AD_029___NOV14_08 Page 1 6/11/08 5:58 PM

How to treat
Pull-out section w w w. a u s t r a l i a n d o c t o r. c o m . a u
Complete How to Treat quizzes online (www.australiandoctor.com.au/cpd) to earn CPD or PDP points.

inside
Natural history of
infection

Diagnosis and
investigation

Referral and
monitoring

Therapy options

The author

DR GORDON JUNG-HYUK PARK,

visiting gastroenterologist and
hepatologist, Royal North Shore
Hospital, St Leonards, and
Concord Hospital, Concord,
New South Wales.

Hepatitis B infection
Background and epidemiology
HEPATITIS B virus (HBV) infection remains
a leading cause of morbidity and mortality
throughout the world. About one-third of the
global population (2 billion) have been
acutely infected with HBV and, of these, an
estimated 400 million have chronic HBV
infection (figure 1).
disproportionately represented, comprising Figure 1: Geographical distribution of chronic HBV infection.
16% of the HBV burden in Australia. Source: US Centers for Disease Control and Prevention.
Although HBV vaccination is on the immu-
nisation schedule, the number of Australians
with HBV is predicted to increase over the
next 5 to 10 years because of:
■ Continued immigration from areas where

In Australia, 90,000 to 160,000 people HBV is endemic.

(0.5-0.8% of the population) are estimated ■ Ongoing transmission among people who

to be chronically infected (figure 2, see page inject drugs and people with high-risk sexual
30). Most people in Australia with HBV were behaviour.
HBsAg prevalence:
born overseas, predominantly in countries of ■ Infection of partners of people with HBV
* 8% - high
high HBV endemicity (about 50% from Asia). infection. 2-7% - intermediate
< 2% - low
In addition, Indigenous Australians are also cont’d next page

1 2 3
Australian Doctor Education presents Internal Mental Dermatology

3
one-day Medicine Health September 2009
March 2009 June 2009
seminars
in 2009
Register this year to Authoritative, independent and relevant education for GPs

receive a 25% discount Register online: www.australiandoctor.com.au/seminars or call 1300 360 126

www.australiandoctor.com.au 14 November 2008 | Australian Doctor | 29

AD_ 0 3 0 _ _ _ NOV 1 4 _ 0 8 . P DF Pa ge 1 1 1 / 6 / 0 8 , 5 : 3 8 PM

How to treat – hepatitis B infection

from previous page
■ Suboptimal prevention pro-
grams among Indigenous Aus-
tralians.
HBV is transmitted by perina-
tal, percutaneous and sexual expo-
sure, as well as by close person-
to-person contact presumably by
open cuts and sores, especially
among children in hyperendemic
areas. The infectious risk of HBV
is 100 times greater than that of
HIV and 10 times greater than
that of hepatitis C virus (HCV).
Immigrants from countries
with high endemicity for HBV
generally present with chronic
infection (incidental detection or
symptomatic flare of chronic
infection). Acquisition by verti-
cal transmission (perinatally
from mother to child) is the most
common source of infection in
this group. Early horizontal
transmission (child to child) or
breastfeeding may also be the
source of infection.
People from non-endemic
Figure 2: Burden of chronic HBV infection in Australia (90,000-160,000 course (especially men having sex Table 1: Who should be screened for
infected). with men) or household contact HBV?
(toothbrush, razor). Table 1
describes patient groups who ■ People born in hyperendemic areas:
Indigenous South-East
should be screened for HBV South-East Asia, China, Korea, Middle
Australians 16% Asian 33%
infection. East, Mediterranean and Eastern Europe,
People with chronic HBV Africa, Pacific Islands, South America
infection, defined as those posi- ■ Household and sexual contacts of HBV-
tive for hepatitis B surface anti- infected persons
gen (HBsAg) for more than six
■ Pregnant women
months, are at increased risk of
developing cirrhosis, liver failure ■ Injecting drug users
and hepatocellular carcinoma. ■ Dialysis patients
Indeed, HBV can be regarded as ■ People with multiple sexual partners
the most common carcinogen
■ Men who have sex with men
after tobacco in humans.
North-East Although most carriers of ■ Inmates of correctional facilities
Other 22% Asian 16% HBV will not develop hepatic ■ HCV- or HIV-infected persons
complications from their infec- ■ Individuals with chronically elevated liver
tion, 15-40% will develop sig- function tests
Injecting drug nificant sequelae during their life-
Homosexual men 8%
users 5% time. The increasing burden of
HBV in Australia and the advent
areas are more likely to present of more efficacious antiviral
with acute HBV infection. Trans- agents pose both challenge and
mission in these patients is via promise in the increasingly com-
sharing injecting equipment, plex therapeutic landscape of
needlestick injury, sexual inter- HBV infection.

Natural history of infection

THE natural history of HBV
infection is related to the
immune response to the
virus, determined in large
part by the age of acquisi-
tion of HBV infection.
Infection at birth or in the
first six months of life leads
to chronic HBV infection in
90% of cases, whereas
acute infection in adult-
hood resolves within six
months in >90% of cases.
Infection acquired in early
childhood (from six months
to five years) results in
chronic infection in 30% of
cases.
Perinatal infection is almost
always asymptomatic. Symp-
tomatic infection, which
occurs in 35% of acute infec-
tions in children older than
five years, may be charac-
terised by fever, jaundice,
The five-year rate Immune escape (HBeAg-
Figure 3: Phases of chronic HBV infection.
negative disease)
of progression Further viraemia and hepati-
from chronic tis may follow, reflecting the
hepatitis to HBV DNA emergence or escape of
HBeAg-negative (precore or
cirrhosis is core promoter mutant)
15-20%. strains of the virus from
immune control. ALT and
HBV DNA levels once again
become elevated. Continuing
hepatitis in this phase may
ALT lead to cirrhosis.
Spontaneous HBeAg sero-
conversion occurs in about
10% of patients a year
HBeAg whereas loss of HBsAg is
less frequent at about 1%
Anti-HBe per year. The five-year rate
of progression from chronic
hepatitis to cirrhosis is 15-
Immune Immune Immune Immune 20%. Predictors of progres-
sion to cirrhosis include:
tolerance clearance control escape ■ High HBV viral load.

anorexia, nausea, vomiting, ■ Recurrent exacerbations.

abdominal pain, myalgia, ■ Older age (longer duration

arthralgia and rash. Up to 1% of infection).

of acute HBV infections in Figure 4: Natural history of HBV infection. ■ Habitual alcohol con-

adults are complicated by ful- sumption.

minant hepatic failure. 10-70% 90% ■ Concurrent infection with
Recovery Perinatal/childhood Adult acute Recovery HCV.
Phases of the immune acute infection infection ■ Infection with hepatitis

response delta virus (HDV) or HIV.

