infant to HSV-infected maternal
genital fluids during passage through the birth canal, by ascending infection, or through use of invasive
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procedures, such as foetal scalp monitoring, that disrupt foetal skin integrity during labour. Congenital
(in utero) HSV acquisition is rare, but can result in devastating coetaneous, ocular, and CNS damage.
The risk of neonatal HSV infection is greatest when an infant is born to a woman with primary HSV
infection. Genital shedding of HSV at the time of delivery is associated with increased risk of
transmission, and prolonged rupture of membranes (greater than six hours) also increases the risk of HSV
transmission to the infant, likely as a consequence of ascending HSV infection from the cervix.
Caesarean delivery significantly lowers the risk of transmission.
The seroprevalence of HSV in pregnant Jamaican women in 1986 was 91%.45 The incidence of
congenital HSV infection in children in the Caribbean is unknown. Recurrent or persistent HSV infection
is the AIDS-indicator condition in approximately 6% of HIV-infected children in Jamaica.46 As in HIV-
infected adults, HIV-infected children may have more frequent and severe episodes of HSV reactivation.
About 5% to 10% of moderately to severely immunosuppressed children with primary gingivostomatitis
develop frequent recurrences that can be associated with severe ulcerative disease and symptoms similar
to primary infection. Children with HIV infection can also have more prolonged shedding of virus with
both primary and re-activation HSV infection than children without HIV infection.
Neonatal HSV can present as disseminated multi-organ disease (occurring in about 25% of neonates with
HSV infection); localised disease of the CNS (approximately 35% of neonates); or disease localised to the
skin, eyes, and mouth (approximately 40% of neonates). Infants with disseminated disease generally
present after the first week of life; encephalitis occurs in the majority of these infants. Vesicular rash is
the most predominant presentation in children with localised skin, eye, or mouth disease, and is less
frequent in children with CNS or disseminated disease. Localised disease generally presents at age ten to
eleven days, and even with treatment, neonates with skin lesions may have coetaneous recurrences during
the first six months after treatment.
Outside of the neonatal period, the most common presentation of HSV infection in children is orolabial
disease. Fever, irritability, tender submandibular lymphadenopathy, and superficial, painful ulcers in the
gingival and oral mucosa and peri-oral area characterise primary HSV gingivostomatitis. HIV-infected
children who develop primary infection when they are immunocompromised can develop severe local
lesions or, more rarely, disseminated HSV with visceral involvement and generalised skin lesions with
primary infection. Other sites of involvement in severely immunocompromised HIV-infected children
with include the oesophagus, CNS, genital disease, and disseminated disease involving the liver, adrenals,
lung, kidney, spleen, and brain.
Diagnosis
Clinical diagnosis is based on the typical appearance of vesicles and ulcers. The virus can be isolated in
culture, and can usually be detected in tissue culture cells within one to three days.
For the diagnosis of neonatal HSV infection, culture specimens should be obtained from blood as well as
skin vesicles, mouth or nasopharynx, eyes, urine, and stool or rectum; positive cultures from any of the
latter sites more than forty-eight hours after birth indicates viral replication rather than contamination
after intrapartum exposure.
Direct immunofluorescence for HSV antigen can be done on cells collected from skin, conjunctiva, or
mucosal lesion scrapings. Giemsa staining (Tzanck preparation) of lesion cell scrapings may show
multinucleated giant cells and eosinophilic intranuclear inclusions, but this does not differentiate HSV
type or HSV from varicella zoster virus (VZV) infection, and is not routinely recommended.
Definitive diagnosis of HSV oesophagitis requires endoscopy with biopsy (histologic evidence of
multinucleated giant cells with intranuclear viral inclusion) and culture.
X-26
Acyclovir is the drug of choice for treatment of HSV in infants and children, regardless of HIV infection
status. Neonatal HSV disease should be treated with high-dose intravenous acyclovir given for twenty-
one days for CNS and disseminated disease and for fourteen days for skin, eye, and mouth disease.
Disseminated HSV disease or encephalitis outside of the neonatal period should be treated with acyclovir
for twenty-one days.
HIV-infected children with symptomatic HSV gingivostomatitis should be treated with either intravenous
or oral acyclovir for seven to fourteen days. Foscarnet may be used for acyclovir resistant HSV infection.
Primary toxicities of acyclovir are phlebitis, renal toxicity, nausea, vomiting, and rash. In infants
receiving high-dose acyclovir for neonatal disease, the major toxicity is neutropaenia (absolute neutrophil
count of <1,000/mm3).
can also occur.
VARICELLA ZOSTER VIRUS (VZV) DISEASE

Epidemiology
Varicella has the potential to cause greater morbidity and mortality in HIV-infected immunocompromised
children than among the general population of children.
It is unknown whether mother-to-child VZV transmission occurs more frequently in HIV-infected women
with primary varicella.
VZV can be transmitted to the foetus in later gestation, resulting in neonatal varicella. When the mother
develops varicella from four days before to two days after delivery, without passive antibody prophylaxis,
the attack rate for infants is about 20%, and mortality approximately 30%. In contrast, if maternal
varicella precedes delivery long enough to allow the transfer of VZV IgG antibodies across the placenta,
infants may be born with coetaneous varicella lesions or develop them in the first five days of life, but
they are generally not at risk for serious complications.
Zoster occurs only in children previously infected with varicella. Zoster is unusual in HIV-infected
children who had primary varicella infection when their CD4+ T cell counts were normal or mildly
suppressed. However, in HIV-infected children with low CD4+ T cell counts (e.g. CD4+ T cell count of
<15%) at the time of primary varicella, the rate of subsequent zoster may be as high as 70%. As in adults,
current CD4+ T cell count in children correlates with the frequency of zoster recurrences.
Congenital varicella infection is characterised by cicatricial skin scarring, limb hypoplasia, neurologic
(microcephaly, cortical atrophy, seizures, and mental retardation), eye (chorioretinitis, microophthalmia,
and cataracts), and renal (neurogenic bladder, hydroureter, hydronephrosis) abnormalities.
More severe disease may occur in HIV-infected children with lower CD4+ T cell counts not receiving
ART. Both the duration of disease may be longer and the rate of complications is still higher than in
normal children hospitalised with varicella.
X-27
HIV-infected children may also develop chronic infection with continued appearance of new lesions for
more than one month after primary or recurrent VZV infection. The lesions are characteristically
varicelliform at onset but evolve into nonhealing ulcers that become necrotic, crusted, and hyperkeratotic.
The classical clinical presentation of varicella, a generalised pruritic vesicular rash and fever, is
diagnostic. However, persistent lesions may be atypical and lack a vesicular component. The classical
clinical presentation of zoster, a frequently painful vesicular eruption with a dermatomal distribution, is
diagnostic. However, less typical rashes, including those that extend beyond dermatomal boundaries or
that are bilaterally distributed or are generalised, may also represent zoster in HIV-infected children.
HIV-infected children may have recurrent episodes of re-activated VZV infection that present with a
disseminated rash more similar to chickenpox than zoster but without visceral dissemination; they may
have multiple episodes of recurrent disease. VZV should be suspected in children with unilateral
vesicular rashes, retinitis when CMV cannot be implicated, or with progressive and otherwise
unexplained encephalitis and a history of previous varicella.
Diagnosis
Clinical diagnosis of varicella and zoster infections is based on the typical appearance of generalised
pruritic vesicular rash and fever in the former and a frequently painful vesicular rash in a dermatomal
pattern in the latter.
Direct immunofluorescence for VZV antigen can be done on cells collected from skin, conjunctiva, or
mucosal lesion scrapings. Giemsa-staining (Tzanck preparation) of cell scrapings from lesions is
nonspecific, as detection of multinucleated giant cells is suggestive of VZV but is also seen with HSV
infection. The optimal sensitivity of these methods requires obtaining cells from the base of a lesion after
unroofing a fresh vesicle.
Acyclovir is the drug of choice for treatment of VZV infection in HIV-infected children. With primary
varicella, acyclovir should be initiated as soon as possible after initial lesions appear. New lesions may
continue to appear for seventy-two hours after initiation of acyclovir and crusting of all lesions may take
five to seven days.
Intravenous acyclovir is recommended for treatment of primary varicella in HIV-infected children with
moderate or severe immunosuppression, or who have high fevers or numerous or deep, necrotic, or
haemorrhagic skin lesions. Oral administration should be used only for treatment of primary varicella in
HIV-infected children with normal or only slightly decreased CD4+ T cell counts or in children with mild
disease.
Acyclovir is also the treatment of choice for zoster in HIV-infected children. With zoster, oral acyclovir
can be given, as the chance for disseminated, life-threatening disease is less with zoster than varicella.
Initial intravenous administration should be considered for HIV-infected children with severe
immunosuppression, trigeminal nerve involvement, or extensive multidermatomal zoster.
Children who continue to develop lesions or whose lesions fail to heal may be infected with acyclovir
resistant VZV. HIV-infected children with acyclovir resistant VZV can be treated with intravenous
foscarnet.
Primary toxicities of acyclovir are phlebitis, renal toxicity, nausea, vomiting, and rash. In infants
receiving high-dose acyclovir for neonatal HSV disease, the major toxicity is neutropaenia (absolute
neutrophil count of <1,000/mm3).
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can also occur.
HUMAN PAPILLOMAVIRUS (HPV) DISEASE

