Panel 4: A New Era in HIV Prevention Research HIV Vaccines

James Kublin, MD, MPH Executive Director, HVTN

Journalist-2-Journalist Program Bangkok, Thailand September 11th, 2011

The HVTN is supported by National Institute of Allergy and Infectious Diseases (NIAID).

Potential Impact of a Vaccine

New Adult Infections in Low- and MiddleIncome Countries by Year and Vaccine Scenario

Even a vaccine with low efficacy and limited coverage can impact the epidemic and play a role in preventing future infections
Stover J, et al. The impact of an AIDS Vaccine in Developing Countries: A New Model and Initial Results. Health Affairs 26(4):1147-1158 (2007)

Results from HIV prevention trials

Study
HIV Vaccine
(Thai RV144)

Length of Study
3.5 y

Effect size 12 mo (CI) effect

31% (1, 51) 39% (6, 60)
44% (15, 63) 57% (42, 68) 50 (28,66) 60* (22,80) 50 (15,72)

1% TDF gel
(Caprisa, Karim et al.)

2.5 y
1.2 y

TDF/FTC PrEP
(iPrEx, Grant et al 2010)

Circumcision
(Orange Farm, Rakai, Kisumu)
0% 10 20 30 40 50 60 70 80 90 100%

Efficacy

*Not a part of the pre-specified analysis

Slide: Glenda Gray, HVTN Conference, Nov 2010; modified by Jerome Kim, 2010 Siegfried N et al. Male circumcision preventing heterosexual acquisition of HIV in men. Int J Epidemiol 2010; 39: 968-972

HVTN 505

Phase 2, Randomized, Placebo-Controlled Trial to Evaluate the Safety and Effect on Post-HIV Acquisition Viremia of a Multiclade HIV-1 DNA Plasmid Vaccine Followed by a Multiclade HIV-1 Recombinant Adenoviral Vector Vaccine in HIV-Uninfected, Adenovirus Type 5 Neutralizing Antibody Negative, Circumcised Men and Male-to-Female Transgender Persons, Who Have Sex with Men
(Version 2.0 December 21, 2009)

VRC Candidate HIV Vaccine

Months 0 1 2 3 6 9 12

CMV-R promoter Env A Env B Env C gag B pol B nef B

rAd5
Env A Env B Env C gag/pol B

HVTN 505: Primary Viral Load Endpoint

Post-infection diagnosis visit schedule
Weeks 0 2 4 6 8 10 12 14 16 20 24

Infection Dx

Primary endpoint

Definition of VL setpoint

Average of all values at week 10 through week 20 post-infection diagnosis study visit VL values prior to ART initiation 20% is an upper bound for censored VL endpoints

FPI to FPI

Who ever crawled across cut glass to make a deal

Previous modifications to HVTN 505

Version 2.0 incorporated
Protocol title change to MTF transgender persons Step results updated (added section 4.1.2.5) Revised I/E criteria
Upper age limit raised to 50 Autoimmune disease exclusion clarified

Revisions per Version 2.0 of DAIDS EAE Manual Updated references to DAIDS AE grading table SICF sections 5-8 reordered and rewritten

Impact of RV144 on HVTN 505

In late 2009, results of the HIV vaccine study RV144 were published, showing a modest reduction in HIV infections among people who received the protocols study vaccines.1
Some of the immune responses to the vaccines in the Thai study were similar to immune responses seen in prior human studies of the HVTN 505 vaccines.2 New results of non-human primate challenge studies also demonstrated a reduction in HIV acquisition among monkeys that received SIV (simian immunodeficiency virus) versions of the HVTN 505 vaccines.3

Based upon results from these human and NHP HIV vaccine studies, HVTN 505 has added a third primary objective:

Assessing whether the 505 vaccines might protect against HIV infection. Study size was increased from 1350 to 2200 participants in 2011.

1. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med. 2009;361:2209-2220. 2. Koup RA. Antibody responses to the VRC vaccine: Implications for HVTN 505. HVTN Full Group Meeting, Washington, DC, May 5, 2010. 3. Letvin NL, Rao SS, Montefiori DC, et al. Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys. Sci Transl Med. 2011;3:81ra36.

HVTN 505 in Evolving Prevention Landscape

Recent advances in drugs for prevention
iPrEx: Pre-exposure prophylaxis in MSM FEM-PrEP: Pre-exposure prophylaxis in women (Truvada) HPTN 052: Treatment of discordant HIV+ partner

Microbicides
CAPRISA 004: topical PrEP (Tenofovir gel)

HVTN 505: Opportunity to adapt and incorporate results as other non-vaccine and vaccine prevention studies emerge

Impact of PrEP on HVTN 505

Immediately following the release of iPrEX results communication with participants
Ensure awareness and educate Web-based questionnaire to assess significance of results, intent to use/access PrEP, attitude towards participation in 505

Series of consultations with CABs, advocacy members, key opinion leaders

What do the results mean to the field and to HVTN 505

Team discussions with DAIDS, VRC, Core, SCHARP and sites

Reach a decision about implications of PrEP for HVTN 505

HVTN 505: Feedback from Consultations and Survey Following iPrEx

Many 505 participants considered iPrEx results very important either to them personally or to their community
31% of responders would consider taking PrEP in the next year Minority indicated that taking PrEP would affect willingness to remain on study

Community representatives, CAB and key opinion leaders

Excitement about the science Many questions about relevance and applicability to the diverse communities of US-based MSM and transgender women

505: Rationale for Monitoring Prophylactic ART Use

Unknown extent of PrEP uptake in MSM and transgender women communities in US
Depend on access to drug, cost, perceived side effects

Knowledge and attitudes towards use of ARTs for prophylaxis are evolving
Distinction between pre- and post-exposure prophylaxis may become less clear
Emerging data about optimal timing and frequency of dosing around exposure