It is useful to categorise
patients by the phase of their
immune response to HBV
infection (figure 3).
Immune tolerance phase
After perinatal transmission
there are high levels of virae-
mia, associated with positiv-
ity for hepatitis B e antigen
(HBeAg) without biochemical
or histological evidence of
hepatitis. This immune toler-
ance phase generally lasts for
the first 2-3 decades of life.
Immune clearance phase
At age 20-30 the immune
system attempts to clear the
virus, leading to fluctuating
HBV DNA and elevated ala-
nine aminotransferase (ALT)
levels. This process leads to
collateral inflammatory nec-
rosis of hepatocytes and, if
prolonged, may result in cir-
rhosis.
Immune clearance eventu-
ally results in HBeAg serocon-
version, when HBeAg is lost
and antibodies to HBeAg
(anti-HBe) develop. After
Decompensation
*Risk of chronic infection is 90% perinatally and 30% in early childhood.
HBeAg seroconversion,
hepatic inflammation subsides
and is accompanied by histo-
logical change from active
hepatitis to normal histology
or minimal hepatitis, or from
active to inactive cirrhosis.
30-90%* <10%
Chronic hepatitis
Cirrhosis
Death/transplantation
Immune control phase
(inactive carrier)
If the immune clearance
phase is successful, the patient
enters a non-replicative phase
of infection where HBV DNA
becomes undetectable or
Inactive carrier
state
Hepatoma
extremely low and ALT level
returns to normal. The
patient’s body fluids should
still be considered infectious
although to a lesser degree
than those of HBeAg-positive
patients.
■ HBV genotype C.
The five-year rate of pro-
gression from cirrhosis to
hepatocellular carcinoma is
10%. Although cirrhosis is
a strong risk factor for hepa-
tocellular carcinoma, about
40% of hepatocellular car-
cinoma associated with
chronic HBV infection
occurs in the absence of cir-
rhosis.
Recently, several prospec-
tive follow-up studies of large
cohorts of HBV carriers from
Asia have found that the pres-
ence of HBeAg and high
levels of HBV DNA are inde-
pendent risk factors for the
subsequent development of
cirrhosis and hepatocellular
carcinoma. Figure 4 sum-
marises the natural history of
HBV infection.
cont’d page 32

