B Positive – all you wanted to know about - ASHM

all you wanted
to know about
hepatitis B
a guide for primary
care providers

all you wanted
to know about
hepatitis B
a guide for primary
care providers
Editors
Gail Matthews and Monica Robotin
funded by:
Produced and distributed by:

B Positive – all you wanted to know about hepatitis B: a guide for primary care providers
is published by the:
Australasian Society for HIV Medicine (ASHM)
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First published 008
Editors: Gail Matthews and Monica Robotin
Copy Editor: Mary Sinclair
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B Positive - all you wanted to know about hepatitis B: a guide for primary care providers
ISBN: 978-1-9 0773-56-4
Includes index.
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b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Contents
Acknowledgments .................................................................................................................... 5
Foreword ...................................................................................................................................... 6
Executive Summary .................................................................................................................. 8
Chapter 1 Prevalence and epidemiology of hepatitis B ........................................ 13
Van TT Nguyen, Gregory J Dore
Chapter Virology: viral replication and drug resistance ..................................... 24
Stephen Locarnini
Chapter 3 Hepatitis B virus testing and interpreting test results ....................... 31
Mark Danta
Chapter 4 Natural history of chronic hepatitis B virus infection ......................... 40
Marianne Guirgis, Amany Zekry
Chapter 5 Primary prevention of hepatitis B virus infection ................................ 46
Nghi Phung, Nicholas Wood
Chapter 6 Clinical assessment of patients with hepatitis B virus infection ...... 51
Darrell HG Crawford, Rebecca J Ryan, Nghi Phung
Chapter 7 Treatment of chronic hepatitis B virus infection .................................. 57
Rebecca J Ryan, Miriam T Levy, Darrell HG Crawford
Chapter 8 Managing patients with advanced liver disease .................................. 65
Robert Batey
Chapter 9 Hepatitis B virus-related hepatocellular carcinoma ............................ 69
Monica Robotin
Chapter 10 Managing hepatitis B virus infection in complex situations ............ 75
Benjamin Cowie
Chapter 11 Infection control and occupational health ............................................ 82
Jacqui Richmond
Chapter 1 Privacy, confidentiality and other legal responsibilities .................... 90
Sally Cameron
Chapter 13 The role of complementary medicine in hepatitis B ........................... 96
Ses J Salmond, Robert Batey
Appendix 1 Patient fact sheet........................................................................................... 102
Appendix 2 Useful resources.............................................................................................. 106
Glossary and abbreviations .................................................................................................... 114
Index ............................................................................................................................................. 119
an electronic version of the latest edition of this resource is available at: http://www.ashm.org.au/publications/
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 3

4 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Acknowledgments
Editors
Gail Matthews and Monica Robotin
Writers
Robert Batey, Sally Cameron, Benjamin Cowie, Darrell H G Crawford, Mark Danta, Gregory J Dore, Marianne
Guirgis, Miriam T Levy, Stephen Lorcanini, Gail Matthews, Van T T Nguyen, Nghi Phung, Jacqui Richmond,
Monica Robotin, Rebecca J Ryan, Ses Salmond, Nicholas Wood, Amany Zekry
Reviewers
Robert Batey, Scott Bowden, Jeremy Bunker, Dennis Chang, Benjamin Cowie, Jacob George, Sharon Reid,
Jacqui Richmond, Steven Tipper, Nicholas Zwar
Expert Reference Group
Sallie Cairnduff (Aboriginal Health and Medical Research Council of NSW), Levinia Crooks and Liza Doyle
(Australasian Society for HIV Medicine), John Hornell (The Hepatitis Foundation of New Zealand), Miriam
T Levy (Department of Gastroentorolgy and Hepatology, Liverpool Hospital), Gail Matthews (National
Centre in HIV Epidemiology and Clinical Research), Tadgh McMahon (Multicultural HIV and Hepatitis
Service), Geoff McCaughan (Ministerial Advisory Committee on Hepatitis), Nghi Phung (Drug and Alcohol
Department, Liverpool Hospital), Vasantha Preetham (Royal Australian College of General Practitioners),
Monica Robotin (The Cancer Council NSW), Helen Tyrrell (Hepatitis Australia), Amany Zekry (Australian
Liver Association)
ASHM Staff
Levinia Crooks, Liza Doyle, Simona Achitei, Shehana Mohammed, Adrian Rigg
Copy Editor
Mary Sinclair
Indexing
Jeanne Rudd
Funding
The Cancer Council NSW
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 5

Foreword
in nsW, just seven cancers—those of prostate, breast, bowel, lung, melanoma and non-
Hodgkin’s lymphoma, and cancers of unknown site—account for 68% of all cancers. in turn,
they account for 60% of cancer deaths. the national response to cancer is quite rightly focused
on these seven cancers.
However, what is true for the population taken as a whole may not be true for all subgroups of
that population. the cancer council nsW report Cancer Incidence in New South Wales Migrants
1991-2001 demonstrates that migrants from some countries have quite a different cancer
profile from that of the australian-born population. 1 Liver cancer is a case in point. although the
overall share of cancer in nsW migrants (24.5%) is commensurate with their representation in
the population, 46% of all primary liver cancers in nsW are diagnosed in overseas-born people.
there are several striking features in the epidemiology of liver cancer in nsW. firstly, it is the
most rapidly increasing of all cancers. between 1995 and 2004, primary liver cancer in nsW
increased by 59% in males and 116% in females. secondly, it is among the most fatal cancer,
with a five-year relative survival of 15% akin to that of lung and pancreatic cancer. thirdly, in
comparison to the australian-born population, immigrants from countries with high prevalence
rates for chronic hepatitis b virus (HbV) infection are at a sixfold or greater risk of developing
liver cancer. in nsW, liver cancer exhibits a striking pattern of geographic clustering, reflecting
in part differences in neighbourhood ethnic composition.
People with chronic HbV infection incur a high burden of chronic disease and premature death.
around 30% will die of liver cancer or liver disease. the population at risk will continue to swell as
immigration from HbV endemic countries continues and increases, and it will be some decades
before universal infant HbV vaccination programs in those countries substantially reduce the
rates of chronicity in adult populations. this situation poses a challenge to the convenient notion
that australia’s program of universal childhood vaccination and protection of the blood supply
are a sufficient response. Presently, there is no systematic approach to vaccinating susceptible
people within high-risk communities.
the difference between australia’s response to hepatitis b and the national Hepatitis c strategy
is dramatic. in stark contrast to the patchy and unfocused response to HbV, the management
of hepatitis c includes a comprehensive response based on building partnerships; involving
affected communities; preventing hepatitis c virus (HcV) transmission; providing clinical
treatment, and community care and support to those with the infection; providing training and
education; and undertaking research and disease surveillance.
a systematic response to HbV is both feasible and affordable. the long latency period between
childhood HbV infection and the development of liver-related disease provides an ample
window of opportunity for case finding, especially among known high-risk groups. Monitoring
6 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

people with chronic HbV infection allows timely identification of cancer and liver disease, and
the institution of effective treatment. furthermore, engaging at-risk communities heightens
awareness and improves participation in a population-based disease control program.
there is now good evidence that such an approach reduces the morbidity and mortality related
to liver disease. one well-conducted randomised controlled trial of screening showed that,
with only a 58% complete participation rate in regular screening, the death rate from primary
liver cancer was reduced by 37%. 2 the new Zealand national Hepatitis b Programme achieved
five-year survival rates of around 50% following liver cancer diagnosis for those screened, and
the initiation of antiviral therapy has averted the need for liver transplantation among many
patients in this screening and follow-up program. 3 there is a genuine prospect that antiviral
therapy may be effective in the primary prevention of liver cancer.
although further intensive measures may be required in populations at high risk, general
practitioners and other primary care professionals are a critical bulwark in any effort to control
the impact of hepatitis b in the population at large. the partnership between asHM and
the cancer council nsW expresses our belief that the time to defeat hepatitis b is now. our
collaboration affirms our confidence in the capacity of general practice to form the front line in
this response.
dr andrew Penman
chief executive officer
the cancer council nsW
Ms Levinia crooks ao
chief executive officer
asHM
References
1. supramaniam r, o’connell dL, tracey ea, sitas f. cancer incidence in new south Wales
Migrants 1991 to 2001. sydney: the cancer council nsW, 2006. available from:
www.cancercouncil.com.au/editorial.asp?pageid=2253
2. Zhang bH, yang bH, tang Zy. randomized controlled trial of screening for hepatocellular
carcinoma. J cancer res clin oncol 2004;130(7):417-22.
3. robinson t, bullen c, Humphries W, Hornell J, Moyes c. the new Zealand Hepatitis b screening
Programme: screening coverage and prevalence of chronic hepatitis b infection. nZ Med J
2005;118(1211):u1345.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 7

Executive Summary
this monograph aims to provide primary
care practitioners with an overview of
current hepatitis b knowledge in australia—
a field which is constantly changing and
evolving. it is not intended to be read as a
cover-to-cover text, but rather to be referred
to as an information resource for advice
and explanation of issues that may arise
in clinical practice. chapters 1 to 5 deal
with the theory of hepatitis b disease from
australian epidemiology through to virology,
natural history, interpretation of hepatitis b
tests and vaccination. chapters 6 to 10 are
more practically based, and deal with the
assessment and treatment of the hepatitis
b-positive patient, the management of
advanced liver disease and hepatocellular
carcinoma (Hcc) and complex situations, such
as pregnancy and HiV co-infection. chapter
11: infection control and occupational health
and chapter 12: Privacy, confidentiality
and other legal responsibilities deal with
occupational and legal issues surrounding
hepatitis b. chapter 13 explores the role of
alternative or complementary therapies.
the information contained in many of the
chapters is related, or has relevance, to
material in other chapters. Hyperlinks placed
at the start of each chapter in the electronic
version and through the text allow the reader
to move between related topics as required.
internet and other related resources that may
be helpful for the providers involved in the
assessment and management of hepatitis
b-positive patients, along with a patient fact
sheet, are also included for further reference.
the effective prevention and management
of hepatitis b virus (HbV) infection
represents a major challenge to health care
providers within australia today. recent
years have seen significant advances in the
management of hepatitis b disease, with the
8 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
wider availability of new sensitive diagnostic
tests and effective therapies, coupled with
a better understanding of the complex
virology and natural history of hepatitis
b. such developments have heightened
awareness of the need to effectively target
those at risk for vaccination and treatment.
the implementation of appropriate strategies
is likely to have a major impact on the
burden of hepatitis b-related disease, and in
particular primary liver cancer (hepatocellular
carcinoma), in australia into the future. the
achievement of these goals rests largely with
the primary care provider, both to screen
and vaccinate those at potential risk of
hepatitis b, and to identify, refer and monitor
those who may benefit from anti-hepatitis b
therapy. this monograph aims to update and
inform the primary care clinician on current
knowledge regarding hepatitis b infection.
the epidemiology of hepatitis b is discussed
in chapter 1: Prevalence and epidemiology
of hepatitis b. World Health organization
(WHo) estimates indicate that over 400
million people worldwide have hepatitis b
infection, the majority of whom live in the
developing world. the asia-Pacific region
bears one of the highest burdens of hepatitis
b infection, with a prevalence rate of more
than 8% throughout the region. Migration
from asian countries, in particular china
and Vietnam, is largely responsible for the
increasing prevalence of chronic hepatitis b
and its complications in australia in recent
years. almost half of the primary liver
cancers diagnosed in australia today arise
in people born overseas. since hepatitis b
testing in australia is not mandatory and
relies on notifications of new diagnoses
to state and territory Health departments
(collated nationally in the national notifiable
diseases surveillance system—nndss),
actual numbers of people with HbV infection

in australia are unknown. the most recent
estimates put the numbers of people with
chronic HbV (defined as Hbsag positive for
more than six months) between 90,000 and
160,000. While the overall prevalence of
hepatitis b in the general population within
australia is low (less than 2%), the prevalence
in specific populations, particularly in people
migrating from the asia-Pacific region, is much
higher. the high prevalence in certain groups
of the australian population is relevant, both
for the targeting of primary prevention, and
for the diagnosis and management of those
people with chronic hepatitis b.
the transmission of hepatitis b is discussed in
chapter 4: natural history of chronic hepatitis
b virus infection. the progression to chronicity
after infection is dependent on the patient’s
age at acquisition of HbV, with over 90% of
infants with the infection at birth developing
chronic hepatitis b. the WHo strategy for the
control of HbV infection is based on universal
infant vaccination programs. although it may
take several decades for this policy to have
a significant effect, it has been shown to be
highly effective at reducing the incidence
of chronic hepatitis b and hepatocellular
carcinoma in countries such as taiwan,
where the prevalence of hepatitis b is high.
universal infant vaccination is recommended
in all australian states and territories, with
additional catch-up vaccination for all
adolescents not vaccinated in childhood.
Vaccination in adulthood should be targeted
at all potential high-risk people (chapter
5: Primary prevention of hepatitis b virus
infection, table 5.1) and should be actively
pursued, given its proven safety and efficacy
in preventing chronic hepatitis b infection
(chapter 5: Primary prevention of hepatitis b
virus infection).
recent advances in hepatitis b virology have
enhanced our understanding of the complex
natural history of hepatitis b (chapter 4:
natural history of chronic hepatitis b virus
infection). the pathogenesis of hepatitis b
disease is dependent on the balance between
the hepatitis b virus and the body’s innate
immune response, with active liver disease
being the result of immune recognition.
this balance may be affected by many
factors including age, immunosuppression
and therapeutic intervention (chapter
7: treatment of chronic hepatitis b virus
infection). the natural history of chronic
hepatitis b is thus dynamic, with the person
with the infection possibly passing through
many different stages during his/her lifetime,
particularly when the infection is acquired in
childhood. such people may pass through an
immunotolerant phase, an immune active
phase, an immune control phase and finally
into the immune escape phase (pre-core
mutant disease). these stages of chronic
hepatitis b are discussed in more detail in
chapter 4: natural history of chronic hepatitis
b virus infection. the appreciation of these
varying states is important and underscores
the value of regular review with appropriate
diagnostic testing for all patients with chronic
hepatitis b infection (chapter 3: Hepatitis b
virus testing and interpreting test results, and
chapter 7: treatment of chronic hepatitis b
virus infection).
the interpretation of diagnostic markers in
hepatitis b has been aided by the widespread
introduction of sensitive Pcr-based methods
for the detection of HbV dna (chapter 3:
Hepatitis b virus testing and interpreting test
results). HbV dna testing, in combination
with serological and biochemical markers,
can now provide accurate assessment
of disease activity and can help guide
decisions on the timing of and indications
for therapeutic intervention. in addition, it
has an important role in assessing treatment
efficacy and the patient’s response to therapy
(chapter 7: treatment of chronic hepatitis b
virus infection). the level of circulating HbV is
an important prognostic factor and has also
been shown to be the strongest predictor
for the future development of hepatocellular
carcinoma (chapter 9: Hepatitis b virusrelated
hepatocellular carcinoma).
Liver biopsy currently remains the gold
standard for the assessment of inflammation,
fibrosis and cirrhosis, and is a valuable tool in
the assessment of HbV, given the frequently
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 9

Executive Summary
variable course of chronic infection. noninvasive
methods of fibrosis assessment,
such as algorithms based on biochemical
markers in serum, or the use of non-invasive
scans, such as the fibroscan® technique to
quantify hepatic fibrosis, are currently under
assessment and may become a useful adjunct
to (and in some cases avoid the need for) liver
biopsies in the future (chapter 3: Hepatitis b
virus testing and interpreting test results).
as virological tests for the diagnosis and
monitoring of hepatitis b have improved, the
goalposts for treatment continue to change.
indications for treatment are discussed in
chapter 7: treatment of chronic hepatitis b
virus infection. treatment should currently be
considered for patients in the immune active
phase of chronic hepatitis b (high HbV dna
> 20,000 iu/mL, elevated aLt and fibrosis or
inflammation on biopsy), but not for patients
in the immune tolerant phase (high HbV dna
> 20,000 iu/mL and normal aLt). treatment is
also recommended for patients with pre-core
mutant disease (Hbeag negative, elevated
aLt and HbV dna > 2000 iu/mL) and should
be considered in all patients with cirrhosis
and any level of detectable HbV dna. the
primary goal of treatment is virological
suppression (particularly in the Hbeag
negative group), but other goals include
Hbeag seroconversion (in Hbeag-positive
patients), and histological improvement.
these goals are often related, but may occur
independently. the therapeutic endpoint
is Hbsag seroconversion, but this outcome
occurs infrequently.
HbV treatment is based around two main
classes of therapy: immunomodulating
agents (interferon based-therapy) and
direct antiviral agents. standard interferon
therapy has now been replaced by the use
of pegylated interferon. therapy is given
by weekly subcutaneous injection for a
fixed duration of 12 months and results in
Hbeag seroconversion in just under a third
of Hbeag-positive patients. it may also have
a role in some Hbeag-negative patients in
whom it is able to induce sustained viral
control. Pegylated interferon has a significant
10 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
side effect profile and is contra-indicated in
decompensated cirrhosis.
the other mainstay of HbV treatment is the use
of antiviral agents, an increasing number of
which is now available. Lamivudine has been
used for the treatment of chronic hepatitis b
infection for many years. While active against
HbV, it results in an increasing rate of drug
resistance when used as monotherapy for any
length of time. additional potent anti-HbV
agents now licensed for use in australia are
entecavir and adefovir; other agents not yet
available here include telbivudine, tenofovir
and emtricitabine. the use of these agents is
discussed in detail in chapter 7: treatment of
chronic hepatitis b virus infection. a major
concern with the use of any antiviral agent is
the development of drug resistance. in chronic
hepatitis b, drug resistance may lead to viral
rebound, hepatic flare and, in patients with
cirrhosis, potential hepatic decompensation.
an understanding of the mechanisms of
HbV resistance development will guide the
appropriate use and combination of these
agents in the future (chapter 2: Virology: viral
replication and drug resistance).
a number of special situations exist in which
the management and therapeutic options
for HbV may be more complex than usual.
these include the management of pregnant
women, children and people who have a
hepatitis c, hepatitis d (delta) or human
immunodeficiency virus (HiV) co-infection
(chapter 10: Managing hepatitis b virus
infection in complex situations). in patients
with HiV co-infection, a number of antiviral
agents have activity against both HbV and
HiV (lamivudine, emtricitabine, adefovir,
tenofovir and entecavir) and thus their
effect on both viruses must be carefully
considered before treatment for either is
initiated. another group in need of careful
management is that of people with HbV
infection undergoing immunosuppressive
therapy (including cancer chemotherapy),
transplant recipients and patients treated
with immunosuppressive agents for autoimmune
disease, steroids, or antimonoclonal
agents such as rituximab. the aggressive

eactivation of hepatitis b infection resulting
in liver decompensation and death has been
reported in these situations. all patients in
these situations should therefore undergo
screening for HbV and antiviral prophylaxis
should be administered to anyone who is
Hbsag positive. reactivation has also been
documented in people who are anti-Hbcab
positive only; careful monitoring should be
performed in anyone with evidence of past
exposure to HbV (chapter 10: Managing
hepatitis b virus infection in complex
situations).
one of the primary aims of treatment is
the prevention of significant fibrosis and
subsequently cirrhosis in the liver. the
consequences of advanced liver disease
are significant and include the sequelae of
decompensated cirrhosis (ascites, hepatic
encephalopathy, portal hypertension
and jaundice) and the development of
hepatocellular carcinoma (Hcc). However,
these complications do not occur universally
and many people with compensated cirrhosis
live many years without illness. during this
time, advice to the patient on minimising
other co-factors of liver disease progression is
vital and includes alcohol abstinence, weight
reduction and drug modification. these
issues and the further management of the
complications of advanced liver disease are
discussed in chapter 8: Managing patients
with advanced liver disease.
Globally, HbV is the leading cause of Hcc
and within australia, HbV-related Hcc is now
responsible for an increasing number of liver
transplants and incidences of death, with
the annual rate predicted to rise further in
the next two decades (chapter 9: Hepatitis
b virus-related hepatocellular carcinoma).
standardised incidence rates for primary
liver cancer in people born overseas, in
areas where HbV is highly endemic (china,
Vietnam, africa, the Mediterranean region,
asia-Pacific region), are two- to 12-fold
greater than those in the australian-born
population. the risk of Hcc development is
greatest in those who are Hbeag positive,
but is also elevated in all people with chronic
HbV infection—even those who are Hbeag
positive (that is, those in the immune control
phase). importantly, unlike HcV where
Hcc almost always occurs in the context of
cirrhosis, HbV-related Hcc may also occur in
non-cirrhotic livers, although this occurs less
frequently. Hcc screening is recommended
for people with chronic HbV infection at high
risk for Hcc (chapter 6: clinical assessment
of patients with hepatitis b virus infection,
table 6.3). screening is recommended every
six months and is usually performed using
a combination of ultrasound and alpha
fetoprotein estimation. although evidence
for the success of this method in reducing
mortality is limited, most clinicians and
patients favour such an approach.
the treatment in early stage Hcc, particularly
if the lesion is small and unifocal, may be
curative, but responses to currently available
treatments in more advanced disease are
generally suboptimal and survival is poor,
especially in the setting of multiple or large
tumours. treatment options for Hcc include
resection, liver transplantation, percutaneous
ablation, transcatheter arterial embolisation
(tae) and transarterial chemoembolisation
(tace). the choice of treatment depends on
a number of factors and these are discussed
further in chapter 9: Hepatitis b virus-related
hepatocellular carcinoma.
irrespective of the stage of hepatitis b disease,
many people choose to use alternative or
complementary medicines at some time
during their diagnosis. as interest in the use of
complementary alternative medicines (caM)
expands, an understanding of the indications
for their use, as well as their potential benefits
and side effects, is important. in chapter
13: the role of complementary medicine in
hepatitis b, caM products which have been
found to be both helpful as well as harmful in
the management of hepatitis b are discussed,
and links to further resources are provided.
as with many chronic infectious diseases,
hepatitis b has particular implications in
terms of transmission, confidentiality and
legal responsibilities. the management
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 11

Executive Summary
of the exposed health care worker and
general infection control issues are discussed
in chapter 11: infection control and
occupational health. Legal requirements
regarding notification to public health
authorities and issues of privacy,
confidentiality and duty of care are dealt with
in chapter 12: Privacy, confidentiality and
other legal responsibilities.
the most effective method of reducing the
burden of advanced liver disease and Hcc
in australia in the future is through primary
prevention and the implementation of
targeted vaccination of individuals at risk.
Vaccination programs, implemented in
countries with high HbV prevalence, have
been shown categorically to reduce the
incidence of Hcc, potentially by 80–85%
within three to four decades of vaccination.
thus, the prevention of disease is optimal.
despite the availability for many decades
of a safe and effective vaccine for hepatitis
b infection, the level of coverage of those
people at greatest risk remains suboptimal,
and strategies to enhance and target
vaccination campaigns are required.
for people who already have hepatitis b
infection, the key to preventing the longterm
complications of progressive liver
disease must lie in achieving virological
control. data on the relationship between
the development of cirrhosis, Hcc and the
level of HbV replication are now starting
to become available and clearly establish
the association between increasing HbV
viral load and an increased risk of liver
disease and Hcc. Many uncertainties still
exist, such as: which patients will benefit
from therapeutic intervention; the optimal
time to initiate therapy; and the extent of
virological suppression required to reduce
disease progression. the expanding number
of effective agents and the availability of
increasingly sensitive tests which monitor the
natural history and the therapeutic response,
improves our knowledge and understanding
of this complex disease. still, the appropriate
1 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
identification, referral and management of
people with HbV infection within the primary
care setting will be key to preventing an
increasing future burden of chronic hepatitis
b disease in australia.
Gail Matthews
National Centre in HIV Epidemiology and Clinical Research

PREVALENCE AND
1
EPIDEMIOLOGY OF HEPATITIS B
Van TT Nguyen School of Public Health and Community Medicine, The University of New South Wales,
Kensington, New South Wales.
Gregory J Dore National Centre in HIV Epidemiology and Clinical Research, The University of New South Wales,
Darlinghurst, New South Wales.
Links: Chapter 5: Primary prevention of hepatitis B virus infection
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
KEY POINTS
� there is an estimate of 90,000 to 160,000 people with HbV chronic infection in australia.
� immigrants from highly endemic countries, such as china, Vietnam and other countries in asia
and Pacific islands, account for more than a half of chronic HbV infections.
� Higher rates of chronic HbV infection are also observed in indigenous populations, injecting
drug users and men who have sex with men.
� HbV vaccination uptake in at-risk populations and HbV treatment uptake among infected
populations are both low.
� a national Hepatitis b strategy encompassing public awareness campaigns, guidelines for HbV
testing and counselling, and strategies to increase treatment uptake is required to develop an
appropriate response to hepatitis b in australia.
Hepatitis B virus disease
epidemiology worldwide
Hepatitis b virus (HbV) infection remains a
major global public health problem, despite
the availability of a highly effective vaccine
and improvements in antiviral therapy.
Globally, of the two billion people previously
infected, more than 350 million people have
developed chronic HbV infection, causing
one million HbV-related deaths each year. 1
HbV infection varies according to geography,
with chronic HbV prevalence ranging from
0.2% to 20%. 2 approximately 45% of the
world’s population lives in highly endemic
areas, such as africa and the asia-Pacific
region (excluding Japan, australia and new
Zealand) (figure 1.1). 3
Ch
1 Final
refs
HBV prevalence in Australia and the
impact on its health system
the prevalence of chronic HbV infection
in australia has increased, predominantly
related to the increase in immigration
from highly endemic regions. 4,5 based on
a national laboratory-based serosurvey,
the number of chronic HbV infection cases
was estimated to be between 90,000 and
160,000, representing a 0.5–0.8% population
prevalence. 6 S.
doc
13/
02/
08
a hospital-based study found
M
5 Figures and 2 Tables
figure 1.1: Geographical distribution of hepatitis b virus endemicity
Figure 1.1. Geographical distribution of hepatitis B virus endemicity[3]
3
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 13
10000
9000
8000
20

5 Figures and 2 Tables
1 Prevalence and epidemiology of hepatitis B
Hbsag prevalence of 2.1%, with 70% of patients
with HbV infection born overseas. 7 Hepatitis
b diagnosis requires mandatory notification
in all australian states and territories. the
annual number of hepatitis b cases reported
to the national notifiable diseases surveillance
system varies from around 5000 in 1992 and
1993 to peaks of close to 9000 cases in 1994 and
1996, and around 6000 cases since 2003 (figure
1.2). 8 the majority of people with chronic HbV
infection come from four high-risk groups:
immigrants from highly endemic countries
(particularly north-east and south-east asia);
injecting drug users (idus); men who have sex
Figure 1.1. Geographical distribution of hepatitis B virus endemicity[3]
with men (MsM); and indigenous australians
(figure 1.3). 6
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
C1992
h 1 Fina1994
l refs
MS1996
. doc
13/
1998 02/
08
2000 2002 2004 2006
figure 1.2: notifications of chronic hepatitis b to the national
notifiable diseases system8 North-East Asian 16%
Figure 1.3. Estimates of proportions of total prevalence
chronic HbV infection in australia is contributing
to an increasing burden of advanced liver
disease, including hepatocellular carcinoma
(Hcc). 9-11 Hcc incidence and mortality rates
have been increasing over the last three
decades, particularly among overseas-born
males. 9,12,13 between 1978 and 1997, agestandardised
Hcc mortality rates increased
from 2.4 to 4.4 per 100,000 for overseas-born
males, and 0.6 to 1.4 per 100,000 for overseasborn
females. 12
14,000
105
12,000
90
10,000
75
8,000
60
6,000
45
4,000
30
2,000
15
0
0
HBV HCC
Figure 1.4. Estimated chronic hepatitis B virus prevalence and HBV-related
hepatocellular carcinoma incidence among China-born residents in Australia
HBV prevalence
Other 22%
figure 1.3: estimates of proportions of total prevalence 6
Indigenous 16%
Figure 1.2. Notifications of chronic hepatitis B to National Notifiable Diseases
System
IDU 5%
South-East Asian 33%
MSM 8%
8
1960
1964
1968
1972
1976
1980
1984
1988
1992
1996
2000
2004
2008
2012
2016
2020
2024
14 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
6
HCC incidence
5
Ch
1 Final
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in new south Wales, the incidence rate of liver
cancer in males per 100,000 increased from 2.0
in 1972 to 7.4 in 2004, and in females from 0.5
in 1972 to 2.9 in 2004. 14 despite the availability
and efficacy of the HbV vaccine, the prevalence
of chronic HbV infection and HbV-related Hcc
among australian residents born in the asia-
Pacific region has been projected to increase
in the next two decades. this is owed primarily
to the continued immigration from highly
endemic countries and the long latency of Hcc
development (figure 1.4). 5
Other 22%
South-East Asian 33%
6
IDU 5%
MSM 8%
North-East Asian 16%
Figure 1.3. Estimates of proportions of total prevalence
HBV prevalence
14,000
12,000
10,000
8,000
6,000
4,000
2,000
0
Indigenous 16%
1960
1964
1968
1972
1976
1980
1984
1988
1992
1996
2000
2004
2008
2012
2016
2020
2024
HBV HCC
figure 1.4: estimated chronic hepatitis b virus prevalence and hepatitis b
Figure 1.4. Estimated chronic hepatitis B virus prevalence and HBV-related
virus-related Hcc incidence among residents of australia born in china
hepatocellular carcinoma incidence among China-born residents in Australia
5
the economic burden related to chronic HbV
infection is substantial. the average annual
direct cost 21
per patient for managing HbV-
related liver disease has been estimated
at $1778 for active hepatitis, $1394 for
compensated cirrhosis and $11,753 for Hcc
(year 2001, a$). 15
HBV prevalence in specific
populations
Culturally and linguistically diverse
(CALD) communities
according to the 2001 census, 30% of the
australian population was born overseas, 24%
of which was born in asia, where HbV infection
is highly endemic. 16 although limited data are
available on HbV infection patterns within
caLd communities in australia, it is likely
that the HbV prevalence among immigrants
reflects infection patterns in their countries of
origin. studies conducted in several countries
have found that Hbsag prevalence among
asian immigrants and refugees is very similar
to the Hbsag prevalence in their countries
of origin. 17-29 for example, Hbsag prevalence
among Vietnamese immigrants and refugees in
several studies is 10.0–16.6%, 17-22 which reflects
105
90
75
60
45
30
15
0
HCC incidence
5
2

the prevalence in population-based studies in
Vietnam (10.0–19.5%). 30-39
immigration from highly endemic countries
has been the major contributor to the
increasing prevalence of chronic HbV infection
in australia. the five largest overseas-born
population groups include people from highly
HbV endemic countries, such as china and
Vietnam. 16 an estimated 50–65% of chronic
HbV infection cases in australia occur in
people born in asia, particularly immigrants
from china and Vietnam. 6,40 overseas-born
residents, particularly from asia, are also more
likely to develop Hcc compared to those born
in australia. 41 a recent linkage study found that
70% of HbV-related Hcc cases were in asianborn
residents, whose risk of developing Hcc
was estimated to be six times higher than
those born in australia. 13 another study found
that Hcc incidence (per 100,000) for nsW male
migrants who were born in mainland china,
taiwan, Hong Kong and Vietnam were 13.5
to 30.9, compared to 1.2 for australian-born
males. 42 increased relative risks for Hcc have
also been found among asian immigrants in
other Western countries. 43,44 Likewise, asianborn
residents have a higher risk of dying from
Hcc than australian-born residents. 45
immigrants from the Middle-east, the
Mediterranean region and africa also have a
higher rate of HbV infection than the general
australian population. People from the
Mediterranean region, the Middle east, the
Pacific islands and africa constituted 18% of
patients with chronic HbV infection in a liver
clinic in Melbourne. 6 in another hospitalbased
study, the adjusted odds ratio of HbV
infection was found to be six times higher in
immigrants from north africa, the Middle east
and the Mediterranean region as compared to
australian-born residents. 7
Meagre HbV knowledge, poor english literacy,
and differences in health beliefs and practices
are obstacles to health service access for
caLd communities. studies in the usa show
that Vietnamese immigrants have poor HbV
knowledge and low testing levels. 46-48 Low
levels of HbV screening and vaccination and
poor knowledge have also been documented
among chinese ethnic populations in the
usa and canada. 49,50 thus, an improved
understanding of hepatitis b, particularly
among immigrants from asia-Pacific countries,
together with an increased awareness of the
need for HbV testing of high-risk groups among
general practitioners and other primary health
care practitioners is required.
Aboriginal and Torres Strait
Islander peoples
While aboriginal and torres strait islander
peoples account for only 2.4% of the australian
population (2001 census), they account for 16%
of chronic HbV infections. 16,6 the prevalence
of Hbsag in the aboriginal and torres strait
islander population ranges from 3.6% to 26.0%,
according to place of residence and age group
(table 1.1). 51-61 Hbsag prevalence increases
with age and is highest in people living in
remote areas. 52 despite the availability of the
HbV vaccine and the implementation of ‘catchup‘
vaccine programs, a significant proportion
of aboriginal and torres strait islander children
are still at risk. a study in north Queensland in
2000 found that only 44% of aboriginal and
torres strait islander teenagers had completed
HbV vaccination. 58 More than 90% of the
incompletely vaccinated teenagers had markers
of HbV infection (anti-Hbc positive), with 26%
having active HbV infection (Hbsag positive). in
addition, levels of HbV immunity, even among
aboriginal and torres strait islander children
fully vaccinated in infancy, have been shown
to be sub-optimal. 62,63 thus, poor vaccine
coverage and low immune responses among
aboriginal and torres strait islander children
should be considered for the implementation
of HbV control measures.
a higher risk of liver cancer among the
aboriginal and torres strait islander population
indicates a higher burden of chronic liver
disease, including HbV. 64 the population-based
incidence of Hcc is five to ten times higher
than in the non-indigenous population. 65 the
rate ratios of age-standardised liver cancer
incidence between indigenous and nonindigenous
australians were 9.8 for males and
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 15

1 Prevalence and epidemiology of hepatitis B
7.4 for females in the northern territory, and
5.7 for males and 10.0 for females in south
australia. 66 in one study, more than 60% of
aboriginal and torres strait islander Hcc cases
were Hbsag positive, indicating that HbV is
the major cause of Hcc among aboriginal and
torres strait islander people. 65
aboriginal and torres strait islander people are
not only at high risk of HbV infection, but also
have difficulties in accessing health services.
the major factors affecting indigenous access
are remote residence, lack of transport and
shortage of health professionals. More than
16 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
a quarter of the aboriginal and torres strait
islander population live in remote areas and
78% of remote aboriginal and torres strait
islander communities are located more than
50km from the nearest hospital. 67 the number
of medical practitioners, particularly specialist
clinicians in remote areas is very low (29 per
100,000) compared to major cities (114 per
100,000). 67 other factors, including cultural
perceptions, low levels of education and limited
private health insurance, are also barriers to
accessing health services in aboriginal and
torres strait islander communities.
table 1.1: Prevalence of Hbsag in the indigenous population in australia51-61 references study population (n) study setting Prevalence of Hbsag+ (%)
burrell cJ et al. 198359 aboriginal (327) south australia 26.0
barrett eJ, 1972 60
aboriginal adults (160)
aboriginal children (731)
torres strait islander adults
(79)
barrett eJ, 1976 61 aboriginal (2193)
Moore et al. 1987 51 aboriginal women (816)
Holman et al. 1987 52
aboriginal population aged
12 or older (1150)
campbell et al. 1989 54 aboriginal (375)
Gill et al. 1990 56 aboriginal children (277)
campbell et al. 1991 53
aboriginal children aged
0-16 years (408)
Gardner et al. 1992 57 aboriginal children (439)
Patterson et al. 1993 55 aboriginal (98)
Malcolm et al. 2000 58
indigenous teenagers
(132 incomplete
vaccination)
Queensland
Queensland
and
northern
territory
nonmetropolitan
Western
australia
Western
australia
north-Western
new south
Wales
Kimberley
Western
australia
Western new
south Wales
northern
territory
condobolin
new south
Wales (urban)
north
Queensland
8.1
3.4
13.9
6.1
3.6
7.0 (3.0-22.0)
19.2
6.1
14.0
8.2
16.9 (1983-1984)
6.0 (1987-1988)
26.0