Epidemiology
HPV infects coetaneous and mucosal squamous epithelium. There are over 100 distinct types of HPV,
nearly half first identified in the genital epithelium. They can be categorised on the basis of the site at
which they occur (genital versus coetaneous) and also as high- or low-risk on the basis of their potential
to induce malignant proliferation (e.g. HPV 16, 18, 31, 33, and 35 are most often associated with
intraepithelial neoplasia). HPV types that cause nongenital warts are usually distinct from those causing
genital infections; however, genital HPV types can cause conjunctival, nasal, oral, and laryngeal warts.
Children with compromised cellular immunity, such as those seen with HIV infection, may have intense
and widespread appearance of warts.
Transmission of HPV-associated coetaneous warts occurs by close person-to-person contact and may be
facilitated by minor trauma to the skin. HPV-associated anogenital warts are transmitted by sexual
contact but also may be acquired at the time of delivery or transmission from nongenital sites. Genital
warts (condylomata accuminata) in young children may be a sign of sexual abuse.
Mother-to-child transmission of HPV can occur. Latent HPV infection has been identified in 5% to 42%
of pregnant women without HIV infection, with higher rates in pregnant women with a history of sexually
transmitted infections (STIs). In nonpregnant women, HPV DNA is detected more frequently among
HIV-infected than -uninfected women, but data related to HPV prevalence in HIV-infected pregnant
women are not available.
HPV DNA has been detected in cord blood peripheral blood cells and amniotic fluid, indicating the
potential for in utero infection. Duration of membrane rupture has been associated with mother-to-child
HPV transmission, and some studies have shown higher HPV infection rates in infants delivered
vaginally than by Caesarean section. In general, no neonatal clinical abnormalities have been associated
with HPV detection.
Infant laryngeal papillomas and juvenile laryngeal papillomatosis are thought to be secondary to HPV
transmitted from mother to child through aspiration of infectious maternal genital secretions during
delivery.
HPV can be detected in the genital tract of 13% to 60% of sexually-active adolescent girls. HPV 16
antibodies or HPV DNA were present in 31% to 39% of women age fifteen to nineteen years and in 18%
of men at a Jamaican STI clinic.47 The predominant risk factors for HPV infection in youth include the
number of lifetime and recent partners.
While the incidence of anogenital HPV infection in sexually-active youth is high, longitudinal studies
have demonstrated that up to 40% to 80% of infections in youth without HIV infection may be transient
and spontaneously regress, although recurrent infections may be observed. Infection with multiple types
or high-risk types of HPV (e.g. 16 and 18), older age, and duration of HPV detection for more than twelve
months were risk factors for persistent infection. There are little published data regarding the rate of
persistence among HIV-HPV-co-infected youth.
Persistent infection with HPV, particularly HPV 16, 18, 31, and 33, is associated with a high risk for
development of cervical intraepithelial neoplasia (CIN) and anal intraepithelial neoplasia (AIN) and risk
of cervical, vulvovaginal, and anal carcinoma in both women and men. Adolescent girls may have
biologic differences from adult women, such as cervical squamous metaplasia, that could increase their
X-29
susceptibility to either development of persistent infection or disease. The risk of HPV-associated
cervical abnormalities may be increased among HIV-infected youth.
HPV causes hyperplastic, papillomatous, and verrucous squamous epithelial lesions on skin and mucus
membranes, including anal, genital, oral, nasal, conjunctiva, gastrointestinal, and respiratory tract mucosa.
Wart lesions appear as verrucous papules; lesions can also be smooth and flat or pedunculated. They may
be soft, pink or white “cauliflower-like” sessile growths on moist mucosal surfaces (condylomata
accuminata), or keratotic lesions on squamous epithelium of the skin, with a thick horny layer. They may
resemble common papular warts that are flesh-coloured, 1mm to 4mm, dome-shaped papules or flat-
topped papules that appear macular to slightly raised and can occur on either moist mucus membrane
surfaces or skin. Most frequently, the hands, feet, face, and genitalia are involved.
Diagnosis
Most coetaneous and anogenital warts can be diagnosed by physical examination.
There are a number of possible treatments for HPV-associated skin and external genital lesions; no one
treatment is ideal for all patients or all lesions, and treatment must be tailored to the individual patient.
Standard topical therapy for HPV-associated lesions in HIV-infected children is often ineffective.
Treatment can induce wart-free periods but the underlying viral infection may persist and result in
recurrence. Additionally, topical treatments seldom work in patients with large or extensive lesions.
However, individual lesions can be destroyed using cryotherapy or electrodesiccation.
Topical treatments include podofilox solution and gel (0.5%) (antimitotic agent), imiquimod cream (5%)
(topical immune enhancer that stimulates production of interferon and other cytokines), trichloroacetic or
bichloroacetic acid 80% to 95% aqueous solution (caustic agents that destroy warts by chemical co-
agulation of proteins), and podophyllin resin (contains antimitotic compounds and mutagens).
Acid cauterisation and podophyllin resin require application by a healthcare provider. Acid cauterisation
should be discontinued if there has not been significant improvement after three treatment sessions or
complete clearance has not occurred after six treatments.
Individual lesions can be removed using cryotherapy or electrodessication. Cryotherapy (application of
liquid nitrogen or dry ice) must be applied until each lesion is thoroughly frozen. Treatment may be
repeated every one to two weeks up to four times. Curettage, electrosurgery, scissor excision, or laser
vaporisation may also be effective.
Management of anogenital HPV infection accompanied by cytologic changes indicating
dysplasia/carcinoma in children/adolescents is analogous to that for the adult population.
HEPATITIS B (HBV) DISEASE