30 | Australian Doctor | 14 November 2008 www.australiandoctor.com.au

AD_032___NOV14_08 Page 3 6/11/08 5:23 PM
How to treat – hepatitis B infection
Diagnosis and investigation
Serological markers for
HBV
HBsAg
HBsAg appears in serum 2-10
weeks after exposure to
HBV and before the onset of
symptoms or elevation in
ALT. In self-limited acute
infection, HBsAg usually
becomes undetectable after
4-6months. Persistence of
HBsAg for more than six
months implies progression
to chronic HBV infection.
The disappearance of
HBsAg is followed several
weeks later by the appear-
ance of antibodies to HBsAg
(anti-HBs). In most patients
anti-HBs persists for life and
provides long-term immu-
nity. In some patients anti-
HBs may not become
detectable after disappear-
ance of HBsAg, but these
patients do not appear sus-
ceptible to recurrent infec-
tion.
Anti-HBs may be unde-
tectable during a window
period of several weeks to
months after loss of HBsAg.
During this period, acute
HBV infection is diagnosed
by detecting IgM antibodies
to hepatitis B core antigen
(anti-HBc) in serum.
Coexistence of HBsAg and
anti-HBs has been reported
in about 25% of HBsAg-
positive persons. In most
instances the anti-HBs is pre-
sent in a low level and
directed against a subtype of
HBsAg which is different
from the subtype present in
the infected patient.
Anti-HBc
Anti-HBc is detectable in
acute and chronic HBV
infection. During acute infec-
tion, anti-HBc is predomi-
nantly IgM and is usually
detectable for 4-6 months
after an acute episode of
hepatitis and rarely for up to
two years. IgM anti-HBc
may also become detectable
during exacerbations of
chronic HBV infection.
Anti-HBc (IgG) persists in
persons who recover from
acute hepatitis B infection
and also in association with
HBsAg in those who
progress to chronic infection.
In areas where HBV is not
endemic, isolated anti-HBc
in serum has been detected
in 1-4% of the general pop-
ulation. The finding of iso-
lated anti-HBc can occur in
the following situations:
■ During the window period
of acute HBV infection
(IgM anti-HBc).
■ Many years after recovery
from acute infection, when
anti-HBs has fallen to
undetectable levels.
■ False-positive serology test
result.
■ After many years of
chronic infection, when
HBsAg concentration has
fallen to undetectable levels.
■ In those co-infected with
HCV or HIV.
32 | Australian Doctor | 14 November 2008
Figure 5: Time course of serological markers in HBV infection A: Acute HBV infection with clearance. B: Progression to chronic HBV infection.
A B Acute Chronic
Symptoms (6 months) (Years)
HBeAg anti-HBe
HBeAg anti-HBe
HBsAg
Total anti-HBc Total anti-HBc
Titre
Titre
IgM anti-HBc anti-HBs
HBsAg
IgM anti-HBc
0 4 8 12 16 20 24 28 32 36 52 100 0 4 8 12 16 20 24 28 32 36 52 Years
Weeks after exposure
Weeks after exposure
the selection of precore or dent on HBV for replication.
Table 2: Serological markers for HBV infection
core promoter mutations that HDV infection can occur in
Name Abbreviation Definition/comment impair HBeAg secretion two forms. The first form is
Hepatitis B surface antigen HBsAg Antigen indicating infection (HBeAg-negative chronic caused by the co-infection of
HBV infection). HBV and HDV. This com-
Hepatitis B e antigen HBeAg Antigen correlating with HBV replication and
monly results in a more severe
infectivity
HBV DNA acute hepatitis with a higher
Hepatitis B surface antibody Anti-HBs Indicates immunity HBV DNA can be measured mortality rate than is seen with
Hepatitis B e antibody Anti-HBe Presence generally indicates a low titre of in serum to evaluate a patient’s acute HBV infection alone, but
HBV, except in HBeAg-negative disease candidacy for antiviral therapy rarely leads to chronic infec-
when DNA is elevated and to monitor response tion.
Hepatitis B core antibody Anti-HBc Indicates previous or ongoing infection with HBV during treatment. The sensi- A second form involves a
tivity of recent assays has superinfection of HDV in an
improved considerably. Cur- HBV carrier, which can mani-
rent PCR-based assays for fest as a severe ‘acute’ hepatitis
Table 3: Interpreting HBV serology HBV DNA can detect down in a previously asymptomatic
Antigen/antibody Test result Meaning to 100 viral copies/mL HBV carrier or as an exacer-
(approximately 20 IU/mL). bation of underlying chronic
HBsAg —
Measurement of HBV DNA HBV infection.
Anti-HBc — Susceptible is now reimbursed by In contrast to co-infection,
Anti-HBs — Medicare (as of 1 July 2008): HDV superinfection in HBV
HBsAg — one measurement a year is carriers almost always results
allowed for pre-treatment in chronic infection with both
Anti-HBc + Resolved HBV infection
screening or for monitoring viruses. Such chronic co-infec-
Anti-HBs + patients with chronic HBV tion is associated with
HBsAg — infection not on antiviral ther- increased rates of cirrhosis,
Anti-HBc — Vaccinated apy, while four assays per year hepatic decompensation and
are allowed for those receiv- hepatocellular carcinoma,
Anti-HBs +
ing antiviral treatment. compared with chronic HBV
HBsAg + The availability of PCR- infection alone.
Anti-HBc + Acute HBV infection based HBV DNA assays has Consider screening for
IgM anti-HBc + altered traditional concepts HDV with anti-HDV and
about the clearance of HBV HDV RNA in persons from
Anti-HBs — DNA after acute and chronic the Mediterranean or South
HBsAg + infection. Small amounts of America or in patients with
Anti-HBc + Chronic HBV infection (HBsAg HBV DNA can be detected in quiescent chronic HBV infec-
IgM anti-HBc — present for more than six months) serum and peripheral tion who experience a severe
Anti-HBs —
mononuclear cells years after flare or deterioration.
recovery from acute HBV.
Even after HBsAg seroconver- Screening for
sion in patients with chronic hepatocellular carcinoma
Table 4: Categorising chronic HBV infection HBV infection, up to 50% Screen for hepatocellular car-
Feature HBeAg-positive CHB HBeAg-negative CHB may have detectable HBV cinoma and portal hyperten-
DNA (1-2 log10 copies/mL). sion with upper-abdominal
Serology HBeAg +, anti-HBe – HBeAg –, anti-HBe +
The time course of the vari- ultrasound and measure serum
HBV DNA High Low to moderate ous serological markers of alpha-fetoprotein (AFP) level.
ALT High or fluctuating Normal or elevated acute and chronic HBV infec- Estimate liver disease
Liver histology Active inflammation Inflammation and often tion is illustrated in figure 5. severity by assessing:
significant fibrosis The significance of the indi- ■ Bilirubin, albumin, INR (or
vidual markers is summarised prothrombin time) as mea-
Age at presentation 20-35 years 35-50 years in table 2. Table 3 provides an sures of liver excretory and
Treatment endpoint HBeAg seroconversion Indefinite or HBsAg interpretation of the various synthetic function.
seroconversion serological profiles. ■ AST/ALT ratio (*1 suggests
cirrhosis).
CHB = chronic HBV infection
Initial screening ■ Platelet count (thrombocy-
HBeAg HBsAg carrier indicates Initial screening should com- topenia may indicate portal
HBeAg is a soluble viral pro- greater infectivity and a high prise HBsAg, anti-HBs and hypertension due to cir-
tein found in serum early level of viral replication. In anti-HBc. If HBsAg is rhosis).
during acute HBV infection. general, seroconversion from detected, determine HBeAg/
HBeAg reactivity usually dis- HBeAg to anti-HBe is associ- anti-HBe and quantify HBV Categorising chronic HBV
appears at, or soon after, the ated with significant reduction DNA. After a diagnosis of infection
peak in ALT level, and persis- in HBV DNA levels and HBV has been established, Categorise chronic HBV
tence beyond three months remission of liver disease. exclude viral co-infection by infection into HBeAg-posi-
after the onset of illness indi- However, some patients testing antibodies to HCV and tive or HBeAg-negative dis-
cates a high likelihood of tran- continue to have active liver HIV in those at risk. ease (table 4). The differ-
sition to chronic HBV infec- disease and detectable HBV ences relate to the immune
tion. DNA due to low levels of HDV stage of chronic infection
HBeAg-positivity in an wild-type (original) virus or HDV is a satellite virus depen- and have prognostic and
www.australiandoctor.com.au
AD_033___NOV14_08 Page 4 6/11/08 5:25 PM

therapeutic implications. A slower rate of cirrhosis of liver damage and to lines for treatment, such as
When to
■

Akin to HCV, HBV can progression. exclude other causes of liver those over 40 with ALT
also be categorised into eight ■ Reduced rate of hepatocel- disease. Unless there are con- values close to, or only just
genotypes (A-H), which dis- lular carcinoma development. traindications to liver above, the upper limit of refer, when
play geographical variation. Studies with pegylated inter- biopsy, such as coagulopa- normal.
Recent data suggest that HBV
genotype may impact on dis-
feron therapy have revealed
that genotypes A and B
thy, liver biopsy is a crite-
rion for subsidised therapy
Such individuals may have
abnormal hepatic histology
to monitor
ease progression as well as on respond better than genotypes in HBV infection under the and be at increased risk of
response to interferon therapy. C and D. Despite these early PBS. liver-related morbidity and THERE are no established
Studies from Asia have found studies, genotypic testing is Although the procedure is mortality. The results of a guidelines about when
that, compared with genotype not readily available and its associated with risks (one in liver biopsy may sway a deci- patients with HBV infection
C, HBV genotype B is associ- clinical value has yet to be 300 risk of haemorrhage, sion to treat such patients. should be referred to spe-
ated with: established. one in 10,000 risk of death) Recent data suggest that the cialist care. The decision to
■ Earlier and more durable and sampling error, liver upper limits of normal for refer should consider patient
HBeAg seroconversion. Liver biopsy biopsy is particularly useful ALT and AST should be profile (age, gender, dura-
■ Reduced liver necro-inflam- The purpose of a liver in HBV-infected people who decreased to 30 U/L for men tion of infection, comor-
mation. biopsy is to assess the degree do not meet clear-cut guide- and 19 U/L for women. bidities), the phase of
infection and risk of
hepatocellular carcinoma.