Injecting drug users
People who inject drugs are at high risk of
HbV infection. an estimated 200,000 people
inject drugs in australia 6 and half of regular
injecting drug users (idus) have markers
of HbV infection (table 1.2). 68-70 idus also
contribute significantly to the number of
newly acquired HbV cases in australia (figure
1.5). 71 the prevalence of Hbsag is considerably
lower than that of anti-Hbc (2% versus
40–50%), 68,72 due to high rates of spontaneous
Hbsag clearance among adolescents and young
adults, and explains the considerably lower
proportion of idu cases among the population
with chronic HbV infection, compared to the
population with newly acquired HbV infection
in australia (5% versus 44%). an estimated
4000 idus have chronic HbV infection. 6 a
table 1.2: Prevalence and incidence of hepatitis b virus infection in injecting drug users and
68-70, 72-76
prisoners
references
study
population
Prevalence of
anti-Hbc (%)
crofts n et al. 1994 68 idus 47.0 1.8
Prevalence of
Hbsag+ (%)
crofts n et al. 1997 69 idus 52.4 1.8
cook Pa et al. 2001 76 idus 26.6
Maher L et al. 2004 72 idus 28.0 2.7
crofts n et al. 1995 73 Prisoners 32.5 2.6 12.6
butler tG et al. 1997 74 Prisoners 31.0 3.2
butler tG et al. 1999 70 Prisoners 35.0
Ch
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butler tG et al. 2005 75 Prisoners 31.0 3.0
Other/unknown 19%
IDU 44%
Heterosexual 28%
MSM 7%
Figure 1.5. Risk factors among groups with newly acquired hepatitis B virus (2002-
2003) 71
figure 1.5: risk factors among newly acquired HbV (2002-2003) 71
similar pattern of HbV infection was found in
prisoners, 44%–46% of whom are idus. 70,73
a third of prisoners have markers of HbV
infection and around 3.0% are Hbsag positive
(table 1.2). 68-70,72-76 notably, only 5% of prisoners
reported having been immunised against HbV. 73
Long-term injecting, having been to prison,
and injecting in prison are independently
associated with HbV infection. 70,76
Limited data are available on the prevalence of
HbV-HcV coinfection in idus. one study of 360
idus found that 20% had markers of infection
for both HbV and HcV (anti-Hbc and anti-HcV
antibody positive), while rates of chronic HbVchronic
HcV co-infection are considerably
lower, at around 1–2%. 76
22
HbV infection
incidence (per 100
person years)
Poor knowledge of HbV infection, poor HbV
vaccine uptake, and high-risk behaviours in idus
all contribute to high levels of HbV exposure. at
the time of a recent study, around a third (30–
36%) of idus had reused injecting equipment
in recent months. 69,77 HbV vaccination uptake
and completion rates are low. 78 a recent
national survey found that only a third of drug
and alcohol agencies in australia routinely
provide HbV testing and vaccination onsite,
and a quarter of the agencies did not offer
this service at all. 79 in addition, the high stigma
relating to injecting drug use often precludes
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 17

1 Prevalence and epidemiology of hepatitis B
idus from accessing health services. education
about hepatitis b risk factors, increased access
to HbV testing, and vaccination for idus are
required to reduce the prevalence of HbV
infection in this group.
Men who have sex with men
the prevalence of HbV infection in MsM
is higher than in the general population.
during the 1980s, the prevalence of HbV
infection among MsM ranged from 34.0% to
81.7%, while Hbsag prevalence was 3.0% to
8.7%. 80-87 in the usa, an estimated 15–20% of
all new HbV infections are in MsM. 88
although an HbV vaccine has been available for
two decades, coverage rates in MsM populations
are low. studies have demonstrated coverage
rates of 9% in the united Kingdom, 25–26%
in the usa, and 53% in australia (sydney). 89-92
a high prevalence of HbV infection is found
among unvaccinated MsM: around 38.0% have
markers of HbV infection and 4.2% are Hbsag
positive. 89,93
factors associated with poor HbV vaccination
coverage in MsM include a lack of knowledge
of HbV infection and HbV vaccination, the high
cost of vaccine, a low level of education and
injecting drug use. 94-96
unsafe behaviours, such as reusing injecting
equipment and unprotected sex, continue to
be risk factors for HbV infection among MsM.
the duration of sexual activity, the number
of partners, oro-anal and genito-anal sexual
contacts, the lifetime number of sexually
transmissible infections, and injecting drug use
are associated with HbV infection. 89,92,97
the MsM population in australia is estimated
at 300,000 (including men who identify as
gay or homosexual and men who identify
as heterosexual but have some history of
sexual contact with other men). 98 due to the
availability of a HbV vaccine and the increased
adoption of safer sex practices, the prevalence
of HbV infection among MsM decreased
from 61% in 1982 to 38% in 1991. 93 However,
ongoing high-risk behaviour 99,100 and low
18 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
rates of HbV vaccination as outlined in recent
studies 91 suggest that MsM remain a highrisk
population. appropriate HbV vaccination
strategies and education about the risk factors
for HbV transmission are required in order to
prevent infection among MsM.
Increasing the burden of HBV-related
liver disease
since the 1970s, increased immigration from
highly endemic HbV countries, particularly
from the asia-Pacific region, has produced an
increasing prevalence of chronic HbV infection
in australia. although population-level HbV
vaccination programs in highly endemic HbV
countries will eventually reduce the HbV
prevalence among immigrants to australia, the
late introduction of these programs in many
countries (e.g. in Vietnam and china in 2000)
means the burden of chronic HbV infection is
likely to continue to rise. this increasing burden
of chronic HbV infection will produce an
increasing incidence of advanced liver disease
(including Hcc) over the coming two decades.
for example, among australians of chinese
origin, the number of HbV-related Hcc cases
is projected to more than double over the
period 2005 to 2025 (see figure 1.4). 5 similar
trends are expected for other high-risk groups
such as Vietnamese-born australians. However,
the improved uptake of HbV therapy has the
potential to limit these trends.
Public health response to hepatitis B
While effective national strategies for HiV and
hepatitis c have been adopted, the public
health response to HbV is very limited and
relies predominantly on universal infant
hepatitis b vaccination. the number of people
with hepatitis b is projected to increase due to
continuing immigration from high endemic
countries and sub-optimal vaccine coverage
among high-risk populations (idus, MsM,
aboriginal and torres strait islander peoples).
to reduce the impact of hepatitis b infection, a
national strategy should be developed focusing
on enhanced HbV prevention, education and
improvement of diagnosis, treatment and care.

the implementation of hepatitis b prevention
and education is crucial to increase public
awareness of hepatitis b including the
risk factors for transmission, measures for
prevention, and the availability of therapy.
these programs should be designed
specifically for at-risk populations, such as
caLd communities, the aboriginal and torres
strait islander populations, idus, MsM, and
prisoners.
the increasing number of people with chronic
HbV infection and the improved availability
of HbV therapy mandate an enhanced
response to treatment and care. this response
should include national guidelines for HbV
diagnosis and monitoring. the establishment
of community hepatitis clinics and the
enhancement of GP shared-care models in
areas with large asian and aboriginal and torres
strait islander populations is also a priority.
finally, barriers to health care service access
among idus, MsM, caLd and aboriginal and
torres strait islander communities include
stigma and discrimination related to high-risk
behaviours, the lack of english proficiency,
and cultural differences. therefore, besides
providing training and essential information
related to hepatitis b for primary care
practitioners, improving their understanding
of health beliefs, language difficulties, and the
cultural attitudes of affected populations is also
crucial to facilitating access to health services
for at-risk groups.
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b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 3

VIROLOGY: VIRAL REPLICATION
AND DRUG RESISTANCE
Stephen Locarnini Victorian Infectious Diseases Reference Laboratory, North Melbourne, Victoria.
Links to: Chapter 7: Treatment of chronic hepatitis B virus infection
KEY POINTS
� the two key events in the viral life cycle of the hepatitis b virus (HbV) are the generation from
genomic dna of the covalently closed circular dna transcriptional template and the reverse
transcription of the viral pregenomic rna to form the HbV dna genome.
� since the virus employs reverse transcription to copy its genome, mutations in the viral genomes
are frequently found. Particular selection pressures, both endogenous (host immune clearance)
and exogenous (vaccines and antivirals), readily select out escape mutants.
� the introduction of nucleoside/nucleotide analogue therapy has seen the emergence of drug
resistance as the major factor limiting drug efficacy.
� the development of drug resistance is not unexpected if viral replication continues in the setting
of ongoing treatment, especially monotherapy.
� Prevention of resistance requires the adoption of strategies that effectively control virus
replication.
Introduction and pathogenesis
the hepatitis b virus (HbV) is a highly evolved
pathogen and, under normal circumstances,
viral infection and subsequent replication
within hepatocytes is not cytopathic. thus,
the replication of the virus in hepatocytes in
the liver does not directly cause cell death. the
liver damage associated with acute or chronic
hepatitis b (cHb) occurs mainly as a result
of attempts by the host’s immune response
to clear HbV from infected hepatocytes. 1 in
particular, it is the adaptive immune response
arm, the cd4+ and cd8+ t-cells responding to
HbV antigens on virus-infected cells, and not
the virus directly, that causes most of the liver
damage in cHb.
the HbV is a member of the family
Hepadnaviridae. the hallmarks of viruses of the
Hepadnaviridae family include a dna genome,
which is copied by a virus-specific reverse
transcriptase (rt), and the production of excess
viral coat/envelope material, the hepatitis b
4 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
surface antigen (Hbsag). the important point
to note is that viral reverse transcriptases lack a
proof-reading capacity and so, by using reverse
transcription to copy its genome (rna � dna),
substantial ‘errors’ (or diversity) are made in
the progeny viruses from a single round of
replication. this diversity ensures the survival
of HbV because, as its environment changes
due to the introduction of an antiviral agent,
a resistant viral sub-population will already
be present in the pool of newly replicating
HbVs in that patient. not surprisingly then, a
number of immune or antiviral drug ‘escape’
(resistant) mutants of HbV are selected out as
the new dominant populations, whenever a
new selection pressure (in immune response
or nucleoside analogue) is stimulated or
introduced.
HBV replication: the virus and
its life cycle
the HbV is a dna virus. the viral dna is found
inside the viral core structure (or hepatitis

core antigen [Hbcag]) with the viral
reverse transcriptase/dna polymerase.
this core structure is then surrounded
by its envelope, the hepatitis b surface
antigen (Hbsag). the life cycle of HbV
begins when its envelope protein attaches
to a receptor on the hepatocyte cell
surface. this allows the virus to enter the
cell. the viral core structure is transported
to the nucleus where the viral genomic
dna is converted into a covalently
closed circular (ccc) dna form, the major
transcriptional template of the virus.
using host cell enzymatic machinery, viral
rna is made and transported out to the
cytoplasm of the hepatocyte where the
viral structural proteins (core [Hbcag]
and surface [Hbsag]) are made, as well
as the replication protein, HbV reverse
transcriptase/dna polymerase. the HbV
reverse transcriptase (rt) then copies the
HbV pregenomic (pg) rna to dna inside
the core particle. the viral envelope
proteins now coat those replicating core
complexes, and mature virions are made and
then released from the cell, completing the
life cycle (figure 2.1). the only viral enzyme
HBV rt HBV
HBsAg
HBcAg
HBsAg
HBV RC DNA
HBV DNA
REVERSE
TRANSCRIPTION
HBV Virions
Figure 2.1
HBcAg
Replicating
Cores
HBV rt
HBV RNA
HBV RC DNA
figure 2.1: Life-cycle of the hepatitis b virus from entry (at the top) to
exiting the cell (shown at the bottom)
identified to date is the viral rt and this is the
target for nucleoside analogue (na) therapy.
the HbV dna genome is organised into four
overlapping open reading frames (orf), the
longest of which encodes the viral reverse
transcriptase/dna polymerase (Pol orf)
(figure 2.2 a). the envelope orf is located
within the Pol orf, while the core (c) and the X
orfs partially overlap with it (figure 2.2 b).
RNA
HBcAg
HBV cccDNA
RNA
RNA
HBV rt
Figure 2.2
B: HBV polymerase-HBsAg link
Polymerase
A: HBV genome
Entecavir Telbivudine
Adefovir Lamivudine
X XX
X X
Terminal Protein Spacer
G F A B C D E RNAse H
Surface PreS1 Pre
S2
figure 2.2 a: Hepatitis b virus (HbV) dna genome showing the circular
arrangement of the four overlapping but frame-shifted
reading frames
figure 2.2 b: the hepatitis b virus polymerase–Hbsag link, demonstrating
the changes observed in the HbV Pol due to the emergence
of drug-resistance, affect the Hbsag directly for all four
nucleos(t)ide analogues approved for chronic hepatitis b
treatment
the life cycle of HbV revolves around two key
processes (figure 2.3):
� Generation of HbV ccc dna from genomic
dna and its subsequent processing by host
enzymes to produce viral rna; and
� reverse transcription of the pregenomic (pg)
rna within the viral nucleocapsid to form
HbV dna, completing the cycle (see figure
2.1).
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 5
S
X X X
Figure 2.3 Intrahepatic
Covalently Closed
(-) (+)
HBV Pol
(-)
Genomic DNA
[HBV RC DNA]
HBV Minus (-) DNA
[Inside Viral Nucleocapsids]
Host DNA Repair Enzymes
HBV DNA Polymerase/
Reverse Transcriptase
[HBV Pol]
Circular (ccc) DNA
[Viral
Minichromosomes]
Host RNA
Polymerase II
Pregenomic HBV
(pg) RNA
AAAA
[Cytoplasm of infected hepatocytes]
figure 2.3: Major processes involved in hepatitis b virus genome
replication: conversion of rc dna into ccc dna; transcription
of ccc dna to produce pgrna; reverse transcription
of pgrna to make minus (-) HbV dna; and HbV dna
polymerase activity to make the rc dna, completing the
cycle. the ccc dna can only be found in the liver within the
nucleus of infected hepatocytes and in the form of a viral
minichromosome 2,3

2 Virology: viral replication and drug resistance
as discussed previously, because HbV uses
reverse transcription to copy its genome (rna
� dna) and the viral rt lacks a proof-reading or
editing function, many ‘mistakes’ are introduced
into the newly replicated HbV dna, resulting
in substantial diversity in the viral genome. as
discussed below, this gives the virus a great
survival advantage as every single nucleotide
in the viral genome of 3200 base-pairs is
mutated or changed every day. thus, single
and double mutations associated with antiviral
drug resistance exist even before therapy is
introduced. However, three or four mutations in
the HbV dna that would be needed to escape
na treatment are very unlikely to be found
pre-therapy. these observations are the basis
for the use of combination chemotherapy for
chronic viral diseases (such as HiV, aids, e.g.:
Highly active antiretroviral therapy [Haart]).
Common mutants of HBV
1. Mutations affecting HBeAg
as well as Hbcag and Hbsag, the HbV also
encodes for an accessory protein, the hepatitis
b e antigen (Hbeag). the Hbeag protein is a
soluble form of the Hbcag and is thought to
act as a tolerogen. 4 the Hbeag is classified as
an accessory protein of HbV, since the virus
can replicate without an Hbeag. However, the
production of Hbeag is an important strategy
for the virus to help avoid immune elimination
by the host’s immunological response. When
put under the immunological pressure of
Hbeag seroconversion, which is part of the
natural history of cHb, HbV has a number of
ways of ‘escaping’ such pressure.
two major groups of mutations have been
identified which result in reduced or blocked
Hbeag expression.
the first group refers to mutations that affect
the basal core promoter (bcP) typically at
nucleotide (nt)1762 and nt1764, resulting
in a transcriptional reduction of the Pre-c/
cmrna. 5 Mutations in the bcP, such as a1762t
plus G1764a, may be found in isolation or
in conjunction with precore mutations (see
below). the double mutation of a1762t plus
G1764a results in a significant decrease in
6 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Hbeag levels and has been associated with
an increase in viral load. importantly, these
bcP mutations do not affect the transcription
of HbV pg rna or the translation of the core
or polymerase protein. thus, by removing the
inhibitory effect of the precore protein on
HbV replication, the bcP mutations appear to
enhance viral replication by suppressing Pre-c/
c mrna relative to pregenomic rna. 5
the second group of mutations includes
HbV mutants with a translational stop codon
mutation at nt position 1896 (codon 28: tGG;
tryptophan) of the precore gene. 6 the single
base substitution (G-to-a) at nt1896 gives rise
to a translational stop codon (tGG to taG;
taG = stop codon) in the second last codon
(codon 28) of the precore gene located within
the ε structure of pgrna. the ntG1896 forms a
base pair with nt1858 at the base of the stem
loop. 6 other mutations have been found within
the precore transcript, which block Hbeag
production, including the abolition of the
initiation codon methionine residue. 7
2. Envelope gene mutations
Viral genomes that cannot synthesise the
envelope proteins have been found to occur
frequently and are often the dominant virus
populations in patients with chronic hepatitis
b. 8 the envelope region overlaps the Pol protein
(figures 2.2 a and 2.2 b).
the existing hepatitis b vaccine contains
the major Hbsag. the subsequent anti-Hbs
response to the major hydrophilic region
(MHr) of Hbsag located from residue 99 to
170 induces protective immunity. Mutations
within this epitope have been selected during
vaccination 9 and following treatment of liver
transplant recipients with hepatitis b immune
globulin (Hbig) prophylaxis. 10 Most vaccine-
Hbig escape isolates have an amino acid
change from glycine to arginine at residue 145
of Hbsag (sG145r) or aspartate to alanine at
residue 144 (sd144a). the sG145r mutation
has been associated with vaccine failure 9 and
has been shown to be transmitted and cause
disease.

3. Polymerase mutations: antiviral
drug resistance
antiviral drug resistance in clinical practice is
discussed further in chapter 7: treatment of
chronic hepatitis b virus infection.
as a result of the development of safe and
efficacious orally available antiviral nucleoside
and nucleotide analogues (na), the treatment
of cHb has advanced significantly during
the past ten years. Lamivudine, a synthetic
deoxycytidine analogue with an unnatural
L-conformation, is the first of these na and
gained approval from the food and drug
administration (fda) of the usa for treatment
of cHb in 1996. related L-nucleosides, including
emtricitabine, telbivudine and clevudine, have
since progressed to late stage clinical trials.
adefovir dipivoxil, a prodrug for the acyclic
daMP analogue, adefovir, gained approval in
2002 and clinical trials of structurally similar
tenofovir disoproxil fumarate, which is currently
used to treat HiV infection, are underway. the
most potent anti-HbV drug discovered to date
is the deoxyguanosine analogue, entecavir, 11
which has recently been approved by the fda
for first-line use against HbV. telbivudine (Ldt)
has also been recently approved for the
treatment of cHb.
(a) Lamivudine and other L-nucleoside
analogue resistance
antiviral resistance to lamivudine (LMV) has
been mapped to the yMdd locus in the catalytic
or c domain of HbV Pol. 12 the mutations within
the rt gene that have been selected during
LMV therapy encode amino acid changes,
which are designated rtM204i/V/s (domain c)
+/- rtL180M (domain b) 12 with mutations in
other regions of the HbV Pol being detected
(figure 2.4). for other L-nucleosides, such as
telbivudine (L-dt), the b-domain (rta181t/V)
and c-domain (rtM204i), changes are most
important for the development of resistance
(figure 2.4).
LMV resistance increases progressively during
treatment at rates between 14% and 32%
annually. at four years of therapy, rates of LMV
resistance reach 70% in HbV monoinfection
Figure 2.4
HBV Pol: primary resistance mutations
Terminal
Protein
Spacer POL/RT RNaseH
1 183 349 (rt1) 692 (rt 344) 845 a.a.
I(G) II(F)
F__V__LLAQ__ YMDD
A B C D
E
LMV Resistance rtA181T/V rtM204V/I
L-dT Resistance rtA181T/V rtM204I
ADV Resistance rtA181T/V rtN236T
TDF Resistance rtL180M rtA181T/V rtA194T/rtM204V/I rtN236T
ETV Resistance rtI169T rtL180M rtS184S/A/I/L/G/C/M
rtS202C/G/I rtM204V rtM250I/V
figure 2.4: the location of the major primary antiviral drug-resistant
mutations associated with lamivudine (LMV), telbivudine
(L-dt), adefovir (adV), tenofovir (tdf), and entecavir (etV)
resistance in the major catalytic domains of the hepatitis b
virus polymerase gene
and exceed 90% in HbV-HiV coinfection. 13,14
factors that increase the risk of development
of resistance include high pre-therapy serum
HbV dna and alanine aminotransferase (aLt)
levels, and incomplete suppression of viral
replication. 13,15 LMV resistance does not confer
cross-resistance to adefovir (table 2.1).
table 2.1: summary of cross-resistance profiles
LMV/ftc adV/tdf L-dt etV
LMV-r X √ X reduced
adV-r √ X √ √
Ldt-r X √ X √
etV-r X √ X X
LMV = lamivudine L-dt = telbivudine
ftc = emtricitabine etV = entecavir
adV = adefovir r = resistant
tdf = tenofovir
X = resistant √ = sensitive
Mutations that confer LMV resistance decrease
in vitro sensitivity to LMV from at least 100fold
to greater than 1000-fold. the rtM204i
substitution has been detected in isolation,
but rtM204V and rtM204s are found only
in association with other changes in the
b or a domains. 16 the four major patterns
of resistance can be identified as follows:
1) rtM204i;
2) rtL180M+rtM204V;
3) rtL180M+rtM204i; and
4) rtV173L+rtL180M+rtM204V.
(b) Adefovir dipivoxil resistance
resistance to adefovir dipivoxil (adV) was
initially associated with changes in the b
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 7

2 Virology: viral replication and drug resistance
(rta181t/V) and d (n236t)-domains of the
reverse transcriptase 17 (figure 2.4). HbV
resistance to adefovir occurs less frequently
(around 2% after two years, 4% after three
years and 18% after four years) than resistance
to LMV. these adV-associated mutations in
HbV Pol result in only a modest (three- to eightfold)
increase in ic50 and provide partial crossresistance
to tenofovir. the rtn236t change
does not significantly affect sensitivity to LMV 17
but the rta181t/V change confers partial crossresistance
to LMV.
(c) Entecavir resistance
resistance to entecavir (etV) has been
observed in patients who were also LMVresistant.
18 Mutations in the viral polymerase
associated with the emergence of etV-
resistance were mapped to the b-domain
(rti169t or rts184G and rtL180M), c-domain
(rts202i and rtM204V), and e-domain (rtM250V)
of HbV Pol (figure 2.4). in the absence of the
LMV mutations, the rtM250V causes a nine-fold
increase in ic50, while the rtt184G+rts202i have
no effect. 18-21
(d) Multi-drug resistance
recently, multidrug-resistant HbV has been
reported in patients who received sequential
treatment with na monotherapies. 18,22-26
the development of multidrug resistance
will almost certainly have implications on
the efficacy of rescue therapy, as in the case
of multidrug-resistant HiV. 27,28 successive
evolutions of different patterns of resistant
mutations have been reported during longterm
LMV monotherapy. 29,30 the isolates of
HbV with these initial mutations appear to be
associated with decreased replication fitness
compared with wild-type HbV; however, as
treatment is continued, additional mutations
that can restore replication fitness are
frequently detected. 31,32
(e) Public health issues: Pol-env
overlap
the polymerase gene overlaps the envelope
gene (see figure 2.2 b) and changes in the HbV
Pol selected during antiviral resistance can
cause concomitant changes to the overlapping
reading frame of the envelope. thus, the major
resistance mutations associated with LMV, adV,
etV, and L-dt failure also have the potential of
8 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
altering the c-terminal region of Hbsag. for
example, changes associated with LMV and
etV resistance, such as the rtM204V, result in a
change at si195M in the surface antigen, while
the rtM204i change that is associated with LMV
and L-dt, is linked to three possible changes,
sW196s, sW196L or a termination codon. to
date, only one published study has examined
the effect of the main LMV resistance mutations
on the altered antigenicity of Hbsag. 33 one of
the common HbV quasispecies that is selected
during LMV treatment is rtV173L + rtL180M +
rtM204V, which results in change in the Hbsag
at se164d + si195M. approximately 20% of
people with HiV-HbV co-infection 14 and 10%
of those with mono-infection encode this
‘triple Pol mutant’. 31 in binding assays, Hbsag
expressing these LMV-resistant associated
residues had reduced anti-Hbs binding. 33 this
reduction was similar to the classical vaccine
escape mutant, sG145r.
the adV resistance mutation rtn236t does not
affect the envelope gene and overlaps with the
stop codon at the end of the envelope gene.
the rta181t mutation selected by adV and LMV
results in a stop codon mutation at sW172stop.
the adV resistant mutation at rta181V results
in a change at sL173f. the HbV with mutations
that result in a stop codon in the envelope
gene, such as those for LMV and adV, would be
present in association with a low percentage of
wild-type to enable viral assembly and release.
the etV resistance-associated changes at
rti169t, rts184G and rts202i also affect Hbsag
and result in changes at sf161L, sL/V176G, and
sV194f. the rtM250V is located after the end of
Hbsag. the sf161L is located within the region
that was defined as the ‘a’ determinant or major
hydrophilic region, which includes amino acids
90 to 170 of the Hbsag. 34 this region is a highly
conformational epitope, characterised by
multiple di-sulphide bonds formed from sets
of cysteines at residues 107-138, 137-149, and
139-147. 34 since distal substitutions such as
se164d significantly affect anti-Hbs binding, 33
the influence of other changes to Hbsag driven
by na resistance, (such as sf161L), needs further
investigation in order to determine the effect
on the envelope structure and subsequent
anti-Hbs binding. the Hbsag change linked to
rtM204V has already been covered.

although evidence for the spread of
transmission of antiviral-resistant HbV is limited,
there has been a report of the transmission of
LMV-resistant HbV to a HiV patient undergoing
LMV as part of antiretroviral therapy. 35
in addition, HbV encoding LMV resistant
mutations was also found in a cohort of dialysis
patients with occult HbV. 36 therefore, it is
important to recognise that both primary and
compensatory antiviral-resistant mutations
may result in associated changes to the viral
envelope that could have substantial public
health relevance.
Conclusions
resistance will remain an important issue in
the management of patients with cHb because
long-term, or probably life-long, therapy with
nas will be required in the majority of patients.
one of the important lessons learned from the
HiV paradigm is that resistance will occur if viral
replication is present during treatment, as may
occur with existing monotherapy regimens. 37
combination therapy for cHb, either as an
initial strategy or in selected groups of patients
with inadequate response to monotherapy, is
likely to be required in the future, and clinical
trials are currently underway to investigate
combination treatment strategies. theoretically,
combination therapy is likely to reduce not
only the viral load and quasispecies pool, but
also the risk of selecting resistance, especially
if differing resistance mutation profiles of the
various antiviral agents are used. another
strong argument for combination therapy is
that, because of the overlap between the Pol
and s genes, the selection of drug-resistant
HbV may have important clinical, diagnostic,
and public health implications. envelope
changes in HbV have been detected with LMV,
adV, etV, and L-dt usage. the significance of
these changes warrants further investigation
to determine what affect they may have on
the natural history of drug-resistant HbV and
its possible transmissibility in the hepatitis bvaccinated
community at large.
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3 newbold Je, Xin H, tencza M, sherman G,
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4 Milich dr, Jones Je, Hughes JL, Price J, raney
aK, McLachlan a. is a function of the secreted
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5 Hunt cM, McGill JM, allen Mi, condreay
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6 Lok as, akarca u, Greene s. Mutations in the
pre-core region of hepatitis b virus serve
to enhance the stability of the secondary
structure of the pre-genome encapsidation
signal. Proc natl acad sci usa 1994;91:4077-
81.
7 bartholomeusz a, schaefer s. Hepatitis b
virus genotypes: comparison of genotyping
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8 Gunther s, fischer L, Pult i, sterneck M, Will
H. naturally occurring variants of hepatitis b
virus. adv Virus res 1999;52:25-137.
9 carman Wf, Zanetti ar, Karayiannis P, Waters
J, Manzillo G, tanzi e, et al. Vaccine-induced
escape mutant of hepatitis b virus. Lancet
1990;336:325-9.
10 carman Wf, trautwein c, van deursen
fJ, colman K, dornan e, Mcintyre G, et al.
Hepatitis b virus envelope variation after
transplantation with and without hepatitis
b immune globulin prophylaxis. Hepatology
1996;24:489-93.
11 shaw t, Locarnini s. entecavir for the
treatment of chronic hepatitis b. expert rev
anti infect ther 2004;2:853-71.
12 stuyver LJ, Locarnini sa, Lok a, richman
dd, carman Wf, dienstag JL, schinazi rf.
nomenclature for antiviral-resistant human
hepatitis b virus mutations in the polymerase
region. Hepatology 2001;33:751-7.
13 Lai cL, dienstag J, schiff e, Leung nW,
atkins M, Hunt c, et al. Prevalence and
clinical correlates of yMdd variants during
lamivudine therapy for patients with chronic
hepatitis b. clin infect dis 2003;36:687-96.
14 Matthews GV, bartholomeusz a, Locarnini s,
et al. characteristics of drug resistant HbV
in an international collaborative study of
HiV-HbV-infected individuals on extended
lamivudine therapy. aids 2006;20(6):863-70.
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15 Leung n. clinical experience with lamivudine.
semin Liver dis 2002;22(suppl 1):s15-s21.
16 delaney Wet, Locarnini s, shaw t. resistance
of hepatitis b virus to antiviral drugs:
current aspects and directions for future
investigation. antivir chem chemother
2001;12:1-35.
17 angus P, Vaughan r, Xiong s, yang H,
delaney iV We, Gibbs c, et al. resistance to
adefovir dipivoxil therapy associated with
development of a novel mutation in the HbV
polymerase. Gastroenterol 2003;125:292-7.
18 tenney dJ, Levine sM, rose re, Walsh aW,
Weinheimer sP, discotto L, et al. clinical
emergence of entecavir-resistant hepatitis b
virus requires additional substitutions in virus
already resistant to Lamivudine. antimicrob
agents chemother 2004;48:3498-507.
19 bartholomeusz a, Locarnini s, ayres a,
thompson G, sozzi t, angus P, et al. Molecular
modelling of hepatitis b virus polymerase and
adefovir resistance identifies three clusters of
mutations (abstr). Hepatology 2004;40:246a.
20 Levine s, Hernandez d, yamanaka G, Zhang s,
rose r, Weinheimer s, colonno rJ. efficacies
of entecavir against lamivudine-resistant
hepatitis b virus replication and recombinant
polymerases in vitro. antimicrob agents
chemother 2002;46:2525-32.
21 Warner n, Locarnini s, colledge d, edwards r,
angus P, sievert W, et al. Molecular modelling
of entecavir resistant mutations in the
hepatitis b virus polymerase selected during
therapy (abstr). Hepatology 2004;40:245a.
22 brunelle Mn, Jacquard ac, Pichoud c,
durantel d, carrouee-durantel s, Villeneuve
JP, et al. susceptibility to antivirals of a
human HbV strain with mutations conferring
resistance to both lamivudine and adefovir.
Hepatology 2005;41:1391-8.
23 fung sK, andreone P, Han sH, rajender
reddy K, regev a, Keeffe eb, et al. adefovirresistant
hepatitis b can be associated with
viral rebound and hepatic decompensation.
J Hepatol 2005;43:937-43.
24 Mutimer d, Pillay d, cook P, ratcliffe d,
o’donnell K, dowling d, et al. selection
of multiresistant hepatitis b virus during
sequential nucleoside-analogue therapy. J
infect dis 2000;181:713-6.
25 Villet s, Pichoud c, aurelie o, Villeneuve JP,
trepo c, Zoulim f. sequential antiviral therapy
leads to the emergence of multiple drug
resistant hepatitis b virus (abstr). Hepatology
2005;42(suppl. 1):581a.
26 yim HJ, Hussain M, Liu y, Wong sn, fung sK,
Lok as. evolution of multi-drug resistant
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Hepatology 2006;44:703-12.
30 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
27 Gonzales MJ, Johnson e, dupnik KM,
imamichi t, shafer rW. colinearity of reverse
transcriptase inhibitor resistance mutations
detected by population-based sequencing.
J acquir immune defic syndr 2003;34:398-
402.
28 shafer rW, Winters Ma, Palmer s, Merigan tc.
Multiple concurrent reverse transcriptase and
protease mutations and multidrug resistance
of HiV-1 isolates from heavily treated patients.
ann intern Med 1998;128:906-11.
29 natsuizaka M, Hige s, ono y, ogawa K,
nakanishi M, chuma M, et al. Long-term
follow-up of chronic hepatitis b after the
emergence of mutations in the hepatitis
b virus polymerase region. J Viral Hepat
2005;12:154-9.
30 yeh ct, chien rn, chu cM, Liaw yf. clearance
of the original hepatitis b virus yMddmotif
mutants with emergence of distinct
lamivudine-resistant mutants during
prolonged lamivudine therapy. Hepatology
2000;31:1318-26.
31 delaney iV We, yang H, Westland ce, das K,
arnold e, Gibbs cs, et al. the hepatitis b virus
polymerase mutation rtV173L is selected
during lamivudine therapy and enhances viral
replication in vitro. J Virol 2003;77:11833-41.
32 ono sK, Kato n, shiratori y, Kato J, Goto t,
schinazi rf, et al. the polymerase L528M
mutation cooperates with nucleotide
binding-site mutations, increasing hepatitis
b virus replication and drug resistance. J clin
invest 2001;107:449-55.
33 torresi J, earnest-silveira L, deliyannis G, edgtton
K, Zhuang H, Locarnini sa, et al. reduced
antigenicity of the hepatitis b virus Hbsag
protein arising as a consequence of sequence
changes in the overlapping polymerase gene
that are selected by lamivudine therapy.
Virology 2002;293:305-13.
34 carman Wf. the clinical significance of
surface antigen variants of hepatitis b virus.
J Viral Hepat 1997;4:11-20.
35 thibault V, aubron-olivier c, agut H, Katlama
c. Primary infection with a lamivudineresistant
hepatitis b virus. aids 2002;16:131-3.
36 besisik f, Karaca c, akyuz f, Horosanli s, onel d,
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HcV infection. J Hepatol 2003;38:506-10.
37 richman dd. the impact of drug resistance on
the effectiveness of chemotherapy for chronic
hepatitis b. Hepatology 2000;32:866-7.