Epidemiology
An important mode of HBV acquisition by children is perinatal, or mother-to-infant transmission. All
pregnant women, including HIV-infected women, should be tested for hepatitis B surface antigen
(HBsAg) during an early prenatal visit. Testing should be repeated in late pregnancy for HBsAg-negative
women at high-risk for HBV infection (e.g. injection drug users, those with intercurrent STIs, those with
multiple sexual partners).
One study in Jamaica showed evidence of HBV infection in 21% of HIV-infected women.48 It is not
known whether HIV-HBV-co-infected women are more likely to transmit HBV to their infants than
women with HBV who are HIV-uninfected. All infants born to known HIV-HBV-co-infected women
X-30
should receive hepatitis B vaccine and hepatitis B immune globulin (HBIG) within twelve hours of birth,
the second dose of vaccine at age one to two months, and the third dose at age six months.
Postvaccination testing for antibody to HBsAg (anti-HBs) and HBsAg should be performed at age nine to
fifteen months, and infants found to be anti-HBs- and HBsAg-negative should be revaccinated.
Evidence of hepatitis B infection was found in 3.2% of sixty-three children from the Dominican Republic
given blood transfusions during 1983 to 1987.49 HIV-infected children may also be at risk of HBV
infection through exposure to HBV-infected household contacts. Horizontal transmission may occur
secondary to frequent interpersonal contact of nonintact skin or mucus membranes to blood or body fluids
that contain blood, such as saliva, from sharing inanimate objects like toothbrushes. All infants and
previously unvaccinated children should receive the three-dose hepatitis B vaccine as part of the
recommended childhood immunisation schedule.
HIV-infected adolescents are at increased risk of HBV infection through sexual activity or injection drug
use. All HBV-susceptible adolescents should be vaccinated against hepatitis B.
Risk of developing chronic HBV infection following acute infection in children without HIV infection is
related inversely to age at the time of infection. In children without HIV infection, chronic HBV
infection develops in up to 90% of infants, 30% of children age one to five years, and 6% of older
children and adolescents who become infected with HBV. A study of HBV core antigen (HBc) found
that 67% of HIV-infected women in Haiti showed no evidence that HIV infection predisposed them to
chronic HBV infection.50
Chronic HBV infection can lead to chronic hepatitis, cirrhosis, and primary hepatocellular carcinoma.
Among individuals without HIV infection who are infected with HBV at birth, the lifetime risk of
hepatocellular carcinoma reaches 50% for men and 20% for women; it is unknown if this risk is higher in
HIV-HBV-co-infected persons.
Humoral response to hepatitis B vaccination is reduced in children with HIV infection. In several studies,
only approximately 25% to 35% of HIV-infected children immunised with hepatitis B vaccine developed
protective antibody titres. Younger children and those with higher CD4+ T cell counts are more likely to
respond to vaccination than older, symptomatic, and immunodeficient HIV-infected children. Booster
doses may increase response rates. HIV-infected infants, children, and adolescents should be tested for
anti-HBs one to two months after completing the vaccination series, and if anti-HBs is negative, they
should be revaccinated.
Most HBV infections in children are asymptomatic. Children with HIV-HBV-co-infection may have a
mild acute illness followed by a smouldering, persistent chronic infection. Symptoms of lethargy,
malaise, fatigue, and anorexia can occur. Jaundice may be present, and less commonly, hepatomegaly
and splenomegaly.
Young children may experience a serum sickness-like prodrome marked by symmetrical arthropathy and
skin lesions. Gianotti-Crosti syndrome (papular acrodermatitis), urticarial, or purpuric lesions can occur.
Extrahepatic conditions associated with circulating immune complexes that have been reported with
children with HBV infection include aplastic anaemia, polyarteritis nodosa, and glomerulonephritis.
Diagnosis
HBsAg is the first marker detectable in serum; it precedes the elevation of serum aminotransferases and
the onset of symptoms. Anti-HBc appears two weeks after HBsAg and persists for life. Passively
transferred maternal anti-HBc may be detectable in the infant up to age twelve months. IgM anti-HBc is
highly specific for acute infection but may not be seen in perinatally-acquired infection.
In self-limited infections, HBsAg is eliminated in one to two months, and anti-HBs develops during
convalescence. Anti-HBs indicates immunity from HBV infection. After recovery from natural
X-31
infection, both anti-HBs and anti-HBc are usually present, whereas only anti-HBs develops in response to
the hepatitis B vaccine. In persons who become chronically infected (e.g. persistently positive for HBsAg
[and anti-HBc] beyond twenty-four weeks), anti-HBs is not detectable. Hepatitis B “e” antigen (HBeAg)
correlates with viral replication, DNA polymerase activity, increased infectivity, and increased severity of
liver disease. With clearance of HBeAg, antibody to HBeAg (anti-HBe) may be detectable. Quantitative
DNA assays may be helpful in evaluating response to therapy.
Early treatment of HBV infection, if started before integration of viral DNA into the nuclear DNA of the
majority of host hepatocytes, may provide improved long-term outcome; however, whether treatment of
acute HBV infection offers additional benefit over treatment once infection is identified as chronic is
unknown and requires further study.
Indications for treatment of chronic HBV infection in HIV-co-infected children are the same as in HBV-
infected children without HIV infection, and include: 1) evidence of ongoing viral replication, as
indicated by the presence of detectable serum HBV DNA, with or without HBeAg positivity, for at least
six months; 2) persistent elevation of serum transaminases (at least twice the upper limit of normal); and
3) evidence of chronic hepatitis on liver biopsy. Patients without necro-inflammation generally do not
warrant antiviral therapy.
The correlates of successful therapy have not been well defined, but markers of improvement would
include improved liver histology on biopsy, normalisation of hepatic transaminases, substantial decrease
in HBV viral load (HBV DNA levels), and loss of e antigen with development of e antibody in patients
who are HBeAg-positive. Although a decline in viral load correlates with response, no target HBV DNA
level has been established as representing a successful virologic response. Monitoring for virologic
response of therapy should include regular determination of serum levels of HBV DNA (if available),
HBsAg, HBeAg, anti-HBe antibody, and serum transaminases.
There are three approved therapies for chronic hepatitis B in adults: interferon-alfa, lamivudine (3TC),
and adefovir. Interferon-alfa and 3TC are also approved for treatment of chronic hepatitis B in children.
3TC is approved for children and adults for the treatment of compensated chronic hepatitis B associated
with evidence of HBV replication and active liver inflammation, and would be the preferred therapy (as
part of a fully suppressive HAART regimen) for chronic hepatitis B in HIV-infected children who require
HIV therapy. In children with HIV-HBV co-infection, 3TC should not be administered as monotherapy
because resistance of HIV to 3TC develops. It is essential in this situation for 3TC to be administered at
the dose sufficient to suppress HIV as well as HBV (4mg/kg twice daily) in the context of a potent
combination ARV regimen. Reports of clinical and laboratory exacerbations of hepatitis after
discontinuation of 3TC treatment have occurred in children with HBV infection who are not infected with
HIV. The optimal duration of therapy is not known, although experts recommend it for at least six
months following HBeAg seroconversion.
For treatment of chronic hepatitis B in HIV-HBV-co-infected adults, some experts recommend that
interferon-alfa be the therapy of choice in individuals who do not yet require ART for HIV infection to
preserve use of 3TC and tenofovir (TDF) for later treatment of HIV infection. For HIV-HBV-co-infected
adults who are ARV-naïve and require both HBV and HIV treatment, 3TC is considered by some experts
to be the therapy of choice for HBV, given in HIV-suppressive doses and in combination with other
ARVs for treatment of HIV infection. Considerations would be similar for HIV-HBV-co-infected
children.
Interferon-alfa-2a or -2b is the therapy that has received the most study in HBV-infected children, and is
recommended for the treatment of chronic hepatitis B with compensated liver disease in patients age two
years or older who warrant treatment. Interferon-alfa therapy is contra-indicated in children with
decompensated liver disease, significant cytopaenias, severe renal or cardiac disorders, and autoimmune
X-32
disease. None of the clinical studies of interferon-alfa therapy of chronic hepatitis B have specifically
studied children with HIV-HBV co-infection.
For children who have not responded to interferon-alfa, treatment with interferon-beta, which shares
common biologic functions with interferon-alfa but is antigenically different, can be considered.
Extended treatment with 3TC can lead to the development of 3TC resistant HBV, with base pair
substitutions at the YMDD locus of DNA polymerase. However, the emergence of variants containing
the YMDD motif mutation did not necessarily prevent HBeAg seroconversion or result in significant
worsening of liver histology. 3TC resistance should be suspected if HBV DNA levels increase or recur
while receiving treatment.
Adverse effects of interferon-alfa in children, while frequent, are generally not severe. Toxicity is dose-
related. Premedication with acetaminophen may reduce the incidence of side effects. The most common
adverse effect of interferon-alfa is a flu-like syndrome that can consist of fever, chills, headache, myalgia,
and arthralgia, abdominal pain, nausea, and vomiting. Fever generally appears within two to six hours
after interferon injection and rarely febrile seizures have occurred; the flu-like symptoms are most severe
during the first month of treatment. Relapsing cases of epistaxis (not associated with thrombocytopaenia
or prolonged prothrombin time) have been reported in some children, and occurred more frequently in the
first months of treatment. Some children experience loss of appetite and a transient weight loss and
impairment in height growth, which resolves following completion of therapy. Subtle personality
changes have been reported in 42% of children that resolve when therapy is discontinued. Neutropaenia,
which resolves upon discontinuation of therapy, is the most common laboratory abnormality; anaemia and
thrombocytopaenia are less common. Some children have developed antinuclear auto-antibodies.
Periodic monitoring of a complete blood count is recommended in children receiving interferon-alfa
therapy. Abnormalities in thyroid function (hypo- or hyper-thyroidism) have been reported with
interferon-alfa therapy; periodic monitoring of thyroid-stimulating hormone (TSH) is recommended.
Interferon should be permanently discontinued if a life-threatening toxicity occurs. For severe but non-
life-threatening reactions, the drug can be temporarily discontinued, and after the reaction has resolved,
treatment can be reinstated in a stepwise fashion, beginning with a maximum of 50% of the last
administered dose. For moderate reactions, the dose can be reduced by 50% and then increased stepwise
by 0.5MU or 1MU/m2 up to the full dose once the adverse effect has resolved. The most common side
effect with interferon-beta is low-grade fever.
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APPENDIX A: RECOMMENDATIONS FOR TREATMENT OF OIS IN HIV-EXPOSED AND -INFECTED CARIBBEAN INFANTS AND CHILDREN*
PATHOGEN PREFERRED THERAPIES AND ALTERNATIVE THERAPIES OTHER OPTIONS/ISSUES
DURATION
Pneumocystis TMP-SMX: TMP, 15-20mg/kg Alternative Therapeutic Regimens (if • Dapsone, 2mg/kg body weight po q.d (max,
jiroveci (formerly body weight plus SMX, 75- TMP-SMX intolerant or clinical 100mg/day) plus TMP, 15mg/kg body weight po
Pneumocystis 100mg/kg body weight, IV or po, treatment failure after 5-7 days of t.i.d has been used in adults, but data in children
carinii) pneumonia divided in 3 or 4 doses per day TMP-SMX therapy): are limited
(PCP) (after acute pneumonitis resolved in • Pentamidine, 4mg/kg body weight IV • Primaquine base, 0.3mg/kg body weight po q.d
mild-moderate disease, IV TMP- q.d is first-choice alternative regimen (max, 30mg/day) plus clindamycin, 10mg/kg body
SMX may be changed to po) (pentamidine may be changed to weight IV or po (max, 600mg IV and 300-450mg
Treatment Duration (followed by atovaquone after 7-10 days IV po) q6h has been used in adults, but data in
chronic suppressive therapy): therapy); or children are not available
21 days • Atovaquone, 15-20mg/kg body • Indications for corticosteriods:
weight (max, 750mg/dose) po b.i.d → pO2 <70mmHg at room air or (A-a)DO2
with food; infants age 3-24 months >35mmHg
may require a higher dose of
45mg/kg/day → Prednisone dose: 1mg/kg body weight po
b.i.d for 5 days, then 1mg/kg body weight po
q.d for 5 days, then 0.5mg/kg body weight po
q.d for days 11-21
• Lifelong suppressive therapy (secondary
prophylaxis) is recommended in children and
adults following initial therapy. Safety of stopping
secondary prophylaxis in children with immune
reconstitution on HAART has not been studied
extensively
Toxoplasma gondii Congenital Toxoplasmosis: For Sulfonamide-Intolerant Patients: • For infants born to mothers with symptomatic
Pyrimethamine loading dose: Clindamycin, 5.0-7.5mg/kg body weight Toxoplasma infection during pregnancy, empiric
2mg/kg body weight po q.d for 2 (max, 600mg/dose) po or IV divided into therapy of the newborn should be strongly
days, then 1mg/kg body weight po 4 doses per day can be substituted for considered irrespective of the mothers’ treatment
q.d for 2-6 months, then 1mg/kg sulfadiazine plus pyrimethamine and during pregnancy
body weight po t.i.w; plus leucovorin • Pyrimethamine use requires complete blood count
leucovorin (folinic acid), 10mg po monitoring weekly to monthly
or IM with each dose of
• TMP-SMX (TMP, 5mg/kg plus SMX, 25mg/kg IV
pyrimethamine; plus sulfadiazine,
or po b.i.d) has been used as an alternative to
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DURATION
50mg/kg body weight po b.i.d pyrimethamine-sulfadiazine in adults, but has not

Treatment Duration: 12 months been studied in children
• Atovaquone (1.5gm po b.i.d) in regimens with
pyrimethamine/leucovorin, with sulfadiazine
Acquired Toxoplasmosis:
alone, or as a single agent in patients intolerant to
Acute Induction Therapy (followed both pyrimethamine and sulfadiazine, has been
by chronic suppressive therapy): used in adults, but these regimens have not been
Pyrimethamine: loading dose, studied in children
2mg/kg body weight (max, 50mg) • Azithromycin (900-1,200mg/day) has also been
po q.d for 3 days, then 1mg/kg body used in adults combined with pyrimethamine-
weight (max, 25mg) po q.d; plus sulfadiazine, but has not been studied in children
sulfadiazine, 25-50mg/kg body
weight (max, 1-1.5gm/dose) po 4x • Corticosteriods (e.g. prednisone or
q.d; plus leucovorin, 10-25mg po dexamethasone) have been used in children with
q.d, followed by chronic CNS disease when CSF protein is very elevated
suppressive therapy (>1,000mg/dL) or if there are focal lesions with
significant mass effects, with discontinuation as
Treatment Duration (followed by soon as clinically feasible
chronic suppressive therapy): at
least 6 weeks • Lifelong suppressive therapy (secondary
prophylaxis) is recommended in children following
initial induction therapy. Safety of stopping
secondary prophylaxis in children with immune
reconstitution on HAART has not been studied
extensively
Cryptosporidiosis Effective HAART: Immune There is no consistently effective therapy Supportive Care: Hydration, correct electrolyte
reconstitution may lead to for cryptosporidiosis in HIV-infected abnormalities, nutritional support
microbiologic and clinical response individuals; several agents have
demonstrated some efficacy in
decreasing the severity of symptoms in
children:
• Nitazoxanide (data from
immunocompetent children,
treatment period, 3 days)
Age 1-3 years: 100mg po b.i.d
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DURATION
Age 4-11 years: 200mg po b.i.d; or