HBV therapy options The following situations

require referral:
■ Patients in the immune

THE approach to HBV therapy has Figure 6: Managing HBV infection. Adefovir clearance or immune
changed significantly in recent years, Adefovir is an oral nucleotide agent escape phases (see above).
largely due to the introduction of A HBsAg + effective in suppressing both wild- ■ Patients seemingly in the

new medications, more sensitive type and lamivudine-resistant HBV. immune control phase but
HBV DNA assays and better under- HBeAg + In Australia it is licensed only as whose HBV DNA con-
4
standing of the natural history of second-line therapy, usually after the centration is >10
chronic HBV infection. Quantify DNA development of lamivudine resistance copies/mL.
The primary aim of treatment of or for primary non-response to other ■ Suspicion of significant
5 5
chronic HBV infection is sustained DNA * 10 copies/mL DNA < 10 copies/mL anti-HBV therapy. liver disease based on
suppression of HBV replication, The original indication for ade- physical examination,
leading to remission of active liver fovir was to substitute for lamivudine blood tests or radiology.
ALT ALT normal ALT normal ALT
disease. Reducing hepatic necro- in patients who had developed lamivu- ■ HBsAg-positive patients

inflammation prevents progression dine resistance, but more recently it requiring chemotherapy or
Treat Monitor Monitor Other cause? or
of liver disease to cirrhosis, prevents or liver biopsy
has been allowed as ‘add-on’ therapy high-dose immunosup-
liver biopsy
hepatocellular carcinoma and ulti- so that patients remain on a combina- pression.
mately prolongs survival. Parameters 3-Monthly LFTs, HBeAg/anti-HBe tion of lamivudine and adefovir. This ■ Acute HBV infection with

used to assess treatment response
include:
■ Normalisation of ALT level.
■ Decrease in HBV DNA level.
■ HBeAg seroconversion (HBeAg to
anti-HBe).
■ HBsAg seroconversion (HBsAg to
anti-HBs).
The indications for treatment
depend on the ALT and HBV DNA
levels, the immune phase of infec-
tion and severity of hepatic histol-
ogy. Acute HBV infection is a self-
limiting illness, with most adults
spontaneously clearing the virus with-
out the need for antiviral therapy.
In chronic infection, antiviral treat-
ment should be considered in the
immune clearance and immune
escape phases, generally when the
ALT level is at least twice the upper
limit of normal.
In younger patients without obvi-
ous advanced liver disease and enter-
ing the immune clearance phase,
with rising ALT levels and positive
HBeAg, it may be worthwhile to
observe for spontaneous HBeAg
seroconversion over 3-6 months.
As mentioned, liver biopsy is a
prerequisite for PBS-subsidised
antiviral therapy and may be partic-
ularly useful in patients who do not
meet clear-cut guidelines for treat-
ment, such as those over 40 with
ALT values close to or only just
above the upper limit of normal. The
presence of significant inflammation
or fibrosis in such patients may be an
indication for treatment.
Patients with HBV-infection and
cirrhosis should all be considered for
treatment irrespective of the ALT
level. Because patients with cirrhosis
have reduced hepatic cell mass and
are at risk of decompensation, any
level of viraemia is disadvantageous
and thus the HBV DNA threshold
B 29% of patients after five years of ade-
HBsAg +
HBeAg -
Quantify DNA
4
DNA * 10 copies/mL
ALT ALT normal
Treat Liver biopsy and
treat if significant
outlined in figure 6.
The therapeutic landscape of HBV
infection has become complex with
the advent of several new agents.
Five agents are now available on the
PBS for the treatment of chronic
HBV infection in Australia: standard
interferon, pegylated interferon,
lamivudine, adefovir and entecavir.
Interferon
Standard interferon-alpha, which is
given as a subcutaneous injection
thrice weekly, has largely been
replaced by pegylated interferon-
alpha (Peg-IFN), the most recent
addition to the antiviral armamen-
tarium for HBV. By binding inter-
feron to polyethylene glycol, the
pharmacokinetic half-life of inter-
feron is prolonged, allowing it to be
administered once weekly.
Interferon works by enhancing
the host’s immune response to the
virus as well as having direct antivi-
ral and antiproliferative effects. In
HBeAg-positive patients, 48 weeks
of Peg-IFN resulted in HBeAg sero-
conversion in 32% of patients,
compared with 19% of those
4
DNA < 10 copies/mL
ALT normal ALT
Monitor Other cause? or
liver biopsy
6-Monthly LFTs
oral agents are a finite duration of
therapy (48 weeks), absence of drug
resistance, and durability of
response, with some HBsAg sero-
conversion.
Disadvantages are toxicities such
as flu-like illness and mood distur-
bance (albeit to a lesser degree than
in HCV patients treated with inter-
feron), and the need to avoid use in
patients with cirrhosis. The main role
for Peg-IFN may be in HBeAg-posi-
tive patients with compensated dis-
ease (eg, women before pregnancy)
who exhibit favourable predictors of
response.
Lamivudine
Lamivudine was the first oral nucle-
oside anti-HBV agent approved in
Australia (in 1996). It directly
inhibits viral replication, with 90%
of patients having undetectable HBV
DNA after one month of treatment.
HBeAg seroconversion is achieved
after one year of therapy in 16-34%
of patients, depending on baseline
ALT level.
Lamivudine has no significant side
effects and is also useful in patients
significantly reduces the development
of adefovir resistance, which occurs in
fovir monotherapy.
Entecavir
Entecavir is the latest oral nucleoside
agent approved for use in chronic
HBV infection in December 2006. It is
more potent in suppressing HBV DNA
than lamivudine and adefovir and is
associated with minimal drug resis-
tance (<2% after four years).
Although entecavir has some activ-
ity against lamivudine-resistant HBV
mutants, it demonstrates cross-resis-
tance with lamivudine. Thus, com-
bining adefovir with lamivudine is
the preferred option when lamivu-
dine resistance develops rather than
switching to entecavir.
Choice of agent
Most international guidelines for
HBV therapy generally avoid recom-
mending one particular drug, and
instead leave the choice between the
available licensed options to the clin-
ician’s discretion. A full discussion
of the relative merits and limitations
of each of the agents, as outlined
above, and recognition of patient
preferences should be considered.
Because of its potency and excel-
lent resistance profile, entecavir has
largely replaced lamivudine as the
initial oral agent of choice in chronic
HBV infection. The question of ini-
tial therapy then becomes either ente-
cavir or Peg-IFN.
Some authorities recommend ini-
tial use of Peg-IFN as the most cost-
effective option in HBeAg-positive
disease, because about one-third of
these patients will seroconvert after
12 months of Peg-IFN therapy. The
remaining two-thirds, who fail to
seroconvert, may be switched to
hepatic decompensation
(eg, falling albumin level
or coagulopathy).
Because of the difficulties
in defining the various
phases of chronic HBV
infection, there should be a
low threshold for specialist
referral, or at least a tele-
phone discussion about an
individual patient.
Patients in the immune
tolerance phase (normal
ALT, HBeAg-positive, high
HBV DNA) should be
monitored every 3-6 months
with liver function tests
(LFTs) and HBeAg/anti-
HBe testing. HBV DNA
could be measured annu-
ally. When LFTs become
elevated, monitoring should
be more frequent and refer-
ral should be considered.
Patients in the immune
control or inactive carrier
phase (normal ALT,
HBeAg-negative/anti-HBe-
positive, low or unde-
tectable HBV DNA) should
be monitored with ALT
determination every three
months in the first year to
verify a true ‘inactive’ state,
then every 6-12 months.
When ALT starts to rise,
more frequent tests includ-
ing HBV DNA and exclu-
sion of other liver diseases
or hepatotoxins should be
conducted and specialist
referral considered.
Screening for hepatocel-
lular carcinoma with six-
monthly AFP and liver
ultrasound should be con-
sidered in those:
■ With cirrhosis.