HEPATITIS B VIRUS TESTING AND
3
INTERPRETING TEST RESULTS
Mark Danta St Vincent’s Clinical School, The University of New South Wales, Darlinghurst, NSW.
Links to: Chapter 4: Natural history of chronic hepatitis B virus infection
Chapter 5: Primary prevention of hepatitis B virus infection
Chapter 6: Clinical assessment of patients with hepatitis B virus infection
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
Chapter 10: Managing hepatitis B virus infection in complex situations
KEY POINTS
� the management of hepatitis b virus (HbV) infection requires a complex interpretation of multiple
parameters.
� HbV dna testing has an important role in the evaluation of chronic HbV and the assessment of the
efficacy of antiviral therapy.
� HbV dna level is predictive of the development of cirrhosis and hepatocellular carcinoma (Hcc).
� non-invasive methods of assessing hepatic fibrosis are being developed.
� normal aLt level does not rule out significant hepatic disease.
Hepatitis b is a complex disease, which can
be defined using biochemical, serological,
virological, and histological parameters.
Management decisions are based on an
accurate interpretation of these parameters.
this chapter will detail the specific tests for
hepatitis b virus (HbV) infection, discussing
their interpretation and focusing
on who should be tested.
A
1. Markers of HBV
infection
the parameters used to define and
characterise HbV infection include:
HbV antigens and host antibodies;
HbV dna and genotype;
biochemical markers, such as
alanine aminotransferase (aLt);
and the degree of hepatic fibrosis
and inflammation (figure 3.1).
% % Maximum Maximum EE levation levation
Serum HBeAg
Serum HBsAg
100
Serum
HBV DNA Serum
ALT Activity
50
anti HBc
anti HBe
anti HBs
0
0
0 1 2 3 4 5
Months after Infection
6 7 8
0 10 20 21 30 31
Years after Infection
40 41 50
Incubation Acute Disease,
References
phase Clinical Symptoms
Recovery
Protective Immunity
Immunotolerance
Immunoactive
phase
Low replicative
phase
Reactivation
phase
1. Milich D, Liang TJ. Exploring the biological basis of hepatitis B e antigen in
hepatitis B virus infection. Hepatology 2003;38(5):1075-86.
figure 3.1: temporal changes in serological, virological and biochemical parameters in HbV. (a) acute
HbV and (b) chronic HbV infection1 H
Serological markers
Hepatitis B surface antigen (HBsAg)
Hbsag is an antigen on the three proteins that
make up the envelope of the HbV virion. it is
secreted as lipoprotein particles in excess of
virions by a ratio of greater than 1000:1. Hbsag
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 31
B
% % Maximum Maximum EE levation levation
anti HBc
Serum HBeAg anti HBe
Serum HBsAg
100
Serum
HBV DNA
50
Serum
ALT activity

3 Hepatitis B virus testing and interpreting test results
is usually detectable between week 4 and week
10 in acute infection. chronic HbV infection is
defined by the persistence of Hbsag for more
than six months.
Antibody to surface antigen (anti-HBs)
this is a protective antibody that develops with
the resolution of acute infection or following
the successful vaccination against HbV. Very
occasionally, anti-Hbs and Hbsag can be
found together, which has no known clinical
significance.
Antibody to core antigen
(anti-HBc)
the HbV core antigen is not found as a discrete
protein in the serum. it is produced in the
hepatocyte cytosol during HbV replication,
surrounding the viral genome and the
associated polymerase. it is then packaged
within an envelope before secretion from the
hepatocyte. the antibody to HbV core (anti-
Hbc) is an antibody to a peptide of this core
protein, which has been processed within an
antigen presenting cell. in acute infection,
anti-Hbc immunoglobulin M (igM) is found in
high concentrations which gradually decline,
complementing the corresponding increase in
anti-Hbc igG over a three to six month period.
elevation of anti-Hbc igM usually signifies
acute infection, but low elevations may also
occur during the reactivation of chronic HbV.
anti-Hbc igG remains positive for life following
exposure to HbV, however, unlike anti-Hbs,
anti-Hbc is not a protective antibody. Most
serological assays do not directly measure anti-
Hbc igG, but test for total anti-Hbc antibody.
Hepatitis B e antigen (HBeAg)
Hbeag is an accessory protein from the
precore region of the HbV genome, which is
not necessary for viral infection or replication. 1
it is, however, produced during active viral
replication and may act as an immunogen or a
tolerogen, leading to persistent infection.
Antibody to e antigen (anti-HBe)
While anti-Hbe is not a protective antibody, its
appearance usually coincides with a significant
immune change associated with lower HbV
3 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
dna replication (

dose response relationships with HbV dna
levels, which were independent of the Hbeag
status and the aLt level. importantly, the
risk of Hcc and cirrhosis started to increase
significantly at 10 4 copies/mL, 1 log lower than
the current level used to signify a low risk of
progression (10 5 copies/mL). these studies
also suggest that effective suppression of HbV
replication with antiviral therapy should be
expected to lower the incidence of significant
fibrosis and Hcc.
HbV dna testing is now a vital part of the
pre-treatment evaluation and assessment
of the efficacy of antiviral treatment. before
the introduction of HbV dna testing, Hbeag
was used as the biomarker of HbV replication.
However, it is clear that there is a population
with HbV infection with active replication (high
level HbV dna) who are Hbeag negative and
have ‘precore mutant’ HbV. this state occurs
as a result of a mutation in this region of the
HbV genome. a major problem with the use of
current antiviral therapy is the development
of resistance, characterised by a rise of ≥1 log
iu/mL in the HbV dna level while on therapy. 8
the development of treatment resistance has
important management implications. based on
increasing evidence of the importance of HbV
dna testing, the Medical services advisory
committee, within the department of Health
and ageing, recently approved HbV dna
testing, recommending one pre-treatment
assay for monitoring of patients not on antiviral
therapy and up to four assays over 12 months
for those on antiviral therapy. 9
HBV genotyping
Genotyping is determined by sequencing the
HbV genome. it is defined as a ≥ 4% divergence
in the s antigen and ≥ 8% divergence in the
entire nucleotide sequence. there are eight
currently recognised genotypes (a-H), which
vary geographically, with the four most
common genotypes being a–d. the most
prominent genotypes in the asia-Pacific region
are b and c. data now suggest that genotype
may have an important influence on disease
progression and treatment response. 10 While
the reasons are unclear, it appears that, in asian
populations, genotype b has increased rates
of Hbeag seroconversion, less aggressive liver
disease and lower rates of Hcc. 11 furthermore,
it has been observed that genotypes a and b
have better response rates to interferon when
compared to genotypes c and d. 12,13 currently,
genotyping is only a research tool; patients are
not routinely genotyped in australia. However,
it may become a relevant test in future clinical
practice, to identify patients at greater risk for
disease progression.
Biochemical markers
Alanine aminotransferase (ALT)
the main biochemical marker used in viral
hepatitis is the serum aLt level, used as a
surrogate marker for necroinflammation in
the liver. an elevated aLt is also associated
with better serological response to antiviral
treatment. However, some studies have
suggested that significant liver fibrosis can
occur in the context of a normal aLt level.
recent data show that between 12% and 43%
of patients with chronic HbV and normal aLt
levels have significant hepatic fibrosis (stage 2
fibrosis or greater). 14,15 in part this may relate
to what is currently considered a normal aLt.
it is likely that the original data to determine
normal reference ranges for aLt levels included
people with subclinical liver disease, which
led to an overestimation of what should be
considered a normal aLt level. a large study of
healthy blood donors revealed the upper limit
of normal for the serum aLt was 30 iu/L for
men and 19 iu/L for women, significantly lower
than our current range. 16
Histological markers
Liver biopsy
the two histological features on liver biopsy
used in the assessment of HbV are fibrosis (stage
of disease) and necroinflammation (grade of
disease). Liver fibrosis is usually graded from
0–4 (1=limited portal fibrosis; 2=periportal
fibrosis; 3=septal fibrosis linking portal tracts or
central vein; and 4=cirrhosis with development
of nodules and thick fibrous septa). Liver
biopsy, either performed percutaneously or
transjugularly in those with ascites or significant
coagulopathy, has been the gold-standard
investigation for determining the stage of HbV.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 33

3 Hepatitis B virus testing and interpreting test results
a number of different scoring systems have
been developed to stage fibrosis and grade
inflammation. Prominent among these are
the Histological activity index (Hai), the ishak
modified Hai, and the MetaVir system. 17-19 the
development of significant fibrosis (stage 2 or
greater) implies progressive disease and the
need for treatment. inflammation is graded on
necroinflammatory score.
Liver biopsy has, however, a number of
disadvantages. it is an invasive, uncomfortable,
costly and time-consuming procedure
that carries a small, but significant risk of
complications. for this reason, some patients
are unwilling to undergo the procedure. it also
suffers from sampling bias, as scarring and
necroinflammation may be heterogeneously
distributed in the liver.
table 3.1: serological, virological and biochemical profiles of hepatitis b virus
Hbsag anti-Hbs anti-Hbc
(total)
34 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Non-invasive assessment of
hepatic fibrosis
as a result of the problems associated with
liver biopsy, non-invasive techniques to
evaluate fibrosis, such as imaging-based
and serum-based analyses, have been
developed. a panel of blood tests that
describe hepatic fibrosis has been proposed
for chronic HbV. 20 However, rather than
describe specific levels of fibrosis, the serum
markers divide fibrosis into mild (MetaVir
score: < f2) and severe (≥ f2). currently, the
most widely validated non-invasive serumbased
tests are the fibrotest® and actitest®,
which use a combination of biochemical
markers: α2-macroglobulin, apolipoprotein
a, haptoglobin, gamma-glutamyltranspeptidase
(GGt), bilirubin (fibrotest®);
Β2-macroglobulin, apolipoprotein a,
haptoglobin, GGt, bilirubin and aLt
(actitest®).
anti-Hbc
igM
Hbeag anti-Hbe
HbV dna
(iu/mL)
Acute HBV + - + + + +/- High �
Natural HBV
immunity
(resolved infection)
- + + - - +/- absent n
Vaccination - + - - - - absent n
Chronic HBeAg positive
immune
tolerance phase
+ - + - + -
immune clearance phase + - + - + -/+
Chronic HBeAg negative
immune control phase + - + - - +
immune escape phase + - + - - +
>20,000
iu/mL
>20,000
iu/mL
(fluctuating)
2 000
iu/mL*
Occult HBV - - + - - +/- Very low n
Reactivation of HBV + - + +/- + +/-
+=positive, -=negative, n=normal, �=elevated.
* HbV dna cut-off levels may change in the future.
>20,000
iu/mL
aLt
n
�
n
�
�

fibroscan® uses ultrasound elastography to
measure liver stiffness. increasing hepatic
fibrosis leads to an increase in liver stiffness,
measured in kiloPascals (kPa). in a french HbVinfected
population (n=170), liver stiffness was
correlated with MetaVir fibrosis score of > 2
and > 3 area under receiver operated curve
(auroc) of 0.81 and 0.92 respectively, equating
to a likelihood of predicting an abnormal
result. 21 in another study of chronic HbV
patients (n=183) comparing non-invasive liver
elastography, fibrotest® and liver biopsy, the
best results were obtained using a combination
of fibroscan® and fibrotest® with auroc 0.88 ≥
stage 2 fibrosis, 0.95 ≥ stage 3 fibrosis and 0.95
= stage 4 fibrosis. 22 these tests will become
available in the future for the assessment and
monitoring of HbV patients.
2. Clinical interpretation
the clinical states of HbV can be characterised
using the serological, virological, biomedical
and histological markers of infection (table
3.1). the definition and characterisation of
the phases of chronic hepatitis b infection are
discussed in more detail in chapter 4: natural
history of chronic hepatitis b virus infection
and chapter 6: clinical assessment of patients
with HbV infection.
Who should be tested?
in australia, there are an estimated 90,000–
160,000 people with HbV infection. 23
individuals at high risk of HbV in developed
countries are those who immigrated from high
or intermediate prevalence countries or those
engaging in risky behaviours. 24-26 the majority
of people in australia with HbV infection were
born in endemic regions: 33% in south-east
asia and 16% in north-east asia. other highrisk
groups include indigenous australians,
men who have sex with men (MsM) and
injecting drug users, with rates of 16%, 8% and
5%, respectively. 23
australia does not currently have a national
HbV testing policy. recent guidelines by the
american association for the study of Liver
disease (aasLd) recommend screening
people born in high and intermediate
prevalence countries, including immigrants
and adopted children (table 3.2). 8 other highrisk
groups identified in the us guidelines
include: household and sexual contacts of
Hbsag-positive people; those with a history
of injecting drug use; people with multiple
sexual partners or any history of sexually
transmitted infection; MsM; prison inmates;
people with chronically elevated alanine and
aspartate aminotransferase (aLt/ast) levels;
people with HiV or HcV infection; patients
undergoing haemodialysis; pregnant women. 8
in australia, these recommendations should
also include indigenous australians. Highrisk
patients undergoing treatment with
immunosuppressive agents should also
be screened for HbV. seronegative people
(susceptible to infection) should be vaccinated.
table 3.2: countries of high to intermediate
HbV prevalence; people born in these
countries are at high risk for HbV infection
and should be screened 8
� asia (except sri Lanka)
� africa
� south Pacific islands (except non-indigenous
populations of australia and new Zealand)
� Middle east (except cyprus)
� europe: Greece, italy, Malta, Portugal and
spain
� eastern europe, all countries (except
Hungary)
� the arctic (indigenous populations)
� south america: argentina, bolivia, brazil,
ecuador, Guyana, suriname, Venezuela, and
the amazon region of colombia and Peru
� central america: belize, Guatemala,
Honduras, Panama
� caribbean: antigua and bermuda, dominica,
the dominican republic, Granada, Haiti,
Jamaica, Puerto rico, st Kitts and nevis, st
Lucia, st Vincent and Grenadines, trinidad
and tobago, turks and caicos
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 35

3 Hepatitis B virus testing and interpreting test results
testing usually involves evaluation of Hbsag
and anti-Hbs. alternatively, anti-Hbc can also
be tested, but needs follow-up with Hbsag
and anti-Hbs testing. if Hbsag is positive, then
further investigation is appropriate with anti-
Hbc, Hbeag, anti-Hbe and aLt. HbV dna assays
are now available and should be used in the
assessment and management of all patients
with HbV infection.
Pre-test and post- test
discussion
Providing support and information about the
HbV testing procedure assists in minimising
the personal impact on the patient of a positive
diagnosis, changing health-related behaviour
and reducing anxiety. Pre-test and post-test
discussion forms an integral part of testing
and should be relevant to the patient’s gender,
cultural beliefs and practices, behaviour and
language. 27 this includes considering local
and cultural issues such as stigma, shame and
concerns around confidentiality.
Pre-test discussion
the key points to be discussed during pre-test
discussion for HbV include:
� risk assessment and reasons for testing
� information about prevention and risk
reduction
� confidentiality and privacy
� testing process and window period
� seeking informed consent
� implications of a positive and negative
result
� Medical consequences of infection
� support mechanisms whilst waiting for test
results and if result is positive
While not all these issues may be relevant to
every patient, assumptions about the patient’s
knowledge and risk practices should be
avoided. the pre-test discussion ensures that
prevention measures are in place, the patient
is prepared for his/her test results, and the
clinician’s ethical and legal responsibilities have
been met.
table 3.3 provides a summary of the key points
to be addressed in the pre-test discussion.
36 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
table 3.3 summary of HbV pre-test
discussion
� reason for testing and risk assessment
� timing of risk and option of post-exposure
prophylaxis (PeP)
� need for other sti and blood-borne virus
testing
� History of testing
� confidentiality and privacy issues around
testing
� ensuring there is informed consent for the
HbV test
� natural history of HbV and HbV
transmission information (if appropriate)
� Prevention of transmission and risk
reduction through behaviour change
� implications of a positive or indeterminate
test result, including availability of
treatment
� implications of a negative test result
� explanation of the window period
� General psychological assessment and
assessment of social supports in the event
of a positive result
� Logistics of the HbV test: time taken for
results to become available and the need
to return for results
Post-test discussion
all HbV test results must be given in person.
as outlined for the pre-test discussion, giving
a test result should also be conducted in a
manner that is confidential, sensitive and
appropriate to gender, cultural beliefs and
practices, behavior, ongoing risk and language.
the post-test discussion should be conducted
where privacy is assured and where there will
be no interruptions.
Giving a positive result
the key points to be discussed in relation to
delivering a positive result and subsequent
consultations have been summarised below
(table 3.4). in addition to the post-test
discussion, patients newly diagnosed may
benefit from the provision of written material

that reinforces key messages and provides
details of local support services (appendix 1
and 2). clinicians inexperienced in managing
patients with HbV should collaborate with
more experienced general practitioners
and/or specialists or specialist centres. see the
asHM directory available at:
www.ashm.org.au/ashm-directory
table 3.4 summary of post-test discussion:
giving a positive result
First post-test consultation
� establish rapport and assess readiness for
the result
� Give positive test result
� avoid information overload
� Listen and respond to needs (the patient
may be overwhelmed and hear little after
being told the positive result)
� discuss immediate implications
� review immediate plans and support
� reassess support requirements and
available services
� arrange other tests and the next
appointment
� begin contact tracing process and discuss
options available to facilitate this
Subsequent consultations
� treatment options, diet and exercise
� effect of diagnosis on relationships and
information about prevention
� issues about disclosure
� assessment of contact tracing process and
difficulties encountered
� access to life insurance may be affected
� Workplace implications
� impact of other issues (eg. drug use,
poverty, homelessness) on the ability to
access health care and treatments
� referral for on-going counselling,
social worker, or medical specialist, as
appropriate
Contact tracing
contact tracing of individuals who may have
been exposed during the infectious period of
acute hepatitis should be undertaken to enable
preventative measures to be implemented.
discussion with the patient regarding how
to proceed with contact tracing may be
appropriate. the clinician may ask the patient
to consider recent blood-to-blood or sexual
contacts as well as recent blood donations. it is
recommended that primary care practitioners
keep up to date with the relevant state or
territory guidelines.
Giving a negative result
Providing a negative test result provides an
opportunity to reinforce harm reduction
strategies and consider vaccination. if
appropriate, the window period should be
discussed and an appointment made for retesting.
table 3.5 below provides a summary
of the key points to be discussed in relation to
giving a negative HbV test result.
table 3.5 summary of post-test discussion:
giving a negative result
� explain the negative test result and the
window period (if relevant)
� reinforce education regarding safe behaviours
� consider vaccination for hepatitis b, hepatitis
a (if indicated), and, for women aged between
9 and 26, human papillomavirus (HPV)
� further discuss anxiety or risk behaviours
� discuss testing for other stis
Summary
While hepatitis b is a complex disease, an
understanding of the parameters used to define
HbV infection is crucial for the assessment and
management of people with hepatitis b. With
the emergence of new data, our accepted
paradigms are changing, particularly relating
to the importance and role of serum HbV dna
levels and the assessment of hepatic fibrosis.
ongoing research is needed to validate new
data for routine clinical use.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 37

References
1. Milich d, Liang tJ. exploring the biological
basis of hepatitis b e antigen in hepatitis b
virus infection. Hepatology 2003;38(5):1075-
86.
2. niederau c, Heintges t, Lange s, Goldmann G,
niederau cM, Mohr L, Haussinger d. Long-term
follow-up of Hbeag-positive patients treated
with interferon alfa for chronic hepatitis b. n
engl J Med 1996;334(22):1422-7.
3. Lindh M, Hannoun c. dynamic range and
reproducibility of hepatitis b virus (HbV)
dna detection and quantification by cobas
taqman HbV, a real-time semiautomated
assay. J clin Microbiol 2005;43(8):4251-4.
4. Weiss J, Wu H, farrenkopf b, schultz t, song
G, shah s, siegel J. real time taqman Pcr
detection and quantitation of HbV genotypes
a-G with the use of an internal quantitation
standard. J clin Virol 2004;30(1):86-93.
5. Lok as, Heathcote eJ, Hoofnagle JH.
Management of hepatitis b: 2000–
summary of a workshop. Gastroenterology
2001;120(7):1828-53.
6. chen cJ, yang Hi, su J, Jen cL, you sL, Lu sn,
et al for the reVeaL-HbV study Group. risk of
hepatocellular carcinoma across a biological
gradient of serum hepatitis b virus dna level.
J am Med assoc2006;295(1):65-73.
7. iloeje uH, yang Hi, su J, Jen cL, you sL, chen
cJ. Predicting cirrhosis risk based on the
level of circulating hepatitis b viral load.
Gastroenterol 2006;130(3):678-86.
8. Lok as, McMahon bJ. chronic hepatitis
b (aasLd guidelines). Hepatology
2007;45(2):507-39.
9. Medical services advisory committee
10.
(Msac). application 1096: Hepatitis b dna
testing for chronic hepatitis b. australian
Government: department of Health and
ageing, June 2007. available at http://www.
health.gov.au/internet/msac/publishing.nsf/
content/app1096-1 (accessed september
2007).
fung sK, Lok as. Hepatitis b virus genotypes:
do they play a role in the outcome of HbV
infection? Hepatology 2004;40(4):790-2.
11. Kao JH, chen PJ, Lai My, chen ds. Hepatitis
b genotypes correlate with clinical outcomes
in patients with chronic hepatitis b.
Gastroenterol 2000;118(3):554-9.
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12. Kao JH, Wu nH, chen PJ, Lai My, chen ds.
Hepatitis b genotypes and the response to
interferon therapy. J Hepatol 2000;33(6):998-
1002.
13. Wai ct, chu cJ, Hussain M, Lok as. HbV
genotype b is associated with better response
to interferon therapy in Hbeag(+) chronic
hepatitis than genotype c. Hepatology
2002;36(6):1425-30.
14. Wang c, shuhart M, Manansala J, corey L,
Kowdley K. High prevalence of significant
fibrosis in patients with immunotolerance
to chronic hepatitis b infection (abstr.).
Hepatology 2005;42(4):573a.
15. Lai Md, Hyatt b, afdal n. role of liver biopsy
in patients with normal aLt and high HbV
dna (abstr.). Hepatology 2005;42(4):720a.
16. Prati d, taioli e, Zanella a, della torre e,
butelli s, del Vecchio e, et al. updated
definitions of healthy ranges for serum
alanine aminotransferase levels. ann intern
Med2002;137(1):1-10.
17. ishak K, baptista a, bianchi L, callea f, de
Groote J, Gudat f, et al. Histological grading
and staging of chronic hepatitis. J Hepatol
1995;22(6):696-9.
18. bedossa P, Poynard t. an algorithm for the
grading of activity in chronic hepatitis c.
the MetaVir cooperative study Group.
Hepatology 1996;24(2):289-93.
19. Poynard t, bedossa P, opolon P. natural
history of liver fibrosis progression in patients
with chronic hepatitis c. the obsVirc,
MetaVir, cLiniVir, and dosVirc groups.
Lancet 1997;349:825-32.
20. Myers rP, tainturier MH, ratziu V, Piton a,
thibault V, imbert-bismut f, et al. Prediction
of liver histological lesions with biochemical
markers in patients with chronic hepatitis b. J
Hepatol 2003;39(2):222-30.
21. Marcellin P, deLedinghen V, dhumeaux d, et
al. non-invasive assessment of liver fibrosis in
chronic hepatitis b using fibroscan® (abstr.).
Hepatology 2005;42(4):715a.
22. castera L, Vergniol J, foucher J, Le bail b,
chanteloup e, Haaser M, et al. Prospective
comparison of transient elastography,
fibrotest, aPri, and liver biopsy for the
assessment of fibrosis in chronic hepatitis c.
Gastroenterol 2005;128(2):343-50.

23. o’sullivan b, Law M, Gidding H, Kaldor J,
Gilbert G, dore GJ. Hepatitis b in australia:
responding to a disease epidemic. sydney:
national centre in HiV epidemiology and
clinical research, university of new south
Wales, 2000.
24. Mast ee, Margolis Hs, fiore ae, brink eW,
Goldstein st, Wang sa, et al. a comprehensive
immunization strategy to eliminate
25.
transmission of hepatitis b virus infection
in the united states: recommendations of
the advisory committee on immunization
Practices (aciP). Part i: immunization of
infants, children, and adolescents. MMWr
recomm rep 2005;54(rr-16):1-31.
Mast ee, Weinbaum cM, fiore ae, alter
MJ, bell bP, finelli L, et al. a comprehensive
immunization strategy to eliminate
transmission of hepatitis b virus infection
in the united states: recommendations of
the advisory committee on immunization
Practices (aciP). Part ii: immunization of
adults. MMWr recomm rep2006;55(rr-
26.
16):1-33; quiz ce31-34.
Lavanchy d. Hepatitis b virus epidemiology,
disease burden, treatment, and current and
emerging prevention and control measures.
J Viral Hepatol 2004;11(2):97-107.
27. bradford d, Hoy J, Matthews G, eds. HiV,
viral hepatitis and stis: a guide for primary
care. sydney: australasian society for HiV
Medicine, 2008;92-4.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 39

NATURAL HISTORY OF CHRONIC
HEPATITIS B VIRUS INFECTION
Marianne Guirgis Gastroenterology and Hepatology Department, St George Hospital, Kogarah, NSW.
Amany Zekry Hepatology Unit, St George Hospital, Kogarah, NSW.
Links to: Chapter : Virology: viral replication and drug resistance
Chapter 3: Hepatitis B virus testing and interpreting test results
Chapter 6: Clinical assessment of patients with HBV infection
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
Chapter 10: Managing hepatitis B virus infection in complex situations
KEY POINTS
Transmission routes and risks
Hepatitis b virus (HbV) infection is a viral
infection spread by contact with infected blood
or bodily fluids, including semen and saliva. the
virus may be transmitted:
� Vertically, between a mother with chronic
infection and her baby
� Horizontally, through close person-to-person
contact, usually in childhood (e.g. through
open cuts or sores)
� Parenterally, via injecting drug use (idu)
� sexually.
40 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
4
� birth in a highly endemic country is a risk factor for developing chronic hepatitis b infection (cHb).
the primary mode of transmission in such cases is vertical (mother-to-child).
� the risk of developing chronic hepatitis b infection is highest in those who acquire hepatitis b virus
(HbV) perinatally and lowest in those who acquire the infection in adulthood.
� the natural history of HbV infection depends on complex host, viral, and environmental
interactions.
� there are four phases of chronic HbV infection and the host immune response in each phase
determines the outcome of infection and the severity of liver injury.
� complications of chronic HbV infection include cirrhosis with hepatocellular failure and
hepatocellular carcinoma (Hcc).
Risk factors
� birth in a highly endemic country, e.g. east
or south asia, european Mediterranean
countries, the Middle east, eastern europe,
south america, the caribbean and south
Pacific islands
� High-risk sexual behaviour, including men
who have sex with men (MsM) and sex
workers
� indigenous australians
� Household contacts of people who are
Hbsag positive
� injecting drug use (idu)
� contaminated blood products
� contaminated surgical equipment
� tattoos
� Previous imprisonment
� Haemodialysis.

Natural history of acute hepatitis
B virus infection
there are four phases in the natural history of
acute hepatitis b: 1
1. incubation phase: the incubation period of
acute HbV infection can last up to twelve
weeks.
2. symptomatic hepatitis: acute hepatitis
develops following the incubation period,
evidenced by elevated aminotransferase
levels, and lasts 4–12 weeks. symptoms
include anorexia, dark urine, jaundice and
right upper quadrant abdominal discomfort.
acute symptoms are uncommon in infants
and children, but common in adults.
3. a recovery period follows with normalisation
of the levels of alanine aminotransferase
(aLt).
4. Hepatitis b surface antigen (Hbsag) clearance
in the serum follows after a few months,
coinciding with the development of hepatitis
b surface antibodies (anti-Hbs).
Progression from acute to chronic
hepatitis B virus infection
the transition from acute to chronic infection
signifies a failure of the immune response to
eradicate the virus. the overall risk of chronic
infection is highest in those who acquire the
virus perinatally (80–90%). 2 in those who
acquire the infection in childhood or adulthood,
the risk is 30% and 5% respectively 3 (table 4.1).
table 4.1: risk of development of chronic
hepatitis b infection by the patient’s age at
infection
development
of chronic
infection
risk of
advanced liver
disease
Perinatal childhood adult
80–90% 30%

4 Natural history of chronic hepatitis B virus infection
table 4.3: Phases of chronic hepatitis b infection
Phase
immune
tolerance
immune
clearance
immune
control
immune
escape
(Hbeagnegative
cHb)
Liver
histology
Minimal
inflammation
Variable
inflammation
+/- fibrosis
Minimal
inflammation
and liver
damage
inflammation
and often
significant
fibrosis
1. Immune tolerance phase
this initial phase is characterised by
hepatitis b e antigen (Hbeag) positivity,
high HbV dna levels (> 20,000 iu/mL),
normal aLt levels and minimal level liver
injury. it is prevalent in those who acquired
the infection vertically. this phase may
persist for decades and is associated with
a low risk of progression to advanced liver
disease.
2. Immune clearance phase
the liver injury in HbV is determined by
the immune response to the virus. this
phase, also called the immune competence
phase, is characterised by fluctuating HbV
dna and aLt levels as an active, immunemediated
cytotoxic response to the
infected liver cells. active inflammation
and eventually fibrosis can be found in
HbV dna aLt Hbeag anti-
Hbe
>20 000
iu/mL
>20 000
iu/mL
(fluctuating)
< 2000
iu/mL
2000–
20,000
iu/mL
normal Present - 20-30 years
elevated
(fluctuating)
Present +/-
normal absent + years
4 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
duration natural history
can be
protracted
elevated absent + -
Low risk of
progression to
advanced liver
disease
associated with
hepatic flares
Low risk of
advanced liver
disease
Hbsag loss: 1% per
year
10–20% have
reactivation of
HbV replication
after many years
can enter this
phase from
immune clearance
or immune control
phase
High risk of
progression to
advanced liver
disease
the liver following these repeated immunemediated
attacks. an important outcome of
this phase is the seroconversion of Hbeag to
Hbe antibody (anti-Hbe), which is associated
with lower level viraemia. importantly, after
Hbeag seroconversion, a small number of
patients can still have active liver disease, most
likely due to the emergence and activation of
HbV mutant variants, particularly the precore
variant (see chapter 2: Virology: viral replication
and drug resistance).
3. Immune control phase
Patients in this phase have also been
described as ‘inactive carriers’ of the infection.
Liver inflammation is minimal, HbV dna is
undetectable or at a low level (

a study assessing the long-term outcome of
Hbsag positive individuals who had normal
Lfts and normal or minimal changes on liver
biopsy, the liver histology and aLt remained
unchanged over a 12-year follow-up period.
a small minority (2%) of these subjects
developed HbV reactivation with aLt flares.
in contrast to the subjects with normal aLt,
subjects with evidence of active liver disease
(high aLt or inflammation on liver biopsy) had
a worse prognosis, with an annual risk rate of
developing cirrhosis and Hcc of 1% and 0.5%,
respectively. 6 However, 10–20% of subjects
in the immune control phase may have
subsequent reactivation of HbV with immune
escape, even after many years. 7
Table 4.4. Factors influencing chronic hepatitis B progression to cirrhosis and
hepatocellular carcinoma
Host factors Viral factors Other factors
Older age High HBV DNA level Alcohol consumption
Male Genotype C 14 Co-infection with hepatitis
4. Immune escape phase (HBeAgnegative
chronic hepatitis B)
this phase is characterised by negative Hbeag,
positive anti-Hbe and detectable viral load
(HbV dna > 2000 iu/mL). it is often termed
precore mutant HbV because a mutation in
the precore region of the dna results in a lack
of Hbeag production. Patients can reach this
phase from the immune control state (5–10%), 8
or can progress directly from Hbeag-positive
chronic hepatitis to Hbeag-negative chronic
hepatitis (10-30%) 6 C, human
immunodeficiency virus
(HIV), hepatitis D
(figure 4.1).
Obesity, diabetes 15
Figure 4.1 The four phases of hepatitis B infection
10-30%
Immune toleranance phase
Immune clearance phase
Immune control phase
Immune escape phase
10-20%
figure 4.1: the four phases of hepatitis b infection
Hbeag-negative chronic HbV infection is
reported in all parts of the world, but is more
common in asian and Mediterranean countries.
it occurs due to the selection of a mutant HbV,
which does not produce Hbeag but is still able
to replicate. this immune selection process
is likely to occur late in the natural history of
chronic HbV infection.
thus, patients who are Hbeag negative tend
to be older and have more advanced liver
disease. the natural course of patients with
Hbeag-negative disease is characterised by
fluctuations in clinical status, and biochemical
and viral load parameters caused by recurrent
hepatic flares. although patients with Hbeagnegative
disease tend to have lower HbV viral
load than those with Hbeag-positive infection
(< 20,000 iu/mL vs > 20,000 iu/mL), they
display more hepatic inflammation on liver
biopsy. 9 consequently, the annual incidence
of cirrhosis is significantly higher (8–10%) in
Hbeag-negative chronic hepatitis b patients,
compared to that in Hbeag-positive patients
(2–6%). 10
Reactivation of HBV following
immunosuppression
in the context of immunosuppression,
subjects in the immune control phase of cHb
may experience a reactivation of the disease.
reactivation can occur in subjects who are
Hbsag positive, and even in those who are
Hbsag negative/anti-Hbc igG positive (occult
HbV). the reactivation is characterised by
positive anti-Hbc igM but at lower titre than
acute infection. it has been reported in 20–50%
of those with hepatitis b infection undergoing
immunosuppressive treatment, and may result
in fulminant hepatic failure. 11 it is important
for people with HbV infection undergoing
immunosuppressive therapy to be carefully
monitored and managed appropriately with
prophylaxis, as indicated (see chapter 10:
Managing hepatitis b virus infection in complex
situations).
Occult HBV
With the emergence of highly sensitive HbV
dna Pcr assays, a population of patients have
been identified with occult HbV infection. occult
hepatitis b infection refers to the presence
of the hepatitis b virus in the blood or liver
without the detection of Hbsag. its presence
may be related to the long-term persistence of
HbV dna reservoir in hepatocytes in the form
of covalently-closed-circular dna (cccdna).
the reactivation of hepatitis b following
immunosuppression has been described
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 43

4 Natural history of chronic hepatitis B virus infection
in patients with occult infection. occult
hepatitis b infection may also contribute to
the development of hepatocellular carcinoma.
currently in clinical practice, the exact role of
HbV occult infection remains unclear.
Complications of hepatitis B virus
infection
sequelae of HbV infection range from
asymptomatic disease to decompensated
liver failure to extrahepatic manifestations.
cirrhosis and hepatocellular carcinoma (Hcc)
are major causes of morbidity and mortality.
it is estimated that over 250,000 patients
worldwide die annually from HbV-related liver
disease. the cumulative 5-year survival rate
once decompensated cirrhosis ensues is 35%. 12
the development of cirrhosis is influenced by
several factors, mostly viral and host related
(table 4.3). Patients with HbV infection have
a 100-fold increased risk of developing Hcc
relative to patients without HbV infection. 13 the
risk of progression to Hcc is also related to host,
viral and environmental factors (table 4.4).
table 4.4: factors influencing chronic hepatitis
b progression to cirrhosis and hepatocellular
carcinoma
Host
Viral factors other factors
factors
older age
High HbV dna
level
Male Genotype c 14
obesity,
diabetes 15
alcohol
consumption
co-infection with
hepatitis c, human
immunodeficiency
virus (HiV),
hepatitis d
in a large prospective cohort study of cHb from
taiwan (the reVeaL study), elevated HbV dna
level (>10 4 copies/mL or approximately 2000
iu/mL) at the time of initial evaluation was
closely linked to the subsequent development
of Hcc. 16,17 a further study demonstrated that
if the HbV dna level fell over the follow-up
period, the risk of Hcc also declined. 17 these
44 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
studies provide strong data that the risk of Hcc
in HbV is linked to levels of serum HbV dna. it
should be noted that in HbV-related Hcc, 30–
40% of hepatoma cases develop in the absence
of cirrhosis. 18
Impact of antiviral therapy on the
natural course of chronic hepatitis B
virus infection
the importance of HbV viral replication to
the natural history of the infection has been
reported in the reVeaL HbV study. 16,17 these
data strongly support a role for antiviral
therapies to alter the natural course of HbV
infection, mitigating the rate of progression to
end-stage liver disease and Hcc through the
suppression of viral replication. this finding
was confirmed in a recent study evaluating
the effect of lamivudine in asian patients
with high HbV dna (>700,000 copies/mL or
approximately 125,000 iu/mL) and advanced
liver fibrosis. 19 in these patients, lamivudine has
been shown to delay the progression of liver
disease and the development of Hcc.
Conclusion
the outcome of HbV infection and progression
to chronicity is determined particularly by age
at acquisition. the natural history of chronic
HbV infection is characterised by four distinct
phases that depend on complex host, viral and
environmental interactions. in each phase, it is
the host’s immune response that determines the
outcome of infection and the severity of liver
injury. sequelae of HbV infection range from
asymptomatic carrier status to decompensated
liver failure and Hcc. 20 antiviral therapy can
alter the natural course of HbV infection.
References
1 Villeneuve JP. the natural history of chronic
hepatitis b virus infection. J clin Virol 2005;34
(suppl 1):s139-42.
2 beasley rP, trepo c, stevens ce, szmuness W.
the Hbe antigen and vertical transmission of
hepatitis b surface antigen. am J epidemiol
1977;105:94-8.