• Paromomycin, 25-35mg/kg body
weight in 2 to 4 divided doses po
daily (max, 2gm q.d); or
• Azithromycin, 10mg/kg body weight
po on day 1, then 5mg/kg body
weight po q.d (max, 600mg q.d)
Treatment Duration: Unknown
Microsporidiosis Effective HAART: Immune • Supportive Care: Hydration, correct electrolyte

reconstitution may lead to abnormalities, nutritional support
microbiologic and clinical response • Fumagillin recommended for treatment of
• Albendazole, 7.5mg/kg body diarrhoeal and ocular infections due to E. bienuesi
weight (max, 400mg/dose) po in HIV-infected adults
b.i.d for intestinal or
disseminated infection by
Microsporidia other than E.
bienuesi
Treatment Duration: Unknown
Mycobacterium Induction Phase (8 weeks): • Alternative drug for RIF is rifabutin, • DOT should be standard of care for children with
tuberculosis (TB) Isoniazid (INH), 10-15mg/kg body 10-20mg/kg body weight (max, TB
weight (max, 300mg/day) po q.d; 300mg/day) po q.d (same dose is • Potential drug interactions, especially with
plus given for intermittent two or three HAART medications, must be carefully reviewed
times weekly regimen) (see text)
Rifampin (RIF), 10-20mg/kg body
weight (max, 600mg/day) po q.d; • Alternative drug for EMB is • In ARV-naïve child, initiate therapy for TB 4-8
plus streptomycin, 20-40mg/kg body weeks prior to starting HAART; for children
Pyrazinamide (PZA), 20-40mg/kg weight (max, 1gm/day) IM q.d (or already receiving HAART who are diagnosed with
(max, 2gm/day) body weight po 20mg/kg given as intermittent b.i.w. TB, the child’s HAART regimen should be
q.d; plus or t.i.w. regimen) reviewed and altered, if needed, to ensure optimal
Ethambutol (EMB), 15-25mg/kg • Ethionamide, 15-20mg/kg body treatment for both TB and HIV and to minimise
weight po (max, 1gm/day) divided potential toxicities and drug-drug interactions
body weight (max, 2.5gm/day) po
q.d into 2 or 3 doses/day should be used • For children with severe immunosuppression,
X-36
DURATION
Continuation Phase (for drug- for TB meningitis continuation phase for drug-sensitive TB disease
sensitive TB): Drug Resistant TB: should include either q.d or t.i.w treatment; b.i.w
Daily: regimens should not be used because they may
Resistance to INH Alone:
lead to rifamycin resistance in immunosuppressed
• INH, 10-15mg/kg body weight • Discontinue INH patients
(max, 300mg/day) po q.d; plus
• RIF plus PZA plus EMB • Pyridoxine should be given if INH is administered
• RIF, 10-20mg/kg body weight (ethionamide or streptomycin can be
(max, 600mg/day) po q.d • Adjunctive treatment with corticosteroids is
substituted for EMB if M. tb isolate is indicated for children with CNS disease and may
OR sensitive to these agents) be considered for children with pleural or
Intermittent: Resistance to RIF Alone: pericardial effusions, severe miliary disease,
• INH, 20-30mg/kg body weight • Discontinue RIF significant endobronchial disease, or severe IRS
(max, 900mg/day) po q.d given (see text)
• INH plus PZA plus EMB plus
b.i.w or t.i.w; plus streptomycin for first 2 months, • Children receiving EMB who are old enough to
• RIF, 10-20mg/kg body weight followed by continuation phase of undergo routine eye testing should have monthly
(max, 600mg/day) po q.d given INH plus PZA plus EMB to complete monitoring of visual acuity and colour
b.i.w or t.i.w 12-month course discrimination if available
Treatment Duration (drug- Multi-Drug Resistance (MDR-TB): • Thiacetazone can cause severe or fatal reactions in
sensitive TB): HIV-infected children including rash and aplastic
• Therapy should be based on anaemia and should not be used
• Pulmonary TB: 9 months for resistance pattern, and children
• For drug resistant strains, at least 2 drugs to which
HIV-infected child (6 months if should be managed in consultation
the isolate is susceptible should be given
not HIV-infected) with an expert consultant
(minimum of 3 drugs should be given through the
• Extrapulmonary TB: 12 Treatment Duration (Drug Resistant continuation phase of therapy)
months TB): For MDR-TB, Second-Line Drugs Include:
• Single-drug INH or RIF resistant TB: • Amikacin, 15-30mg/kg body weight (max,
12 months 1gm/day) IM q.d
• MDR-TB: 12-24 months • Ciprofloxacin, 10-15mg/kg body weight po b.i.d
(max, 1.5gm/day); levofloxacin, 500-1,000mg po
q.d; or moxifloxacin, 400mg po q.d
(fluoroquinolones are not labelled for use in
children <age 18 years due to concerns regarding
potential effects on cartilage; use in younger
persons requires an assessment of potential risks
and benefits)
X-37
DURATION
Mycobacterium Initial Treatment (at least 2 Azithromycin, 10-12mg/kg body weight • Combination therapy with a minimum of 2 drugs is
avium Complex drugs): (max, 500mg/day) po q.d if intolerant to recommended
(MAC) • Clarithromycin, 7.5-15mg/kg clarithromycin • Children receiving EMB who are old enough to
body weight (max, 500mg/dose) undergo routine eye testing should have monthly
po b.i.d; plus monitoring of visual acuity and colour
• EMB, 15-25mg/kg body weight discrimination if available
(max, 2.5gm/day) po q.d; • Fluoroquinolones (e.g. ciprofloxacin, levofloxacin)
• followed by chronic suppressive are not labelled for use in children <age 18 years
therapy due to concerns regarding potential effects on
If Rifabutin Cannot Be Administered cartilage; use in younger persons requires an
For Severe Disease, Add:
(or if a fourth drug is needed for assessment of potential risks and benefits
• Rifabutin, 10-20mg/kg body
patients with more severe symptoms or • Lifelong suppressive therapy (secondary
weight (max, 300mg/day) po q.d
disseminated disease): prophylaxis) is recommended in children and
• Ciprofloxacin, 20-30mg/kg body adults following initial therapy. Safety of stopping
weight (max, 1.5gm/day) IV or po secondary prophylaxis in children with immune
q.d); OR reconstitution on HAART has not been studied
extensively
• levofloxacin, 500mg po q.d; OR
• If rifabutin is used, potential drug interactions,
• amikacin, 15-30mg/kg body weight especially with HAART medications, must be
IV in 1 or 2 divided doses per day carefully reviewed (see text)
(max, 1.5gm/day)
Syphilis Congenital: Congenital: • For treatment of congenital syphilis, repeat entire

Proven or Highly Probable Alternative for Proven or Highly course of treatment if even 1 day of treatment is
Disease: Probable Disease (less desirable if CNS missed
• Aqueous crystalline penicillin involvement): • Children with congenital syphilis should be
G, 100,000-150,000U/kg body Procaine penicillin G, 50,000U/kg body evaluated at age 1, 2, 3, 6, and 12 months, and
weight per day, administered as weight IM q.d for 10 days have nontreponemal testing at 3, 6, and 12 months
50,000U/kg body weight IV Infants with Possible Congenital after conclusion of therapy or until test becomes
q12h for the first 7 days of life Syphilis (maternal treatment and negative. Children with increasing titres or
then q8h for a total of 10 days response adequate, normal physical persistently positive titres (even if low levels) at
age 6-12 months should be evaluated and
• If diagnosed after age 1 month, examination, normal CSF studies, but
serum quantitative nontreponemal considered for retreatment
aqueous penicillin G, 200,000-
serologic titre that is the same or 4-fold • Children and adolescents with acquired syphilis
X-38
DURATION
300,000U/kg body weight IV higher than maternal titre): should have clinical and serologic response
q6h (max, 18-24MU/day) for 10 Benzathine penicillin G, 50,000U/kg monitored at 3, 6, 9, 12, and 24 months after
days body weight IM in a single dose (max, therapy
Acquired: 2.4MU)
Early Stage (primary, secondary,
early latent):
Benzathine penicillin, 50,000U/kg
body weight (max, 2.4MU) IM for
1 dose
Late Latent:
Benzathine penicillin, 50,000U/kg
body weight (max, 2.4MU) IM q.w
for 3 doses
Neurosyphilis (including ocular):
Aqueous penicillin G, 200,000-
300,000u/kg body weight IV q6h
(max, 18-24MU/day) for 10-14
days
Candida Oropharyngeal: Oropharyngeal (fluconazole- • Itraconazole cyclodextrin oral solution should not
• Fluconazole, 3-6mg/kg body refractory): be used interchangeably with itraconazole
weight (max, 400mg/dose) po • Itraconazole cyclodextrin oral capsules. Itraconazole capsules are generally
q.d for 7-14 days; OR solution, 2.5mg/kg body weight po ineffective for treatment of oesophageal disease
• Itraconazole cyclodextrin oral b.i.d (max, 200-400mg/day) for 7-14 • Central venous catheters should be removed when
solution, 2.5mg/kg body weight days; OR feasible in HIV-infected children with fungaemia
po b.i.d (max, 200mg/day) for • Amphotericin B oral suspension, • Fluconazole should not be used for the empiric
7-14 days; OR 1mL (100mg/mL) po 4x q.d for 14 treatment of fungaemia because resistance of non-
• Clotrimazole troches: 10mg days albicans Candida species to fluconazole has been
troche po 4x q.d for 14 days; reported
OR → In uncomplicated catheter-associated C.
• Nystatin suspension: 4-6mL po albicans candidaemia, an initial course of
4x q.d OR 1 to 2 200,000U amphotericin B followed by fluconazole to
flavoured pastilles po q4-5d for complete treatment may be used
X-39
DURATION
7-14 days • Amphotericin B initiation doses:

Oesophageal Disease: Oesophageal Disease: → Mild to moderate disease: Initiate at doses of
• Fluconazole, 6mg/kg body Amphotericin B, 0.3-0.5mg/kg body 0.25-0.5mg/kg body weight IV q.d, then
weight po q.d on day 1, then 3- weight IV q.d for a minimum of 7 days increase as tolerated to 0.5-1.5mg/kg body
6mg/kg body weight (max, weight IV q.d
400mg/dose) po q.d for → Severe disease: Initiate treatment at target
minimum of 14-21 days; OR daily dose
• Itraconazole cyclodextrin oral • Following stabilisation and resolution of fever on
solution, 2.5mg/kg body weight daily therapy in children with invasive disease,
po b.i.d or 5.0mg/kg body amphotericin B may be given as 1.5mg/kg body
weight po q.d for minimum of weight IV q.o.d
14-21 days • Lipid formulation of amphotericin B may be used
Invasive Disease:
Invasive Disease: in patients with renal insufficiency or infusion-
• Fluconazole, 5-6mg/kg body weight
Amphotericin B, 0.5-1.5mg/kg IV or po b.i.d (max, 800mg/day) for related toxicity to amphotericin B
body weight IV q.d minimum 4 weeks (if uncomplicated • Caspofungin has been used to treat oesophageal
Treatment Duration: Based on C. albicans candidaemia) and invasive candidiasis in adults but data in
presence of deep tissue foci and children are limited and a definitive paediatric
• Lipid formulations of amphotericin
clinical response in patients with dose has not been defined
B:
candidaemia, treat until 2-3 weeks • Flucytosine dose should be adjusted to keep drug
after last positive blood culture → Lipid Complex (Abelcet®),
5mg/kg body weight IV q.d for levels 40-60µg/mL
at least 2-4 weeks
→ Liposomal (AmBisome®), 3-
5mg/kg body weight IV q.d for
at least 2-4 weeks
• Amphotericin B (as per preferred
therapy dose) plus flucytosine, 100-
150mg/kg body weight po divided
into 4 doses for severe invasive
disease, especially involving CNS
X-40
DURATION
Cryptococcus Mild, Isolated Pulmonary Mild, Isolated Pulmonary Disease: • Flucytosine dose should be adjusted to keep drug
neoformans Disease: Itraconazole, 2-5mg/kg body weight po levels 40-60µg/mL
Fluconazole, 3-6mg/kg body weight q.d or b.i.d (max, 400mg/day), followed • An alternative for treatment of cryptococcal
po q.d followed by chronic by chronic suppressive therapy meningitis is fluconazole, 5-6mg/kg body weight
suppressive therapy IV or po b.i.d (max, 800mg/day) plus flucytosine,
Severe, Isolated Pulmonary 25mg/kg body weight po given 4x q.d, but there is
Disease: little data in children and toxicity of this regimen
Amphotericin B, 0.7-1.5mg/kg limits its utility
body weight IV q.d (usually with an • In cases of refractory cryptococcal meningitis with
initial 2 weeks of flucytosine) until failure of systemic therapy, intrathecal or
stable followed by chronic intraventricular amphotericin B has been used
suppressive therapy with • Oral acetazolamide should not be used for
fluconazole or itraconazole reduction of elevated intracranial pressure in
Meningeal and Extrameningeal Meningeal and Extrameningeal cryptococcal meningitis
Disseminated Disease: Disseminated Disease: • CSF cryptococcal antigen titres >1:8 suggest
Acute Therapy (minimum 2-week Acute Therapy (minimum 2-week failure or relapse
induction followed by induction followed by consolidation • Lifelong suppressive therapy (secondary
consolidation therapy): therapy): prophylaxis) with fluconazole is recommended in
Amphotericin B, 0.7-1.5mg/kg Amphotericin B, 0.7-1.5mg/kg body children and adults following initial therapy.
body weight IV q.d plus weight IV q.d alone Safety of stopping secondary prophylaxis in
flucytosine, 25mg/kg body weight • Liposomal amphotericin B children with immune reconstitution on HAART
po given 4x q.d has not been studied extensively
(AmBisome®), 3-5mg/kg body
Consolidation Therapy (followed weight IV q.d (with or without an
by chronic suppressive therapy): initial 2 weeks of flucytosine) in
Fluconazole, 5-6mg/kg body children with renal insufficiency or
weight IV or po b.i.d (max, infusion-related toxicity to
800mg/day) for a minimum of 8 amphotericin B
weeks or until CSF cultures are Consolidation Therapy (followed by
sterile chronic suppressive therapy):
Itraconazole, 2-5mg/kg body weight
(max, 200mg/dose) IV or po b.i.d for a
minimum of 8 weeks or until CSF
cultures are sterile
X-41
DURATION
Histoplasma Mild Disseminated Disease: Mild Disseminated Disease: Lifelong suppressive therapy (secondary prophylaxis)
capsulatum Intraconazole, 4-10mg/kg body Fluconazole, 5-6 mg/kg body weight IV with itraconazole is recommended in children and
weight IV or capsules po b.i.d for 3 or po b.i.d (max, 800mg/day) for at least adults following initial therapy. Safety of stopping
days (max, 600mg/day), followed 12-16 weeks followed by chronic secondary prophylaxis in children with immune
by 2-5mg/kg body weight (max, suppressive therapy reconstitution on HAART has not been studied
200mg/dose) po b.i.d for at least extensively
12-16 weeks followed by chronic
suppressive therapy
Severe Disseminated Disease: Severe Disseminated Disease:
Acute Therapy (minimum 2-3 Acute Therapy (minimum 2-3 weeks
weeks induction until improved, induction until improved, followed by
followed by consolidation therapy; consolidation therapy; meningitis
meningitis should be treated with should be treated with 12-16 weeks of
12-16 weeks of amphotericin): amphotericin):
Amphotericin B, 1mg/kg body Liposomal amphotericin B
weight IV q.d until stable (a (AmBisome®), 3-5mg/kg body weight
minimum 2-3 weeks) IV q.d in children with renal
Consolidation Therapy (followed insufficiency or infusion-related toxicity
by chronic suppressive therapy): to amphotericin B
Itraconazole capsules, 2-5mg/kg
body weight (max, 200mg/dose) po
b.i.d given for 3-6 months
Coccidioides Diffuse Pulmonary or Diffuse Pulmonary or Disseminated • Surgical debridement of bone and lung lesions
immitis Disseminated Non-Meningitic Non-Meningitic Disease (in stable may be helpful
Disease: patient): • Lifelong suppressive therapy (secondary
Amphotericin B, 0.5-1.0mg/kg • Fluconazole, 5-6mg/kg body weight prophylaxis) with fluconazole or itraconazole is
body weight IV q.d until clinical IV or po b.i.d (max, 800mg/day), recommended in children and adults following
improvement (minimum of several followed by chronic suppressive initial induction therapy. Safety of stopping
weeks), followed by chronic therapy secondary prophylaxis in children with immune
suppressive therapy with • Itraconazole, 4-10mg/kg body weight reconstitution on HAART has not been studied
fluconazole or itraconazole IV or po b.i.d for 3 days, followed by extensively
Meningeal Infection: 2-5mg/kg body weight po b.i.d (max,
X-42
DURATION
Fluconazole, 5-6mg/kg body 400mg/day), followed by chronic

weight IV or po b.i.d (max, suppressive therapy
800mg/day), followed by chronic Meningeal Infection (unresponsive to
suppressive therapy fluconazole):
Amphotericin B plus intrathecal
amphotericin B, followed by chronic
suppressive therapy
Cytomegalovirus Symptomatic Congenital • Valganciclovir is used in adults for treatment of

(CMV) Infection: CMV retinitis: induction dosing in adults is 900mg
Ganciclovir, 6mg/kg body weight po b.i.d for 14-21 days, followed by chronic
IV q12h for 6 weeks suppressive therapy; however, data on
valganciclovir dosing in children is unavailable
Disseminated Disease and Disseminated Disease and Retinitis:
Retinitis: • Cidofovir is also used for treatment of CMV
Induction Therapy (followed by chronic
Induction Therapy (followed by retinitis in adults: induction dosing in adults is
suppressive therapy):
chronic suppressive therapy): 5mg/kg body weight IV q.w for 2 weeks, followed
Foscarnet, 60mg/kg body weight IV q8h by chronic suppressive therapy; however, data on
Ganciclovir, 5mg/kg body weight for 14-21 days, then 90-120mg/kg q.d dosing in children is unavailable
IV q12h for 14-21 days (may be for chronic suppression
increased to 7.5mg/kg body weight • Intravitreal injections not practical for most
Alternative for Retinitis (followed by children
IV b.i.d), then 5mg/kg per day for 5 chronic suppressive therapy):
to 7 days per week for chronic • Intraocular implant should not be used in children
suppression • IV ganciclovir plus IV foscarnet (at <age 3 years due to small size of eyes
above induction doses) – may be
considered as initial induction • Lifelong suppressive therapy (secondary
therapy in children with sight- prophylaxis) is recommended in children and
threatening disease adults following initial induction therapy. Safety
of stopping secondary prophylaxis in children with
• Older Children: Ganciclovir immune reconstitution on HAART has not been
intraocular implant plus oral studied extensively
ganciclovir, 30mg/kg t.i.d or if old
enough to receive adult dosing, oral
valganciclovir, 900mg po q.d
X-43
DURATION
Herpes Simplex Neonatal CNS or Disseminated Acyclovir-Resistant HSV Infection: • For neonatal CNS disease: Repeat CSF HSV
Virus (HSV) Disease: Foscarnet, 40mg/kg body weight given DNA PCR should be performed at day 19-21 of
Acyclovir, 20mg/kg body weight IV t.i.d or 60mg/kg body weight given therapy; do not stop acyclovir until repeat CSF
IV t.i.d for 21 days IV b.i.d HSV DNA PCR is negative
Neonatal Skin, Eye, or Mouth • Suppressive secondary prophylaxis with oral
Disease: acyclovir can be considered for children with
Acyclovir, 20mg/kg body weight severe and recurrent gingivostomatitis
IV t.i.d for 14 days
CNS or Disseminated Disease in
Children Outside the Neonatal
Period:
Acyclovir, 10mg/kg body weight
IV t.i.d for 21 days
Moderate to Severe Symptomatic Mild Symptomatic Gingivostomatitis:
Gingivostomatitis:
Acyclovir, 20mg/kg body weight (max,
Acyclovir, 5-10mg/kg body weight 400mg/dose) po t.i.d for 7-14 days
IV t.i.d for 7-14 days
Genital Herpes (Adults and
Adolescents):
(max, 400mg/dose) po t.i.d for 7-10
days.
Varicella Zoster Primary Varicella (Chickenpox): For Patients Not Responding to Some experts base IV acyclovir dosing in children
Virus (VZV) Children with Moderate or Severe Acyclovir: >age1 year on body surface area (500mg/m2/dose IV
Immune Suppression, High Fever, Foscarnet, 40-60mg/kg body weight IV q8h) instead of body weight
or Necrotic Lesions: t.i.d for 7-10 days
IV t.i.d for 7 days after no new
lesions
Children with Mild Immune
Suppression and Mild Disease:
X-44
DURATION