for initiating treatment should be treated with lamivudine. The main with cirrhosis, even with decompen- long-term oral antiviral therapy. ■ With a family history of

lowered. Furthermore, because of the predictors of response to Peg-IFN sation. The main limitation is the In HBeAg-negative disease, in hepatocellular carcinoma.
risk of decompensation from inter- are a high pre-treatment ALT level, emergence of drug resistance, devel- which patients tend to be older and ■ Aged >40.

feron, oral nucleoside or nucleotide low HBV DNA level, and genotype oping in 20% of patients after one have more established liver disease, ■ Of African descent, aged

agents are favoured in cirrhosis. A A and B disease. year and 60% after four years of entecavir may be a better option. >20.
management algorithm for HBV is Advantages of Peg-IFN versus the treatment. cont’d next page

www.australiandoctor.com.au 14 November 2008 | Australian Doctor | 33

AD_034___NOV14_08 Page 5 6/11/08 5:26 PM

How to treat – hepatitis B infection

Special considerations Summary

Vaccination
UNIVERSAL vaccination of all babies born in
Australia with recombinant HBsAg subunits
was introduced in 2000, with an adolescent
catch-up program available till 2012. Three
IM doses are given in a schedule of zero, one
and six months, or, for babies, zero, two, four
and six or 12 months.
Protective antibody levels (*10mIU/mL) are
expected to be achieved in >95% of young
healthy adults and >98% of babies and chil-
dren. Thus, quantitative testing of anti-HBs
1-2 months after vaccination should be
reserved for patients:
■ At increased risk of infection (eg, health care
workers, infants born to HBsAg-positive
mothers, dialysis patients).
■ At risk of severe or complicated disease (eg,
the immunocompromised, those with pre-
existing liver disease unrelated to HBV).
■ In whom a poor response to vaccine is
expected (eg, over 40, obese).
If adequate levels of anti-HBs are not
reached, test for HBsAg carriage. If HBsAg-
negative, try a fourth injection of a double
dose or three further injections of a single dose
at monthly intervals, with further testing four
weeks after the last dose. Persistent non-
responders should be informed about the need
for HBV immune globulin (HBIG) within 72
hours of parenteral exposure to HBV.
Booster doses are generally not recom-
mended in immunocompetent persons with a
documented serological response to the pri-
mary course of vaccination. Anti-HBs becomes
undetectable after 4-10 years in 30% of
healthy vaccinated persons. However, these
people are still protected against HBV because
of pronounced immunological memory, which
persists even after anti-HBs have disappeared.
Boosters are recommended in the immuno-
compromised and those with chronic renal
failure. Double doses of the vaccine are needed
for haemodialysis patients, and their anti-HBs
levels should be monitored annually.
Immunosuppressed patients with chronic
HBV infection
Reactivation of HBV replication with elevation
of HBV DNA and ALT levels has been
reported in 20-50% of HBV carriers under-
going immunosuppressive or cancer chemo-
therapy. Most hepatitis flares are asympto-
matic but icteric flares and even hepatic
decompensation and death have been
observed.
HBsAg testing should be performed in
people with HBV risk factors (table 1) before
chemo- or immunosuppressive therapy is
started. Referring infected patients for pro-
phylactic antiviral therapy with lamivudine or
entecavir should be considered for those
receiving:
■ Chemotherapy (especially regimens including
steroids or anthracyclines).
■ High-dose immunosuppression (insufficient
data on low-dose steroid monotherapy).
■ Anti-tumour necrosis factor or other biolog-
ical therapy for rheumatoid arthritis or
inflammatory bowel disease.
■ Transarterial chemoembolisation for hepa-
tocellular carcinoma.
Although HBV reactivation may develop
in people who are HBsAg negative but anti-
HBc and anti-HBs positive and in those with
isolated anti-HBc, this is infrequent, and data
are insufficient to recommend routine pro-
phylaxis for these individuals.
Counselling
Patients with chronic HBV infection should be
counselled regarding lifestyle modifications to
maintain liver health. Alcohol intake should be
limited (no more than 1-2 standard drinks a
day, with at least two alcohol-free days a
week) to minimise development of cirrhosis.
Regular exercise and a balanced diet will
decrease the development of fatty liver, which
may coexist with chronic HBV infection. Vac-
cination for hepatitis A should be offered, par-
ticularly in patients with significant liver dis-
ease.
General advice to reduce transmission
should be provided. Household and sexual
contacts should be vaccinated if they test neg-
ative for HBV. Toothbrushes and razors
should not be shared and blood spills should
be cleaned with detergent or bleach. Children
and adults who are HBsAg-positive may still
participate in contact sports and should not be
excluded from day care or school activities.
They can also share food and kiss others.
Pregnant women should inform their health
care providers of their HBV status to ensure
their babies receive immediate HBIG and vac-
cination. Infants born to HBeAg-positive
mothers have on average an 80% chance of
being infected, with more than 90% pro-
gressing to chronic infection.
HBIG and concurrent HBV vaccine is more
than 95% efficacious in preventing perinatal
transmission of HBV, although the efficacy is
lower for maternal carriers with very high
HBV DNA levels (>8 log10 IU/mL).
■ Just under 1% of Australia’s population is
infected with HBV.
■ Screening should target people born in
hyperendemic areas, close contacts of infected
individuals, pregnant women, injecting drug
users, dialysis patients and men who have sex
with men.
■ Perinatal infection leads to chronic HBV
infection in 90% of cases, whereas acute
infection in adulthood resolves spontaneously in
90%.
■ HBV infection passes through four phases of
immune response — immune tolerance,
clearance, control and escape.
■ After cigarette smoking, HBV is the most
common carcinogen in humans.
■ Chronic HBV infection can be categorised into
HBeAg-positive or -negative disease.
■ HBV DNA viral load has prognostic and
therapeutic implications, and testing is now
reimbursed by Medicare.
■ Several new antiviral agents have been
introduced, with initial choice of treatment
mainly between oral entecavir and pegylated
interferon.
■ Patients with chronic HBV infection need
lifelong monitoring, particularly with regard to
hepatocellular carcinoma screening (age >40,
Africans aged >20, family history of
hepatocellular carcinoma, cirrhosis).