3 beasley rP, Hwang Ly, Lin cc, Leu ML. stevens
ce, szmuness W, et al. incidence of Hepatitis
b virus infections in preschool children in
taiwan. J infect dis 1982;146:198-204.
4 Lok as, McMahon bJ. american association
for the study of Liver diseases Practice
Guidelines. chronic Hepatitis b. Hepatology
2007;45(2):507-39.
5 Manno M, camma c, schepis f, bassi f,
Gelmini r, Giannini f, et al. natural history
of chronic HbV carriers in northern italy:
morbidity and mortality after 30 years.
Gastroenterology 2004;127(3):756-63.
6 Zacharakis GH, Koskinas J, Kotsiou s,
7
Papoutselis M, tzara f, Vafeiadis n, et al.
natural history of chronic HbV infection: a
cohort study with up to 12 years follow-up
in north Greece (Part of the interreg i-ii/ec-
Project). J Med Virol 2005;77(2):173-9.
Hsu ys, chien rn, yeh ct, sheen is, chiou
Hy, chu cM, Liaw yf. Long-term outcome
after spontaneous Hbeag seroconversion in
patients with chronic hepatitis b. Hepatology
2002;35:1522-7.
8 Liaw yf, chu cM, su iJ, Huang MJ, Lin dy,
chang-chien cs. clinical and histological
events preceding Hepatitis b e antigen
seroconversion in chronic hepatitis b.
9
Gastroenterology 1983;84:216-9.
yuen Mf, tanaka ; ng io, Mizokami M, yuen Jc,
Wong dK, et al. Hepatic necroinflammation
and fibrosis in patients with genotypes b and
c, core-promoter and precore mutations. J
Viral Hepat 2005;12(5):513-8.
10 Liaw yf, tai di, chu cM, chen tJ. the
development of cirrhosis in patients with
chronic type b hepatitis: a prospective study.
Hepatology 1988;8:493-6.
11 yeo W, Johnson PJ. diagnosis, prevention and
management of hepatitis b virus reactivation
during anticancer therapy. Hepatology
12
2006;43(2):209-20.
fattovich G, Giustina G, schalm sW, et al.
occurrence of hepatocellular carcinoma
13
and decompensation in western european
patients with cirrhosis type b. the euroHeP
study Group on Hepatitis b Virus and
cirrhosis. Hepatol 1995;21(1):77-82.
yu MW, Hsu fc, sheen is, et al. Prospective
study of Hepatocellular carcinoma and
liver cirrhosis in asymptomatic chronic
hepatitis b virus carriers. am J epidemiol
1997;145(11):1039-47.
14 Kao JH, chen PJ, Lai My, chen ds. Hepatitis b
virus genotypes and spontaneous hepatitis
b e antigen seroconversion in taiwanese
hepatitis b carriers. J Med Virol 2004;72:363-9.
15 yuan JM, Govindarajan s, arakawa K, yu
Mc. synergism of alcohol, diabetes and
viral hepatitis on the risk of hepatocellular
carcinoma in blacks and whites in the us.
cancer 2004;101:1009-17.
16 iloeje uH, yang Hi, su J, Jen cL, you sL, chen cJ
for the risk evaluation of Viral Load elevation
and associated Liver disease/cancer in HbV
(the reVeaL–HbV) study Group. Predicting
cirrhosis risk based on the level of circulating
hepatitis b viral load. Gastroenterology
2006;130:678-86.
17 chen cJ, yang Hi, su J, Jen cL, you sL, Lu sn
for the reVeaL–HbV study Group. risk of
hepatocullular carcinoma across a biological
gradient of serum hepatitis b virus dna level.
J am Med assoc 2006;295(1):65-73.
18 bosch fX, ribes J, cleries r, diaz M.
epidemiology of hepatocellular carcinoma.
clin Liver dis 2005;9:191-211.
19 Liaw yf, sung JJ, chow Wc, farrell G, Lee cZ,
yuen H, et al. cirrhosis asian Lamivudine
Multicentre study Group. Lamivudine
20
for patients with chronic hepatitis b and
advanced liver disease. n engl J Med
2004;351:1521-31.
raimondo G, Pollicino t, squadrito G. What is
the clinical impact of occult hepatitis b virus
infection? Lancet 2005;365:638-40.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 45

PRIMARY PREVENTION OF
HEPATITIS B VIRUS INFECTION
Nghi Phung Department of Drug and Alcohol, Department of Gastroenterology and Hepatology,
Westmead Hospital, Westmead, NSW.
Nicholas Wood National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases,
The Children’s Hospital at Westmead, Westmead, NSW.
KEY POINTS
Introduction
Hepatitis b vaccination aims to prevent hepatitis
b virus (HbV) infection and its complications,
which include fulminant hepatitis, cirrhosis,
liver failure, and hepatocellular carcinoma
(Hcc). in acute cases, fulminant hepatitis
occurs rarely, but is associated with significant
mortality, especially in infants. 1 the bulk of the
disease burden is in chronic infection. chronic
hepatitis b (cHb) develops in about 90% of
infants who acquire the infection at birth,
20–50% of children who acquire the infection
between 1 and 5 years of age and about 1–10%
of older children and adults who acquire HbV
infection. 2
the World Health organization (WHo) strategy
for the control of HbV infection aims to provide
universal infant hepatitis b immunisation,
with the first dose given at birth. 3 the vaccine
induces antibodies to hepatitis b surface
antigen (anti-Hbs) and a titre of 10 iu/mL or
more is considered to be protective against the
HbV infection. With the introduction of universal
infant vaccination programs in countries with a
high prevalence of hepatitis b such as taiwan
the immunisation against hepatitis b has had
a profound impact on reducing the incidence
of chronic infection, dropping the Hbsag
46 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
5
� universal hepatitis b vaccination programs have had a profound impact on reducing the incidence
of chronic hepatitis b infection.
� all infants should receive hepatitis b vaccination, with the first dose given at birth.
� adolescents not vaccinated in childhood are recommended to receive hepatitis b vaccines.
� HbiG should be given to infants born to Hbsag-positive mothers within 12 hours of birth and the
first dose of HbV vaccine should be administered concomitantly.
prevalence rate in children from 10% to 1% 4
and halving the incidence of Hcc in children
aged 6 to14 years. 5,6
in australia, the impact of universal vaccination
on the incidence of hepatocellular carcinoma
will not be evident for at least another 15
years.
Target groups for vaccination in
Australia
transmission of HbV is a result of inoculation or
mucosal contact with blood or body fluids from
people with Hbsag-positive HbV infection.
transmission of HbV through blood transfusion
and organ transplant has been almost entirely
eliminated due to the screening of blood and
organ donors in australia. However, there
remains a small risk of exposure to HbV for
patients with clotting disorders who receive
blood-product concentrates.
the modes of transmission still relevant in
australia include:
� Perinatal
� Household contacts
� sexual contact
� reuse of injecting or tattooing equipment
� occupational exposure

in addition to screening blood, organ donors
and health care workers for HbV, the strategy to
control HbV infection in australia, which began
in 1988, includes vaccination and hepatitis
b immunoglobulin (HbiG) given at birth to
neonates born to Hbsag-positive mothers. in
the northern territory, the hepatitis b vaccine
has been routinely given at birth to aboriginal
and torres strait islander infants since 1988 and
to all infants since august 1990. HbV vaccination
for all adolescents commenced in 1997 in some
states and territories, and the universal infant
HbV vaccination program began in 2000 with
the first dose given at birth. the adolescent
program will continue until those immunised
for hepatitis b in the childhood program reach
adolescence.
Groups at risk of exposure or significant
morbidity from exposure to HbV infection
should be targeted for vaccination, including:
(1) as part of the australian national
immunisation Program:
� infants
� adolescents aged between 10 and 13 years
(2) People exposed to community groups with
high prevalence of HbV infection (table 5.1):
� Men who have sex with men (MsM)
� female commercial sex workers (fcsW)
� aboriginal and torres strait islander people
� injecting drug users (idu)
� Prison inmates
� cultural and linguistically diverse (caLd)
communities
� People adopting children from overseas
countries with high prevalence rates
� frequent or long-term travellers to endemic
areas
� Household contacts of people with acute
and chronic hepatitis b
the risks in caLd groups reflect the rates of
chronic infection in first generation immigrants
from countries with high prevalence of HbV
infection. the high prevalence of HbV infection
in the aboriginal and torres strait islander
population reflects the barriers for access to
public health education and vaccination. the
risks in MsM, fcsW, idu and prison inmates
often relate to unsafe practices, for example,
inmates who engage in amateur tattooing,
homosexual contact and reusing injecting
equipment. While the burden of disease is
largely carried by people born in endemic
regions, a significant portion (40%) of acute
cases result from the unsafe use of injecting
drugs, which reflects the low uptake of
vaccination in this group.
table 5.1: Prevalence of chronic hepatitis b in
australia by risk group
Group
Hbsag prevalence in
risk group (%)
Proportion
of cHb in
australia (%)
blood donors 0.1 n/a
MsM 3.3 8
indigenous
communities
2.3 (urban)
8.2 (rural)
12 (prisoners)
0.9 (Middle east/
16
caLd
communities
africa)
3.7 (Pacific islands)
4.9 (ne asia)
5.4 (se asia)
16 (ne asia)
33 (se asia)
idu 1.6 5
Prison inmates 1.6-3.0
Modified from o’sullivan et al. 2004 5
cHb: chronic hepatitis b
MsM: men who have sex with men
caLd: cultural and linguistically diverse
idu: injecting drug user
(3) People prone to exposure or at risk of
significant morbidity from exposure:
� Haemodialysis patients
� Patients with clotting disorders
� Human immunodeficiency virus (HiV) positive
and other immunosuppressed people
� transplant recipients
� Patients with chronic liver disease or hepatitis
c
� intellectually disabled people
(4) People at risk of occupational exposure:
� Health care workers, dentists, police,
tattooists, body piercers
� staff of facilities for people with intellectual
disabilities
� People playing contact sport.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 47

5 Primary prevention of hepatitis B virus infection
Vaccines available
1. Monovalent vaccines
Hepatitis b
surface antigen
(Hbsag)
engerix-b (adult formulation) 20 µg per 1 mL
engerix-b (paediatric
formulation)
10 µg per 0.5
mL
H-b-VaX ii (adult formulation) 10 µg per 1 mL
H-b-VaX ii (paediatric
formulation)
H-b-VaX ii (dialysis
formulation)
5 µg per 0.5 mL
40 µg per 1 mL
2. Combination vaccines
a) combination vaccines that include both
diphtheria, tetanus, acellular pertussis (dtPa)
and hepatitis b
� Infanrix HepB: diphtheria-tetanus-acellular
pertussis-hepatitis b (GlaxosmithKline)
� Infanrix Hexa: diphtheria-tetanus-acellular
pertussis-hepatitis b-inactivated poliomyelitis
vaccine-Haemophilus influenzae type b
(GlaxosmithKline)
� Infanrix Penta: diphtheria-tetanusacellular
pertussis-hepatitis b-inactivated
poliomyelitis vaccine (GlaxosmithKline).
b) other combination vaccines that include
hepatitis b:
� Comvax: Haemophilus influenzae type b
– hepatitis b (csL biotherapies; Merck & co
inc.)
� Twinrix Junior (360/10): combined hepatitis
a virus (HM175 strain) and recombinant
hepatitis b vaccine (GlaxosmithKline)
� Twinrix (720/20): hepatitis a virus (HM175
strain) and recombinant hepatitis b vaccine
(GlaxosmithKline).
Current National Immunisation
Program: 2007
Infants
all infants are recommended to receive
hepatitis b vaccine within eight days of birth,
followed by three further doses in infancy
(table 5.2). the type of HbV vaccine used differs
between states and territories.
48 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
table 5.2: the national immunisation Program
for Hepatitis b 11
age antigen
nsW, act,
Wa, tas
Vic, QLd,
sa
birth Hep b monovalent monovalent monovalent
2 mth Hep b
4 mth Hep b
6 mth Hep b
dtPa-HibiPV-
Hep b
dtPa-HibiPV-
Hep b
dtPa-HibiPV-
Hep b
Hib-Hep b
Hib-Hep b
12 mth Hep b Hib- Hep b
dtPa: diphtheria-tetanus-acellular pertussis
Hib: Haemophilus influenzae type b
iPV: oral inactivated poliomyelitis vaccine
nt
dtPa- iPV-
Hep b
dtPa- iPV-
Hep b
dtPa-
iPV- Hep b
Premature infants
Preterm babies do not respond as well to the
hepatitis b vaccine as term babies. 7 for babies
under 32 weeks gestation or less than 2000g
birth weight, it is recommended to give the
vaccine at 0, 2, 4 and 6 months of age and
either:
(a) measure anti-Hbs at 7 months of age
and give a booster at 12 months of age if
antibody titre is less than 10 miu/mL, or
(b) give a booster at 12 months of age without
measuring the antibody titre. 11
Adolescents
adolescents not vaccinated in childhood
are recommended to receive the hepatitis b
vaccine. two regimens are available:
� three-dose regimen for adolescents aged
up to 20 years: Hepatitis b (paediatric
formulation): 3 doses of 0.5 mL. the optimal
interval is one month between first and
second dose and a third dose given five
months after the second dose.
� two-dose regimen for adolescents aged 11 to
15 years: H-b-Vax ii 10 µg (adult formulation)
or engerix-b 20 µg (adult formulation) at 0
and 4–6 months.
Accelerated vaccination schedules
two products, engerix-b (adult) and twinrix
(720/20), are registered for use in accelerated
schedules. accelerated schedules should only
be used if there is very limited time before
departure to endemic regions (table 5.3).

table 5.3: accelerated hepatitis b vaccination
schedules
Vaccine age
engerix-b
(paediatric)
engerix-b
(adult) *
twinrix
(720/20) *
up to 20
years
>20
years
>15
years
dose
(Hbsag
protein)
Volume
10 µg 0.5 mL
20 µg 1.0 mL
20 µg 1.0 mL
schedule
0, 1, 2, 12
months
0, 7, 21
days;
booster
at 12
months
0, 7, 21
days;
booster
at 12
months
* if time permits, it is recommended that the 0, 1, 2 month schedule be used,
as higher seroprotective rates are observed following this schedule compared
to 0, 7, 21 day schedule; a booster dose at 12 months is recommended for
long-term protection.
Catch-up vaccination schedules
if the infant received the birth dose of hepatitis
b vaccine, three catch-up doses can be given
4–8 weeks apart. if the infant did not receive
the birth dose, a catch-up of this dose is not
necessary. in this circumstance, the hepatitis b
vaccination should commence at 2 months of
age. there should be a minimum interval of 8
weeks between doses 2 and 3.
Booster doses
although vaccine-induced antibody
levels decline with time and may become
undetectable, booster doses are not
recommended in immunocompetent people
after a primary course, as there is good evidence
that a completed primary course of hepatitis b
vaccination provides long-lasting protection.
testing for post vaccination response four
weeks after the third dose is recommended
for:
� Health care workers involved with exposure
prone procedures (see chapter 11: infection
control and occupational health)
� those at risk of severe or complicated
disease (e.g. immunosuppressed patients
and patients with chronic liver disease)
� those expected to have a poor response
to hepatitis b vaccine (e.g. haemodialysis
patients).
Adverse events following
hepatitis B vaccination
� soreness at the injection site (5%, common),
fever (usually low grade, 2–3%, common),
nausea, dizziness, malaise, myalgias and
arthralgias. fever can be expected in
neonates (0.6–3.7%, common).
� anaphylaxis has been reported very rarely in
adults.
� although various adverse events, such as
demyelinating diseases, multiple sclerosis,
Guillain-barré syndrome and arthritis have
been reported, there is no evidence of a
causal relationship with the hepatitis b
vaccination. 8,9
Hepatitis B immunoglobulin (HBIG)
Hepatitis b immunoglobulin (HbiG) is prepared
from pooled plasma from the blood bank, with
samples selected on the basis of high levels of
anti-Hbs. use is recommended in infants born
to Hbsag-positive mothers and non-immune
people exposed to blood of people with cHb
infection.
HbiG should be given to newborns within
12 hours of birth exposure or to adults
not previously vaccinated within 72 hours
of exposure, as efficacy diminishes after
48 hours. this should be followed by the
administration of the hepatitis b vaccine as
per the usual schedule. Previous vaccination
in the exposed adult should be verified by
evidence of detectable anti-Hbs. if the anti-Hbs
is undetectable, HbiG should be administered
as follows:
� 100 iu children (30kg weight)
Non-response or vaccination failure
firstly, Hbsag carriage should be excluded as
a cause of failure in vaccine non-responders.
for those subjects who have not achieved
adequate anti-Hbs levels (≥10miu/mL) after
the third dose of vaccine, booster doses should
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 49

5 Primary prevention of hepatitis B virus infection
be given, as a fourth double dose or further
three doses at monthly intervals, followed by
testing for response four weeks later. Persistent
non-responders should be informed about the
need for HbiG within 72 hours of parenteral
exposure to HbV.
Vaccination failure may occur in people
exposed to HbV variants with mutations
in the HbV surface gene (vaccine-induced
escape mutant). current HbV vaccines are not
effective in preventing infection with these
mutants. the majority of such vaccine-induced
escape mutants were initially reported in
neonates through vertical transmission and in
transplant recipients. these vaccine-induced
escape mutants were responsible for most of
the 3.4% vaccine failure rate reported in the
chinese adult population undergoing an HbV
vaccination program. 10
HBV vaccination programs in the
CALD and Indigenous populations
caLd and indigenous populations are
confronted with different issues from the
general population, which often hamper the
success of vaccination programs in australia.
Language and cultural differences are obvious
barriers. People not captured by the universal
infant and adolescent vaccination program
can present, related to their age at migration
to australia. some practices transferred to
australia, such as eyebrow tattooing and
vacuuming (a form of therapy involving the
use of suction cups applied to the skin), could
continue to be routes of transmission.
the high prevalence rate of HbV infection in
the indigenous population requires targeted
public health policies to overcome the barriers
to accessing public health education and
medical services.
for further information about these
recommendations, please refer to The Australian
Immunisation Handbook. 9th edition (2007). 11
References
50 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
1. Kao JH, Hsu HM, shau Wy, chang MH, chen
ds. universal hepatitis b vaccination and the
decreased mortality from fulminant hepatitis in
infants in taiwan. J Pediatr 2001;139:349-52.
2. Heymann dL, editor. control of communicable
diseases manual. 18th ed. Washington:
american Public Health association, 2004.
3. Goldstein s, fiore a. towards the global
elimination of hepatitis b virus transmission. J
Pediatr 2001;139:343-5.
4. ni yH, Huang LM, chang MH, yen cJ, Lu
cy, you sL, et al. two decades of universal
hepatitis b vaccination in taiwan: impact
and implication for future strategies.
Gastroenterology 2007:132(4):1287-93.
5. o’sullivan bG, Gidding Hf, Law M, Kaldor
JM, Gilbert GL, dore GJ. estimates of chronic
hepatitis b virus infection in australia, 2000.
aust n Z J Public Health 2004;28(3):212-6.
6. Williams a. reduction in the hepatitis b
related burden of disease-measuring the
success of universal immunisation programs.
commun dis intell 2002;26:458-60.
7. saari tn for the american academy of
Pediatrics committee on infectious diseases.
immunization of preterm and low birth
weight infants. Pediatrics 2003;112:193-8.
8. duclos P. safety of immunisation and
adverse events following vaccination against
hepatitis b (review). expert opin drug saf
2003;2(3):225-31.
9. World Health organization (WHo). the
Global advisory committee on Vaccine
safety rejects association between hepatitis
b vaccination and multiple sclerosis (Ms).
2006. available at: http://www.who.int/
vaccine_safety/topics/hepatitisb/ms/en/
(Last accessed october 2006).
10. chuan He, fumio nomura, sakae itoga,
Kazumasa isobe, toshiaki nakai. Prevalence
of vaccine-induced escape mutants of
hepatitis b virus in the adult population in
china: a prospective study in 176 restaurant
employees. J Gastroenterol Hepatol 2001:16
(12); 1373–7.
11. national Health and Medical research
council (nHMrc). the australian
immunisation Handbook. 9th edition.
canberra: commonwealth department of
Health and ageing, 2007.

CLINICAL ASSESSMENT OF
PATIENTS WITH HEPATITIS B
VIRUS INFECTION
Darrell HG Crawford School of Medicine, University of Queensland, Greenslopes Private Hospital; Department of
Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD.
Rebecca J Ryan School of Medicine, University of Queensland, Greenslopes Private Hospital; Department of
Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD.
Nghi Phung Department of Addiction Medicine, Department of Gastroenterology and Hepatology,
Westmead Hospital, Westmead, NSW.
Links to : Chapter : Virology: viral replication and drug resistance
Chapter 3: Hepatitis B virus testing and interpreting test results
Chapter 4: Natural history of chronic hepatitis B infection
Chapter 7: Treatment of chronic hepatitis B virus infection
Chapter 8: Managing patients with advanced liver disease
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
Chapter 11: Infection control and occupational health
KEY POINTS
6
� the assessment of a patient should be considered in the context of the natural history of hepatitis
b infection.
� transmission risks, lifestyle modification, cultural factors and long term complications associated
with chronic hepatitis b infection are important elements for patient education.
Introduction
following acute hepatitis b virus (HbV)
infection, 95% of adult patients will mount an
immune response adequate to clear the virus.
furthermore, only one third of adult patients
experience symptoms of acute hepatitis
following exposure, while the remaining
patients usually have subclinical disease. in
contrast, 90% of infants born to Hbeag-positive
mothers and 30% of infants exposed before five
years of age will develop chronic HbV infection
(cHb), but symptomatic acute infection occurs
very infrequently in this age group. 1
therefore, the majority of patients with HbV
infection who are encountered in primary
care will have cHb. such patients are usually
asymptomatic until they develop features
associated with hepatic decompensation. as
a consequence of the silent clinical course
of cHb, the management for the majority of
affected patients is not centred upon symptom
relief but rather, care is primarily aimed at
preventing disease progression to cirrhosis and
hepatocellular carcinoma (Hcc). 1-3
Assessment of patients with
chronic HBV infection
History and physical examination
the assessment of patients with cHb should
commence with a thorough clinical history and
physical examination. aspects of the clinical
history that deserve close attention are risk
factors for acquisition of cHb, such as ethnic
background, a family history of cHb, and a family
history of Hcc; and host or viral factors that are
associated with an increased risk of cirrhosis,
including older age (related to a longer duration
of infection), heavy alcohol consumption,
cigarette smoking and co-infection with other
viruses, e.g. hepatitis c virus (HcV), hepatitis
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 51

6 Clinical assessment of patients with hepatitis B virus infection
d virus (HdV), and human immunodeficiency
virus (HiV). Hepatitis a vaccination should be
offered to patients with chronic hepatitis b.
the severity of the underlying liver disease
should be clinically evaluated by examining for
peripheral signs of chronic liver disease, hepatic
encephalopathy, splenomegaly, ascites, and
peripheral oedema. 1
extra hepatic manifestations of cHb
occur in 10–20% of patients for which
effective antiviral therapy is pivotal. such
manifestations include polyarteritis nodosa
with multiple organ systems involvement,
such as the gastrointestinal tract (colitis),
kidney (glomerulonephritis), neurological
(neuropathy), and dermatological systems
(vasculitic skin rashes, palpable purpura).
conversely, approximately 50% of patients
with polyarteritis nodosa are Hbsag positive.
HbV infection-associated glomerulonephritis
usually presents with nephrotic range
proteinuria, which may progress to renal failure
in the absence of effective antiviral therapy.
Transmission risk
an evaluation of the patient’s risks for
transmission to contacts is essential. the risk
of transmission is proportional to the level of
viraemia. However, all Hbsag-positive patients
should be considered infectious. Patients
should be counselled regarding vaccination
of household members and sexual contacts,
and the use of barrier protection for sexual
contact with partners who are not completely
immunised. occupational risk of transmission
is important—particularly for health care
workers who should be counselled regarding
the legislative restrictions on performing
exposure-prone procedures. Hepatitis a
vaccination should be offered to patients with
cHb in the absence of hepatitis a immunity.
Laboratory investigations
complete HbV serology—hepatitis b surface
antigen (Hbsag), antibody to surface antigen
(anti-Hbs), antibody to hepatitis b core antigen
(anti-Hbc), hepatitis b envelope antigen
(Hbeag), antibody to hepatitis b e antigen
(anti-Hbe)—and measurement of HbV dna
level should be performed initially to evaluate
5 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
HbV replication status 1 (see table 3.1, chapter
3: Hepatitis b virus testing and interpreting test
results). Hbsag is the first serological marker
to appear and its presence for more than six
months indicates cHb infection. Hbsag appears
in serum 4–10 weeks after exposure, preceding
the onset of symptoms of acute hepatitis and
elevated alanine aminotransferase (aLt). Hbsag
will become undetectable 4–6 months after
acute exposure in those patients who achieve
successful immune clearance 2,3 (table 6.1).
table 6.1: Hepatitis b serology
serological marker interpretation
HBsAg Hepatitis b infection
Anti-HBs immunity to HbV infection
Anti-HBc Previous exposure
HBeAg Viral replication and infectivity*
Anti-HBe
immune control phase
(if HbV dna negative)*
HBV DNA Viral replication
*except in Hbeag-negative chronic hepatitis b where there may
be viral replication as evidenced by detectable HbV dna, despite
negative Hbeag and positive anti-Hbe
anti-Hbs indicates immunity to HbV when it
emerges following the disappearance of Hbsag.
anti-Hbs usually persists for life, conferring
long-term immunity.
Hbcag is only expressed in liver tissue and
therefore not used in routine clinical practice.
anti-Hbc is a marker of exposure. anti-Hbc igM
is seen in high titres in acute HbV infection and
at lower levels in patients with cHb undergoing
a flare in disease activity. anti-Hbc is not found
in subjects with anti-Hbs who are immune
through HbV vaccination.
Hbeag is considered to be a marker of HbV
replication and infectivity. seroconversion (i.e.
loss of Hbeag and development of anti-Hbe)
often signals transition from an active phase
of the disease to the immune control phase
(Hbeag negative, anti-Hbe positive, low HbV
dna level). over time patients can fluctuate
between the active (Hbeag positive, anti-Hbe
negative, high HbV dna level) and immune
control phases of the disease. the absence

of Hbeag, however, does not necessarily
preclude active viral replication, since specific
mutations in the HbV genome can prevent
Hbeag synthesis—so-called precore and core
promoter mutants. Patients with these HbV
mutants have elevated HbV dna and aLt levels,
despite the absence of Hbeag (Hbeag-negative
cHb). the frequency of Hbeag-negative cHb
is increasing, representing 20–40% of cHb
infection in australia. 2,3
HbV dna is a measure of viral replication, often
used as a criterion for commencing antiviral
therapy in patients with cHb. furthermore, in
population studies, a HbV dna level greater
than 2000 iu/mL is found to be a strong
predictor of increased risk for cirrhosis and Hcc. 4
Levels of HbV dna were previously expressed
as copies/mL, but these should be converted
to the accepted standard of international
units (iu)/mL. the conversion factor is
1 iu/mL = 5–6 copies/mL (the range from
5.2–5.8 depends on the laboratory). currently,
most HbV dna assays are based on realtime
polymerase chain reaction (Pcr),
which provides increased sensitivity and
greater dynamic range quantification than
hybridisation assays. an earlier version of a
hybridisation assay, used commonly until a
few years ago, had a threshold of detection
greater than 20,000 iu/mL (>141,500 copies/
mL). Hence the clinical status for some patients
may need to be reinterpreted with results
from newer assays. in particular, patients with
Hbeag-negative cHb might be erroneously
diagnosed as in the immune control phase, due
to the inability of older assays to demonstrate
viraemia below the level of the assay detection
threshold. 2
the threshold of HbV dna level associated with
liver disease is unknown. However, treatment is
usually considered in Hbeag-positive patients
with HbV dna level ≥ 20,000 iu/mL, and in
Hbeag-negative patients with HbV dna ≥ 2000
iu/mL. 1
HbV dna levels may fluctuate widely in
cHb, so a more accurate assessment of the
patient’s clinical status requires serial HbV dna
measurements over time.
Laboratory evaluation should also include an
assessment of liver enzymes, hepatic synthetic
function (including coagulation profile), as
well as liver ultrasound and alpha fetoprotein
estimation. a complete laboratory screen for
other causes of liver dysfunction and testing
for co-infection with other viruses (hepatitis c
and d) is recommended. 1
Liver biopsy should be only performed on the
recommendation of a specialist clinician. Liver
biopsy provides an accurate assessment of
the degree of necroinflammatory activity and
the extent of hepatic fibrosis, as well as the
exclusion of other liver diseases. such results
can be vital in informing the need for antiviral
therapy. However, some patients resist liver
biopsy because of its invasive nature and risk
of complications, such as haemorrhage and
gall bladder perforation. further research into
non-invasive assessment of hepatic fibrosis
is required (see chapter 3: Hepatitis b virus
testing and interpreting test results).
Acute HBV infection
the incidence of acute HbV infection has been
decreasing in Western countries for a number of
years, probably due to widespread vaccination.
acute HbV infection is characterised by the
onset of symptoms 1–4 months after exposure.
a serum sickness-like syndrome may occur,
followed by an illness characterised by
symptoms of anorexia, nausea, jaundice, and
right upper quadrant pain. symptoms usually
disappear after 1–3 months, but some patients
have prolonged fatigue even after the liver
function tests have normalised.
elevated alanine and aspartate
aminotransferase (aLt/ast) with values up
to 1000–2000 iu/L are characteristic of acute
HbV. Prothrombin time is the best guide to
prognosis. in the early phase of infection,
Hbsag, anti-Hbc igM and Hbeag are all positive.
the disappearance of Hbsag is usually followed
by the appearance of anti-Hbs. However, the
appearance of this antibody may be delayed,
thus creating a window period where the
diagnosis of recent HbV infection can only be
made by the detection of anti-Hbc igM.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 53

6 Clinical assessment of patients with hepatitis B virus infection
a small proportion of patients (0.1–0.5%)
will develop fulminant hepatic failure. this is
believed to be due to the massive immunemediated
lysis of infected hepatocytes and
therefore, such patients may have no evidence
of active viral replication at the time of
presentation.
the management of acute HbV is symptomatic
care. bed rest and nutritional support are
central. anti-nausea medications may be of
benefit and limited doses of paracetamol (< 2g/
day) or codeine may be cautiously administered
for abdominal pain or fevers. since most
patients recover, antiviral therapy is not usually
recommended. However, case reports and
small series of patients suggest some benefits
of early therapy. current recommendations
support the use of nucleoside analogues at
the first sign of severe liver injury or impending
hepatic failure. Patients should be monitored
regularly with laboratory tests during the acute
phase of their illness and referred for specialist
review if they have a prolonged prothrombin
time, elevated serum bilirubin concentration,
signs of encephalopathy, or if the illness
is uncharacteristically lengthy (table 6.2).
continued serological assessment following
recovery from the icteric illness is important to
identify the small proportion of patients who
develop cHb.
54 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Managing patients with chronic
HBV infection
chronic HbV can be a life-long disease
and it is important to counsel patients as
carefully as possible about the disease, the
risks of transmission, and the role of therapy
and its limitations. the epidemiology and
natural history of HbV suggest that the
vast majority of patients will come from
culturally and linguistically diverse (caLd)
backgrounds. indigenous australians also
have a high prevalence of cHb. a number of
issues inherent in the ethnic diversity arise
when counselling patients about cHb. apart
from language difficulties, health practitioners
have to be sensitive to the cultural beliefs of
specific patient groups and be aware of the
implications of a diagnosis of cHb in various
patient populations. it is often important to
provide consultation in the presence of other
family members or with an interpreter. HbV
information packages in various languages are
usually available in major tertiary hospitals.
Various lifestyle issues should be addressed.
alcohol consumption should be ceased or
minimised and cigarette smokers should
quit. Weight reduction with sound nutritional
advice for those with increased body mass
index should be encouraged. issues related
to vaccination and transmission have been
previously addressed.
table 6.2: referral guidelines for specialist review of patients with hepatitis b virus infection
Investigations to be performed
before referral
Investigations for
hepatocellular carcinoma
surveillance
Criteria for referral of patients
with acute hepatitis B
Criteria for referral of patients
with chronic hepatitis B
Criteria for referral of anti-HBspositive
patients
complete HbV serology (Hbsag, anti-Hbs, anti-Hbc, Hbeag, anti-Hbe)
HbV dna
Liver function tests, full blood count, coagulation profile
Hepatitis c antibody
Hepatitis d antibody
alpha fetoprotein
abdominal ultrasound
elevated prothrombin time, international normalised ratio or serum bilirubin
concentration
signs of decompensated liver disease (encephalopathy, ascites)
uncharacteristically lengthy illness
all Hbsag-positive patients: particularly if HbV dna > 2000 iu/mL, elevated aLt
levels or features of significant liver damage
if considering immunosuppression (including corticosteroids)
annual monitoring by GP for all other anti-Hbs-positive patients (consider inactive
cirrhosis in the older patient)

irrespective of language difficulties, patients
should understand the aims of treatment,
namely:
� to achieve prolonged suppression of HbV
replication and
� to arrest (or reverse) the progression of liver
damage, with the ultimate goal of preventing
cirrhosis, Hcc and liver failure.
it is important that patients have an
understanding of the key factors, including
the role of liver biopsy, which influence the
decision to commence treatment.
Pegylated interferon, lamivudine and entecavir
are approved for reimbursement by the
Pharmaceutical benefits advisory committee
(Pbac) for initial antiviral treatment in patients
with cHb. Patients should be advised that the
selection of the most appropriate antiviral
therapy depends on many factors, including
safety, efficacy and cost. Pegylated interferons
are administered for a defined duration—but
patients require pre-treatment education and
ongoing support while on therapy, due to the
adverse events associated with their use.
nucleoside analogues (na), e.g. lamivudine
and entecavir, are generally very well tolerated,
with a limited number of side effects. a
major concern with their long-term use is the
emergence of antiviral resistant mutations.
the emergence of antiviral resistant mutants
is related to previous exposure to nas, the
duration of therapy, the pre-treatment HbV
dna level and the rate of decline of HbV dna
levels after therapy has commenced. adefovir,
while effective in suppressing wild type and
lamivudine-resistant HbV, is only available
under the Pharmaceutical benefits scheme
(Pbs) in australia for the treatment of resistant
HbV. entecavir is also available for the treatment
of lamivudine-resistant HbV, but a higher dose
(1.0 mg) is recommended than for treatmentnaïve
patients (0.5 mg). 5
Hbeag-positive patients are treated until they
establish Hbeag seroconversion and maintain
the immune control phase (Hbeag negative,
Hbsag positive and low HbV dna). Hbeagnegative
patients often need to be treated
indefinitely, as relapse is common. for this
reason, the decision to use nas needs to be
considered carefully because of the risk of viral
resistance. treatment is often deferred until
later for patients in their twenties or younger,
unless there are indicators of significant liver
disease or a family history of Hcc. 2
combination antiviral therapy has proved to
be highly beneficial in preventing antiviral
resistance in HiV and it is likely that a similar
scenario will emerge in HbV treatment (see
chapter 2: Virology: viral replication and drug
resistance).
Patients interested in starting a family
should consider the safety profile of various
treatment options and the restricted access to
treatment under Pbs section100 criteria. the
management decision for patients initiated on
treatment who later become pregnant must be
individualised. there are abundant safety data
for lamivudine in HiV-treated patients that may
facilitate a discussion on the risks and benefits
of treatment cessation, including a potential
flare of disease activity during pregnancy.
initiating a patient prior to family planning with
pegylated interferon may be an alternative
option, as interferon treatment is limited to a
defined duration.
treatment of chronic hepatitis b is discussed in
more detail in chapter 7: treatment of chronic
hepatitis b virus infection.
Screening for hepatocellular
carcinoma
an important element in the assessment
of a patient with cHb is the issue of Hcc
screening. Hcc screening is recommended for
patients with cHb at high risks for Hcc (table
6.3). screening is recommended every six
months using ultrasound or a combination of
ultrasound and alpha fetoprotein estimation. 2
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 55

6 Clinical assessment of patients with hepatitis B virus infection
table 6.3: recommendations for
hepatocellular carcinoma screening in
patients with chronic hepatitis (adapted
from sherman M.) 6
any patient with cirrhosis
asian men over 40 years of age
asian women over 50 years of age
africans over 20 years of age
family history of hepatocellular carcinoma
Conclusion
the assessment of patients with cHb infection
is complex, as it demands an intimate
knowledge of the natural history of HbV
infection. our understanding of cHb has
improved dramatically. new therapeutic agents
have altered the management of patients in
recent years. treatment paradigms of cHb are
constantly changing. Primary care providers will
need to keep abreast of these developments
to effectively advise their patients of the most
appropriate management plan. imparting
current knowledge is particularly relevant, as
migration patterns suggest that the prevalence
of disease in australia will continue to increase.
References
56 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
1. Lok asf, McMahon bJ. chronic hepatitis b.
Hepatology 2007;45(2):507-39.
2. Keeffe eb, dieterich dt, Han sb, Jacobson
iM, Martin P, schiff er, et al. a treatment
algorithm for the management of chronic
hepatitis b virus infection in the united
states: an update. clin Gastroenterol Hepatol
2006;4(8):936-62.
3. McMahon bJ. epidemiology and natural
history of hepatitis b. semin Liver dis
2005;25(suppl 1):3-8.
4. chen, cJ, yang Hi, Jun Md, Jen cL, you sL, Lu
sn, et al for the reVeaL-HbV study Group. risk
of hepatocellular carcinoma across a biological
gradient of serum hepatitis b virus dna level.
J am Med assoc 2006;295(1):65–73.
5. Hoofnagle JH, doo e, Liang tJ, fleischer r,
Lok as. Management of hepatitis b: summary
of a clinical research workshop. Hepatology
2007;45(4):1056-75.
6. sherman M. Pathogenesis and screening
for hepatocellular carcinoma. clin Liver dis
2004;8:419-43, viii.