HVTN 505: Rationale for Behavioral and Biological Monitoring of Prophylactic ART
ART used as prophylaxis may influence
HIV incidence Post-infection disease course Study participation, risk behavior over time, and perception of risk

Important opportunity to ask a number of questions and monitor prophylactic ART use in 505
Lessons can be applied broadly to vaccine field and prevention field

HVTN 505 v3: Modifications

Increased sample size to enable evaluation of HIV-1 acquisition Modified inclusion and exclusion criteria anticipating increased use of prophylactic ART Opportunity to evaluate self reported use in correlation with objective measures of drug levels Opportunity for further education and risk reduction counseling of participants

505: Proposed Assessment of Prophylactic ART Use

Behavioral monitoring: Self report
ACASI questionnaire administered very 3 months Describe patterns of use over 3 months with greater precision over past 2 weeks

505: Proposed Assessment of Prophylactic ART Use

Biological monitoring: Plasma drug levels
Samples collected and stored every 3 month

Analysis of samples
Chosen retrospectively to capture levels on HIV negative individuals reporting ART use Random sampling of HIV negative individuals who do not report prophylactic ART At HIV diagnosis visit and visit with earliest evidence of infection

HVTN 505: Proposed assessment of prophylactic ART use contd

Participant counseling and education
At every visit assessment of PEP/PrEP use and risk reduction counseling
Inform and educate participants about results of other HIV prevention studies Risk reduction counseling as appropriate for the participant Referrals to services as appropriate

HVTN 505 Protocol Team

Chair: Scott Hammer Co-Chairs: Magdalena Sobieszczyk & Michael Yin Protocol Team Leader: Shelly Karuna Biostatisticians: Peter Gilbert & Doug Grove & Holly Janes DAIDS Medical Officers: Adam Sherwat VRC Developer Representatives: Barney Graham & Mary Enama VRC Immunologist: Richard Koup HVTN Laboratory Program: John Hural Clinical Trials Manager: Tamra Madenwald Protocol Development Coordinator: Carter Bentley SDMC Senior Project Manager: Drienna Holman SDMC Project Manager: Marianne Hansen SDMC Clinical Affairs: Hsiu-Ying Huang & Pat Farrell DAIDS Pharmacist: Ana Martinez DAIDS Regulatory Affairs: Michelle Conan-Cibotti HVTN Regulatory Representative: Renee Holt HVTN Pharmacist: Jan Johannessen Community Ed Unit Representative: Gail Broder Communications: Sarah Alexander Community Engagement: Steve Wakefield & Niles Eaton Community Educators/Recruiters: Gavin Morrow-Hall & Coco Alinsug CAB Members: Rick Church & Rich Trevino Clinic Coordinator: Steven Chang HVTN Investigators: Susan Buchbinder, Mike Keefer, Beryl Koblin, & Mark Mulligan Technical Editor: Anya Luke-Killam

HVTN MTN Collaboration (synergy!)

Evaluate vaccine with and without oral FTC/TDF or topical TDF 1% gel
Study arm Group 1a (Vaccine + Oral PrEP) Number 40 Study productsa Vaccine Oral FTC/TDF Month -1 (Day -28 on)b Daily Daily Daily Daily Daily Daily Daily Daily Daily Daily Daily Daily Month 0 (Day 0) DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily Month 1 (Day 28) DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily Month 2 (Day 56) DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily DNA-C Daily Daily placebo Daily Daily Month 5 (Day 140) NYVAC-C Daily Daily placebo Daily Daily NYVAC-C Daily Daily placebo Daily Daily NYVAC-C Daily Daily placebo Daily Daily

Group 1b (Vaccine Placebo + Oral PrEP)

Group 2a (Vaccine + Topical PrEP) Group 2b (Vaccine Placebo + Topical PrEP) Group 3a (Vaccine only) Group 3b (All placebos)

Vaginal TDF Gel placebo Vaccine placebo Oral FTC/TDF

Vaginal TDF Gel placebo Vaccine Oral FTC/TDF placebo Vaginal TDF Gel Vaccine placebo Oral FTC/TDF placebo Vaginal TDF Gel Vaccine Oral FTC/TDF placebo Vaginal TDF Gel placebo Vaccine placebo Oral FTC/TDF placebo Vaginal TDF Gel placebo

40

40

8 144 (120:24)

Total

Social Science

Social research is the systematic observation of social life for the purpose of finding and understanding patterns among what is observed
(Earl Babbie, sociologist)

What is measured is as important as how it is measured.

Potential Priorities for Sociobehavioral Research

Better engagement of communities in the conduct of our trials Effective informed consent process to achieve what we want it to Addressing racial and ethnic health disparities in our work Assessing impact of our trials on participants and communities Effective risk reduction counseling

HVTN.org/Science/HVTNews
Informs readers about the science of the HVTN, the management of the Networks many multilateral collaborations, and our outstanding clinical sites. Current issue includes articles on Epitope Mapping, Adaptive Trial Design, and Exploring Barriers and Facilitators in the Recruitment of Transgender Women.

Acknowledgements
Magda Sobieszczyk 505 Protocol Team HVTN 505 Sites, Staff and Participants HVTN Community Education & Communications Team HVTN 505 PrEP Monitoring Working Groups
PK substudy Working Group
John Hural, Peter Gilbert, Carter Bently, Shelly Karuna, Magda Sobieszczyk, Scott Hammer, Adam Sherwat, Angela Kashuba, Jim Rooney, HVTN Lab Jonathan Fuchs, Beryl Koblin. Ken Mayer, Susan Buchbinder, Al Liu, Michele Andrasik

Behavioral substudy Working Group