PBS Information: This

product is listed on the PBS
as an agent acting on the
renin-angiotensin system.

Please review the Product Information before

prescribing Atacand. The full disclosure Product
Information is available from AstraZeneca on
1800 805 342. = refs 1-5. References: 1.
Cuspidi C et al. J Hypertens 2002; 20: 2293-300.
2. Lithell H et al. J Hypertens 2003; 21: 875-
86. 3. Mogensen CE et al. BMJ 2000; 321: 1440-4.
4. Pfeffer MA et al. Lancet 2003; 362: 759-66. 5.
Atacand approved Product Information 7 Aug 2007.
Atacand (candesartan cilexetil). INDICATIONS:
Hypertension; heart failure and impaired left ventricular
systolic function (LVEF 40%) as add-on therapy to
ACE inhibitor or when ACE inhibitor not tolerated.
CONTRAINDICATIONS: Hypersensitivity, pregnancy
(Category D), lactation. PRECAUTIONS: Severe CHF;
ischaemic cardiopathy; ischaemic cerebrovascular
disease; hepatic impairment, renal artery stenosis;
renal transplant; haemodialysis; monitor K+ and
serum creatinine; primary hyperaldosteronism; volume
depletion; aortic, mitral stenosis; obstructive hypertrophic
cardiomyopathy; anaesthesia, surgery; concomitant ACE
inhibitor, thiazide diuretic, and NSAID/COX-2 inhibitor
(monitor creatinine). Adverse reactions: Hypotension;
hyperkalaemia; renal, hepatic effects; raised creatinine,
urea; GI upset; flu-like symptoms; back pain; others, see
full PI. INTERACTIONS: Lithium; drugs which increase
K+, K+ supplements, salt substitutes containing K+;
K+ sparing diuretics. DOSAGE: Hypertension; initially
8-16mg once daily, up to 32mg once daily; add thiazide
if needed. Elderly: initially 8mg daily. Severe renal
impairment/haemodialysis: initially 4mg daily. Heart
Failure; initially 4mg once daily. Double dose at 2 week
intervals up to 32mg once-daily if tolerated. Can be
administered with ACE inhibitors, beta-blockers, diuretics,
digitalis or their combination. Date of TGA approval: 7
Aug 2007. Date of safety-related notification: 7 Dec
2006. Atacand 4mg PBS dispensed price for maximum
quantity $20.49. Atacand 8mg PBS dispensed price
for maximum quantity $24.30. Atacand 16mg PBS
dispensed price for maximum quantity $30.13. Atacand
32mg PBS dispensed price for maximum quantity
$46.19. AstraZeneca Pty Ltd. ABN 54 009 682 311,
Alma Road, North Ryde NSW 2113. ® Registered
trademark of AstraZeneca group. Manufactured under
license from the Takeda Pharmaceutical Company.
AZAT0987/AD/HDPS/N. 09/08. Ward6.