TREATMENT OF CHRONIC
HEPATITIS B VIRUS INFECTION
Rebecca J Ryan School of Medicine, University of Queensland, Greenslopes Private Hospital; Department of
Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD.
Miriam T Levy Department of Medicine, The University of New South Wales, South Western Sydney Clinical
School, Liverpool Hospital, Liverpool, NSW.
Darrell HG Crawford School of Medicine, University of Queensland, Greenslopes Private Hospital; Department of
Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD.
Links to : Chapter : Virology: viral replication and drug resistance
Chapter 3: Hepatitis B virus testing and interpreting test results
Chapter 4: Natural history of chronic hepatitis B virus infection
Chapter 6: Clinical assessment of patients with hepatitis B virus infection
Chapter 11: Infection control and occupational health
Chapter 13: The role of complementary medicine in hepatitis B
KEY POINTS
7
� treatment is considered for patients with high HbV dna, elevated aLt levels and evidence of
inflammation or fibrosis on liver biopsy.
� Patients in the immune clearance and reactivation phases of infection, but not in the immune
tolerance phase, are candidates for therapy.
� the primary goal of therapy is control of viral replication. in Hbeag-positive patients, Hbe
seroconversion is an endpoint of therapy. in Hbeag negative-patients, no therapeutic endpoint
exists and therapy is usually indefinite.
� direct antiviral agents can be chosen according to their potency, their side effects and the chance
of resistance. for treatment-naïve patients, entecavir is the best currently available antiviral
therapy. for lamivudine-resistant patients, adefovir added to lamivudine therapy is most effective.
Long-term therapy is commonly required and resistance is likely, with all agents in current use.
� Pegylated interferon has comparable efficacy to antiviral agents, with the disadvantage of increased
side effects and the advantage of a shorter, fixed duration therapy without drug resistance.
� therapy should be individualised. regular monitoring is required to identify resistance, hepatitis
flares and response.
Goals of therapy
the primary goal of therapy of chronic hepatitis
b (cHb) is to reduce and maintain suppression
of hepatitis b virus (HbV) replication to the
lowest possible level, as evaluated by highly
sensitive assays for HbV dna. the ultimate
aim of durable viral suppression is to prevent
the progression of liver disease to cirrhosis and
reduce (or eliminate) the risk of liver failure or
the development of hepatocellular carcinoma
(Hcc) in those patients who have established
liver injury. 1
High viral replication is associated with a worse
outcome, as evidenced in natural history
studies of untreated hepatitis b surface antigen
(Hbsag) positive patients. adverse liver-related
outcomes (i.e. risk of cirrhosis and Hcc) in
taiwanese patients with cHb have been
reported predominantly in patients with HbV
dna levels >10 5 copies/mL (>20,000 iu/mL). 2
these outcome data may not be applicable
to younger patients in the immunotolerant
phase, where high levels of HbV dna are not
accompanied by necroinflammatory activity
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 57

7 Treatment of chronic hepatitis B virus infection
and progressive liver damage. data from
recent clinical trials have shown that prolonged
control of viral replication may reduce the
likelihood of liver decompensation and death.
these results are also reflected in clinical
experience, particularly in liver transplant
centres, where the clinical recovery of patients
with cHb after commencing antiviral therapy
is well documented and the proportion of
patients undergoing liver transplantation for
cHb is decreasing. 2
Loss of Hbsag is the only absolute endpoint of
therapy in Hbeag-positive and Hbeag-negative
chronic disease, but Hbsag seroconversion is
uncommon and has not been used as a primary
endpoint in most short-term clinical trials.
an objective of antiviral therapy in Hbeagpositive
patients is the loss of Hbeag and
the development of anti-Hbe—the so-called
eag seroconversion. Hbeag seroconversion
is infrequent, although rates increase with
prolonged antiviral therapy. sustained
Hbeag seroconversion indicates that antiviral
therapy may be discontinued after a period
of consolidation (six to nine months) and that
viral suppression may be maintained even
after the cessation of treatment. in some cases,
however, the Hbeag loss is not durable and
sero-reversion may occur. thus, all patients
require careful ongoing monitoring.
in the majority of patients with Hbeag-positive
disease, Hbeag seroconversion does not occur
and thus many years of therapy are required.
the emergence of drug resistance in these
patients can become a significant therapeutic
challenge. 1
therapy for Hbeag-negative patients is more
difficult to assess, as Hbeag seroconversion
cannot be used as an endpoint. the suppression
of HbV dna and the normalisation of aLt levels
are markers of a virological and biochemical
response, but both usually rebound shortly
after therapy is ceased. in general, the
decision to commence a patient with Hbeagnegative
disease on a nucleoside analogue is
a commitment to indefinite therapy. Problems
with viral resistance may emerge, although
58 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
the rates of resistance vary with the chosen
antiviral agent.
Indications for antiviral therapy
the decision to commence antiviral therapy
is based upon a number of factors, including
the patient’s age, the Hbeag status, the
serum HbV dna concentration, aLt levels,
and the risk of Hcc. in australia, liver biopsy
remains a compulsory requirement for the
reimbursement of therapy (unless the patient
has an underlying coagulation disorder) and
the histological severity of the underlying
liver disease is an important element of the
decision-making process to initiate treatment.
When choosing the most appropriate anti-
HbV therapy, it is important to consider the
advantages and disadvantages of each therapy
based on the available clinical evidence. the
choice of therapy must take into account the
drug’s efficacy, safety, chance of achieving
desired endpoints, anticipated duration of
therapy and the likelihood of developing
resistance. the likelihood of patient adherence
to therapy regimens should be considered,
as non-adherence may be associated with
significant flares in disease activity.
HBeAg-positive patients
Hbeag-positive patients with an elevated
serum aLt greater than two times the upper
limit of normal (uLn) and a serum HbV dna
level of greater than 20,000 iu/mL should be
considered for antiviral therapy. under current
Pbs recommendations, these patients require
a liver biopsy demonstrating histological
evidence of cHb. 3
in general, Hbeag-positive patients with a
serum HbV dna level of less than 20,000 iu/mL
are not recommended for therapy, because the
vast majority of these patients will have inactive
disease and a normal aLt level. the HbV dna
level and the necroinflammatory activity of the
liver disease are subject to significant variability
and these patients should be monitored to
ensure constant levels of HbV dna and the
persistence of a normal aLt level. at present,
an annual HbV dna measurement will be
reimbursed by the australian Pbs, although it

is recommended that serum aLt be monitored
every three to six months and the HbV dna
level be reassessed if the serum aLt increases.
occasionally, patients with low level viral
replication have significant necroinflammatory
activity or hepatic fibrosis; antiviral therapy is
indicated in these patients. 4
Hbeag-positive patients with a serum HbV
dna level of greater than 20,000 iu/mL with a
persistently normal aLt level are often young
and within the immunotolerant phase of their
illness. it is advisable to monitor such patients
for an extended period to observe changes in
aLt levels. However, some patients with normal
aLt levels and a markedly elevated HbV dna
level may have significant liver injury. a liver
biopsy should be considered in older patients
(over 40 years of age) with this laboratory
profile, or in those patients in whom a clinical
evaluation suggests significant underlying
disease. the patient should then be offered
antiviral therapy if significant liver injury is
discovered. 4
HBeAg-negative patients
serum HbV dna levels are often lower in
patients with Hbeag-negative cHb than
in patients with Hbeag-positive cHb, but
many affected patients have significant
necroinflammatory activity or hepatic fibrosis
on liver biopsy. therefore, it is recommended
that the threshold serum HbV dna level for
initiating antiviral therapy should be 2000
iu/mL in this group of patients. in general,
other recommendations for therapy in Hbeagnegative
patients are similar to those for
Hbeag-positive disease. 4
Therapeutic options
there are two main classes of therapy: direct
antiviral agents, which inhibit the function of
the viral polymerase to prevent viral replication,
and the interferons that are synthetic cytokines
which act via multiple intracellular biological
pathways to eradicate the viral infection.
in practical terms, three agents are
currently accepted and approved by the
australian Government’s therapeutic Goods
administration (tGa), and listed on the
Pharmaceutical benefits scheme (Pbs) for the
initial treatment of cHb patients in australia.
these agents are pegylated interferon (180
µg weekly), lamivudine (100 mg daily) and
entecavir (0.5 mg daily). a further agent, adefovir
dipivoxil (10 mg daily), is licensed by the Pbs to
treat patients who have developed resistance
to lamivudine or entecavir. entecavir is also
approved to treat patients with lamivudine
resistance, although the recommended dose is
higher than for previously untreated patients.
several other agents are either currently
under evaluation for reimbursement by the
Pharmaceutical benefits advisory committee
(Pbac) or are in the advanced stages of clinical
trial programs, so recommendations for the
most appropriate antiviral therapy in different
patient populations are likely to change,
based on the future availability of these drugs.
However, the following discussion will be
largely confined to the treatments that are
currently registered for use in australia.
Pegylated interferon
use of conventional interferon (ifn) has been
supplanted by the use of pegylated interferon
(PeG-ifn), which has the advantage of weekly
dosing and improved efficacy. this drug has
a pegylated moiety, which confers improved
pharmacokinetics to allow less frequent dosing.
PeG-ifn is given weekly for 12 months. the side
effects are similar to conventional ifn, including
troublesome flu-like symptoms, fatigue,
leukopenia, irritability, sleep disturbance and
depression. 1 in Hbeag-positive patients, Hbeseroconversion
occurs in 32% of patients six
months after the end of treatment. 5 sustained
responses are better in patients with genotype
a cHb (47%) than in those with genotype d
cHb (25%) infection. better response rates to
ifn-based therapies are seen in patients who
are young, female, and have an elevated aLt, a
relatively low HbV dna level and genotype a
cHb. 4,6-8 Long-term studies suggest that Hbeag
seroconversion continues to occur in the years
after therapy is completed at a greater rate than
would be expected to occur naturally.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 59

7 Treatment of chronic hepatitis B virus infection
a small but significant proportion
(approximately 5%) of patients treated with
ifn also achieves Hbsag seroconversion. this is
seen particularly in those with genotype a, the
most common genotype in caucasian patients.
Loss of Hbsag is significantly less common with
direct antiviral agents (see below).
PeG-ifn also has a role in the treatment of
Hbeag-negative patients. a sustained control
of viral replication (< 2000 iu/mL) is seen in
approximately 30% of patients six months
after the completion of therapy. 9 the control of
viral replication at these levels should reduce
the progression to clinically significant liver
disease.
the main advantage of PeG-ifn is the fixed
duration of therapy and the chance for Hbsag
seroconversion. the main disadvantage is
the side effect profile, predominantly fatigue,
irritability and leukopenia. flares of viral
hepatitis can result from the enhanced immune
clearance. flares can be seen in 12%–18%
of patients and can be severe in those with
advanced underlying liver disease. 1 PeG-ifn is
contraindicated in decompensated cirrhosis.
the main concern when using PeG-ifn is the
ongoing viral replication that persists at the
completion of therapy in many patients. it
is possible for patients who have ongoing,
clinically significant viral replication after the
completion of PeG-ifn therapy to receive oral
antiviral therapy. However, this approach has
not been validated in clinical trials. 1
Lamivudine
Lamivudine was the first antiviral agent
available for treatment of HbV infection. it is
an oral nucleoside analogue, well tolerated
and without significant side effects. it induces
profound inhibition of viral replication in
almost all patients, which results in improved
liver histology, improved liver function in
decompensated disease and, in some studies,
a reduction in the rate of Hcc in patients with
advanced fibrosis. it may be taken with or
without food, and is well tolerated, with a side
effect profile similar to the placebo. 1
60 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
the endpoint of therapy for Hbeag-positive
disease is Hbeag seroconversion with
associated control of viral replication. Hbeag
seroconversion only occurs in a minority of
patients; this is more likely to occur in those
with a markedly elevated aLt. seroconversion
rates continue to increase the longer a patient
remains on therapy (17% after one year of
treatment, 27% after two years of treatment
and 50% by year five of treatment). 10 therapy
is indefinite if Hbeag seroconversion does not
occur. therapy for Hbeag-negative infection
is indefinite, as relapse after the cessation of
therapy is almost universal. unfortunately,
prolonged therapy with lamivudine is limited
by the high rates of viral resistance, occurring
in 14%–32% after one year of therapy and in
60%–70% after five years of therapy. 11 When
resistance develops, efficacy is lost and in some
patients severe exacerbations of liver disease
can occur. 1 as a consequence, lamivudine is no
longer the best option for first-line therapy, now
that other agents with an improved resistance
profile are available.
Entecavir
entecavir is a purine-derived nucleoside
analogue. it is highly effective at inhibiting viral
replication, and early studies confirmed that
this inhibition of viral replication was associated
with improvements in liver histology. entecavir
has few side effects, the most common being
headache (2–4%) and fatigue (1–3%), although
adverse events were equally seen in the
lamivudine-treated group when the two agents
were compared. 12 unlike other antiviral agents,
entecavir must be taken on an empty stomach,
two hours before or after a meal.
compared with lamivudine and adefovir,
entecavir has the greatest potency (measured
by the decrease in viral load from baseline) of
the available direct antiviral agents, compared
with lamivudine and adefovir. Hbeag rates of
clearance are similar to those seen with other
antiviral agents. importantly, entecavir has
the lowest rate of resistance (less that 1% in
nucleoside-naïve patients after one to two
years). 1,13 from november 2006, the Pbs agreed
to support the use of entecavir for treatment-
naïve patients with HbV infection. entecavir has

now largely superseded lamivudine as the firstline
therapy of choice for the treatment of cHb
in australia.
entecavir can be used in patients who have
developed resistance to lamivudine. Higher
doses of 1.0 mg daily are required to suppress
lamivudine-resistant HbV. despite higher
doses, antiviral activity remains lower than that
seen with wild-type HbV. despite its improved
potency, patients with lamivudine-resistant
mutants are more likely to develop resistance to
entecavir (17% after four years of treatment). 14
entecavir is thus not the best choice for patients
with lamivudine resistance, who should ideally
be treated with adefovir. 1
Adefovir
adefovir, an acyclic phosphorate nucleoside
analogue, is an effective antiviral agent. the
control of viral replication and improved
biochemical, histological and clinical outcomes
have been demonstrated. adefovir is orally
active and well tolerated at the 10 mg daily
dose recommended for use in HbV infection.
it may be taken without regard to food. the
potency of adefovir at this dose is less than that
of other available antivirals. Higher doses, while
more effective, cannot be used because of
nephrotoxicity. the renal function at the 10mg
dose does, however, need to be monitored, as
renal toxicity can occur with long-term use. 1
While in the us adefovir is used in the first
line setting, currently the Pbs requires that
adefovir be limited in the setting of lamivudine
resistance. in this setting, adefovir is added
to lamivudine therapy for the first three
months in patients with compensated disease,
and for the first 12 months in patients with
decompensated disease; adefovir is then
used on its own, as monotherapy. the rate of
resistance to adefovir in the first line setting is
much lower than lamivudine (0% after one year
of treatment, 1% after three years and 30% after
five years of treatment). 15 unfortunately, the
rates of resistance to adefovir are much higher
in patients already resistant to lamivudine.
Long term combination therapy with adefovir
and lamivudine in patients with lamivudine
resistance is associated with much lower rates
of resistance. 1 although the Pbs does not
currently fund this approach, combination
lamivudine/adefovir in this setting is likely to
gain approval in the near future.
Future therapies (not yet approved in
Australia)
emtricitabine, tenofovir and telbivudine are
agents not yet available in australia, but with
known efficacy against HbV replication. it is
likely that some or all will be available as Pbs
subsidised therapy in australia in the near
future, depending on their efficacy, tolerability
and rates of resistance. overseas data suggest
that tenofovir may have the most beneficial
profile of these three new agents. 1
tenofovir, like adefovir, is an acyclic adenine
nucleotide, with potent activity against HbV.
it is currently in use for the treatment of HiV
infection. as a result of its potency, tenofovir
is particularly effective in patients with
lamivudine-resistant cHb, and is likely to have
an important role in treatment-naïve patients
with HbV infection. 1
emtricitabine, like lamivudine, is an Lnucleoside
agent with a level of potency and
resistance similar to lamivudine. telbivudine is
also an L-nucleoside agent that may be more
potent than lamivudine, with rates of resistance
that are lower than those of lamivudine, but
substantially higher than those of entecavir and
adefovir. 1 both emtricitabine and telbivudine
are ineffective in the setting of a lamivudineresistant
virus. these drugs may find their place
in combination therapy regimes, which are
under investigation at the present time.
Monitoring patients on antiviral
therapy
Patients should be monitored regularly while
on therapy to document their response to
antiviral therapy, to detect adverse side effects
of therapy and to facilitate the early detection
of antiviral resistance. Monitoring needs to
be more frequent in patients treated with
pegylated interferons compared to those
treated with nucleoside analogues because
of the risk of bone marrow suppression,
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 61

7 Treatment of chronic hepatitis B virus infection
neuropsychological side effects and other
complications of interferon-based therapy.
for patients treated with pegylated interferon,
frequent (e.g. fortnightly) monitoring is
recommended until the treatment dose
is stabilised. Patients can then reduce the
frequency of their visits to every four to six
weeks. Particular attention should be paid to
the full blood count, white cell count differential
and platelet count at each visit, in case dose
adjustments are required.
in patients treated with nucleoside analogues,
monitoring should occur on a three monthly
basis—particularly for patients with advanced
fibrosis or cirrhosis, and for those patients on
antiviral therapy who have a high incidence of
viral resistance. full blood count, liver function
tests and HbV serology (for Hbeag-positive
patients) should be performed at each of
these visits. the optimal frequency for HbV
dna testing remains to be determined. threemonthly
HbV dna testing appears appropriate
for patients with high viral resistance rates or
in those for whom the likelihood of clinical
complications due to delaying therapy for
resistance is judged to be high. the frequency
may be reduced to four or six monthly for
patients with low resistance rates and in those
for whom the risk of complications of resistance
is judged to be low. 4,16
Antiviral drug resistance
the emergence of antiviral drug resistance
is the major challenge confronting clinicians
who manage patients with cHb. recently, the
following definition for antiviral resistance
to nucleoside analogue treatment was
proposed: a confirmed 10-fold increase in
serum HbV dna level (> 1 log 10 iu/mL) from
nadir following initially effective treatment
constitutes secondary treatment failure
which, in the absence of poor adherence or
drug substitution, is almost always due to
the emergence of the drug-resistant HbV
mutants. a rebound in serum HbV dna always
precedes the biochemical and histological
markers of increased HbV disease activity, and
patients with underlying cirrhosis are at an
increased risk of decompensation following
6 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
the emergence of resistance. early diagnosis of
secondary treatment failure and the institution
of appropriate antiviral therapy remain key
to preventing hepatic decompensation, liver
failure, death or liver transplantation in patients
who develop drug resistant mutations. 16
Predictors of lamivudine resistance include
high pre-treatment HbV dna levels, non-asian
ethnicity, male gender and persistent viral
replication with continued antiviral therapy. 1
the molecular characterisation of genotypic
changes that confer resistance is not usually
performed in clinical practice, and there is no
indication that such laboratory analysis will
be reimbursed by Medicare in the near future.
While the sequencing of HbV drug-resistant
mutations is largely regarded as a research tool
at present, it can provide important information
and influence the selection of the most
appropriate therapeutic antiviral strategy.
in relation to reimbursement options by the
Pbs, the management of patients who develop
lamivudine resistance is limited to switching
therapy to either adefovir or entecavir. However,
the risk of the emergence of subsequent
adefovir or entecavir resistance is much higher
in this cohort of patients than in treatmentnaïve
patients. there is now abundant evidence
that the addition of adefovir to lamivudine
therapy, rather than a switch to adefovir
monotherapy, is the preferred management
strategy for patients who develop lamivudine
resistance. in those patients who have
been placed on adefovir monotherapy, (for
lamivudine resistance), the development of
resistance to adefovir can often be managed
by the re-introduction of lamivudine and the
continuation of adefovir. at present the Pbs
will not provide reimbursement for combined
therapy in this patient group. However, it
is expected that combination therapy with
adefovir and lamivudine for this patient group
only will be approved in the near future.
the molecular virology of HbV viral resistance is
discussed in more detail in chapter 2: Virology:
viral replication and drug resistance.

Treatment-related side effects
the safety profile of nucleoside and nucleotide
analogues is similar to that of the placebo.
in general, these drugs are remarkably well
tolerated. their major concerns are the risks of
resistance and safety in pregnancy.
tenofovir, an oral nucleoside agent currently
in clinical studies, may be the safest option
for women in their child-bearing years, given
its recent category b pregnancy listing.
it is currently only approved for HbV/HiV
coinfection, but not for HbV monoinfection. 1
(category b: Presumed safety based on animal
studies, with no controlled studies in pregnant
women, or if animal studies have shown
an adverse effect that was not confirmed
in controlled studies in women in the first
trimester and there is no evidence of a risk in
later trimesters. available at: http://www.tga.
gov.au/docs/html/medpreg.htm).
in contrast, pegylated interferon has many
side effects. anecdotally, it seems to be better
tolerated in patients with HbV rather than
patients with hepatitis c virus (HcV). despite
this observation, patients taking interferon
may experience many different side effects that
require careful consideration and appropriate
intervention. treatment is usually supportive
and symptom-based. the most common side
effects early on are flu like symptoms and the
following measures may be of benefit:
� simple antiemetics, such as metoclopramide,
for nausea and vomiting
� antispasmodics, such as buscopan, for
abdominal cramps
� Paracetamol for headaches, fevers, myalgia
and arthralgia (avoid nsaids because
of concomitant thrombocytopenia with
treatment).
Mood disturbances become more common
as therapy continues and appropriate
interventions may include:
� benzodiazepines or zolpidem for insomnia
� antidepressants: ssris are preferred for
anxiety and depression.
if the patient has a history of depression, a
low threshold should exist for starting ssri
therapy pre-treatment. Patients already on
antidepressants may need a dose increase
during interferon therapy. for patients starting
an ssri during treatment, the ssri is usually
continued for six months post-cessation of
interferon therapy.
skin changes are common during therapy and
patients often complain of dry, itchy skin and
a multitude of skin rashes. therapy is usually
based on keeping the skin hydrated, with
regular use of moisturisers and emollients.
antihistamines can be used, particularly if
pruritus is exacerbating insomnia. steroidbased
creams can be trialled for rashes that do
not respond to any of the above measures.
Lifestyle issues while on therapy appear to be
important. Patients can trial a variety of lifestyle
changes during therapy to help with interferonrelated
side effects. regular exercise before and
during therapy seems to help with lethargy and
myalgias. anecdotally, patients who exercise
regularly seem to tolerate treatment better
than those who are sedentary. Patients should
avoid alcohol if possible.
for information about reimbursed therapy:
http://www.pbs.gov.au/html/healthpro/
home
for information about the listing of drugs in
pregnancy: http://www.tga.gov.au/docs/
html/medpreg.htm
Alternative therapies
the use of complementary, alternative or
chinese medicine has not been well studied
in patients undergoing treatment with
interferon-based therapies; because of the
risk of hepatoxicity, the use of these therapies
should be discouraged while the patient is
undergoing interferon-based therapy. Massage,
hypnotherapy, acupuncture and other nonmedicinal
based therapies may provide
symptom-based relief during treatment. chapter
13: the role of complementary medicine in
hepatitis b provides further details about the
benefits and dangers of using alterantive
therapies in the treatment of hepatitis b.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 63

7 Treatment of chronic hepatitis B virus infection
References
1 Lok asf, McMahon bJ. chronic Hepatitis b.
Hepatology 2007;45(2):507-39.
2 chen, cJ, yang Hi, Jun Md, Jen cL, you sL, Lu sn,
et al for the reVeaL-HbV study Group. risk of
hepatocellular carcinoma across a biological
gradient of serum hepatitis b virus dna level. J
am Med assoc 2006;295(1):65–73.
3 Liaw yf, sung JJ, chow Wc, farrell G, Lee cZ,
yuen H, et al. Lamivudine for patients with
chronic hepatitis b and advanced liver disease.
n engl J Med 2004;351:1521-31.
4 Keeffe eb, dieterich dt, Han sb, Jacobson
iM, Martin P, schiff er, et al. a treatment
algorithm for the management of chronic
hepatitis b virus infection in the united
states: an update. clin Gastroenterol Hepatol
2006;4(8):936-62.
5 Lau GK, Piratvisuth t, Luo KX, Marcellin P,
thongsawat s, cooksley G, et al. Peginterferon
alfa-2a, lamivudine, and the combination for
Hbeag-positive chronic hepatitis b. n engl J
Med 2005;352(26):2682-95.
6 schiff er. treatment algorithms for hepatitis
b and c. Gut 1993;34(suppl 2):s148-s149.
7 chan HL, Leung nW, Hui ay, Wong VW, Liew
ct, chim aM, et al. a randomized, controlled
trial of combination therapy for chronic
hepatitis b: comparing pegylated interferonalpha
2b and lamivudine with lamivudine
alone. ann intern Med 2005;142:240-50.
8 Janssen HL, van Zonneveld M, senturk H,
Zeuzem s, akarca us, cakaloglu y, et al.
Pegylated interferon alfa-2b alone or in
combination with lamivudine for Hbeagpositive
chronic hepatitis b: a randomised
trial. Lancet 2005;365:123-9.
9 Marcellin P, Lau GK, bonino f, farci P,
Hadziyannis s, Jin r, et al. Peginterferon
alfa-2a alone, lamivudine alone, and the
two in combination in patients with Hbeagnegative
chronic hepatitis b. n engl J Med
2004;351:1206-17.
10 Leung nW, Lai cL, chang tt, Guan r, Lee cM,
ng Ky, et al. extended lamivudine treatment
in patients with chronic hepatitis b enhances
hepatitis b e antigen seroconversion rates:
results after 3 years of therapy. Hepatology
2001;33(6):1527-32.
64 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
11 Locarnini s. Molecular virology and
the development of resistant mutants:
12
implications for therapy (review). semin Liver
dis 2005;25(suppl 1):s9-s19.
chang tt, Gish rG, de Man r, Gadano a,
sollano J, chao yc, et al. a comparison
of entecavir and lamivudine for Hbeag
positive chronic hepatitis b. n engl J Med
2006;354(10):1001-10.
13 colonno rJ, rose r, baldick cJ, Levine s,
Pokornowski K, yu cf, et al. entecavir resistance
is rare in nucleoside naïve patients with
hepatitis b. Hepatology 2006;44(6):1656-65.
14 tenney dJ, Leine sM, rose re, Walsh aW,
Weinheimer sP, discotto L, et al. clinical
emergence of entecavir-resistant HbV
15
requires additional substitutions in virus
already resistant to lamivudine. antimicrob
agents chemother 2004;48:3498-507.
Hadziyannis sJ, tassopoulos nc, Heathcote
eJ, chang tt, Kitis G, rizzetto M, et al; adefovir
dipivoxil 438 study Group. Long-term
16
therapy with adefovir dipivoxil for Hbeagnegative
chronic hepatitis b for up to 5 years.
Gastroenterology 2006; 131(6):1743-51.
Hoofnagle JH, doo e, Liang tJ, fleischer r,
Lok as. Management of hepatitis b: summary
of a clinical research workshop. Hepatology
2007;45(4):1056-75.

MANAGING PATIENTS WITH
ADVANCED LIVER DISEASE
Robert Batey University of New South Wales, Bankstown Hospital, Bankstown, NSW.
Links to: Chapter 7: Treatment of chronic hepatitis B virus infection
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
KEY POINTS
� address the underlying HbV infection
- define the severity of disease
- offer anti-viral therapy where appropriate
� Minimise other hepatic injury
- exclude other causes of liver disease
- advise on healthy living
� Manage the complications of cirrhosis
People with chronic hepatitis b virus (HbV)
infection are at an increased risk of developing
liver cirrhosis, hepatic decompensation
and hepatocellular carcinoma (Hcc), with
15–40% developing serious sequelae during
their lifetime. cirrhosis is a histopathological
diagnosis, describing liver fibrosis with nodule
formation subsequent to liver cell necrosis and
regeneration. fibrosis in response to hepatocyte
death is due to stellate cell activation and is at
first limited in extent, then forms portal-toportal
or portal-to-central vein bridging, finally
leading to nodule formation. cirrhosis leads
to altered liver perfusion with a decrease in
portal vein flow and a compensatory increase
in hepatic artery input. this adversely affects
hepatocyte function over time. nevertheless,
patients with stable cirrhosis may survive many
years without major complications.
in HbV infection, the progression of
inflammatory and fibrotic processes is more
active in those with raised aLt levels and in
those with a high HbV dna.
Patients with advanced liver disease, with
or without ongoing hepatitic inflammation,
8
present clinicians with significant management
challenges. the presence of untreated or
untreatable HbV or hepatitis c virus (HcV)
infection or continuing damage from other
factors, such as alcohol use or non alcoholic
fatty liver disease, or insulin resistance, adds
to the complexity of the management process.
if treated well, these patients may still enjoy
months to years of an acceptable quality of
life, even if the underlying condition cannot be
cured. ultimately, liver transplantation provides
a better outcome if it can be achieved, but this
is not realistic for many patients. this chapter
will focus on the management of advanced liver
disease in patients with chronic HbV infection.
there are three issues that should be addressed
in managing this group of patients.
1. Addressing the underlying HBV
infection
the treatment of chronic HbV is discussed
in detail in chapter 7: treatment of chronic
hepatitis b virus infection. all patients should
be evaluated for possible antiviral therapy with
pegylated interferon or an oral nucleoside or a
nucleotide analogue agent such as entecavir,
as these drugs can significantly modify the
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 65

8 Managing patients with advanced liver disease
progression of the disease. interferon-based
therapies are contra-indicated in patients with
decompensated cirrhosis, but oral antiviral
agents are generally very well tolerated.
2. Reducing other hepatic insults
all patients should have a detailed history and
examination performed to establish:
� underlying medical conditions, including
co-infection with hepatitis c, hepatitis d or
the human immunodeficiency virus (HiV).
� Medication use
� Prescribed
� alternative or complementary medicine
and over-the-counter drugs
� tobacco use
� alcohol use
� recreational drug use
� family history of liver disease, diabetes
� Weight, body mass index (bMi)
� evidence of diabetes or other organ system
disease.
Patients with advanced liver disease should
have all co-existing disorders addressed as far
as possible, in addition to having the primary
disease and its complications managed.
specifically, weight reduction when obesity is an
issue and cessation of alcohol use (or markedly
reducing alcohol consumption if abstinence
is not an option) are critical processes in the
management of this group of patients. Patients
should also avoid excessive use of paracetamol
and non steroidal anti-inflammatory therapy.
drugs known to cause liver disease should
be used with caution, although underlying
liver disease does not increase the risk of side
effects.
Having advised the patient about other factors
that can aggravate liver disease, the clinician
must then focus on a specific management
plan for advanced liver disease.
3. Managing the complications of
advanced liver disease
it is important to document the extent of liver
disease through a detailed history and clinical
examination. it is imperative that the patient is
regularly reviewed in the same detailed manner,
66 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
as the disease process evolves over time. in
the initial examination, the patient’s history,
his/her examination and all investigations are
required to document or rule out the following
conditions:
� Chronic liver disease
� Hepatosplenomegaly
� spider naevi
� Hepatic palms (palmar erythema)
� Hepatic lunules (changes at nail base)
� Loss of body hair distribution in men
� Hirsutism in women
� testicular atrophy
� Fluid and electrolyte balance problems
� oedema
� ascites, pleural effusion
� decreased urine output
� Hyponatraemia
� Hypo/hyperkalaemia
� rising creatinine
� Portal hypertension
� Hepatomegaly and splenomegaly
� collateral vessels on anterior abdominal
wall
� caput medusae
� ascites
� overt or occult gastrointestinal
haemorrhage
� Portal systemic encephalopathy (Pse)
� Varices (evidence by ultrasound, computed
tomography or endoscopy)
� Portal systemic encephalopathy
� reversed sleep pattern (day time
somnolence and nocturnal waking)
� Metabolic flap or asterixis
� slowing of normal response times,
reflexes
� impaired driving skills
� Lack of energy
� confusion
� increasing drowsiness
� coma
� Advancing hepatic decompensation
� anorexia
� Jaundice
� bruising and bleeding problems
� spontaneous bacterial peritonitis
� Metabolic bone disease and risk of
fractures
� impaired glucose homeostasis
� impaired renal function

� Extrahepatic manifestations of advanced
liver disease
� cirrhotic cardiomyopathy
� Hepatopulmonary syndromes
� Hormonal complications
- testicular atrophy and feminisation
in men
- hirsutism, amenorrhoea in women
� increased risk of generalized infectious
complications
� Hepatocellular carcinoma
readers are referred to chapter 9: Hepatitis
b virus-related hepatocellular carcinoma and
standard texts on liver disease for a more
detailed description of this condition.
Management strategies
Management strategies should address all of
the conditions identified above and strategies
will need to be monitored to assure treatment
efficacy, to minimise complications and to
allow changes to the management plan as the
disease progresses or improves.
Fluid and electrolyte problems are managed
by:
� restricting salt and water intake where
necessary
� ensuring electrolyte balance
� cautious diuretic usage to minimise the
risk of hepatorenal syndrome
- spironolactone is the preferred agent,
in doses from 25–400 mg per day
- Low dose frusemide
� Potassium supplements as necessary
� a diet low in saturated fat with adequate
protein, fruit and vegetables
� Monitoring progress with regular serum
creatinine and urine electrolyte assays.
When urine sodium falls below 20 mmol/
day, decreased renal perfusion is likely
(reduce diuretic, consider saline infusion
over one hour)
� drainage of ascites may be necessary. in
some patients this may need to become
a regular process, as diuretics and other
conservative management approaches often
fail to control the problem. the procedure is
described in standard texts. some patients
are treated with transjugular intrahepatic
portosystemic shunt (tiPs) to lower portal
pressure and decrease ascites accumulation.
� All patients presenting with ascites should
have a diagnostic tap to exclude or diagnose
spontaneous bacterial peritonitis
Portal hypertension is managed by:
� all patients with newly diagnosed cirrhosis
should undergo endoscopy to determine if
varices are present
� reducing hepatic inflammation when
possible
� Prophylactically modifying portal pressure
with beta-blocking agents or nitrate therapy
� banding oesophageal varices when they are
identified
� treating acute bleeding when it occurs
� considering more active interventions if
conservative measures fail
� tiPs (transjugular, intrahepatic
portosystemic shunts)
� surgery for portal hypertension (rarely
undertaken these days), which includes
shunting procedures and oesophageal
transection).
Portal systemic encephalopathy is managed
by:
� regulating protein intake ensuring a
reasonable intake to maintain nutritional
status, while reducing total protein and
animal protein
� Maintaining optimal electrolyte balance
� using lactulose to both clear the colon and
alter ammonia metabolism and diffusion.
use doses to ensure two soft stools per day
and continue use long term
� using neomycin and metronidazole short
term if lactulose is not tolerated or if it is not
effective. these agents also act to reduce
ammonia levels, but they have significant
side effects with long-term use
agents such as L-dopa, bromocriptine, and
branch chain amino acid solutions (oral
and parenteral) have been trialled in portal
systemic encephalopathy, but their efficacy is
not proven.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 67

8 Managing patients with advanced liver disease
Advancing hepatic failure is managed by:
� avoiding and managing factors that
aggravate the liver disease
� alcohol
� some medications (e.g. excess
paracetamol, ibuprofen, anti-tuberculosis
agents)
� obesity
� injecting drug use
� iron overload
� diabetes
� Hepatitis c infection
� Monitoring Mg, Zn, ca, fat soluble vitamins
(monthly at first to determine the patient’s
ability to maintain normal levels)
� regularly checking for infection, e.g.
spontaneous bacterial peritonitis (sbP)
� avoiding certain infection risks, e.g. avoiding
oysters with their risk of vibrio vulnificans
infection
� Providing routine vaccination against
influenza and pneumococcal disease
� aggressively treating infections
� Managing portal hypertension
� Managing portal systemic encephalopathy
� Managing ascites
� ongoing screening for the risk of Hcc.
the risk of Hcc must be addressed in patients
with chronic HbV infection. both cirrhotic and,
to a lesser extent, non-cirrhotic patients are at
risk of this complication.
Recommended reading
1. bruix J, sherman M. Practice Guidelines
committee, american association for the
study of Liver diseases. Management of
hepatocellular carcinoma. Hepatology
2005;42:1208-36.
2. schiff er, sorrell Mf, Maddrey Wc. schiff’s
diseases of the Liver (10th edition); Vol 1 and
2. Philadelphia: Lippincott Williams & Wilkins;
2007.
3. sherlock s, summerfield Ja. a colour atlas
of liver disease. London: Wolfe Medical
Publications Ltd; 1979.
68 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