po (max, 200mg/dose) 4x q.d,
continued for 7 days after no new
lesions
Zoster:
Children with Severe Immune
Suppression, Trigeminal Nerve
Involvement, or Extensive Multi-
Dermatomal Zoster:
IV t.i.d for 7-10 days
Children with Mild Immune
Suppression and Mild Disease:
po (max, 200mg/dose) 4x q.d for 7-
10 days
Human Individual lesions can be removed • Podofilox solution/gel (0.5%) applied • Standard topical therapy in children is often
Papillomavirus by cryotherapy or topically b.i.d for 3 consecutive days ineffective
(HPV) electrodessication; may be repeated a week for up to 4 weeks • Cidofovir topical gel (1%) is an experimental
q.w to b.i.w up to 4 times • Imiquimod cream (5%) applied therapy studied in HIV-infected adults, but is not
topically at night and washed off in commercially available and has very limited use in
the morning for 3 nonconsecutive children; systemic absorption can occur
days a week for up to 16 weeks • HAART has not been consistently associated with
• Trichloroacetic acid applied topically reduced risk of HPV-related cervical abnormalities
q.w for up to 3-6 weeks in HIV-infected women
• Podophyllin resin applied topically • Laryngeal papillomatosis generally requires
and washed off several hours later referral to a paediatric otolaryngologist. Treatment
q.w for 3-6 weeks is directed at maintaining the airway, rather than
removal of all disease. Adjuvant therapy with
interferon-alfa or intralesional cidofovir is being
used investigationally for invasive disease
X-45
DURATION
Hepatitis B Virus For Children Who Require HIV Interferon-alfa, 10MU/m2 body surface • Indications for treatment include:
(HBV) Therapy: area subcoetaneously t.i.w for 6 months → Detectable serum HBV DNA, with or without
3TC, 4mg/kg body weight po (max, (sometimes used for retreatment of failed +HBeAg, for at least 6 months;
150mg/dose) b.i.d as part of a fully lower dose interferon therapy)
→ Persistent elevation of serum transaminases (at
suppressive HAART regimen for a
least 2x the upper limit of normal); and
minimum of 12 months or 6 months
after HBeAg seroconversion → Evidence of chronic hepatitis on liver biopsy
For Children Who Do Not Require • Interferon-alfa is contra-indicated in children with
HIV Therapy: decompensated liver disease, significant
cytopaenias, severe renal or cardiac disorders, and
• Interferon-alfa, 5MU/m2 body
auto-immune disease
surface area subcoetaneously
(max, 10MU/dose) t.i.w • Prednisone co-administration not recommended
• If HBeAg-positive, • Interferon-beta 5MU/m2 body surface area IM t.i.w
recommended duration of for 6 months for children who have not responded
interferon-alfa therapy is 6 to interferon-alpha
months; if HBeAg-negative, a • In children receiving 3TC and responding to
duration of 12 months or longer therapy, clinical and laboratory exacerbations of
may be desirable hepatitis may occur if 3TC is discontinued; thus,
once anti-HBV/HIV therapy has begun, it should
be continued unless contra-indicated or until the
child has been treated for >6 months after HBeAg
seroconversion and can be closely monitored on
discontinuation
*Note: Information contained in these guidelines might not represent U.S. Food and Drug Administration (FDA) approval or approved labelling for products or
indications. Specifically, the terms ‘safe’ and ‘effective’ might not be synonymous with the FDA-defined legal standards for product approval. Letters and
Roman numerals in parentheses after regimens indicate the strength of the recommendations and the quality of evidence supporting it.
X-46
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Geoghagen M, Farr JA, et al., 2004.
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Espinal MA, 1996 and Geoghagen M, Farr JA, et al., 2004.
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Pierre, 2004.
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E, Soto SI, Alburquerque D. Pediatric AIDS: characteristics of 17 Dominican cases. Arch Domin
Pediatr 1990;26(2):38-40.
27
Williams KP, Monteil MA. A retrospective analysis of invasive Streptococcus pneumoniae infections
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28
McGregor D, Barton M, Thomas S, Christie CD. Invasive pneumococcal disease in Jamaican children.
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McGregor D et al, 2004.
31
Tamargo I, Torano G, Rodriguez O, Perez M, Llop A. Characterization of Haemophilus influenzae
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vaccination. Epidemiol Infect 2000;125(3):549-54.
32
Tamargo I, Fuentes K, Llop A, Oteo J, Campos J. High levels of multiple antibiotic resistance among
938 Haemophilus influenzae type b meningitis isolates from Cuba (1990-2002). J Antimicrob
Chemothe. 2003;52(4):695-8. Epub 2003 Sep 01.
33
Pierre, 2004.
34
Johnson N, Mullings A, Harvey K, Alexander G, McDonald D, Williams E, et al. HIV seroprevalance,
uptake of interventions to reduce mother to child transmission and birth outcomes in Greater Kingston,
Jamaica. West Indian Med J 2004;53(5):297-302.
35
Figueroa JP. An overview of HIV/AIDS in Jamaica: strengthening the response. West Ind Med J
2004;53(5):277-82.
36
Ali Z. Resurgence of congenital syphilis in Trinidad. J Trop Ped 1990;36(3):104-8.
X-48
37
Fitzgerald DW, Behets F, Preval J, Schulwolf L, Bommi V, Chaillet P. Decreased congenital syphilis
incidence in Haiti's rural Artibonite region following decentralized prenatal screening. Am J Pub
Health 2003;93(3):444-6.
38
Kumar, 2000 and Pierre, 2004 and Cruz, 1990.
39
Pierre, 2004.
40
Ibid.
41
Nicholson AM, Rainford L, Elliott V, Christie CDC. Disseminated histoplasmosis and AIDS at the
University Hospital of the West Indies. West Indian Med J 2004;53(2):126-130.
42
Prabhakar, 1991.
43
Prabhakar P, Bailey A, Smikle MF, Ashley D. Seroprevalence of cytomegalovirus infection in a
selected population in Jamaica. W Ind Med J 1992;41(4):133-5.
44
Kumar, 2000 and Pierre, 2004.
45
Prabhakar, 1991.
46
Pierre, 2004.
47
Figueroa JP, Ward E, Luthi TE, Vermund SH, Brathwaite AR, Burk RD. Prevalence of human
papillomavirus among STD clinic attenders in Jamaica: association of younger age and increased sexual
activity. Sex Transm Dis 1995;22(2):114-8 and Strickler HD, Kirk GD, Figueroa JP, Ward E,
Braithwaite AR, Escoffery C, et al. HPV 16 antibody prevalence in Jamaica and the United States
reflects differences in cervical cancer rates. Int J Cancer 1999;80(3):339-44.
48
Smikle MF, Heslop O, Vickers I, Dowe G, Deer D, Sue-Ho R, et al. A serosurvey of hepatitis B virus,
hepatitis C virus, human T lymphotropic virus type-1 and syphilis in HIV-1-infected patients in
Jamaica. West Ind Med J 2003;52(1):14-7.
49
Feris JM, Batista Genao R, Ramirez Fernandez A, Sanchez Mieses EA, Vasquez E. Human
immunodeficiency virus and hepatitis B virus in children transfused in the Dr. Luis Manuel Morillo
King Hospital. Arch Domin Pediatr 1990;26(2):41-4.
50
Boulos R, Ruff AJ, Nahmias A, Holt E, Harrison L, Magder L, et al. Herpes simplex virus type 2
infection, syphilis, and hepatitis B virus infection in Haitian women with human immunodeficiency
virus type 1 and human T lymphotropic virus type I infections. The Johns Hopkins University
(JHU)/Centre pour le Développement et la Santé (CDS) HIV Study Group. J Infect Dis.
1992;166(2):418-20.
X-49
XI. POST-EXPOSURE PROPHYLAXIS (PEP)
TABLE OF CONTENTS
OCCUPATIONAL EXPOSURE TO HIV .................................................................................................... XI-1

Risk of Transmission Associated with an Occupational Exposure .................................................. XI-1
Efficacy and Timing of PEP ............................................................................................................. XI-1
Risks and Benefits of PEP ................................................................................................................ XI-2
PEP Regimens .................................................................................................................................. XI-2
Recommendations for Management of Occupational Exposures to HIV......................................... XI-3
Follow-Up......................................................................................................................................... XI-4
PEP FOLLOWING SEXUAL EXPOSURE TO HIV.................................................................................... XI-5
PEP SCENARIOS AND RECOMMENDATIONS ......................................................................................... XI-6
Needlestick Involving HIV-Infected Source Patient ........................................................................ XI-6
Exposure Involving a Source Patient Whose HIV Status Is Not Known ......................................... XI-6
Exposed Healthcare Worker with a Positive Baseline HIV Test...................................................... XI-7
Exposure Involving Sexual Assault.................................................................................................. XI-7
TABLE
Table 1: Variables that Likely Increase Risk of HIV Transmission in
Occupational Exposures............................................................................................................................... XI-1
Table 2: PEP Management Recommendations: Percoetaneous
(Needlestick) Exposures ............................................................................................................................... XI-4
Table 3: PEP Management Recommendations: Mucocoetaneous
or Non-Intact Skin Exposures....................................................................................................................... XI-4
Table 4: Average Per-Exposure Risk Associated with Exposures to HIV........................................................ XI-5
XI-i
XI. POST-EXPOSURE PROPHYLAXIS
Post-exposure prophylaxis (PEP) refers to the use of antiretroviral agents (ARVs) to reduce the risk of
HIV transmission following a potentially infectious exposure to HIV. Typical situations in which PEP
may be indicated include occupational exposures involving healthcare personnel or sexual exposures.
OCCUPATIONAL EXPOSURE TO HIV