34 | Australian Doctor | 14 November 2008 www.australiandoctor.com.au

AD_ 0 3 5 _ _ _ NOV 1 4 _ 0 8 . P DF
Author’s case studies
Spontaneous
seroconversion after
immune clearance
A 24-year-old Chinese
woman presented to her GP
with a one-week history of
anorexia, nausea and vague
upper-abdominal pain. She
was noted to have scleral
icterus, with mild, right upper-
quadrant tenderness. Blood
tests revealed a bilirubin level
of 68mol/L, ALP 145 U/L,
GGT 70 U/L, AST 1105 U/L,
ALT 1677 U/L and albumin
40g/L. She was referred to the
local hospital emergency
department.
Upper-abdominal ultra-
sound revealed a mildly het-
erogeneous liver echo-texture,
with normal biliary tree and
spleen. Subsequent tests
revealed a normal INR, posi-
tivity for HBsAg, negativity
for HBeAg and equivocal
anti-HBe. HBV DNA was 22
million copies/mL. She was
discharged from the emer-
gency department with an
outpatient follow-up in the
liver clinic.
Her ALT peaked at 2800
U/L and gradually declined to
normal levels after two
months. During this time
there was no evidence of
hepatic decompensation, so
Pa ge 1 1 1 / 6 / 0 8 ,
Figure 7: CT scan of hepatoma in a 42-year-old Korean man with chronic HBeAg-negative disease.
she was managed as an out-
patient, with close communi-
cation between her GP and
liver specialist. HBeAg
remained negative and she
eventually became positive for
anti-HBe. HBV DNA also
declined to undetectable levels.
Further history revealed
that more than a year ago in
China she had been HBeAg-
positive. Thus, this episode
represents spontaneous HBeAg
seroconversion after the
5 : 4 2 PM
immune clearance phase of
chronic HBV infection. She
should now be monitored
long-term with six-monthly
LFTs and HBV serology
(HBeAg/anti-HBe) to detect
immune escape or reactiva-
tion, with hepatocellular car-
cinoma screening starting
from age 40.
Complications associated
with chronic HBV infection
A 42-year-old Korean man
tacand is also a vers atile instrument
www.australiandoctor.com.au
presented to his GP with
lethargy and minor weight loss.
He was known to be HBsAg
positive but had failed to
attend for regular review.
Blood tests revealed normal
haemoglobin and LFTs but a
9 Hepatitis.html
platelet count of 130 x 10 /L.
Serum AFP was elevated at
340ng/mL. Ultrasound and
triple-phase CT scan of the
abdomen revealed no focal
hepatic abnormality or any evi-
dence of portal hypertension.
After referral to a special-
ist, HBV DNA was found to
be mildly elevated at 220,000
copies/mL, with HBeAg nega-
tive. To exclude AFP secretion
from a testicular tumour, a
testicular ultrasound was
arranged and was found to be
normal.
The patient refused a liver
biopsy but did start entecavir
to determine if the elevated
AFP level reflected HBV
viraemia. Three months later,
HBV DNA was undetectable
but AFP had risen to
560ng/mL.
A further triple-phase CT
scan of the liver was arranged.
A 2cm diameter, arterially
enhancing lesion was noted in
the right lobe of the liver, con-
sistent with hepatocellular car-
cinoma (figure 7). The patient
was referred for surgery and
underwent successful hemi-
hepatectomy (uninvolved liver
was not cirrhotic). He is being
considered for entry into a trial
of post-surgical chemotherapy.
This case illustrates the
occasional difficulties of
screening and diagnosing
hepatocellular carcinoma
and the potential complica-
tions of chronic HBeAg-neg-
ative disease.
cont’d next page
14 November 2008 | Australian Doctor |
Reference
1. Lau G et al.
Peginterferon Alfa-2a,
lamivudine, and the
combination for HBeAg-
positive chronic hepatitis B.
New England Journal of
Medicine 2005; 352:2682-
95.
Further reading
■ Lok AS, McMahon BJ.
Chronic Hepatitis B. Hepa-
tology 2007; 45:507-39.
■ Thomas HC. Best practice
in the treatment of chronic
hepatitis B: A summary of
the European Viral Hepati-
tis Educational Initiative
(EVHEI). Journal of Hepa-
tology 2007; 47:588-97.
Online resources
■ Hepatitis Australia:
www.hepatitisaustralia.
com
■ Gastroenterological
Society of Australia:
www.gesa.org.au
■ NSW Multicultural
Health Communication
Service:
www.mhcs.health.nsw.gov.
au/mhcs/topics/
35
AD_ 0 3 6 _ _ _ NOV 1 4 _ 0 8 . P DF Pa ge 1 1 1 / 6 / 0 8 , 5 : 4 4 PM

How to treat – hepatitis B infection

GP’s contribution
Case study detected HBsAg, as well as tions. I also suggested to likely that they would still
KAREN, a 50-year-old anti-HBs (3.59 mIU/mL). him that his sister may want be protected from HBV via
Korean woman, migrated to The comment from pathol- her hepatitis B status pronounced immunological
Australia with her Aus- ogy was that this was not checked as well, as she was memory, but it is appropri-
tralian husband 30 years evidence of immunity to going to Korea with him. ate to re-vaccinate them as
ago. They have two chil- HBV. Samantha’s HBV serology you have suggested.
dren — John, 22, and John, who has only been a was:
Samantha, 18. patient at my practice for ■ HBsAg — not detected. I have offered both John and
DR PHILIP LYE
Karen initially presented two years, recently came in ■ HBeAg — not detected. Samantha HBV vaccinations
Sutherland, NSW
at my practice about eight for an STI check because he ■ Anti-HBc — not detected. (ie, three vaccinations on the
years ago. After several con- was now in a steady rela- ■ Anti-HBs: <10 mIU/mL. 0, 1 and 6 month schedule).
sultations she revealed to me tionship. It became obvious ■ Anti-HBe — not detected. Should I recheck their
that she was a “hepatitis B to me during the consulta- The comment from hepatitis B status after the
carrier”. This was when she tion that he was not aware pathology was that Saman- courses? If yes, when should
presented with right upper- that his mother was a tha did not have evidence of this be done?
quadrant abdominal pain. hepatitis B carrier. past or current HBV infec- Because of the family his-
At that time her LFTs were John’s HBV serology was: tion or vaccine-induced tory of HBV in their mother
normal and her HBV serol- ■ HBsAg — not detected. immunity. and no previous documenta-
ogy was: ■ HBeAg — not detected. tion of post-vaccination anti-
■ HBsAg — detected. ■ Anti-HBe — not detected. Questions for the author HBs levels, anti-HBs levels
■ HBeAg — not detected. ■ Anti-HBs: <10 mIU/mL. Am I correct in assuming should be checked 1-2
■ Anti-HBc — detected. The comment from that John and Samantha months after the last dose.
■ Anti-HBe — detected. pathology was that he had have NOT had any previous
At the time Karen also no evidence of immunity to HBV vaccinations? Karen Should Karen’s children be
told me that her two chil- HBV. says these were done inter- informed that she has previ-
dren (both born in Australia) Incidentally, John was state by another GP and she ously had hepatitis B? I have
had had hepatitis B immu- also planning his first visit has lost the immunisation told her that she should tell
nisations. to Korea to visit his records. them. She keeps saying she
Last year, when blood mother’s relatives, so I took It is possible they have will but has not done so yet.
tests were repeated for the opportunity to talk to had vaccinations but the Karen should probably
another reason, her LFTs him about HBV and sug- anti-HBs levels have now inform her children but there
were again normal. At this gested that he have a course declined to undetectable is no clinical concern if she
time her HBV serology of hepatitis B immunisa- levels. In that situation it is does not.