HEPATITIS B VIRUS-RELATED
HEPATOCELLULAR CARCINOMA
Monica Robotin The Cancer Council NSW and the School of Public Health, University of Sydney, Camperdown, NSW.
Links to: Chapter 1: Prevalence and epidemiology of hepatitis B
Chapter 6: Clinical assessment of patients with hepatitis B virus infection
KEY POINTS
� Worldwide, hepatocellular carcinoma (Hcc) is the third most common cause of cancer-related
mortality.
� in australia, the Hcc incidence has been increasing over the last 20 years.
� Hepatitis b virus (HbV)-associated Hcc may occur in non cirrhotic and, more commonly, in cirrhotic
patients.
� in nsW, the burden of disease is greatest in migrants from countries where HbV infection is endemic:
people born in southern and eastern asia are 6–12 times more likely to be diagnosed with Hcc
than australian-born people.
� traditionally, measuring serum alpha fetoprotein levels and performing liver ultrasound have been
used for Hcc screening.
� despite a lack of agreement on whether screening improves disease-specific mortality, informal
screening is widely practiced.
� curative treatments for early stage Hcc include surgical resection, liver transplantation and
percutaneous ablation of tumours.
� systemic chemotherapy has a low response rate, but targeted chemotherapy infused through the
hepatic artery may be effective in select cases.
� the most effective prevention strategy is universal HbV vaccination.
� there are effective treatments for chronic HbV; they may alter the course of the disease and they
may reduce the incidence of end-stage liver disease and liver cancer.
Worldwide, hepatocellular carcinoma (Hcc) is
the fifth most common cancer and the third
most common cause of cancer-related death,
with incidence rates two to three times higher
in men than in women. 1 over 80% of Hcc
worldwide is attributable to the combined
effects of chronic hepatitis b and c infections.
People with these infections have a 20 to 100fold
increased risk of developing Hcc relative
to those without these infections. 2,3 Hcc
prevalence is highest in eastern asia, middle
africa and some countries of Western africa,
with large variations in Hcc incidence observed
in different world regions. the estimated
age-adjusted incidence rates of liver cancer
per 100,000 men are approximately 10 times
9
higher in eastern asia, compared to the rates in
australia and new Zealand. 4 Hepatitis b is the
most common cause of Hcc worldwide and
almost a third of all people with HbV infection
live in china. annually, 300,000 chinese die
from HbV-related conditions, including 180,000
deaths from Hcc. 5
in australia, the liver cancer incidence ranks
fifteenth in males and twentieth in females,
but incidence and mortality figures have
progressively risen over the last two decades.
in nsW, primary liver cancer incidence rates
have been rising faster than rates for any
other cancer, 6 surpassing cancers of the lung,
mesothelioma, and brain and thyroid cancer. 7
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 69

9 Hepatitis B virus related hepatocellular carcinoma
the burden of liver cancer is greatest among
populations born in countries with a high
HbV prevalence. standardised incidence rates
(sir) of primary liver cancer in nsW are at
least six times higher in men born in Vietnam,
Hong Kong and Macau, Korea, indonesia and
china, and in women born in Vietnam and
china, as compared to the australian-born
population. this mirrors trends in the usa and
the netherlands, where rising rates of Hcc are
reported disproportionately in migrants from
asia and the Pacific islands compared to the
locally-born populations. 8,9
While most Hccs occur in cirrhotic livers,
tumours can also occur in livers with minimal
histological changes. this phenomenon is
more common in southern africa (where about
40% have minimal liver damage) than in asia,
america and europe (where more than 90% are
associated with cirrhosis). 10 among people with
cirrhosis, the annual incidence of Hcc ranges
from 2–3% in Western countries to 6–11% in
asian populations. 11
Screening assays for HCC
traditional screening regimes for the detection
of Hcc have included measuring serum
alpha-fetoprotein (afP) levels and performing
liver ultrasounds, used together in order to
improve screening accuracy, as their individual
sensitivity and specificity is relatively low,
particularly among people with cirrhosis. 11
Generally, a six-month interval is recommended
between screenings, which takes into
consideration the estimated doubling time of
Hccs smaller than 5cm in diameter. 12 as the
serum afP level is usually normal in early stage
Hcc, afP is not a reliable indicator of early
disease, although it can assist in ascertaining
the individual level of risk for developing Hcc
or in monitoring patients following tumour
removal. 13 the liver ultrasound is considered
the screening test of choice, as it can detect
tumours as small as 1–2cm in diameter, but it
is operator-dependent and does not reliably
discriminate between a Hcc and other liver
pathology (such as haemangiomas or cirrhotic
nodules). Patients with abnormal screening
tests need an unequivocal diagnosis reached
through additional investigations, which may
70 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
include computed tomography (ct) scanning,
magnetic resonance imaging (Mri) or liver
biopsy. 14 as negative screening results cannot
reliably exclude the presence of Hcc, regular
follow-up is required. 15
one randomised controlled trial (rct) enrolling
over 18,000 people with chronic hepatitis
b (cHb) infection has demonstrated a 37%
reduction of mortality in people screened for
Hcc compared to those randomised to usual
medical care. 16 More answers are needed
regarding the appropriate targeting of mass
screening programs, the cost-effectiveness
of screening protocols and the effect antiviral
treatment may have on screening and
treatment algorithms for preventing Hcc.
although rates of survival estimated by nonrandomised
studies are better for patients
with Hcc detected by screening compared
to those detected clinically, many studies do
not take into account the effect of lead time
bias on survival (lead time is the period by
which screening advances diagnosis of the
disease), so the real benefits of surveillance
remain the source of debate. 11,17 currently there
is no consensus on whether screening with
afP or a combination of afP and ultrasound
improves disease-specific or all-cause mortality
for Hcc. 12,18 due to the low cure rate for
symptomatically diagnosed Hcc, (five-year
survival rates less than 10%), and as cancers
detected by screening are generally smaller in
size and more likely to be unifocal, compared
to those clinically detected, 19 screening is
commonly used in clinical practice as a means
to increase the proportion of cancers amenable
to liver resection or liver transplantation. 11
informal screening is widely practised, with
a national survey of us gastroenterologists
finding that 84% of the respondents screened
their cirrhotic patients for Hcc. 20
due to the limitations of existing Hcc markers,
the search for new prognostic markers
continues. several markers are currently under
evaluation for their potential to predict disease
prognosis and for their possible roles as targets
for therapeutic interventions in the future. 21

Treatment of HCC
traditionally, Hcc has been diagnosed in
advanced stages, when prognosis is uniformly
poor, but with earlier detection, outcomes have
been improving. Predictors of Hcc prognosis
include: the stage and size of the tumour at
diagnosis; 22 the alpha-fetoprotein level; 23,24 age;
the presence of liver cirrhosis and the degree
of existing functional reserve; 25 and tumourrelated
factors, including size, number and the
degree of tumour spread. 26
therapeutic options for early-stage
disease (where cure is possible) include
surgical resection, liver transplantation and
percutaneous ablation. as no rcts have
compared the relative effectiveness of these
three types of interventions, it remains unclear
which should be the first-line treatment
option for people with early disease. 27 surgical
resection for small tumours in people with
normal liver function is associated with five-year
survival rates in excess of 50%, 28 but disease
recurrences are common, both locally and
related to new tumour formations in a cirrhotic
liver. 23,29-31
Orthotopic liver transplantation remains the
only option for those with resectable tumours
and decompensated cirrhosis, as it not only
removes the tumour but also the underlying
liver disease. 32 results of earlier surgical series
were fairly poor, but later series demonstrated
that in carefully selected patients, with single
or relatively small cancers (tumours ≤5 cm in
diameter, or ≤3 tumour nodules, each 3cm
or less in diameter—known as the Milan
criteria) and without vascular invasion, fiveyear
survival rates of 50–70% can be achieved,
with low recurrence rates. 30,33 although
HbV infection can be associated with lower
survival rates, combining transplantation with
antiviral therapy achieved a five-year survival
rate in excess of 75%. 34 However, the lack of
available livers for transplantation means that
a significant proportion of those on the waiting
list may end up ultimately being denied
transplantation, due to tumour advancement
during the waiting period. 35
Percutaneous ablation of tumours using
chemicals (ethanol or acetic acid) has been
successful in select case series, with best results
achieved with small, solitary tumours. 36,37
other means of destroying tumour cells
include extreme temperatures, achieved using
techniques such as radiofrequency ablation,
microwaves, laser or cryotherapy. 14
Transcatheter arterial embolisation (TAE)
and transarterial chemoembolisation (tace)
may be indicated in non-surgical patients free
of vascular invasion or extrahepatic tumour
extension. 14 these techniques aim to obstruct
the blood supply to intermediate-sized tumours
and use an embolising agent (such as gelfoam,
starch microshperes and metallic coils), 38
which in the case of tace is combined with a
chemotherapeutic agent (such as doxorubicin
or cisplatinum). 14
overall, systemic chemotherapy for advanced
Hcc has not been very effective, with response
rates below 20% and significant toxicity in
cirrhotic patients. 28 targeted therapy using
hepatic artery infusion of chemotherapeutic
agents may prove useful for some patients with
advanced Hcc, 39 but validation in larger trials
is awaited.
Public health approaches for HCC
prevention
the most effective and practical approaches
to controlling HbV infection and its longterm
sequelae are primary prevention
approaches, which aim to reduce or eliminate
viral transmission. Key interventions include
universal vaccination against HbV, ensuring
a safe blood supply (through screening of all
blood donations), and harm minimisation
approaches. to date, more than 100 countries
have instituted HbV vaccination programs
and there is strong evidence that infant
vaccination is effective in reducing the
incidence of liver cancer and the rate of chronic
infection in children. Within 15 years from
the commencement of mass immunisation
against HbV in taiwan, the rate of chronicity
in children decreased from 9.8% to 0.7% 40 and
was paralleled by a reduction of the incidence
rate of Hcc in children aged 6–14 years. 4
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 71

9 Hepatitis B virus related hepatocellular carcinoma
However, due to the long latency period and
the large burden of undiagnosed disease in
the community, the overall impact of universal
vaccination in reducing morbidity and mortality
from liver disease is not expected for another
30 or more years. experts of the Hepatitis
control committee in taiwan estimate that
vaccination could result in 80–85% decreases
in the incidence of Hcc in all adults within
three to four decades of vaccination. 42
secondary prevention aims to reduce the
proportion of people progressing to end-stage
liver disease and Hcc by optimising their medical
management. emerging evidence suggests
that reducing viral replication may reduce the
risk of developing Hcc and cirrhosis, so earlier
identification and treatment for chronic HbV
could be a valid cancer control option in wellresourced
settings, such as australia. one metaanalysis
of rcts using interferon for cancer
prevention suggests that this agent may have a
protective role for cancer development, but the
trials have been performed mostly in people
without advanced cirrhosis, so these findings
are difficult to generalise. 43 the demonstration
of a close correlation between HbV replication
and the risk of disease progression and liver
cancer, 44-46 coupled with data suggesting
that effective suppression of viral replication
may be associated with a reduced risk of
Hcc, 44-47 represent significant advances in
our understanding of the natural history of
cHb infection. However, long-term studies
that evaluate the benefits of antiviral therapy
or interferon-based therapies in reducing
the incidence of Hcc in people with chronic
HbV infection are likely to present significant
challenges, due to the prolonged course of
HbV infection. 43
Population-based Hcc screening of high-risk
groups is not practised uniformly in australia.
it has been recommended for asian-born
males over the age of 40, asian-born females
over the age of 50, african-born people over
the age of 20, those with cHb-related cirrhosis
(irrespective of age) and those with a family
history of primary liver cancer 48 (see table 6.4,
chapter 6: clinical assessment of patients with
hepatitis b virus infection).
7 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
since 1999, new Zealand has had a targeted
national screening and follow-up program
for hepatitis b among Maori, Pacific and asian
people aged over 15 years, developed in
response to the high morbidity and mortality
and the significant economic impact of
untreated HbV infection. the program provides
active surveillance for more than 12,000 people
and has identified approximately 100 people
with Hcc, with 65% of them amenable to
curative resection or transplantation. their fiveyear
survival exceeds 50%, which compares to
0% in 150 people with chronic HbV-related liver
cancer diagnosed during the same period, but
not enrolled in a screening program. 49
a similar initiative, the asian-american Hepatitis
b Program in new york city, aims to identify
people with chronic HbV infection among
the asian and Pacific islander communities;
it provides a pathway for preventing the
complications of chronic liver disease in those
with the infection and offers HbV vaccination
to susceptible contacts. 50
in conclusion, hepatitis b-related Hcc is a
complex disease, with no ideal treatment
currently available. Primary prevention remains
the most effective intervention, but for those
people diagnosed with chronic disease, early
detection and treatment have led to improved
outcomes. While screening for Hcc remains
a topic for debate, the earlier detection of
these tumours has been associated with good
short- and intermediate-term results. disease
recurrence and the treatment of advanced
cancer remain a challenge. it is likely that the
treatment of chronic HbV infection will make
a significant impact on end-stage disease and
reduce the probability of developing liver
cancer, but these benefits will take a long time
to become apparent. the burden of chronic
HbV infection suggests that the incidence of
liver cancer is likely to continue to rise over the
next two decades.

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MANAGING HEPATITIS B
VIRUS INFECTION IN
COMPLEX SITUATIONS
Benjamin Cowie Victorian Infectious Diseases Service, Royal Melbourne Hospital and Victorian Infectious
Diseases Reference Laboratory, North Melbourne, VIC.
Links to: Chapter 3: Hepatitis B virus testing and interpreting test results
Chapter 4: Natural history of chronic hepatitis B virus infection
Chapter 5: Primary prevention of hepatitis B virus infection
Chapter 7: Treatment of chronic hepatitis B virus infection
Chapter 8: Managing patients with advanced liver disease
Chapter 9: Hepatitis B virus-related hepatocellular carcinoma
KEY POINTS
there are a number of special situations in
which the complexity of managing the care of
a patient with hepatitis b virus (HbV) infection
is increased. Primary care practitioners are
optimally placed to recognise and respond to
these situations, and coordinate a management
plan that maximises the health and wellbeing
of the patient with HbV infection.
Pregnant women and HBV
Worldwide, the majority of people with
chronic HbV infection acquired the infection
at birth or in early childhood. Given that age
at infection determines the risk of progression
10
Facts
� ninety per cent of the mother-to-child transmission of hepatitis b virus (HbV) is preventable.
� several antiviral drugs used in the treatment of human immunodeficiency virus (HiV) infection are
also effective against HbV.
� the reactivation of HbV infection in the setting of immunosuppression can also occur in people who
have a history of resolved acute HbV infection.
Myths
� Mothers with HbV infection should not breastfeed.
� children with HbV do not develop cirrhosis, hepatocellular carcinoma (Hcc) or other manifestations
of advanced liver disease.
� People with HiV should not be concerned about viral hepatitis, as complications take many years to
develop.
to chronicity (see chapter 4: natural history of
chronic hepatits b virus infection), with 90%
of neonatal infections resulting in chronic
infection, averting the vertical transmission
of HbV is critical. for many women with HbV
infection who are pregnant or planning
pregnancy, the possibility of HbV transmission
to their child is a cause of significant distress.
adequate counselling and addressing the
mother’s concerns are crucial, emphasising
the availability of highly effective treatment to
prevent transmission. it is also an opportunity
to assess the HbV status of other family and
household members and to vaccinate all those
who are susceptible.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 75

10 Managing hepatitis B virus infection in complex situations
routine antenatal Hbsag screening is essential
to allow the identification and treatment of as
many neonates at risk of infection as possible. 1
if pre-test counselling identifies maternal risk
factors for HbV infection, but serology indicates
Hbsag negativity and no immunity, plans
should be made to initiate vaccination of the
mother following delivery.
the risk of vertical transmission is determined
by the intensity of maternal HbV replication,
with highly replicative infection characterised
by a high HbV dna viral load and Hbeag
positivity (see chapter 3: Hepatitis b virus
testing and interpreting test results). up to
90% of infants born to Hbeag-positive mothers
acquire the infection if untreated, compared to
less than 10% of those born to Hbeag-negative
mothers. 2,3 When the appropriate prophylactic
treatment is given, there is no evidence
that mode of delivery (vaginal or caesarean)
affects the risk of infection, and although
Hbsag and HbV dna are detectable in breast
milk, breastfeeding is not associated with an
increased risk of transmission and should not
be discouraged.
a pregnant woman diagnosed with HbV
should be referred to a physician experienced
in the management of viral hepatitis. Pregnant
women with established chronic hepatitis,
especially those with cirrhosis, should be
monitored for any deterioration in their liver
disease throughout their pregnancy. a flare
in the mother’s hepatitis is sometimes seen
after delivery, presumably secondary to the
recovery from the pregnancy-induced immune
tolerance state. although HbV antiviral therapy
is not approved in pregnancy, lamivudine has
been taken by many pregnant women for the
treatment of HiV infection without evidence of
adverse foetal effects.
for a susceptible woman exposed to HbV
during pregnancy, prophylaxis should be
initiated immediately (table10.1). if acute
HbV infection occurs during pregnancy, the
risk of infection to the foetus is low in the first
two trimesters but rises to 75% in the third
trimester. 2 the mother should be referred for
supportive care and monitored for features
76 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
table 10.1: Prophylaxis for women exposed
to hepatitis b virus during pregnancy
1. HBIG* 400 iu, iM, single dose
2. Hepatitis B vaccine 1.0 mL, iM, 3 doses at 0,
1 and 6 months
3. Other considerations:
� both HbiG and hepatitis b vaccine should be
administered without delay
� HbiG and HbV vaccine can be administered
simultaneously at different sites
� serological monitoring for infection must
extend to at least six months post-exposure
� Vaccinate the infant as per usual schedule
unless infection occurs in the mother
� if the mother acquires infection, manage the
infant as per maternal chronic HbV infection
* Hepatitis b immunoglobulin (HbiG) is only available
through the australian red cross blood service
of fulminant hepatitis (see chapter 4: natural
history of chronic hepaitits b virus infection,
and chapter 7: treatment of chronic hepatitis
b virus infection). the infant should receive
hepatitis b vaccine and HbiG at birth as
described in the next section.
Should pregnant women with HBV
infection receive lamivudine?
for some time, it has been observed that
the efficacy of vaccination plus hepatitis
b immunoglobulin (HbiG) in preventing
perinatal infection is below the expected 90%
in women with highly replicative infection
(e.g. HbV dna viral load >10 8 copies/mL).
earlier studies suggested a reduction in
neonatal infections could be achieved if
women received lamivudine therapy. a recent
randomised controlled trial supported this
hypothesis, although significant loss to follow
up in the placebo arm complicated analysis. 4
furthermore, there is a real concern that using
lamivudine in women with highly replicative
disease will induce HbV resistance mutations
that will complicate the future treatment for
the mother, and could also be transmitted to
the infant if infection occurs despite therapy.
Lamivudine is not licensed, nor funded
through the section 100 (Highly specialised
drugs Program) of the Pharmaceutical
benefits scheme (Pbs) for this use, but it is
offered to women with high viral burdens in
some institutions.

Paediatric management
for a neonate born to a mother with HbV
infection, hepatitis b vaccination reduces the
risk of infection by 70%; the addition of HbiG,
derived from the plasma of blood donors
with high anti-Hbs levels, augments this risk
reduction to 90%. 5 this combined active and
passive vaccination approach for the prevention
of perinatal infection is outlined in table 10.2.
children diagnosed with HbV infection should
be referred to a paediatrician experienced in
viral hepatitis.
acute HbV infections in infants and children
are more commonly asymptomatic than
these infections in adults, but when clinical
manifestations do occur, they are generally
similar to those in adults. fulminant disease
is uncommon, but in infants it appears
to be associated with maternal Hbeagnegative
chronic hepatitis. Most chronic
infections are asymptomatic and do not affect
development. 6
the management principles for children with
chronic HbV are generally the same as those
for adults (see chapter 5: Primary prevention of
hepatitis b virus infection, chapter 7: treatment
of chronic hepatitis b virus infection, chapter
8: Managing patients with advanced liver
disease, chapter 9: Hepatitis b virus-related
hepatocellular carcinoma). counselling the
patient and family regarding the natural
history of the disease, modes of transmission
and treatment options should be undertaken.
all susceptible household members should be
vaccinated against HbV, and the affected child
should also be vaccinated against hepatitis
a. as with adults with chronic HbV infection,
children should be periodically monitored
for disease activity, progression and the
development of hepatocellular carcinoma.
although there are even less data informing
the frequency of monitoring in children than
in the adult context, annual screening for
Hcc with serum alpha fetoprotein testing has
been recommended, together with periodic
table 10.2: Prophylaxis for perinatal hepatitis b virus exposure
1. HBIG* 100 iu, iM, single dose
2. Hepatitis B vaccine 0.5 mL, iM, 4 doses at 0, 2, 4 and 6 or 12 months
3. other considerations:
� Preferably both HbiG and hepatitis b vaccine should be administered immediately after birth in
opposite thighs (i.e. not into the same site)
� HbiG should not be delayed beyond 12 hours after birth
� Hepatitis b vaccine should be given within 24 hours of birth; if delay is unavoidable, vaccine must be
given within seven days
� doses of hepatitis b vaccine subsequent to the birth dose are combined vaccines as per the standard
schedule (final dose at 6 or 12 months depending on vaccine used)
� serological assessment for infection (Hbsag and anti-Hbs) should be performed three months after
the final dose of hepatitis b vaccine (not before nine months of age)
* Hepatitis b immunoglobulin (HbiG) is only available through the australian red cross blood service
liver ultrasounds, and clinical and biochemical
monitoring of disease activity every six to 12
months. 6
the selection of patients for antiviral therapy
is similar to the adult context. treatment is
generally reserved for patients with aLt values
repeatedly more than twice the upper level of
normal, as treatment efficacy is much higher
in this setting (see chapter 7: treatment of
chronic hepatitis b virus infection). the available
treatments are conventional interferon-alfa and
lamivudine. 6,7 the advantages of interferon-alfa
are the finite duration of therapy and the lack of
induction of antiviral resistance. both efficacy
and toxicity profiles in children are similar to
those in adults, and patients with normal aLt
(being the majority of children who acquired
the infection at birth) are unlikely to achieve
favourable outcomes. the use of pegylated
interferon to treat HbV in children has not
yet been investigated (but was examined
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 77

10 Managing hepatitis B virus infection in complex situations
in children with hepatitis c virus [HcV]
infection). Lamivudine is an alternative that
is well tolerated and effective at suppressing
viral replication, but this antiviral therapy is
associated with the relatively rapid emergence
of viral resistance. Paediatric use of adefovir
remains under investigation. 7
Co-infections
an estimated 0.5–1% of australians with
chronic HbV infection also have HiV infection;
4–6% of Hbsag-positive people are believed
to be co-infected with HcV. these rates are
higher than in the general population, related
to the shared modes of transmission and hence
epidemiological associations of these viruses.
Hepatitis d virus (HdV) only exists as a coinfection
with HbV.
HBV/HIV co-infection
the majority of HiV-positive men who have sex
with men (MsM) have serological evidence of
past or chronic HbV infection. in the australian
HiV observational database cohort of more
than 2000 HiV-positive participants, over 6%
of those tested were seropositive for Hbsag. 8
the progression to chronic infection following
acute HbV is much more common in people
with HiV infection, with the likelihood of
failing to clear HbV related to the degree of
immunodeficiency. 9
co-infection with HiV has a significant impact
on the natural history of chronic HbV infection.
High HbV dna levels and detectable Hbeag are
more common in patients with HiV co-infection,
and the rate of viral reactivation is also higher,
particularly in more immunocompromised
patients. 10 even anti-Hbs-positive patients
with a history of resolved HbV infection can
experience reactivation, with reappearance
of Hbsag and HbV dna in the setting of
advanced immunodeficiency. occult chronic
HbV infection (Hbsag negative but HbV dna
positive) is also more common in patients with
HiV infection.
in the setting of HbV/HiV co-infection, the
progression to advanced liver disease, such
as cirrhosis and Hcc, is more rapid and liver-
78 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
related mortality is higher, despite typically
lower aLt values and reduced inflammatory
activity on biopsy. this disparity of less necroinflammatory
activity, but faster disease
progression is incompletely understood.
in contrast to the significant impact of coinfection
on the natural history of HbV, there is
little evidence to suggest that HbV affects the
progression of HiV infection.
With the profound reduction in acquired
immune deficiency syndrome (aids)-related
mortality and in the incidence of opportunistic
infections since the introduction of highly
active antiretroviral therapy (Haart), liverrelated
morbidity and mortality has assumed an
increasing burden on the health of people with
HiV infection. the co-infection with hepatitis
viruses explains a significant proportion of this
burden. another cause of hepatic damage in
people with HiV infection is the toxicity of a
number of antiretroviral agents; this toxicity is
more pronounced in patients with pre-existing
liver disease, such as chronic viral hepatitis. 11
the selection of patients requiring treatment for
HbV in the setting of HiV co-infection is similar
to the HiV-negative context, and the aims
are essentially the same. one very important
consideration is that some of the agents used
to treat HiV (such as lamivudine, tenofovir and
emtricitabine) are also active against HbV. thus,
the incorporation of one or more of these drugs
into a Haart regimen allows treatment of
both infections without increasing the therapy
burden. furthermore, co-infection is the only
context in which combination therapy for HbV
is possible under the Pbs, an approach which is
likely to delay the development of HbV antiviral
resistance (as it does in HiV). 7,11 in patients
not requiring HiV therapy, monotherapy for
HbV with agents also active against HiV (such
as lamivudine) should be avoided, as this can
induce resistance mutations that will make
designing subsequent Haart regimens more
difficult. it was previously thought that the anti-
HbV drug, entecavir, had no anti-HiV activity,
however, recent reports indicate that entecavir
can induce resistance mutations in HiV 12 and its
use as HbV monotherapy in the context of HiV
co-infection is being re-evaluated. Pegylated

interferon-alfa, as a non-nucleoside-based
therapy, can be considered for patients in this
context, provided they have adequate hepatic
reserve, although its efficacy is reduced in the
context of HiV infection, particularly with more
advanced immunodeficiency. 11
another reason to incorporate HbV active
agents in a Haart regimen is to avert
immune reconstitution hepatitis. the
immune reconstitution inflammatory
syndrome describes a pathology deriving
from resurgent immune attacks on chronic
infections in patients with HiV, following the
commencement of Haart. HbV flares in the
setting of immune reconstitution are more
common in patients with a high baseline HbV
viral load 11 , and can result in significant liver
disease and mortality, particularly in patients
with advanced liver disease and poor hepatic
reserve. However, flares can also lead to
Hbeag clearance and the suppression of viral
replication in some patients. 9 caution when
changing Haart regimens in co-infected
patients is also necessary, as ceasing HbV-active
agents can cause reactivation. continuation of
these antivirals should be considered even if
they add little to the patient’s HiV therapy.
HBV/HCV co-infection
in contrast to the co-infection with HiV, it is
common for patients with HcV co-infection
to have a reduced replication of HbV, with
lower viral loads than in patients with HbV
monoinfection. this is because HcV directly
interferes with the HbV replication. it is a
common finding in HbV/HcV co-infection that
one of the viruses predominates in terms of viral
replication, with the suppression of the other
virus. 9 as with HiV, occult (Hbsag-negative)
HbV infection is also seen more commonly in
patients with HcV co-infection.
acute co-infection (usually arising through
injecting drug use) has been associated with
an increased incidence of fulminant hepatitis.
chronic HbV/HcV co-infection is usually
associated with a more severe liver disease, an
increased risk of progression to cirrhosis and
a higher incidence of Hcc. a recent australian
study showed that co-infection with HbV and
HcV was associated with much higher mortality
rates (liver-related and all cause) than infection
with either HbV or HcV alone; patients with
co-infection had mortality rates approximately
three times higher than patients with HbV
infection only. 13
in patients with chronic HbV/HcV co-infection
meeting the criteria for therapy for either
infection, consideration should be given to
combination therapy with pegylated interferonalfa
plus ribavirin, even if the HbV infection
predominates. reactivation of previously
suppressed HbV replication following treatment
of HcV with standard interferon plus ribavirin
has been reported, leading to suggestions that
combination with additional anti-HbV agents
should be considered. this approach is not
universally followed.
HBV/HDV co-infection
in non-endemic countries such as australia,
HdV infection is most commonly associated
with injecting drug use (idu). HdV is a defective
virus that requires co-infection with HbV to
synthesise new virions. similar to the situation
of HbV/HcV co-infection, HdV infection results
in the suppression of HbV replication with
sometimes low or even undetectable Hbsag
levels.
acute co-infection with HbV/HdV is typically
indistinguishable from HbV monoinfection, but
has been associated with a higher incidence
of fulminant hepatitis. the rate of progression
to chronicity is no different from that for HbV
infection alone. HdV superinfection of a patient
with existing chronic HbV can present as an
acute hepatitis flare, and progression to chronic
HdV infection is almost universal. chronic HbV/
HdV co-infection has been associated with a
more severe liver disease and the increased
incidence of Hcc and mortality. treatment of
HbV/HdV co-infection is with interferon-alfa,
conventional or pegylated, for a period of
one year 7 , although treatment eradicates the
virus in only a minority of patients and relapse
following therapy is common. Lamivudine is
ineffective against HdV and the addition of
ribavirin to interferon also confers no benefit.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 79

10 Managing hepatitis B virus infection in complex situations
Reactivation during
immunosuppression
the natural history of HbV infection is
fundamentally related to the dynamic
balance between the viral replication and
the host’s immune response (see chapter 4:
natural history of chronic hepatitis b virus
infection). therefore, it is not surprising that
immunosuppressive therapy can have a
marked impact on chronic HbV infection.
reactivation of HbV replication is common
during cancer chemotherapy and following
immunosuppression for transplantation or
for the treatment of autoimmune diseases. it
is particularly associated with glucocorticoid
therapy as, in addition to suppressing host
immunity, glucocorticoids act directly on the
virus to enhance transcription.
HbV reactivation due to the institution of
immunosuppressive medication is initially
associated with a rise in the serum HbV
dna viral load. a hepatitis flare with a rise in
aLt levels can follow, particularly when the
immunosuppressive therapy is reduced or
withdrawn; restoration of the immune function
causes a sudden increase in the destruction
of infected hepatocytes. this is similar to the
immune reconstitution inflammatory syndrome
seen with Haart for HiV infection.
although most hepatitis flares in the context
of immunosuppression are asymptomatic,
a full spectrum of presentations is possible,
through to liver failure and death. suggested
risk factors for reactivation have included
use of glucocorticoids, high baseline HbV
dna viral load, Hbeag positivity, young age
and male gender. 14 the rate of withdrawal
of immunosuppression is an important
determinant of the severity of flares. the
increased incidence of flares observed in the
setting of cancer chemotherapy, compared
with other immunosuppressive regimens, may
relate to the cyclical nature of such therapy,
with repeated episodes of immune suppression
and restoration.
80 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Prophylaxis with lamivudine has been
shown to markedly reduce the incidence of
reactivation, hepatic flares and associated
mortality. Prophylaxis should be given to all
Hbsag-positive patients prior to chemotherapy
or other immunosuppressive therapy; 7 such
pre-emptive treatment has been shown to be
superior to starting treatment once reactivation
has been detected. 14 to allow prophylaxis
to occur, all patients being prepared for
such treatment should be screened for the
presence of Hbsag, anti-Hbs and anti-Hbc.
although most experience in such prophylaxis
has been with lamivudine, the possibility
of inducing drug resistance mutations is a
significant concern. entecavir is associated
with a lower rate of resistance induction
and is likely to assume an increasing role in
this setting. interferon is contraindicated in
patients with significant autoimmune disease
or in the post transplantation setting, due to its
immunomodulatory activity.
HbV is detectable in the hepatocytes of any
person who has ever had the infection, even
those who are anti-Hbs positive. in the setting
of profound immunosuppression, Hbsagnegative
patients can also reactivate and
develop severe flares. this situation is more
common in isolated anti-Hbc-positive patients
than in those with detectable anti-Hbs, but the
occurrence in the latter group is also described.
some protocols extend the recommendation
for antiviral prophylaxis to isolated anti-
Hbc-positive patients, but few recommend
prophylaxis in anti-Hbs-positive patients.
recognising the possibility of reactivation and
acting promptly is therefore important in all
patients undergoing immunosuppression.

References
1 national Health and Medical research
council. the australian immunisation
handbook. 9th edition. canberra:
commonwealth department of Health and
ageing, 2007.
2 buttery J. Hepatitis b Virus. in: Palasanthiran
P, starr M, Jones c, editors. Management
of Perinatal infections. emendation 2006
edition. sydney: australasian society for
infectious diseases 2002 (emendation
2006):9-12.
3 Mast ee, Margolis Hs, fiore ae, brink eW,
Goldstein st, Wang sa, et al. a comprehensive
immunization strategy to eliminate
4
transmission of hepatitis b virus infection
in the united states: recommendations of
the advisory committee on immunization
Practices (aciP). Part 1: immunization of
infants, children, and adolescents. MMWr
recomm rep 2005;54(rr-16):1-31.
Xu W-M, cui y-t, Wang L, yang H, Liang Z-Q, Li
X-M, et al. efficacy and safety of lamivudine
in late pregnancy for the prevention of
mother-child transmission of hepatitis b;
a multicentre, randomised, double-blind,
placebo-controlled trial. 55th annual
5.
Meeting of the american association for the
study of Liver diseases (aasLd). boston, Ma;
usa. 2004; abstract 246.
Wong Vc, ip HM, reesink HW, Lelie Pn,
reerink-brongers ee, yeung cy, et al.
Prevention of the Hbsag carrier state
in newborn infants of mothers who are
chronic carriers of Hbsag and Hbeag by
administration of hepatitis-b vaccine and
hepatitis-b immunoglobulin. double-blind
randomised placebo-controlled study.
Lancet 1984;1(8383):921-6.
6 broderick a, Jonas MM. Management
7
of hepatitis b in children. clin Liver dis
2004;8(2):387-401.
Lok as, McMahon bJ. american association
for the study of Liver diseases Practice
Guidelines. chronic Hepatitis b. Hepatology
2007;45(2):507-39.
8 Lincoln d, Petoumenos K, dore GJ. HiV/HbV
and HiV/HcV coinfection, and outcomes
following highly active antiretroviral therapy.
HiV Med 2003;4(3):241-9.
9 shukla nb, Poles Ma. Hepatitis b virus
infection: co-infection with hepatitis
c virus, hepatitis d virus, and human
immunodeficiency
2004;8(2):445-60, viii.
virus. clin Liver dis
10 Matthews G, dore GJ. the epidemiology
of HiV and viral hepatitis coinfection. in:
dore GJ, sasadeusz J, editors. coinfection
– HiV and viral hepatitis: a guide for clinical
management. darlinghurst: australasian
11
society for HiV Medicine inc., 2003.
sasadeusz J. the management of HiV and
hepatitis b virus coinfection. in: dore GJ,
sasadeusz J, editors. coinfection - HiV
and viral hepatitis: a guide for clinical
management. darlinghurst: australasian
12
society for HiV Medicine inc., 2003.
McMahon Ma, Jilek bL, brennan tP, shen L,
Zhou y, Wind-rotolo M, et al. the HbV drug
entecavir – effects on HiV-1 replication and
resistance. n engl J Med 2007;356(25):2614-21.
13 amin J, Law MG, bartlett M, Kaldor JM,
dore GJ. causes of death after diagnosis of
hepatitis b or hepatitis c infection: a large
community-based linkage study. Lancet
14
2006;368(9539):938-45.
Lalazar G, rund d, shouval d. screening,
prevention and treatment of viral hepatitis b
reactivation in patients with haematological
malignancies. br J Haematol 2007;136(5):699-
712.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 81

INFECTION CONTROL AND
OCCUPATIONAL HEALTH
Jacqui Richmond St Vincent’s Hospital, Melbourne, VIC.
Links to: Chapter 4: Natural history of chronic hepatitis B virus infection
Chapter 5: Primary prevention of hepatitis B virus infection
Chapter 1 : Privacy, confidentiality and other legal responsibilities
KEY POINTS
Myths and facts
MytH – Wearing gloves means you do not need to wash your hands.
fact – Gloves are not a substitute for effective hand-washing.
MytH – Health care workers should use additional precautions when caring for a patient with HbV to prevent
transmission.
fact – the implementation of standard precautions ensures a high level of protection against the transmission of HbV
in the health care setting.
MytH – Health care workers need to have booster doses of hepatitis b vaccine every five years.
fact – booster doses are no longer recommended in immunocompetent individuals after a primary course of HbV
vaccine, as evidence suggests that a completed course of HbV vaccination provides long-lasting protection.
MytH – Health care workers with HbV must not have contact with patients because of the risk of transmission.
fact – Health care workers with HbV are generally advised to avoid performing exposure prone procedures, however,
they can still have non-invasive contact with patients.
8 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
11
� the potentially infectious nature of all blood and body substances necessitates the implementation
of infection control practices and policies in the health care setting.
� the current best practice guidelines for infection control procedures in australian
health care settings are outlined in Infection Control Guidelines for the Prevention
of Transmission of Infectious Diseases in the Health Care Setting (2004), accessible at
http://www.health.gov.au/internet/wcms/Publishing.nsf/content/icg-guidelines-index.htm
� the universal application of standard precautions is the minimum level of infection control
required in the treatment and care of all patients to prevent the transmission of hepatitis b virus
(HbV). these include personal hygiene practices—particularly hand-washing, the use of personal
protective equipment such as gloves, gowns and protective eye wear, aseptic techniques, safe
disposal systems for sharps and contaminated matter, the adequate sterilisation of reusable
equipment and environmental controls.
� Vaccination is an important infection control strategy for the prevention of HbV. all health care
workers should be vaccinated and be aware of their vaccination status.
� clinicians and other health care workers who regularly perform exposure-prone procedures have
a responsibility to be regularly tested for the human immunodeficiency virus (HiV), the hepatitis c
virus (HcV) and HbV if they are not immune. Health care workers who are infected with HiV, HbV or
HcV should not perform exposure prone procedures.