RISK OF TRANSMISSION ASSOCIATED WITH AN OCCUPATIONAL EXPOSURE
Potentially infectious exposures of healthcare personnel to the body fluids of HIV-infected patients are
not uncommon; fortunately, however, transmission of HIV from these exposures is rare. Potentially
infectious bodily fluids include blood, spinal fluid, pleural fluid, pus, and amniotic fluid; urine, sweat, and
faeces are not considered infectious unless visibly bloody.
The average risk of transmission associated with a percoetaneous (needlestick) injury involving an HIV-
infected source patient is estimated to be approximately 0.3%. A retrospective case-control study of
healthcare workers who sustained needlestick injuries involving HIV-infected source patients found that
the risk of HIV transmission was significantly increased by the following factors: deep injury, visibly
bloody needle/device, injury involving a device used in a vein or artery, or end-stage AIDS in the source
patient (probably because end-stage AIDS is associated with elevated HIV viral load titres). Other
evidence suggests that hollow-bore needles and lack of glove use by the healthcare worker also likely
increase the risk of HIV transmission.
Table 1: Variables that Likely Increase Risk of HIV Transmission in Occupational Exposures
PERCOETANEOUS INJURY MUCOCOETANEOUS INJURY
(e.g. needlestick) (e.g. splash to eye, mouth, or broken skin)
• Deep injury • Large volume of fluid
• Visibly bloody needle/device • Prolonged contact with fluid
• Needle used in vein or artery • Source patient with end-stage AIDS
• Hollow-bore needle • High serum viral load in source patient
• Source patient with end-stage AIDS
• High serum viral load in source patient
• Healthcare worker not wearing gloves
HIV can also be transmitted in the occupational setting via splashes of infectious material to nonintact
skin or mucous membranes such as the eyes or mouth. The average risk of HIV transmission associated
with a mucocoetaneous exposure is estimated to be approximately 0.09%, or roughly 1 in 1,000. Similar
risk factors likely apply; the risk of transmission may be increased by a high volume of potentially
infectious fluid or a high concentration of HIV in the source patient’s serum.
EFFICACY AND TIMING OF PEP
A retrospective case-control study of PEP found that administration of a four-week course of zidovudine
(AZT) following an occupational needlestick exposure to an HIV-infected source patient reduced the risk
of HIV transmission by approximately 80%. Animal studies suggest that PEP is more effective when
initiated within hours, rather than days, following an exposure. However, the exact interval beyond
which PEP offers no benefit to humans is unclear. Hence, these guidelines recommend that for
XI-1
occupational exposures that warrant PEP, the medications should be initiated as soon as possible (e.g.
within one to two hours). Initiation of PEP more than thirty-six hours after a significant exposure may be
considered, but consultation with an expert HIV clinician is recommended.
RISKS AND BENEFITS OF PEP
Decision-making regarding possible initiation of PEP for a healthcare worker following an occupational
exposure can be difficult. Such a decision is best made by an informed healthcare worker who
understands the potential risks and benefits associated with four weeks of combination antiretroviral
therapy. Hence, extensive counselling of the exposed healthcare worker is recommended. While prompt
initiation of PEP following an exposure may significantly reduce the risk of HIV transmission, adverse
medication effects are common. Studies suggest that most healthcare workers will experience one or
more side effects from PEP such as nausea, headache, fatigue, and gastrointestinal upset. However, these
adverse effects can usually be managed with symptomatic treatment or by modification of the PEP
regimen in order to allow completion of four weeks of therapy, and adverse reactions typically resolve
upon cessation of PEP.
PEP REGIMENS
PEP regimens are typically classified as basic or expanded. Basic regimens consist of two nucleoside
reverse transcriptase inhibitors (NRTIs), typically zidovudine (AZT, Retrovir®) plus lamivudine (3TC,
Epivir®); other combinations of NRTIs can be recommended as alternative regimens. An expanded
regimen consists of a basic regimen plus one or more additional ARV(s) such as nelfinavir (NFV) or
efavirenz (EFV). Expanded regimens offer the possibility of greater potency, but there is no direct
evidence that expanded PEP regimens are more effective in this setting than basic regimens, and
expanded regimens typically involve a higher pill burden and more potential for toxicity.
XI-2
RECOMMENDATIONS FOR MANAGEMENT OF OCCUPATIONAL EXPOSURES TO HIV
Following an occupational exposure to HIV, the exposed area should be immediately decontaminated
(e.g. soap and water to percoetaneous injury sites; saline rinse for eye exposures). The healthcare worker
should be counselled regarding the potential risks and benefits of PEP, and a decision should be made
promptly regarding possible initiation of PEP. Because the efficacy of PEP is thought to wane with time,
emergency departments or urgent care centres are appropriate facilities to manage exposures and
initiation of PEP. Baseline laboratory testing of the healthcare worker, including HIV serology, is also
indicated but should not interfere with the initiation of PEP if warranted. The exposure should also be
promptly reported to the employee’s supervisor.
Decision-making regarding whether to initiate PEP hinges largely upon the severity of the exposure itself
and knowledge of the source patient’s HIV status. For exposures involving source patients known to be
HIV-infected, PEP is generally recommended, consisting of a basic regimen for low-risk exposures and
an expanded regimen for higher-risk exposures. Where the HIV status of the source patient is not known,
it may be reasonable to initiate PEP if the source patient is strongly suspected to have undiagnosed HIV
infection; however, attempts should be made to test the source patient for HIV, and if source patient
testing fails to confirm HIV infection, PEP should be discontinued.
Selection of the components of the PEP regimen itself may also depend in part on exposure and source
patient characteristics. AZT is generally included in PEP regimens because it has demonstrated efficacy
in this setting; however, other agents, such as stavudine (d4T) or tenofovir (TDF) can be substituted if the
AZT causes intolerable side effects. 3TC is generally included as well because this agent is generally safe
and well-tolerated. If an expanded regimen is indicated, nelfinavir (NFV) is a popular choice because it
can be taken twice daily, does not need to be refrigerated, and is generally regarded as safe. EFV can also
be considered in expanded PEP regimens, but not for women who may be pregnant due to its potential for
teratogenicity. NVP should not be included in PEP regimens because unacceptably high rates of
life-threatening toxicity have been reported in healthcare workers taking NVP-containing PEP
regimens.
If antiretroviral drug resistance is suspected in the source patient, the selection of agents for a PEP
regimen may need to reflect this possibility by incorporating at least one or more agents to which the
source patient’s strain of HIV is likely sensitive. Consultation with an expert HIV clinician is highly
recommended if source patient drug resistance is suspected.
Recommendations regarding PEP initiation and regimen selection are summarised in Table 2 and Table 3.
XI-3
Table 2: PEP Management Recommendations: Percoetaneous (Needlestick) Exposures
SOURCE PATIENT FEATURES
EXPOSURE HIV+, High-Risk1 HIV+, Low-Risk2 Serostatus Unknown3
FEATURES
HIGH-RISK Recommend three-drug Recommend two-drug Consider two-drug regimen if
EXPOSURE4 regimen regimen; third drug significant possibility that
optional source patient is HIV+
LOW-RISK Recommend two-drug Recommend two-drug Consider two-drug regimen if
EXPOSURE5 regimen; third drug regimen significant possibility that
Table 3: PEP Management Recommendations: Mucocoetaneous or Nonintact Skin Exposures

SOURCE PATIENT FEATURES
EXPOSURE HIV+, High-Risk* HIV+, Low-Risk† Serostatus Unknown‡
FEATURES
LARGE VOLUME Recommend three- Recommend two-drug Consider two-drug regimen if
(E.G. MAJOR drug regimen regimen; third drug significant possibility that
SPLASH) optional source patient is HIV+
SMALL VOLUME Recommend two-drug Consider two-drug Consider two-drug regimen if
(E.G. FEW DROPS) regimen; third drug regimen significant possibility that
FOLLOW-UP
Following a potential exposure to HIV, serologic testing is indicated to screen for HIV transmission.
Seroconversion typically occurs within a few weeks of infection, but cases of delayed seroconversion
have been documented. HIV antibody screening at six weeks, three months, and six months is suggested.
Use of HIV viral load testing to screen for HIV transmission is not recommended except in circumstances
where acute HIV infection is suspected. Though the risk of HIV transmission is low, an occupational
exposure can be a psychologically traumatic event for the involved healthcare worker; counselling is
often indicated and should be offered. For healthcare workers who initiate PEP, it is reasonable to
perform screening laboratory tests for antiretroviral toxicity two weeks after starting PEP, though the
efficacy of this strategy in preventing serious PEP-related morbidity has not been established.
1High-risk features include known high HIV viral load, CD4+ T cell count of <200 cells/mm3, or advanced
HIV/AIDS.
2
Low-risk features include known low HIV viral load or clinically well on HAART.
3
e.g. known source patient with unknown HIV status, or identity of source patient is unknown.
4
e.g. deep injury or injury involving needle that was used in an artery or vein, was visibly bloody, or was hollow-
bore.
5
None of the high-risk variables apply.
XI-4
PEP FOLLOWING SEXUAL EXPOSURE TO HIV
The risks of HIV transmission associated with many sexual exposures to HIV are comparable to or
exceed those associated with occupational exposures. Furthermore, the risk is probably significantly
elevated if the exposure was traumatic (e.g. sexual assault) or if ulcerative lesions were present on either
the source or the exposed individual. Many HIV specialists therefore endorse the use of PEP in certain
situations following a sexual exposure to HIV. U.S. Centers for Disease Control and Prevention (CDC)
Guidelines have recently endorsed the concept of PEP following nonoccupational exposures to HIV that
carry a significant risk of transmission.6 The levels of risk associated with various occupational and
sexual exposures to HIV are summarised in Table 4.
Table 4: Estimated Average Per-Exposure Risk Associated with Exposures to HIV
EXPOSURE AVERAGE PER-EPISODE RISK
OCCUPATIONAL
Percoetaneous (blood) 0.3%
Mucocoetaneous (blood) 0.09%
SEXUAL
Receptive Anal Intercourse 1% to 2%
Insertive Anal Intercourse 0.06%
Receptive Vaginal Intercourse 0.1% to 0.2%
Insertive Vaginal Intercourse 0.03% to 0.14%
Receptive Oral (male) 0.06%
Female-Female Orogenital 4 case reports
In general, the management of PEP for sexual exposures is extrapolated from the management of
occupational exposures. Regimen selection may consist of a basic, two-drug NRTI combination for low-
risk exposures or an expanded three-drug regimen for higher-risk exposures. Recently released CDC
guidelines endorse the use of expanded three-drug regimens for sexual exposures. It is recommended to
initiate PEP as soon as possible following an exposure; many protocols that have been developed for PEP
following sexual exposures have used seventy-two hours following the exposure as the upper limit
beyond which PEP should not be offered. If initiated, PEP should be continued for twenty-eight days
unless the source patient is subsequently discovered to be HIV-uninfected. While concern has been raised
that offering PEP for sexual exposures may encourage unsafe sexual behaviour, a study in San Francisco,
California, designed to assess this possibility found that risky sexual behaviour decreased, rather than
6Centers for Disease Control and Prevention. Antiretroviral postexposure prophylaxis after sexual, injection-drug
use, or other nonoccupational exposure to HIV in the United States: recommendations from the U.S. Department of
Health and Human Services. MMWR [serial on the Internet] 2005;54(RR02):1-20. Last accessed 2005. Available
at: http://www.cdc.gov/mmwr.
XI-5
increased, in patients who received PEP and behavioural counselling following sexual exposures to HIV.
As it is for occupational PEP, the use of NVP is discouraged, as is the use of EFV in women who are
pregnant or anticipate possible imminent pregnancy.
PEP SCENARIOS AND RECOMMENDATIONS