How to Treat Quiz
Hepatitis B infection
— 14 November 2008
1. Which TWO statements about the
epidemiology of hepatitis B virus (HBV)
infection are correct?
a) In Australia, 0.5-0.8% of the population is
estimated to be chronically infected with
HBV
b) About half of those people in Australia with
chronic HBV infection were born in Asia
c) Indigenous Australians make up only about
5% of people in Australia with chronic HBV
infection
d) The number of Australians with HBV is
expected to decrease over the next
5-10 years because of inclusion of HBV
vaccination in the immunisation schedule
2. Which TWO statements about
transmission of HBV are correct?
a) The infectious risk of HBV is 10 times
greater than that of HIV
b) HBV is not spread by close person-to-
person contact
c) Perinatal transmission from mother to child
is the most common source of infection
among immigrants from countries with high
endemicity for HBV
d) People from non-endemic areas are more
likely to present with acute HBV infection
3. For which THREE groups is screening for
HBV infection recommended?
a) Pregnant women
b) All patients undergoing elective surgical
procedures
c) Injecting drug users
d) Men who have sex with men
4. Which TWO statements about the natural
history of HBV infection are correct?
a) Perinatal infection leads to chronic HBV
infection in 90% of cases
b) Acute infection in adulthood resolves within
six months in >90% of cases
c) Perinatal infection with HBV is almost always
symptomatic
d) The five-year rate of progression from chronic
hepatitis to cirrhosis is 1-2%
5. Which THREE statements about interpreting
initial HBV serology results are correct?
a) HBsAg-negative, anti-HBc-positive and anti-
HBs-positive serology indicates resolved HBV
infection
b) HBsAg-negative, anti-HBc-negative and anti-
HBs-positive serology indicates previous HBV
vaccination
c) HBsAg-positive, anti-HBc-positive, IgM anti-
HBc-negative and anti-HBs-negative serology
indicates acute HBV infection
d) HBsAg-positive (for longer than six months),
anti-HBc-positive, IgM anti-HBc-negative
and anti-HBs-negative serology indicates
chronic HBV infection
6. Mrs X, 25, tests positive for HBsAg on
antenatal screening in her first pregnancy.
She is known to have tested positive for
HBsAg when she arrived two years ago from
China. Additional tests reveal she is anti-HBc
positive, IgM anti-HBc negative and anti-HBs
negative. Which THREE statements about
further testing in HBV infection are correct?
a) After a diagnosis of chronic HBV infection has
INSTRUCTIONS
Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes
by post or fax.
The mark required to obtain points is 80%. Please note that some questions have more than one correct
answer.
ONLINE ONLY
www.australiandoctor.com.au/cpd/ for immediate feedback
been established, HBeAg/anti-HBe status
should be determined
b) After a diagnosis of chronic HBV infection has
been established, HBV DNA should be
quantified
c) There is no Medicare reimbursement for HBV
DNA measurement in patients with chronic HBV
infection who are not receiving antiviral therapy
d) After a diagnosis of HBV infection has been
established, co-infection with hepatitis C
virus (HCV) and HIV should be excluded in
those at risk
7. Which TWO statements about the
treatment of HBV infection are correct?
a) Unless there are contraindications, liver
biopsy is a criterion for subsidised therapy in
HBV infection under the PBS
b) Patients with HBV infection and cirrhosis
should all be considered for treatment
irrespective of the ALT level
c) About two-thirds of patients will undergo
HBeAg seroconversion after 12 months of
pegylated interferon-alpha therapy
d) In Australia adefovir is the initial oral agent of
choice in chronic HBV infection
8. Which TWO statements about monitoring
patients with chronic HBV infection are
correct?
a) Liver disease severity may be estimated by
assessing bilirubin, albumin, and INR as
measures of liver excretory and synthetic
function
b) Liver disease severity may be estimated by
assessing the AST/ALT ratio, with a ratio of
<1 being suggestive of cirrhosis
c) Liver disease severity may be estimated by
assessing the platelet count, with
thrombocytopenia being possibly indicative of
portal hypertension
d) Screening for hepatocellular carcinoma with
serum alpha-fetoprotein and liver ultrasound
every two years should be considered in
those at high risk
9. Which TWO statements about vaccination
against HBV are correct?
a) People who persistently fail to demonstrate
adequate levels of anti-HBs post vaccination
should be informed about the need for HBV
immune globulin if exposed to HBV
b) Levels of anti-HBs disappear after 4-10 years
in 10% of healthy vaccinated persons
c) Booster doses of HBV vaccine are generally
not recommended in immunocompetent
persons with documented serological
response to the primary course of vaccination
d) Haemodialysis patients should have their anti-
HBs levels monitored every five years
10. Which TWO statements about
counselling patients with chronic HBV
infection are correct?
a) Alcohol intake should be limited (no more
than 1-2 standard drinks a day, with at least
two alcohol-free days a week)
b) Toothbrushes and razors must not be shared
c) Children and adults who are HBsAg-positive
should not participate in contact sports
d) People who are HBsAg-positive should not
share food

CPD QUIZ UPDATE

The RACGP now requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the 2008-10 triennium. You
HOW TO TREAT Editor: Dr Wendy Morgan
can complete this online along with the quiz at www.australiandoctor.com.au. Because this is a requirement, we are no longer able to accept the quiz by post
Co-ordinator: Julian McAllan
or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online.
Quiz: Dr Wendy Morgan

NEXT WEEK The next How to Treat looks at aetiology, presentation, investigation and treatment of malignant disease of the bladder, a common disease in Western countries. The authors are Mr Sam Gray,
fellow in urological surgery, Monash Medical Centre; and Associate Professor Mark Frydenberg, head of urology, Monash Medical Centre, Clayton, Victoria.

36 | Australian Doctor | 14 November 2008 www.australiandoctor.com.au