Introduction
Maintaining the safety of the health care
environment for patients and health
professionals is essential and necessitates the
implementation of infection control guidelines.
the current best practice guidelines for
infection control procedures in australia are
outlined in Infection Control Guidelines for the
Prevention of Transmission of Infectious Diseases
in the Health Care Setting. 1 these guidelines are
based on the model of universal precautions
developed in 1987 by the united states centers
for disease control and Prevention (cdc).
state and territory Health departments in
australia have adopted a broader definition
of universal precautions and have introduced
the principle of standard precautions. standard
precautions ensure a high level of protection
against transmission of infection in the health
care setting and represent the level of infection
control required in the treatment and care of all
patients to prevent the transmission of bloodborne
infections.
the implementation of standard precautions
minimises the risk of transmission of the
infection from patient-to-clinician, clinician-topatient
and patient-to-patient, even in high-risk
situations. the use of additional precautions
is only recommended during the care of
patients known or suspected to be infected or
colonised with disease agents that may not be
contained by standard precautions alone, such
as tuberculosis.
clinicians and other health care workers
need to be aware that infection control
guidelines are relevant in social and domestic
contexts, as well as in occupational settings.
the implementation of infection control
guidelines in social and domestic settings can
assist patients with hepatitis b virus (HbV) to
reduce the risk of transmission to family and
household contacts. clinicians should be able
to answer patients’ questions about a clinic’s
infection control policies and provide advice
for patients in relation to infection control in
their daily environment. this chapter provides
an overview of the current australian infection
control guidelines and their relevance in
treating patients with HbV.
Transmission
chapter 4: natural history of chronic hepatitis b
virus infection, outlines the modes and risks of
HbV transmission. the transmission of HbV is
approximately 100 times more efficient than
the transmission of HiV and approximately 10
times more efficient than HcV. 2
the risk of blood-borne virus transmission is
dependent on a number of factors. incidents
involving blood-to-blood contact with
infectious blood are associated with a high risk
of infection when:
� there is a large quantity of blood, indicated
by visible contamination
� a needle is inserted directly into a vein or
artery or body cavity
� the patient has high levels of HbV dna and
detectable Hbeag; HcV ribonucleic acid
(rna) detected by polymerase chain reaction
(Pcr); the patient suffers from advanced HiV
disease and has a high HiV viral load.
Patient-to-patient transmission of HbV,
although rare, has been associated with oral
surgery, and inadequate use or disinfection of
medical devices, such as blood glucose finger
stick devices and acupuncture needles. 2-4
Worldwide, published incident reports indicate
that a total of 12 health care workers with
HbV infection have transmitted the virus to
approximately 91 patients. 5 the transmission of
HbV in the health care setting can be prevented
through health care worker, patient and
community hepatitis b vaccination programs
and strict adherence to standard precautions.
Standard precautions
standard precautions ensure a high level
of protection against the transmission of
infections, including blood-borne viruses in the
health care setting, and are recommended for
the care and treatment of all patients and in the
handling of:
� blood, including dried blood
� all other body substances, secretions and
excretions (excluding sweat), regardless of
whether they contain visible blood
� non-intact skin
� Mucous membranes.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 83

11 Infection control and occupational health
the universal application of standard
precautions is the minimum level of infection
control required in the treatment and care
of all patients to prevent the transmission of
blood-borne viruses. these include personal
hygiene practices—particularly hand-washing;
the use of personal protective equipment such
as gloves, gowns and protective eyewear;
aseptic techniques; the safe disposal systems
for sharps and contaminated matter; the
adequate sterilisation of reusable equipment;
and environmental controls.
standard precautions should be implemented
universally, regardless of existent information
or assumptions about a patient’s bloodborne
virus status. this process would
ensure the reduction of potential stigma and
discrimination in the health care setting.
Hand hygiene
Hand-washing is generally considered the most
important hygiene measure in preventing the
spread of infection. clinicians should wash
their hands before and after contact with any
patient and after activities that may cause
contamination.
Hand-washing should occur:
� before and after each clinical contact with a
patient
� before and after eating
� after using the toilet
� before and after using gloves
� after contact with used equipment
� immediately following contact with body
substances.
it is important to note that gloves are not
a substitute for effective hand-washing. a
routine hand-wash should include the removal
of jewellery and the use of a cleaning solution
(detergent with or without disinfectant) and
water for 15 to 20 seconds, followed by drying
with a single-use towel.
skin care is important because healthy,
unbroken skin provides a valuable, natural
barrier to infection. skin breaks should be
covered with a water-resistant occlusive
84 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
dressing. alcohol-based hand rubs can be
used in the absence of appropriate washing
facilities.
Gloves
Gloves are a form of personal protective
equipment. clinicians and other health care
workers should wear gloves whenever there is
a risk of exposure to blood or body substances
and should change their gloves and wash
their hands after contact with each patient
and during procedures with the same patient
if there is a chance of cross-contamination.
Gloves must be used when:
� Handling blood and body substances
� Performing venepuncture
� touching mucous membranes
� touching non-intact skin
� Handling contaminated sharps
� Performing invasive procedures
� cleaning body substance spills or any
equipment (instruments) or materials (linen)
or surface that may have been contaminated
by body substances.
for further information about the appropriate
use of sterile, non-sterile and general purpose
gloves refer to Infection Control Guidelines for
the Prevention of Transmission of Infectious
Diseases in the Health Care Setting. 1
Other personal protective equipment
Personal protective equipment should be
readily available and accessible in all health
care settings. the type of protective equipment
required depends on the nature of the
procedure, the equipment used and the skill of
the operator. for example, the use of protective
equipment is recommended in the following
circumstances:
� Protective eyewear and face shields must
be worn during procedures where there is
the potential for splashing, splattering or
spraying of blood or other body substances
� impermeable gowns and plastic aprons
should be worn to protect clothing and skin
from contamination with blood and body
substances
� footwear should be enclosed to protect
against injury or contact with sharp objects.

Needlestick or sharps injury
prevention
inappropriate handling of sharps is a major
cause of accidental exposure to blood-borne
viruses in health care settings. to minimise the
risk of a needlestick or sharps injury, needles,
sharps and clinical waste should be handled
carefully at all times. specifically, clinicians and
other health care workers should:
� Minimise their handling of needles, sharps
and clinical waste
� not bend or recap needles or remove needles
from disposable syringes
� use safe needle-handling systems, including
rigid containers for disposal, which should
be kept out of the reach of toddlers and
small children
� Have ‘sharps’ containers available at the point
of use or in close proximity to work sites to
aid easy and immediate disposal.
importantly, the person who has used a sharp
instrument or needle must be responsible for
its immediate safe disposal following its use.
Issues for health care workers
Hepatitis B vaccination
Vaccination is an important infection control
strategy to prevent the transmission of HbV. a
safe and effective vaccine to protect against
HbV has been available in australia since
1988. The Australian Immunisation Handbook
(2007) 6 recommends the following groups be
vaccinated against hepatitis b:
� infants and young children
� adolescents aged between 10 and 13 years
� sexual contacts of people with acute and
chronic hepatitis b
� other household contacts of people with
acute and chronic hepatitis b
� People on haemodialysis, individuals with
HiV and other adults with weakened immune
systems
� injecting drug users
� recipients of certain blood products
� individuals with chronic liver disease and
hepatitis c
� residents and staff of facilities for persons
with intellectual disability
� individuals adopting children from overseas
� Liver transplant recipients
� inmates and staff from long-term correctional
facilities
� Health care workers, dentists, embalmers,
tattooists and body-piercers
� others at risk including:
� Police, members of the armed services
and emergency services staff
� Long-term travellers to regions with high
endemicity
� staff of child day-care centres
� People playing contact sport.
in addition, consideration for HbV screening
and vaccination should be given to people from
other community groups with high prevalence
of HbV infection. these include:
� indigenous peoples
� cultural and linguistically diverse
communities (caLd).
there is a significant variation between
australian jurisdictions in the availability of
funded hepatitis b vaccination programs for
people considered at high risk of exposure to
hepatitis b infection. for further information
about the availability of local HbV vaccination
programs, contact relevant state and territory
health departments.
Hepatitis B vaccination regime
for adults over 20 years of age, a full course of
HbV vaccine consists of three doses at 0, 1 and 6
month intervals. adolescents aged between 11
and 15 years should receive a two-dose regimen
of the adult formulation of HbV vaccine at 0
and 4–6 months intervals. it is recommended
that children have a total of three doses of the
paediatric formulation of HbV vaccine at 0, 1
and 6 month intervals. infants should receive a
birth dose of HbV vaccine, followed by doses at
2, 4 and either 6 or 12 months.
Post-vaccination serological testing is
recommended four weeks after the third dose
of HbV vaccine for people in the following
categories:
� People at significant occupational risk (e.g.
clinicians and other health care workers
whose work involves frequent exposure to
blood and body substances)
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 85

11 Infection control and occupational health
� People at risk of severe or complicated disease
(e.g. people who are immunocompromised
and people with pre-existing liver disease
not related to HbV)
� People in whom a poor response to HbV
vaccination is expected (e.g. patients
undergoing haemodialysis).
if a person’s anti-Hbs level is

in general, if an injury or incident occurs where
blood or body substances come into contact
with non-intact skin or membranes, the
following action should be taken:
� Wash exposed membrane or injury with
soap and water (an antiseptic could also be
used on the skin)
� if eyes have been exposed, thoroughly rinse
the eyes with tap water or saline while open
� if mouth has been exposed, thoroughly rinse
the mouth with water and spit out
� seek medical advice immediately for
assessment of the nature of the exposure, the
risk of transmission of blood-borne viruses
and the need for HiV or HbV post-exposure
prophylaxis (PeP)
� if the exposure is significant and the source
patient is known, his or her consent for HiV
antibody, HcV antibody and Hbsag testing
should be sought.
for more information, contact the nsW
needlestick injury Hotline (1800 804 823). the
Hotline is a free 24-hour service for health care
and emergency services workers who require
assistance following a needlestick injury or
other occupational exposure.
Hepatitis B post-exposure
prophylaxis (PEP) in the health
care setting
Unvaccinated individual
in the case of an unvaccinated individual who
is exposed to HbV-infected blood or body
substances, HbiG should be administered
within 72 hours of the exposure to prevent
HbV infection. the first dose of the HbV
vaccine should also be administered as soon as
possible.
Vaccinated individual
for people who have been vaccinated and who
have a documented protective response after
vaccination (anti-Hbs level ≥ 10 iu/mL), PeP is
not recommended. a person’s response to the
vaccine should be determined immediately. if
there is no protection, the individual should be
offered a dose of HbiG and HbV vaccine.
clinicians and other health care workers should
always refer to the most recent protocols and
seek appropriate advice, as the field of PeP
and post-exposure management is constantly
evolving.
Health care workers with hepatitis B
virus infection
clinicians and other health care workers have a
legal obligation to care for the safety of others
in the workplace, which includes colleagues
and patients. clinicians and other health care
workers with HbV infection should consult
state or territory regulations to determine what
restrictions are placed on their clinical practice.
in general, it is recommended that they do not
perform procedures that carry a high risk of
transmission of the virus from the health care
worker to the patient, such as exposure-prone
procedures (table 11.1). 1
Infection control in the
primary care setting
Infection Control Guidelines for the Prevention
of Transmission of Infectious Diseases in the
Health Care Setting (2004) provides detailed
information relating to the application of
infection control in an office or primary health
care setting, including: routine cleaning;
disinfectants and antiseptics; the design and
maintenance of health care premises; the
management of clinical waste and linen; and
reprocessing of instruments and equipment.
specific procedures relating to the office
practice, and home and community care are
included in the guidelines. 1
the general principles of infection control that
apply to large health care settings also apply to
office practices. issues that relate to preventing
transmission of blood-borne viruses include:
� all clinical waste, such as dressings
containing expressible blood, human matter
(excluding hair, nails, urine and faeces) and
blood sharps, must be appropriately packed
for transport and disposal according to local
regulations.
� sharps are to be disposed of in yellow, rigidwalled
containers displaying the ‘biological
Hazard’ label and symbol.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 87

11 Infection control and occupational health
� injecting equipment (including hypodermic
syringes, needles, vials of local anaesthetic
agent, dental local anaesthetic cartridges,
dental needles, intravenous lines and giving
sets) must be discarded after single use.
syringes used to hold single-use anaesthetic
cartridges must be sterilised between
patients.
� dressings, suture material, suture needles,
scalpels, intracranial electrodes, pins or
needles used for neurosensory testing,
spatulas, electric clips and razors blades
must also be discarded after single use.
� Linen must be managed using standard
precautions. contaminated linen should
have body substances removed with paper
towels and cold running water, before being
washed in cold or hot water. drying at high
temperature aids disinfection. Linen which
is to be treated off-site must be packed in
labelled, water-resistant, regulation bags.
� re-usable equipment and instruments
should be re-processed, and sterilisation
and disinfection procedures followed in
accordance with the manufacturers’ and the
national guidelines.
� sterile equipment must be used on critical
sites (sterile tissue).
� sterile equipment is generally recommended
for semi critical sites (intact mucous
membrane), except in the case of single-use
clean tongue depressors and vaginal specula,
which are used in procedures unlikely to
penetrate the mucosa.
� When steam or dry heat sterilisation is
not suitable, other sterilisation systems,
such as ethylene oxide or automated, lowtemperature
chemical sterilisation, may
be used if acceptable to the instrument’s
manufacturer.
Management of blood and body
substance spills in the health care
setting
the management of blood and body
substance spills depends on the nature of the
spill, likely pathogens, type of surface and the
area involved. the basic principles of spills
management are:
88 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
� standard precautions (including the use of
personal protective equipment) apply where
there is a risk of contact with blood or body
substances.
� spills should be cleaned up before the area is
disinfected.
� the generation of aerosols from spilled
material should be avoided.
all spills must be dealt with as soon as possible.
in general, cleaning blood and body substance
spills should take into account the following
factors:
� the nature of the spill (e.g. sputum, vomit,
faeces, urine, blood or laboratory culture).
� the pathogens most likely to be involved in
the spill.
� the size of the spill (spot, small or large
spill).
� the type of surface (e.g. carpet or impervious
flooring).
� the area involved (i.e. whether the spill
occurs in a contained area, such as a
microbiology laboratory or in a public area
such as a hospital ward or outpatient area).
� the likelihood of bare skin contact with the
soiled surface.
in the case of a small spill, wipe the area clean
using a paper towel and then clean with
detergent and warm water. a disposable alcohol
wipe also may be used. Quarantine areas where
soft furnishings are involved (carpet, curtains
or seating) until dry. in the case of larger spills,
mop up with paper towel or use ‘kitty litter’ or
granular chlorine, picking up the larger amount
with cardboard.
in general, it is unnecessary to use sodium
hypochlorite for managing spills, because there
is no evidence of any benefit from an infection
control perspective. However, it is recognised
that some health care workers may feel more
reassured that the risk of infection is reduced
through the use of sodium hypochlorite.

Legal and ethical issues
Legal liability may occur if inadequate care
has been taken to prevent the transmission
of infection. regulatory authorities
(e.g. environmental protection) and
commonwealth, state and territory and local
governments enforce laws and regulations
relating to infection control and waste disposal.
these regulations can vary considerably
throughout australia, and such regulations
should take precedence over the general
information presented in this chapter. for
further information contact state and territory
health departments, and medical and other
professional boards. Legal issues are considered
in greater detail in chapter 12: Privacy,
confidentiality and other legal responsibilities.
Summary
standard precautions and infection control
procedures protect against the transmission of
blood-borne viruses, including HbV, HcV and
HiV in the health care setting. regardless of
the perceived risk, infection control procedures
must be followed in all clinical settings to
minimise the risk of accidental transmission
of blood-borne viruses. clinicians and other
health care workers should be vaccinated
against HbV and be aware of their vaccination
response. exposures to blood and body
substances should be reported immediately
and monitored in case the administration of
PeP is appropriate.
References
1. communicable diseases network of australia
(cdna), national Public Health Partnership
(nPHP), and australian Health Ministers’
advisory council (aHMac). infection control
guidelines for the prevention of transmission
of infectious diseases in the health
care setting. canberra: commonwealth
2.
department of Health and ageing; 2004.
available from urL: http://www.health.gov.
au/internet/wcms/Publishing.nsf/content/
icg-guidelines-index.htm
centers for disease control and Prevention
(cdc). recommendations for preventing
transmission of human immunodeficiency
virus and hepatitis b virus to patients during
exposure-prone invasive procedures. MMWr
Morbid Mortal Wkly rep 1991; 40:1-9.
3. redd Jt, baunbach J, Kohn W, nainan o,
Khristova M, Williams i. Patient-to-patient
transmission of hepatitis b virus associated
with oral surgery. J inf dis 2007;195:1311-4.
4. Polish Lb, shapiro cn, bauer f, Klotz P, Ginier
P, roberto rr, et al. nosocomial transmission
of hepatitis b virus associated with the use of
a spring-loaded finger-stick device. n engl J
Med 1992;326:721-5.
5. Perry JL, Pearson rd, Jagger J. infected health
care workers and patient safety: a double
standard. am J infect control 2006;34:313–9.
6. national Health and Medical research council
(nHMrc). the australian immunisation
Handbook – 9th edition. canberra:
commonwealth department of Health and
ageing; 2007.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 89

PRIVACY, CONFIDENTIALITY
AND OTHER LEGAL
RESPONSIBILITIES
Sally Cameron Australian Federation of AIDS Organisations, NSW.
Note: This chapter refers to a number of key Australian laws and policies relating to privacy, confidentiality and
duty of care, and includes a summary of significant legal cases. Although addressing some important questions,
this information does not constitute legal advice. In some instances, legislation has been summarised. Practitioners
faced with uncertainty in this area are strongly advised to contact their local health department, or the applicable
privacy office and they ahould seek independent legal advice.
This chapter has been adapted from:
Australasian Society for HIV Medicine (ASHM). Australasian Contact Tracing Manual. Edition 3 006. Canberra:
Commonwealth of Australia, 006: 48-51.
Available at: http://www.ashm.org.au/contact-tracing/
Links to: Chapter 11: Infection control and occupational health
KEY POINTS
Why is privacy and
confidentiality important?
the australian Medical association (aMa) code
of ethics requires medical practitioners to
maintain a patient’s confidentiality. ‘exceptions
90 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
1
� Many people are extremely sensitive about the collection and use of information related to their
health and health-related treatment.
� Health care practitioners should generally only collect health information about a patient with
that patient’s informed consent, and should advise the patient of the potential uses of that
information.
� Health care practitioners should have sophisticated systems in place governing the storage and
access to health information records, including physical and technological security controls, and
staff training. this is particularly important for those venues where multi-disciplinary care by
different treating practitioners and allied staff may occur.
� The Privacy Act 1988 (Commonwealth) (subsequently referred to as ‘the Privacy act’) is the primary
piece of legislation governing the privacy of health care information in australia. state and
territory governments also have laws and regulations affecting privacy practices, which may
intersect or overlap with the Privacy act. Health care practitioners must make themselves aware of
their privacy and confidentiality obligations in their respective situations.
� Hepatitis b virus infection is a notifiable disease in every australian state and territory. notification
does not legally breach a patient’s right to privacy, although patients should be informed that
notification will occur.
� in australia, it is illegal to discriminate against a person on the basis of their perceived hepatitis b
virus infection or their perceived human immunodeficiency virus (HiV) infection.
to this must be taken very seriously. they may
include where there is a serious risk to the
patient or another person, where required by
law, or where there are overwhelming societal
interests.’

in australia, the protection of health-related
information has attracted special treatment,
partly as a response to many people
considering health information to be extremely
sensitive. this point cannot be overemphasised.
Most enquiries to the office of the Privacy
commissioner are from the health sector, and
the health sector is second only to the finance
sector in the number of complaints received.
While the terms ‘privacy’ and ‘confidentiality’
are commonly used interchangeably, they are
not identical concepts. Privacy laws regulate
the handling of personal information (including
health information) through enforceable
privacy principles. on the other hand, the legal
duty of confidentiality obliges health care
practitioners to protect their patients against
the inappropriate disclosure of personal
(health) information.
it is important to maintain privacy and
confidentiality because:
� Patients are concerned about the stigma and
discrimination associated with their hepatitis
b virus (HbV) status and related conditions
� Patients want to know that they can choose
who has access to information about them
� Patients are far more likely to seek medical
care and give full and honest accounts of
their symptoms if they feel comfortable,
respected and secure
� a health system with strong privacy
mechanisms will promote public confidence
and trust in health care services generally.
Legal requirements
there are no nationally agreed laws or
guidelines specifically relating to the diagnosis,
treatment and tracing of contacts of patients
with HbV or other notifiable diseases. australian
states and territories have approached the
issue differently. some jurisdictions have gone
to great lengths to develop specific, targeted
laws and policies, while others have relied
on more generic laws and processes. (Please
refer to the asHM Viral Hepatitis Models of
care database available on the asHM website
at www.ashm.org.au/hbv-moc/). However,
issues relating to the management of privacy
in the health sector are usually covered by the
Privacy act, which applies to all private sector
organisations that provide health services and
hold health information. in summary, a ‘health
service’ can be broadly defined as including any
activity that involves:
� assessing, recording, maintaining or
improving a person’s health; or
� diagnosing or treating a person’s illness or
disability; or
� dispensing a prescription drug or a medicinal
preparation by a pharmacist.
consequently, health services include
traditional health service providers, such as
private hospitals and day surgeries, medical
practitioners, pharmacists and allied health
professionals, as well as complementary
therapists, gyms, weight loss clinics and many
others.
in general terms, the Privacy act covers all
those in the health sector (such as medical
practitioners, nurses, administrators, trainers
and cleaners) not directly employed by state
or territory governments (as they are usually
covered by state laws). further information
on the jurisdiction of the act is available at
http://www.privacy.gov.au/publications/hg_
01.html#a2.
the Privacy act contains 10 national Privacy
Principles (nPPs) (available at http://www.
privacy.gov.au/publications/npps01.html),
which govern the minimum privacy standards
for handling personal information. some nPPs
state that health service professionals must
meet certain obligations, while other nPPs
require that they ‘take reasonable steps’ to
meet stated obligations. Practitioners should
familiarise themselves with the national Privacy
Principles (which are legally binding), and seek
advice if necessary.
the different layers of federal, state and
territory laws and regulations do, in some
instances, complicate privacy obligations. in
most cases, the privacy protections required
by commonwealth and state or territory
privacy laws are similar. under the australian
constitution, when a state/territory law is
inconsistent with a commonwealth law, the
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 91

12 Privacy, confidentiality and other legal responsibilities
commonwealth law prevails. consequently,
across australia, all private sector health service
providers are required to comply with the
provisions of the commonwealth Privacy act
as well as any state/territory laws.
in nsW, for example, state privacy legislation
(the Health Records and Information Privacy
Act 2002) applies to public sector, and private
sector health care providers and holders of
health records located in nsW. consequently,
private sector health service providers must
comply with two sets of privacy legislation
(federal and nsW), which are largely, but not
wholly, compatible. the two sets of legislation
impose similar obligations on private health
care providers. However, it could be argued that
the nsW legislation has a higher compliance
threshold, so that if a health care practitioner
complies with the nsW Health Records and
Information Privacy Act, they will generally also
comply with the federal act (although the two
sets of legislation have different enforcement
regimes).
Most states now have laws severely restricting
the transfer of information in the health sector,
and in some states, breaches of confidentiality
amount to a criminal offence. in addition to
these intersecting laws, many states also have
multiple layers of regulation. for example,
Queensland Health’s Privacy Plan points out
that in addition to any relevant commonwealth
and Queensland laws, ‘Queensland Health
has developed a number of policies related to
the management of information at corporate
office, directorate, district, facility and unit
levels’.
a brief overview of state and territory privacy
laws (and their intersection with the federal
Privacy act) is provided by the office of the
Privacy commissioner at http://www.privacy.
gov.au/privacy_rights/laws/index.html#1, but
for those wishing to seek specific advice (not to
be confused with ‘legal advice’), the following
agencies can be contacted:
9 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
All States obligations under the Privacy Act
1988 (Commonwealth)
The Office of the Privacy Commissioner
tel: 1300 363 992
email: privacy@privacy.gov.au
State and Territory specific obligations
� Australian Capital Territory
the office of the Privacy commissioner
tel: 1300 363 992
email: privacy@privacy.gov.au
� New South Wales
Privacy nsW (office of the nsW Privacy
commissioner)
tel: (02) 8688 8585
email: privacy_nsw@agd.nsw.gov.au
� Northern Territory
the centre for disease control
tel: (08) 8922 8044
the department of Health and community
services
tel: (08) 8922 7049
email: infoprivacy@nt.gov.au.
� Queensland
Queensland Health
tel: (07) 3235 9051
email: privacy@health.qld.gov.au
� South Australia
the Privacy committee of south australia
tel: (08) 8204 8786
email: privacy@saugov.sa.gov.au
� Tasmania
the office of the ombudsman
tel: 1800 001 170
email: ombudsman@justice.tas.gov.au
� Victoria
the office of the Health services
commissioner
tel: 1800 136 066
email: hsc@dhs.vic.gov.au
� Western Australia
the office of the information commissioner
tel: 1800 621 244
email: info@foi.wa.gov.au

Privacy issues
there are a number of broad privacy-related
issues that face general practitioners and other
primary health care providers. these include:
� Collecting information
normally, general practitioners should only
collect health information about patients with
their consent. it is usually reasonable to assume
that consent is implied if the information is
noted from details provided by the patient
during a consultation, as long as it is clear that
the patient understands what information is
being recorded and why. it is also vital to ensure
that record keeping is thorough and accurate:
both to ensure the best-possible ongoing
treatment of a patient and, in the worst-case
scenario, to be used as defence if a case is made
against a treating doctor.
� Ensuring consent is ‘informed’
all medical procedures require informed
consent. Given that the consequences of being
tested may be substantial, it is important to
realise that, while running tests may be standard
for the health care practitioner, receiving the
results may be anything but routine for the
patient. the provision of information should
allow the health care practitioner to discuss
the risks and benefits to the patient in their
particular situation, thereby facilitating their
decision-making process.
� Advising use
Patients are not able to consent to the use of
their information if they are unclear where
the information will go and why. if possible,
patients should be advised of the use of their
information when it is collected, which can occur
through usual communication during a regular
consultation. this point also relates to instances
when personal information cannot be shared
or disclosed. in a recent legal case, a doctor
failed to inform two patients attending a joint
consultation that the results of each person’s
test could not be disclosed to the other person,
and consequently failed to seek either their
understanding of that situation or their consent
for their test results to be shared. Please refer to
asHM Viral Hepatitis Models of care Models of
care database for a summary of relevant case
law (available at www.ashm.org.au/hvb-moc/).
� Notification
it might be argued that reporting details of a
patient’s health status involves breaching his
or her privacy, however, this practice is legal
because there is no ‘absolute’ right to privacy
under australian or international law. the
Privacy act provides exceptions to privacy
where use or disclosure is required by law. in
developing australian privacy laws, the right
to individual privacy has been weighed against
the rights of others and against matters that
benefit society as a whole.
HbV is a notifiable disease in all australian
states and territories. Legal obligations around
notification are mandated by state laws, which
define a doctor’s duty to notify the respective
Health department of a notifiable disease. in
nsW, for example, the Public Health act 1991
requires doctors to notify their local Public
Health unit by phone or mail of any cases of
acute viral hepatitis. notifications are not to be
made by facsimile, in order to protect patient
confidentiality. doctor and hospital notification
forms are available at http://www.health.nsw.
gov.au/public-health/forms.
� Accessing personal records
Patients are entitled to access their health
records, except for a limited number of
important exceptions outlined under nPP
6, for example if the request for access is
frivolous or vexatious, or providing access
would be likely to prejudice an investigation
of possible unlawful activity. the full list of nPP
6 exceptions are listed at http://www.privacy.
gov.au/publications/npps01.html#npp6. the
office of the Privacy commissioner’s fact sheet
relating to access is available at http://www.
privacy.gov.au/publications/is4_01.html.
Patients, including an index case (original
person identified with an infection) or a
contact, are not entitled to any information that
relates to their contact’s identity, behaviour or
diagnosis without that person’s consent, even
if that information is in the patient’s records.
should a patient wish to access their own
record, details of the identity of any contacts
contained in their record should be deleted.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 93

12 Privacy, confidentiality and other legal responsibilities
� Security and storage of health
information
a range of laws apply to the storage of health
information. Health agencies should have in
place:
� Procedures to give access to information
only to those people who are authorised to
have access in order to use or disclose the
information
� security measures to prevent unauthorised
access to the records
� Procedures for storing the information,
where practical, in a way that the identity
of the person is not readily apparent from
the face of the record, e.g. by the use of
identification codes
� Procedures for destroying the records that
protect the privacy of the information.
electronic records pose new challenges. While
they offer greater convenience of data retrieval
and transfer, electronic record systems also
create greater risks of data leakage, access
by unauthorised staff and ‘browsing’ by
unauthorised people. agencies and businesses,
including medical practices need to consider
the security of their data storage and transfer
systems and the problem of staff intentionally
or inadvertently accessing prohibited electronic
records. this issue is currently being addressed
by the commonwealth and a number of states
in the development of their electronic health
records systems, and has proven enormously
complex to date.
� Information for teams
Multidisciplinary treating teams are common
practice in australian health care. Health
care practitioners work together and share
necessary information to deliver optimum
health care. all transfers of information without
the knowledge of the patient require careful
ethical consideration.
although the question has not yet been legally
tested, private sector health service providers
do not always require a patient’s consent to
disclose specific health information to another
member of a multidisciplinary team for a health
care purpose, as long as the patient would
reasonably expect that disclosure. therefore, it
is advisable to tell a patient being treated by a
94 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
multidisciplinary team how this will affect the
handling of their health information. it is also
advisable to gain patient consent to avoid
relying on implied consent. other limited
exceptions under nPP 2 permit disclosure
without consent in certain circumstances,
including to lessen a serious and imminent
threat to an individual’s life, health or safety; or
where the disclosure is required or authorised
by law.
there is a need for doctors in group practices
to formulate clear internal communication
protocols in order to exercise reasonable care,
for example, when communicating test results
or considering contact tracing issues. the
cross-referencing of files per se will generally
not breach statutory confidentiality because
results need to be checked, though information
should not be disclosed without explicit
permission. it is vital that all staff are aware of
their obligations and that systems are in place
for protecting patient privacy.
Exemptions to privacy and
confidentiality obligations
the use and disclosure of health information
is defined in the Privacy act under nPP 2
(available at http://www.privacy.gov.au/
publications/npps01.html#npp2), which states
that an organisation must not use or disclose
personal information about an individual for
a purpose other than the primary purpose of
collection, except for a number of situations,
including where an organisation reasonably
believes that the use or disclosure is necessary
to lessen or prevent a serious and imminent
threat to a person’s life, health or safety, or a
serious threat to public health or public safety.
in short, health care workers must not disclose
a person’s health information except in a very
limited number of circumstances. these may
generally be summarised as:
� communicating necessary information to
others directly involved in the treatment of a
patient during a particular episode of care
� cases of needlestick injury where a
professional is aware of a patient’s HbV
positive status, and a health care worker
has been exposed to circumstances where
there is a real risk of transmission and it is

not possible to conceal the identity of the
source patient who has refused to consent to
disclosure
� Provision of medical services in a particular
instance of care where there is a need to know
the patient’s infection status for treatment
purposes of benefit to the patient (e.g. in an
emergency or if the patient is unconscious).
this should not, however, detract from the
observance of standard infection control
precautions.
it is strongly recommended that practitioners
familiarise themselves with the national Privacy
Principles (which are legally binding) and
contact the office of the Privacy commissioner
if they wish to clarify the manner in which
the national Privacy Principles might relate
to specific situations. Legal advice should be
sought from a legal practitioner.
Contact tracing
the practice of contact tracing raises the
question of potential conflict between
breaching a patient’s privacy and
confidentiality, and alerting a third party to the
fact that they may be at risk of HbV infection.
although a case on this specific point is yet
to be heard in australia, it seems likely that a
health practitioner could be found negligent to
a third party if they did not warn the third party
that they were at risk. this potential conflict
may be further complicated by a statutory
obligation to counsel patients regarding
sexually transmissible medical conditions.
fortunately, public health services afford
practitioners expert guidance to resolve
the conflict between the duties to maintain
confidentiality and privacy, and a possible
duty of care owed to third parties. in instances
where practitioners suspect a person may
be putting others at risk, the practitioner
should notify the health department using the
methods prescribed by the relevant state or
territory. Public health authorities then become
responsible for making decisions around
contact tracing, including the management of
privacy issues. for a more detailed account of
the contact tracing responsibilities of health
care providers, please consult the Australasian
Contact Tracing Manual Ed 3, available at: http://
www.ashm.org.au/contact-tracing/ .
Criminal law
there are two types of criminal offences
associated with HbV and other blood-borne
viruses. the first relates to the disclosure of
information regarding a person who has an
infection, or is suspected of having HbV or other
blood-borne virus infections—as discussed
above. there are also laws in every state and
territory making it an offence to transmit an
infection to another person. as with other areas
of legislation, specifications around definition
and scope differ across jurisdictions. the
majority of these laws are not specific to bloodborne
viruses, but instead refer to infectious
diseases generally; more generic criminal
offences, for example, causing grievous bodily
harm, may also be applied.
Anti-discrimination
anti-discrimination provisions exist across
all australian states and territories, making
it illegal to discriminate against people on
the basis of their (perceived) HbV infection.
discrimination is prohibited on the basis of
disability or impairment. it is important that
health care practitioners consider behaviours
they must avoid when testing and managing
people with HbV. discrimination on the
basis of disability or impairment includes
treating a person less favourably as a result
of their (perceived) disability or impairment.
in a health care setting, this may include
refusing to see a patient, offering different or
inappropriate treatment, or placing a patient
last on a consultation or operating list. as
outlined in chapter 11: infection control and
occupational health, standard precautions
ensure a high level of protection against the
transmission of infection in the health care
setting and represent the level of infection
control required in the treatment and care of
all patients to prevent transmission of bloodborne
infections.
Health care workers with HBV
infection
Please refer to chapter 11: infection control and
occupational health for obligations of health
care practitioners who perform exposure prone
procedures.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 95