1. NEEDLESTICK INVOLVING HIV-INFECTED SOURCE PATIENT
A nurse sustains a percoetaneous injury (needlestick) to her thumb while transferring a phlebotomy
needle she just used to draw blood from an HIV-infected patient who is currently hospitalised for
treatment of Pneumocystis jivoreci pneumonia (PCP). The source patient was recently started on
antiretroviral therapy, but his CD4+ T cell count and viral load are not immediately available. What
steps should be taken, and how should the nurse be counselled regarding HIV PEP?
The phlebotomist should immediately wash the injured region with soap and water, and then seek
evaluation for initiation of PEP. An aggressive three-drug PEP regimen is recommended because the
exposure was high-risk (involving a hollow-bore needle used in the source patient’s vein) and the source
patient is also high-risk (advanced HIV disease as evidenced by his PCP); note that either of these high-
risk conditions alone would be sufficient to warrant an expanded PEP regimen. A regimen of AZT plus
3TC plus NFV or lopinavir/ritonavir (LPV/r) would be a reasonable option. These medications should be
initiated as soon as possible, and continued for four weeks. A baseline HIV test and a pregnancy test are
also indicated, but may be performed after initiation of PEP. Counselling and psychological support
should be offered. She should be monitored clinically for adverse effects of the medications; if available,
laboratory monitoring after two weeks of therapy may also be helpful but is not mandatory. An
antidiarrhoeal agent may be recommended to counteract this common side effect of the protease inhibitor
(PI) in her regimen. Changes to her PEP regimen may be made for intolerable side effects (e.g.
substitution of d4T for AZT). She should be tested for HIV infection by standard serology (ELISA with
confirmatory Western blot if the ELISA is positive) periodically, e.g. at six weeks, three months, and six
months following the exposure. She should not be tested for HIV using the viral load assay unless she
develops signs and symptoms suggestive of primary (acute) HIV infection.
2. EXPOSURE INVOLVING A SOURCE PATIENT WHOSE HIV STATUS IS NOT KNOWN

A dentist is splashed in the eye with bloody saliva from a patient whose HIV status is not known, but
is from a region where the HIV prevalence is high. What steps should be taken, and is PEP
recommended for the dentist?
The dentist should rinse his/her eye immediately and thoroughly with a sterile rinse. A decision should
be made promptly about possible administration of PEP. Prompt initiation of a two-drug PEP regimen
(e.g. AZT plus 3TC) would be reasonable given that the prevalence of HIV in the local population is high,
but it would also be reasonable for the dentist to decline PEP given that the risk of HIV transmission in
this situation is low and PEP is often associated with adverse effects. The decision regarding possible
initiation of PEP should not be deferred until HIV testing of the source patient can be performed, because
PEP is most effective when initiated promptly. However, if rapid HIV testing is available, and the source
patient consents to immediate testing, initiation versus deferral of PEP can be based on the results of this
rapid test.
Testing of the source patient should be attempted even if rapid HIV testing is not available. If the source
patient tests negative for HIV infection, PEP for the dentist should be stopped. If PEP has been initiated
and the source patient tests positive for HIV, or refuses to be tested, PEP should be continued for four
weeks. Counselling and psychological support should be offered to the dentist, and baseline and follow-
up HIV serology testing should be performed, e.g. at six weeks, three months, and six months following
XI-6
the exposure. If testing of the source patient reveals previously undiagnosed HIV infection, the source
patient should be offered counselling and referred to an HIV/AIDS treatment centre for further
management.
The dentist should also be tested for HIV at baseline as soon as possible, though this testing does not need
to be performed before PEP is initiated.
3. EXPOSED HEALTHCARE WORKER WITH A POSITIVE BASELINE HIV TEST

A nursing assistant sustains a needlestick injury while disposing of a phlebotomy needle; it is not
clear who the source patient is. After counselling, she elects to receive PEP, and a two-drug regimen
is initiated. Three days later, her baseline HIV serology test reveals previously undiagnosed HIV
infection. How should she be managed?
PEP should be discontinued. She should be offered counselling and promptly referred to an HIV/AIDS
treatment centre for further management.
4. EXPOSURE INVOLVING SEXUAL ASSAULT

A woman reports being sexually assaulted (vaginal penetration) approximately twenty-four hours
previously by a male acquaintance that is HIV-infected. Physical examination reveals perineal
bruising and a shallow vaginal laceration. What recommendations should be made regarding HIV
PEP?
This sexual assault, involving traumatic vaginal penetration by an HIV-infected source, involves a risk of
HIV transmission comparable to (and perhaps higher than) that of a needlestick exposure. Hence, many
expert HIV clinicians as well as recently published CDC guidelines7 would endorse initiation of an
expanded PEP regimen in this scenario. As with an occupational exposure, the exposed patient should be
offered counselling and psychological support as well as baseline and follow-up HIV testing. Other
concerns such as the potential for pregnancy, prophylaxis against other sexually transmitted infections
(STIs), and collection of evidence for possible legal action should also be addressed. If she initiates PEP,
monitoring for antiretroviral toxicity should be performed.
7Ibid.
XI-7

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Caribbean Guidelines for

the Care and Treatment of

14/03/2005 02:37 PM iii

14/03/2005 02:37 PM vii

14/03/2005 02:37 PM viii

Dr. James C. Hospedales

Ms. Yolanda Y. Simon

THE NEEDS-BASED APPROACH TO PERSONS WITH HIV INFECTION .................................................... I-1

APPENDIX A: SAMPLE PATIENT ADHERENCE RISK ASSESSMENT QUESTIONNAIRE .............................. I-13

THE NEEDS-BASED APPROACH TO PERSONS WITH HIV INFECTION

Table 2: Counselling& Needs of PLWHA†

Table 3: Counselling& Needs of Family and Friends of PLWHA∞

Table 4: Self-Care Needs of PLWHA*

Table 5: Social Support Needs of PLWHA†

MANAGING ADHERENCE EFFECTIVELY

OBJECTIVE: To ensure continued patient adherence to the HAART regimen.

CLINICAL CONSULTATION RESOURCES FOR THE CARIBBEAN

If Yes: □ Part-Time □ Full-Time

10. To be completed by a physician:

If Yes, please specify:_____________________________

Strongly Agree DK Disagree Strongly

HIV/AIDS IN THE CARIBBEAN REGION

HIV/AIDS IN CAREC MEMBER COUNTRIES

CAREC CASE DEFINITION FOR HIV INFECTION

CAREC CASE DEFINITION FOR AIDS

CAREC CLASSIFICATION OF HIV INFECTION IN ADOLESCENTS AND ADULTS

CDC HIV/AIDS CLASSIFICATION SCHEME

Table 11: Diagnostic Methods for Indicator Diseases of AIDS

CLINICAL STAGE III

APPENDIX A: IMAGES OF COMMON MANIFESTATIONS OF HIV INFECTION ........................................... II-13

Mycostatin Ointment or Cream: Contains nystatin 100,000 units/g.

Mycelex® Troche: Contains clotrimazole. Tablets

Herpes Zoster Prodrome of pain, Clinical As above.

HIV AND SICKLE CELL DISEASE ........................................................................................................... III-1

HIV AND DENGUE FEVER

HIV AND MALARIA

HIV AND HTLV-I

APPENDIX A: CHARACTERISTICS OF ARVS ...................................................................................................... IV-24

OVERVIEW OF ANTIRETROVIRAL THERAPY (ART)

© 2004 University of Washington

CLASSES AND CHARACTERISTICS OF ARVs

© 2004 University of Washington

PRINCIPLES OF HAART: INITIAL THERAPY

IF CD4+ T CELL COUNT TESTING IS UNAVAILABLE

SELECTION OF INDIVIDUAL AGENTS IN THE HAART REGIMEN

TREATMENT FAILURE AND TREATMENT TOXICITY

© 2004 University of Washington

© 2004 University of Washington

• NVP-related severe rash (but not • Switch NVP Æ EFV‡

• NVP-related severe rash (but not • Switch NVP Æ EFV‡

AZT/3TC/EFV • AZT-related persistent GI • Switch AZT Æ d4T

SECOND-LINE AND SALVAGE ANTIRETROVIRAL THERAPY

HAART CONSIDERATIONS FOR PATIENTS WITH CO-MORBID DISEASES

METABOLIC COMPLICATIONS OF HAART AND HIV INFECTION

LPV, 400mg capsules or respectively room hypertri-

Table 15: Interactions between PIs

Glucose BL; q6-12m Recommended Insulin resistance associated with EFV

Glucose BL; q6-12m Recommended Insulin resistance associated with EFV

RESISTANCE TO NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NSRTIS) AND

Table 19: Major Mutations Associated with Reduced Susceptibility to NNRTIs

SEQUENCE OF THE REVERSE TRANSCRIPTASE GENE

SQV I V V A/F/S/T A/V M

NFV I I I/L V/L/M/T I A/F/S/T A/V