THE ROLE OF
COMPLEMENTARY MEDICINE
IN HEPATITIS B
Ses J Salmond Drug and Alcohol Clinical Services, Hunter New England Area Health Service, Arkana Therapy Centre
and Leichhardt Women’s Community Health Centre, NSW.
Robert Batey Drug and Alcohol Services, North Sydney Central Coast Area Health, Wyong Hospital, NSW.
KEY POINTS
� flavonoids isolated from the following plants have demonstrated anti-HbV activity in various in
vitro and in vivo models: wogonin (scutellaria baicalensis) and apigenin (ocinum basilicum).
� a multicentre study of chronic hepatitis b patients found that two different oxymatrine
preparations administered for 24 weeks improved HbV dna clearance compared to placebo
(p = 0.001). a randomised, double blind placebo controlled clinical trial of cpd 861 for 24
weeks in chronic hepatitis b patients with fibrosis and early cirrhosis found that the overall
reversal rate in the grade of fibrosis was 52% in the cpd 861 group compared to 20% in
the placebo (p < 0.05). this effect was more pronounced in those with more advanced
fibrosis. Herbal medicines with well documented evidence of hepatotoxicity are: teucrium
chamaedrys (wall germander) and teucrium polium, Mentha pulgeium (pennyroyal)
atractylis gummifera (pine thistle) (current name carlina gummifera), certain pyrrolizidine
alkaloids and Larrea tridenta (chapparal).
� Patients with chronic hepatitis b virus infection interested in pursuing complementary medicine
are advised to consult an accredited practitioner of traditional chinese medicine or western herbal
medicine or naturopathy. Qualified practitioners can be found at: australian acupuncture and
chinese Medicine association (aacMa) at www.acupuncture.org.au or phone 07 3324 2599 or the
national Herbalists association of australia (nHaa) at www.nhaa.org.au or phone 02 8765 0071.
complementary and alternative medicine
(caM) is increasingly used by the public in
parallel with, and instead of conventional
medicine. 1 approximately half of the australian
population use caM totalling an estimated
a$2.3 billion in expenditure in 2000, almost
four times the public contribution to all
pharmaceuticals. 2 these local figures represent
a 120% increase in the use of caM products
and a 63% increase in expenditure on caM
therapists respectively since 1993. 2 in 2004,
the total expenditure fell to a$1.3 billion on
caM products and to a$494 million on caM
therapists despite the percentage of people
using caM remaining constant at 50% in 1993,
52.1% in 2000 and 52.2% in 2004. 3
96 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
13
in the past decade, the interest in
complementary medicine and its use in the
treatment of chronic liver disease has also
increased. 1
The role of complementary
medicine in the treatment of
chronic hepatitis B patients
there is evidence to suggest that acupuncture,
herbal medicines or the isolated active
ingredients in certain herbal medicines can
play a role in the management of people
with chronic hepatitis b virus (HbV) infection.
these complementary medicines appear to

e targeting different aspects of the disease
process such as: altered viral replication 4,5 antiinflammatory
actions 6 and chemoprevention
of malignant change. 7,8 if proven, these actions
would be useful adjuncts to the standard
antiviral therapies in chronic hepatitis b. these
agents are also used in symptom management
during antiviral treatment and more generally
to improve quality of life and wellbeing. 8
The pharmacological actions
of complementary medicines
traditional chinese medicine (tcM) and western
herbal medicine use a number of plant-based
chemicals with synergistic and overlapping
pharmacological actions. Herbal medicines
are chosen for their intrinsic characteristics to
treat diseases, regulate yin and yang and help
the body to re-establish normal physiological
function and restore health. 9–11
Studies demonstrating specific
activities relevant to HBV
management include:
Activity on viral replication
a flavonoid (wogonin) isolated from the
traditional chinese medicinal plant scutellaria
baicalensis (baical skullcap) suppressed
Hbsag production in a HbV transfected liver
cell line (Ms-G2) and inhibited duck HbV dna
polymerase in HbV infected ducks. 12
a study examining the effect of another
flavonoid (apigenin) isolated from ocium
basilicum (sweet basil) showed this agent had
the capacity to reduce the production and
release of Hb s and e antigens in HepG 2.2.15
cell lines using the Xtt assay. this effect was
more marked than that of lamivudine. the
significance of this finding in terms of sustained
viral suppression is unknown. 13
a multicentre study of chronic hepatitis b
patients found that two different oxymatrine
preparations administered for 24 weeks
improved HbV dna clearance compared to
placebo (p = 0.001). no follow-up period was
included in the study protocol or reported in
the research paper. 14
in a small study, patients receiving 400 mg a day
kurorinone (extracted from sophora flavescens)
intramuscularly (n=45) for three months or
3Miu interferon α 2a (n=49) daily for the first
month and on alternate days for the next
two months showed that aLt normalisation
was achieved in 50% of the kurorinone group
and in 61.3% in the interferon α 2a group
with loss of Hbeag or HbV dna. 15 the 12month
follow-up period showed a sustained
virological response (sVr) of 26.7–36.7% in the
kurorinone group compared to 44.4–46.7%
in the interferon group. 15 no further reports
have been published. no recommendations for
clinical use can be made from these studies.
Anti-inflammatory activity
tJ-9 (sho-saiko-to; Xiao-chai-Hu-tang) is
a Japanese and chinese herbal medicine
which has been widely investigated in both
animal and human studies of liver disease.
in the treatment of HbV it has been shown
to significantly reduce liver inflammation
as evidenced by reduced aLt levels 16 and
improved liver histology (the latter particularly
evident in animal studies). 17-19 the main
ingredients are bupleurum chinensis (chai Hu),
scutellaria baicalensis (baical skullcap; Huang
Qin) and Glycyrrhiza (liquorice; Gan cao) root:
all of these ingredients are regarded as potent
anti-inflammatory agents as well as having
other pharmacological actions. 16,20 However,
there have been about 10 case reports of
pneumonitis related to sho-saiko-to in the past
decade. 21-23 some of these case reports may be
related to interactions with interferon-based
therapy. 23
Antifibrotic activity
there are limited but interesting data on the
use of herbal preparations to modify fibrosis in
HbV.
in one study, a tcM formulation compound
861 (0.03 mg/mL) significantly inhibited
human hepatic stellate cell (LX-2) proliferation
compared to the control. in addition, LX-2
cells exposed to cpd 861 (0.01mg/mL) had
significantly lower alpha-smooth muscle actin
(α-sMa) expression (59% at 48 hours [p < 0.05])
and (60% at 72 hours [p < 0.01]) compared to
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 97

13 The role of complementary medicine in hepatitis B
the control. 24 the three main ingredients of
cpd 861 are salvia miltiorrhiza (scarlet root; dan
shen), astragalus membranaceus (milk-vetch
root; Huang Qi) and spatholobus suberectus
(millettia root; Ji Xue teng).
a randomised, double blind, placebo
controlled, clinical trial of cpd 861 for 24
weeks in cHb patients with fibrosis and early
cirrhosis found that the overall reversal rate
in the grade of fibrosis was 52% in the cpd
861 treatment group compared to 20% in
the placebo (p < 0.05). this effect was more
pronounced in those with more advanced
fibrosis. 6
Anticancer activity
andrographis paniculata (green chiretta;
chuan Xin Lian) is a traditional medicinal herb
of china and india with anti-inflammatory
and anticancer activity. andrographolide, a
diterpenoid lactone isolated from the herb,
markedly reduced the number of surviving
hepatoma-derived Hep3b cells in a Mtt
assay and induced cell apoptosis (p ≤ 0.001).
However, it had a weak effect on normal human
hepatocytes (L-02 cells). 25
silibinin, the most biologically active
flavonolignan in silybum marianum (saint
Mary’s thistle) (300 µmol/L), significantly
reduced the viability of human hepatocellular
carcinoma Hep3b cells after 12 hours of
treatment (p ≤ 0.001) and also induced
apoptosis. 26
at this stage, the clinical implications for
patients with HbV infection are unclear.
Antiviral therapy and herbal medicine
Chinese herbal medicines and interferon
in 2002, a meta analysis of randomised,
controlled trials using the combination of
chinese herbal medicine and interferon in
chronic hepatitis b patients showed that the
isolated ingredient bufotoxin combined with
interferon alpha significantly increased Hbeag
seroconversion in treated patients. Kurorinone
was equivalent to interferon alpha in causing
Hbeag seroconversion of Hbeag. 27
98 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Herbal medicines with interferon or
lamivudine
studies with Phyllanthus species and artesunate
(derived from artemisinin extracted from
artemisia annua [chinese wormwood; Qing
Hao]) have suggested a possible beneficial
effect when these agents are combined with
interferon or lamivudine respectively in HbV
viral kinetics. the significance of these findings
clinically is yet to be demonstrated. 8,28
Safety of herbal medicines
a major area of concern in western medicine
relates to the safety of herbal products in
patients with liver disease.
Hepatotoxicity
Herbal medicines with well documented
evidence of hepatotoxicity are: teucrium
chamaedrys (wall germander) and teucrium
polium, both cause zonal necrosis, hepatitis
and fibrosis 29–31 ; Mentha pulgeium (pennyroyal)
causes necrosis and microvesicular steatosis 30 ;
atractylis gummifera (pine thistle) leads
to panlobular hepatic necrosis and renal
failure 29–34 ; certain pyrrolizidine alkaloids can
cause veno-occlusive disease 29,30,32–34 and Larrea
tridenta (chapparal) ingestion showed zonal
necrosis. 29–34
there are, however, conflicting reports of
hepatotoxicity in the literature and case
reports alone without laboratory testing and
verification of the presence of each of the
listed ingredients make firm conclusions of
hepatotoxicity elusive.
in australia, a recent death was attributed to
the ingestion of Kava 1800 Plus. on laboratory
analysis, Piper methysticum (kava) and Passiflora
incarnata (passionflower) were found to be
present in the formulation. However, scutellaria
lateriflora (skullcap) which was also listed as
an ingredient in this product was not found.
the identity of the third ingredient remains to
be established. 35 teucrium (wall germander)
is similar in appearance to skullcap and there
have been other reports of substitution of
teucrium for scutellaria. teucrium can lead to
hepatotoxicity and renal failure and has been
banned as a slimming agent in europe.

every attempt must be made to verify each
listed ingredient in a formulation when
hepatotoxicity occurs, to accurately identify
the causative agent so that both general
practitioners and complementary medicine
practitioners are aware of herbal medicines
with demonstrated hepatotoxicity. However,
kava should be avoided in patients with chronic
liver injury.
the australian and new Zealand expert
group reviewing the safety of black cohosh
(actea racemosa formerly named cimicifuga
racemosa) concluded that ‘there appears to be
an association between the use of black cohosh
and liver damage, but that it is very rare’. it is a
tGa requirement that this advice appear on the
label of products containing black cohosh. 36
from January to december 2004, all chronic
hepatitis b patients admitted to a Hong Kong
hospital for liver biochemistry irregularities
were prospectively screened for an intake of
tcM within six months prior to admission. the
inclusion criteria: bilirubin > 2 x upper limit of
normal (uLn), aLt or ast > 5 x uLn, aLP, GGt
> 2 x uLn. exclusion criteria: HbV exacerbation
associated with HbV dna level > 1,000,000
viral copies/mL, co-infection with hepatitis
a,c,d,e; intake of western medicine with known
hepatotoxicity, alcohol intake > 20g a day for
women and > 30g a day for men, and any other
liver disease apart from cHb. 37
of the 45 hospital admissions due to liver
dysfunction in chronic hepatitis b patients,
15.6% were attributed to tcM-induced
hepatoxicity. there were two deaths related
to tcM intake, one of whom appeared to have
pre-existing cirrhosis. in another two patients,
hepatotoxicity was based on a temporal
relationship, although specific hepatotoxic
elements were not found in the herbal
formulae. 37
Conclusion
there are emerging data suggesting
complementary medicines may have a role
in the treatment and management of chronic
hepatitis b. Phyllanthus species, compound
861, kurorinone and oxymatrine may influence
viral replication or liver inflammation in a
beneficial way. further investigations of
these agents are warranted. the poor quality
of many randomised, controlled trials of
traditional chinese medicines to date limits
the conclusions that can be drawn about
these agents. the consensus is clear that more
rigorous studies are required to provide more
definite results to guide the management of
our hepatitis b patients. 38–39
it is advisable that patients consult an
accredited practitioner of traditional chinese
medicine or western herbal medicine if they
are interested in complementary medicines.
useful contacts include the australian
acupuncture and chinese Medicine
association (aacMa) at www.acupuncture.
org.au or phone 07 3324 2599 or the national
Herbalists association of australia (nHaa) at
www.nhaa.org.au or phone 02 8765 0071.
Acknowledgment
songmei Wu, bilingual research officer,
centre for complementary Medicine research,
university of Western sydney who translated
selected research articles from china.
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b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 101

Appendix 1
Hepatitis B Fact sheet – for people living with chronic infection
What is hepatitis B?
Hepatitis means inflammation of the liver. it may be caused by infection with a virus, such as the
hepatitis b virus. When hepatitis b virus enters the body it travels to the liver, where it lives and
multiplies in liver cells. the presence of the virus in the liver stimulates the immune system to kill it.
unfortunately, it is the body’s immune response, not the virus, that causes most of the inflammation
and damage to the liver.
the impact of hepatitis b infection depends on a person’s age when they become infected. infants
with hepatitis b infection almost always develop a long-term (chronic) infection, whereas people
who get the infection as adults have a 95% chance of clearing the virus from their body.
Many people with hepatitis b do not get sick and do not know they have hepatitis b virus infection.
some people experience tiredness, nausea (feeling sick) and jaundice (yellowing of the eyes and
skin). infants rarely develop symptoms of infection. about 50% of adolescents and adults develop
jaundice when they first get the infection, which is called acute hepatitis b.
Chronic hepatitis B
a person is diagnosed with chronic hepatitis b when they have the virus infection for longer than
6 months (confirmed through blood tests). chronic hepatitis b develops in approximately 5%
of adults, some children and most infants with the infection. People with chronic hepatitis b are
likely to have a lifelong infection, and although they generally remain in good health, they have an
increased risk of developing serious complications, such as cirrhosis (scarring of the liver) and liver
cancer. importantly, people with chronic hepatitis b have the potential to spread the infection if
they do not follow some simple precautions.
How is hepatitis B spread?
Hepatitis b is spread when blood and other infected bodily fluids (including saliva, semen and vaginal
fluids) enter the bloodstream either through a break in the skin or through mucous membranes.
Hepatitis b virus can be spread as follows:
� a pregnant woman with hepatitis b infection can transmit the infection to her baby at the time
of birth—this is the most common way the virus is spread in developing countries around the
world
� Vaginal, anal or oral sex without a condom
� reusing injecting equipment
� tattooing or body piercing
� close contact, including the sharing of toothbrushes, razors, nail files or other personal items that
may lead to the exchange of body fluids
� blood transfusion (donated blood is now screened in most developed countries and so there is
only a very small risk of infection. receiving a blood transfusion in some areas of the world can
still be extremely risky)
� accidental needlestick injury or splashing of infected blood or body fluids, especially for health
care workers
� contact sports
10 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 1 – Continued
Managing and testing for hepatitis B
there are several blood tests available to diagnose and monitor hepatitis b (some are outlined in
the table below). the interpretation of these tests is not always straightforward and may require the
expertise of your GP or liver specialist.
blood test abbreviation What it means
Hepatitis b surface antigen Hbsag Hepatitis b infection
anti-hepatitis b surface antibody anti-Hbs immunity to hepatitis b infection
Hepatitis b e antigen Hbeag Viral replication and infectivity
Hepatitis b virus dna HbV dna Viral replication
alanine aminotransferase aLt estimates liver inflammation or damage
there are other tests that can detect changes in the liver, such as liver ultrasound or scan, and liver
biopsy (the removal of a tiny piece of the liver under local anaesthetic). these tests are used to
diagnose cirrhosis and liver cancer.
ndix 1- Continued
Treatment for hepatitis B
there are several types of antiviral medicines available to treat hepatitis b in australia.
oral medicine: Lamivudine, adefovir or entecavir are taken as an oral tablet and have very few side
effects. However, these treatments often need to be taken for a long time, which means the virus
may develop resistance to the medicine.
injections: Pegylated interferon is given as a weekly injection for up to 12 months. it often causes
significant side effects.
each treatment has different benefits and side effects. you need to discuss your treatment options
with your liver specialist.
before starting treatment, people with hepatitis b should have a liver biopsy to check if there is
any damage to the liver. if there is no damage, treatment may not be recommended. However, if
you have high HbV dna, and elevated aLt levels, and your liver biopsy shows liver inflammation or
damage, your doctor will discuss treatment with you.
Reducing the risk of liver damage; lifestyle issues
People with hepatitis b should eat a balanced diet that includes a variety of foods to meet the body’s
need for energy, growth and repair. unless a person with hepatitis b has significant liver damage,
there are no particular foods that should be favoured or avoided. if you are in doubt, you can see a
dietician for advice.
alcohol intake should be minimised to one standard drink per day and should be completely
avoided if severe scarring or cirrhosis are present. similarly, smoking cigarettes should be reduced
and preferably stopped.
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 103

Appendix 1 – Continued
support is available to help you reduce your alcohol intake and quit smoking.
some prescribed medicine, over-the-counter medicine and herbal remedies, including chinese
medicines, can be harmful to the liver, especially if taken in high doses or for a long period of time. it
is important to discuss all your medication with your liver specialist and GP.
it is also important to avoid contracting other blood-borne viruses, such as hepatitis c or HiV, as this
can dramatically affect your health and cause further liver damage. therefore, avoid unsafe sex and
reusing injecting equipment. following these precautions also helps stop the spread of hepatitis b.
Preventing the spread of hepatitis B
Precautions
� Practise safe sex – use condoms during vaginal, anal and oral sex
� do not allow anyone to have contact with your blood–cover cuts and clean up spilt blood
yourself
� do not share toothbrushes, razors or other personal items
� do not share needles, syringes or other injecting equipment
� do not donate blood, sperm, organs or any other tissues
� Make sure people in close contact with you are vaccinated (see below)
� be careful about blood contact when playing contact sport
� Get advice from your doctor if your job involves the potential for blood exposure to other
people
Vaccination
the hepatitis b vaccine is very safe and provides immunity more than 95% of the time. the vaccine
is usually given by three injections over six months. in australia, all infants and adolescents aged 10
to 13 years are provided with hepatitis b vaccination at no cost. it is strongly recommended that the
following groups of people are also vaccinated against hepatitis b:
� Long-term or regular sexual partners of people with hepatitis b
� Household contacts of people with acute and chronic hepatitis b
� Health care workers
� emergency services workers, such as ambulance officers
� Men who have sex with men
� sex industry workers
� indigenous australians
� injecting drug users
� Prisoners and prison staff
� cultural and linguistically diverse (caLd) communities
� People adopting children from overseas countries with high rates of hepatitis b
� frequent or long-term travellers to areas with high rates of hepatitis b
� People with other forms of liver disease
People at high risk of contracting hepatitis b, such as health care workers, should be tested one
month after the final dose of vaccine to assess whether they are immune to hepatitis b.
104 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 1 – Continued
Do I need to tell others?
your hepatitis b test result is personal. you do not have to tell anyone straight away, however, you
are required to take precautions to prevent transmission of hepatitis b to others (Please refer to
Precautions). you are advised to inform sexual partners and your close household contacts so that
they can be tested and vaccinated.
there is no legal requirement to tell any of your treating doctors, nurses, dentists or other healthcare
providers that you have hepatitis b. However, it is advisable that you do this so that you get the
best treatment for your needs. if you decide to tell any of these professionals, they are required to
keep that information confidential unless you give your consent or unless this is required by law,
court order or in exceptional circumstances. unfortunately you cannot donate any blood or body
fluids and if you are a health care worker with hepatitis b you must not perform “exposure prone”
procedures.
Where can I find out more information?
if you need more information, please talk to your GP or liver specialist.
state and territory Hepatitis c councils can also provide information about hepatitis b and
refer you to liver clinics and support services in your local area.
Please contact Hepatitis australia for details of your local Hepatitis c council.
infoLine: 1300 HeP abc
Website: www.hepatitisaustralia.com
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 105

Appendix 2
List of useful organisations and resources on hepatitis B
ORGANISATIONS:
the following list provides websites for a range of organisations/groups that can be contacted for
further resources and support information. it is anticipated that these contacts may be useful for
primary health care providers and patients.
Please consult the online ASHM Directory: HIV, hepatitis and related services at:
http://www.ashm.org.au/ashm-directory/ for additional services and support organisations.
NATIONAL
Australian Acupuncture and Chinese Medicine Association Ltd (AACMA) – able to provide contact details
of qualified practitioners.
Web: www.acupuncture.org.au
Australian Chapter Sexual Health Medicine of RACP (ACSHM) – register of Public sexual Health clinics
in australia and new Zealand
Web: http://www.racp.edu.au/index.cfm?objectid=1f34610e-9e38-fc12-2068745b56942524
Australian Chinese Medical Association Inc (ACMA) – offers a wide range of services including acMa
Medical Practitioner directory
Web: www.acma.org.au
Australian Drug Foundation (ADF) – provides information and resources alcohol and other drug problems.
Web: www.adf.org.au
Australian Federation of AIDS Organizations (AFAO)
Web: http://www.afao.org.au/
» Hepatitis b briefing Paper – hepatitis b fact sheet
http://www.afao.org.au/view_articles.asp?pxa=ve&pxs=170&pxsc=173&id=657
Australian Government Department of Health and Ageing – provides information and support on
infectious diseases and health related issues
Web: http://www.health.gov.au
» australian immunization Handbook – the online resource provides information on vaccination
procedures http://www9.health.gov.au/immhandbook/
» infection control Guidelines – outlines the principles involved in, and the procedures necessary for, the
prevention of the transmission of infectious diseases
http://www.health.gov.au/internet/wcms/publishing.nsf/content/icg-guidelines-index.htm
» Medical services advisory committee (Msac) – Hepatitis b dna testing for chronic hepatitis b
http://www.health.gov.au/internet/msac/publishing.nsf/content/app1096-1
» national notifiable diseases surveillance system (nndss) – surveillance program
http://www9.health.gov.au/cda/source/rpt_4_sel.cfm
» the national stis strategy – provides information on the action plan for prevention and treatment of
stis in australia
http://www.health.gov.au/internet/wcms/publishing.nsf/content/phd-sti-index.htm
106 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 2 – Continued
» national aboriginal and torres strait islander sexual Health and blood borne Virus strategy – provides
information on the action plan for prevention and treatment of sti among aboriginal and torres strait
islander populations
http://www.health.gov.au/internet/wcms/Publishing.nsf/content/6d7d47cde56bfc88ca25722b008342bc/
$file/sexhealthandcover.pdf
» national strategic framework for aboriginal and torres strait islander Health 2003-2013 australian
Government implementation Plan 2007-2013
http://www.health.gov.au/internet/wcms/publishing.nsf/content/health-oatsih-imp2
Australian Injecting and Illicit Drug Users League (AIVL) – provides information and education on illicit drug use
Web: www.aivl.org.au/default.asp
Australian Research Centre in Sex, Health and Society
Web: www.latrobe.edu.au/arcshs/
» national Hepatitis b needs assessment report – aims to raise public awareness of hepatitis b and
advocate for a national strategy
http://www.latrobe.edu.au/arcshs/hep_b_needs_assesmnt.html
Australian Society for HIV Medicine (ASHM) – clinical guidelines, resources and training
Web: www.ashm.org.au
» australasian contact tracing Manual ed 3 – reflects best practice for contact tracing in australasia
http://www.ashm.org.au/contact-tracing/
» coinfection – HiV and Viral Hepatitis: a guide for clinical management
http://www.ashm.org.au/coinfection-management/
» HiV, Viral Hepatitis and stis: a guide for primary care
http://www.ashm.org.au/hiv-hep-guide/
» Viral Hepatitis Models of care database
http://www.ashm.org.au/resources/
Federal Privacy Commissioner – legislation, regulations, codes, determinations and guidelines which
affect health service providers
Web: www.privacy.gov.au
Gastroenterological Society of Australia (GESA) – guidelines and promotion of research and clinical standards
Web: www.gesa.org.au
» a Guide to Management for Health Professionals: chronic Hepatitis b
http://www.gesa.org.au/professional/guidelines/chronic-hep-b.cfm
» Hepatitis b Virus fact sheet – information and facts about hepatitis b
http://www.gesa.org.au/leaflets/hepatitis-b.cfm
» Liver fact sheet
http://www.gesa.org.au/digestive-system/liver.cfm
Hepatitis Australia – provides useful information on hepatitis b
Web: www.hepatitisaustralia.com
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 107

Appendix 2 – Continued
» Hepatitis b fact sheet
http://www.hepatitisaustralia.com/about_hepatitis/hep_b.html
» Hepatitis b forum – an email distribution source that allows subscribers to keep up to date with
current events and knowledge on hepatitis b
http://hepbforum.hepatitisaustralia.com/mailman/listinfo/list_hepbforum.hepatitisaustralia.com
National Aboriginal Community Controlled Health Organisation (NACCHO) – the national peak
aboriginal health body representing aboriginal community controlled Health services throughout
australia
Web: www.naccho.org.au
National Centre for Education and Training on Addictions (NCETA) – provides resources for health care
workers on issues of drug and alcohol
Web: www.nceta.flinders.edu.au
National Centre in HIV Epidemiology and Clinical Research – surveillance program on HiV, viral
hepatitis and sexually transmissible infections
Web: www.med.unsw.edu.au/nchecr
» annual surveillance reports http://www.nchecr.unsw.edu.au/ncHecrweb.nsf/page/annual%20surve
illance%20reports
National Centre in HIV Social Research – provides social research information in relation to HiV/aids and hepatitis c.
Web: www.arts.unsw.edu.au/nchsr
National Hepatitis B Alliance (NHBA) – provides a forum for those working in hepatitis b to exchange
ideas, findings and information.
Web: http://alliance.hepatitis.org.au
National Herbalists Association of Australia (NHAA) – qualified herbalist
Web: www.nhaa.org.au/
Sexual Health and Family Planning Australia – national voice of sexual Health (sH) and family Planning
organisations (fPos)
Web: www.shfpa.org.au
Telephone Interpreter Services (TIS) – provides free telephone service
Web: www.immi.gov.au/tis
STATE AND TERRITORY
nsW
Aboriginal Health and Medical Research Council of NSW (AH&MRC)
Web: www.ahmrc.org.au
Cancer Council NSW – provides support and practical information to patients and other affected populations
Web: www.cancercouncil.com.au/metro
» Hepatitis b screening and Liver cancer surveillance Program – prevention strategy for liver cancer
www.cancercouncil.com.au/editorial.asp?pageid=2384
108 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 2 – Continued
Hepatitis C Council of NSW – provides information and resources to health care practitioners and
affected communities
Web: www.hepatitisc.org.au
Multicultural Health Communication Service NSW – provides information and service to assist health
professionals communicate with culturally and linguistically diverse communities throughout nsW
Web: www.mhcs.health.nsw.gov.au
Multicultural HIV/AIDS and Hepatitis C Service (MHAHS).
Web: www.multiculturalhivhepc.net.au/
NSW Health – provides resources, information and statistical data on health issues
Web: www.health.nsw.gov.au/index.html
» Hepatitis b fact sheet
www.health.nsw.gov.au/public-health/phb/sept01html/factsheetsept01.html
» Questions and answers about Hepatitis b Vaccination
www.health.nsw.gov.au/PublicHealth/immunisation/school_prog/hepb_qa.asp
» Hepatitis b notifications in nsW residents by Quarter of disease onset
www.health.nsw.gov.au/data/diseases/hepb.html
The Children’s Hospital at Westmead
» Hepatitis b fact sheet for parents
http://www.chw.edu.au/parents/factsheets/hepb.htm
act
ACT Health – provides resources and information on health issues
Web: www.health.act.gov.au/c/health
The Hepatitis C Council of ACT – provides support, resources and information on hepatitis c
Web: www.acthepc.org
Winnunga Nimmityjah Aboriginal Health Service
Web: www.winnunga.org.au
QLd
Department of Health QLD – provides resources and information on health issues
Web: www.health.qld.gov.au/about_qhealth/default.asp
» Hepatitis b fact sheet
http://access.health.qld.gov.au/hid/infectionsandParasites/sexuallytransmitteddiseases/hepatitisbsex
ualHealthcontacts_fs.asp
Ethnic Communities Council of Queensland Ltd (ECCQ) – represents in the interests of people from
caLd backgrounds
» Hepatitis b fact sheet
http://www.eccq.com.au/eccq/index.php?module=menu&action=view&id=683
Queensland Aboriginal and Islander Health Council (QAIHC)
Web: www.qaihc.org.au
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 109

Appendix 2 – Continued
The Hepatitis C Council Queensland – provides support and information and education on hepatitis c
to affected communities, health organizations, businesses and schools
Web: www.hepatitisc.asn.au
University of Queensland – schools of Medicine – provides information on viral hepatitis
» Hepatitis b fact sheet for General Practitioners
http://www.som.uq.edu.au/hivandhcvprojects
Vic
Department of Health Victoria – provides information and resources on public health issues
Web: www.health.vic.gov.au
» Hepatitis b – information on epidemiology and surveillance
http://www.health.vic.gov.au/ideas/bluebook/hepatitis_b#period
» Hepatitis b fact sheet
http://www.health.vic.gov.au/ideas/diseases/hepb
» Hepatitis b- immunization for children
http://www.betterhealth.vic.gov.au/bhcv2/bhcarticles.nsf/pages/Hepatitis_b_immunisation_for_children
HIV, Hepatitis & STI Education and Resource Centre – provides resources and information on HiV/aids,
hepatitis and sexually transmissible infections
Web: www.hivhepsti.info
» treatment for Hepatitis b – fact sheet
http://www.hivhepsti.info/documents/hepb_000.pdf
The Hepatitis C Council Victoria – provides support and information to people affected by hepatitis c
Web: www.hepcvic.org.au
Victorian Aboriginal Comunity Controlled Health Organisation
Web: www.vaccho.org.au
sa
Aboriginal Health Council of South Australia (AHCSA)
Web: www.ahcsa.org.au
Department of Health SA – provides resources and information on health issues
Web: www.health.sa.gov.au/PeHs/default.aspx
» you’ve Got What? Prevention and control of notifiable and other infectious
diseases in children and adults.
http://www.health.sa.gov.au/PeHs/youve-got-what.htm
The Hepatitis C Council South Australia- SA – provides information, education and support for those
affected by hepatitis c
Web: www.hepccouncilsa.asn.au
Wa
Aboriginal Health Council of Western Australia (AHCWA)
Web: www.ahcwa.org
Department of Health WA – provides resources and information on health issues
Web: www.health.wa.gov.au/home/
» Hepatitis b fact sheet
http://www.health.wa.gov.au/health_index/h/hepatology.cfm
110 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 2 – Continued
The Hepatitis C Council Western Australia – provides information services and promotes community
awareness about viral hepatitis
Web: www.hepatitiswa.com.au
nt
Aboriginal Medical Services Alliance Northern Territory (AMSANT)
Web: www.amsant.com.au
Department of Health NT – centre for disease control – provides resources and information on health issues
Web: www.health.nt.gov.au
» Hepatitis b Vaccination Policy and Public Health Management- treatment protocol
http://www.nt.gov.au/health/cdc/protocols.shtml
The Hepatitis/AIDS Council Northern Territory – works to prevent transmission of HiV, Hepatitis c & stis
Web: www.ntahc.org.au
tas
Department of Health and Human Services Tasmania – provides resources and information on health issues
Web: www.dhhs.tas.gov.au/index.php
» Hepatitis b facts
http://www.dhhs.tas.gov.au/healthyliving/factsheet.php?id=723
Tasmanian Aboriginal Health Service
email: ahs@tacinc.com.au
The Hepatitis/AIDS Council of Tasmania – provides information and resources and works to minimize
the impact of HiV/aids and hepatitis c in the community
Web: www.tascahrd.org.au
NEW ZEALAND
The Hepatitis Foundation of New Zealand – promotes education and research of viral hepatitis, early
detection and long-term follow up of chronic hepatitis b & c
Web: www.hepfoundation.org.nz
» Hepatitis b Virus fact sheet
http://www.hepfoundation.org.nz/hepatitisb.html
» Liver fact sheet
http://www.hepfoundation.org.nz/liver.html
» Hepatitis b – 'b Positive support Programme'
http://www.adhb.govt.nz/hepbfree/
Hepatitis C Resource Centre (Auckland) – provides and resources and information on viral hepatitis and
liver disease
Web: www.hepc.org.nz/index.php/Main_Page
Hepatitis C Resource Centre (Christchurch) – provides resources and information on viral hepatitis and
liver disease
Web: www.hepc.org.nz/index.php/Main_Page
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 111

Appendix 2 – Continued
otHer onLine resources
ABC Radio National
Hepatitis B: a call for wider screening – educational material on HbV screening program
http://www.abc.net.au/rn/scienceshow/stories/2007/2086864.htm
ACT HBV Advancing the Clinical Treatment of Hepatitis B Virus – provides information on HbV
treatment
» Hepatitis b in australia: responding to a diverse epidemic (actHbV)
http://www.ashm.org.au/uploads/Hep-b-in-australia.pdf
Australian Indigenous Health Info Net
infectious diseases – Hepatitis b – provides information and facts on hepatitis a & b
http://www.healthinfonet.ecu.edu.au/html/html_health/specific_aspects/infectious/hepatitis/hepatitis_
ab.htm#hepb
LAB Tests Online
Liver disease – provides information on liver complications
http://www.labtestsonline.org.au/understanding/conditions/liver_disease-2.html
Teen Health- Child and Youth Health
Hepatitis b fact sheet – provides information and facts on hepatitis b
http://www.cyh.com/Healthtopics/Healthtopicdetails.aspx?p=243&np=292&id=2177
The University of Queensland, School of Medicine: HIV & HCV Education Projects
summary of hepatitis b for general practitioners
http://www.som.uq.edu.au/hivandhcvprojects/resourcing/HbV_fact_sheet_.pdf
INTERNATIONAL
ACT HBV Advancing the Clinical Treatment of Hepatitis B Virus – provides information on HbV
treatment
» online resources – act-HbV links page
http://www.act-hbv.com/tools/resources.asp
American Gastroenterological Association (AGA) – provides resources and information on liver disease
to health professionals and consumers
Web: www.gastro.org/wmspage.cfm?parm1=2
American Liver Foundation (ALF) – provides resources and information on liver disease to health
professionals and consumers
Web: www.liverfoundation.org/
» download aLf educational materials/brochures – Hepatitis , cirrhosis, Liver cancer
http://www.liverfoundation.org/education/downloads/
British Society of Gastroenterology (BSG) – provides resources and information on liver disease to
health professionals and consumers
Web: www.bsg.org.uk
11 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Appendix 2 – Continued
Centers for Disease Control and Prevention – national centre for HiV, Viral Hepatitis, std, and tb Prevention
Web: www.cdc.gov
» Viral Hepatitis b – facts and educational materials
http://www.cdc.gov/ncidod/diseases/hepatitis/b/index.htm
» Viral Hepatitis b: frequently asked Questions
http://www.cdc.gov/ncidod/diseases/hepatitis/b/faqb.htm
Hepatitis B Foundation
Web: www.hepb.org
» ‘Living with Hepatitis b’ – information and resources on hepatitis b
http://www.hepb.org/living/index.htm
New Zealand Society of Gastroenterology – provides resources and information on liver disease to
health professionals and consumers
Web: www.nzsg.org.nz
Think B, Hepatitis B and Asian Americans – provides information on chronic infections among asianamerican
populations
Web: www.thinkb.org
World Health Organization Factsheet (WHO)
Web: www.who.int/en
» Hepatitis b – fact sheet and information
http://www.who.int/mediacentre/factsheets/fs204/en/index.html
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 113

GLOSSARY AND ABBREVIATIONS
Viral hepatitides
HAV: hepatitis a virus
HBV: hepatitis b virus
HCV: hepatitis c virus
HDV: hepatitis d (delta) virus
HEV: hepatitis e virus
Ab: antibody
An immunoglobulin essential to the immune system, produced in response to bacteria or viruses. In
the case of hepatitis B, antibodies are produced in response to the virus
AFP: alphafetoprotein
Elevated values may indicate active cirrhosis or hepatocellular carcinoma
Ag: antigen
A substance (usually a protein) that causes the formation of an antibody and reacts specifically with
that antibody
AIDS: acquired immune deficiency syndrome
ALP: alkaline phosphatase
ALT: alanine aminotransferase
An enzyme which may indicate liver damage when found in high levels in the blood. Also known as
serum glutamic pyruvic transaminase (SGPT)
Antiviral resistance:
The selection of antiviral-resistant mutations usually in association with the use of antiviral drugs. The
rate at which resistant mutants are selected in HBV depends on various factors including: pretreatment
serum HBV DNA levels; rapidity of viral suppression; duration of treatment; prior exposure to NA
therapy. The first indication of resistance is virological breakthrough (10-fold [1 log] increase in serum
HBV DNA above nadir after achieving virological response during treatment), followed by biochemical
breakthrough (increase in ALT above ULN after achieving normalisation during treatment)
AST: aspartate aminotransferase
An enzyme normally present in liver and heart cells, which may indicate liver damage when found in
high levels in the blood. Also known as serum glutamic oxaloacetic transaminase (SGOT)
B-cell:
A type of immune cell
Biochemical markers of liver disease
Include ALT, AST, GGT and ALP. Elevated levels of these markers may indicate liver damage (note
that ALT and AST can also rise in other medical conditions). The upper limit of normal levels varies
depending on the laboratory used
CALD:
Culturally and Linguistically Diverse communities
114 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Carrier:
A person with chronic hepatitis B infection. Preferred terminology is ‘a person with hepatitis B’
CD4 T-cell:
A helper T-cell which carries the CD4 surface antigen
CD8 T-cell:
A killer or cytotoxic T-cell which carries the CD8 surface antigen
Chronic hepatitis B:
Chronic necroinflammatory disease of the liver caused by persistent infection with HBV, usually defined
as HBsAg positivity for more than six months
» HBeAg-negative chronic hepatitis B:
HBeAg negative, anti-HBe positive
» HBeAg-positive chronic hepatitis B:
HBeAg positive, anti-HBe negative
Cirrhosis:
End stage liver disease characterised by fibrosis and nodular regeneration within the liver, may lead to
complications, such as liver failure or liver cancer
CMV: cytomegalovirus
Co-infection:
Infection with two or more infectious agents at the one time (e.g. HBV/HCV co-infection; HBV/HIV;
HBV/HDV)
Contact tracing:
The following up, notification and diagnosis of household contacts and sexual partners of a person
with a notifiable infectious disease such as hepatitis B. Also called partner notification
CT: Computed tomography
An imaging method that uses x-rays to create cross-sectional pictures of the body
Diagnostic markers of HBV infection:
The diagnosis of chronic hepatitis B is based on markers of HBV infection (serological and virological
markers) and on markers of liver disease (biochemical and histological markers)
DNA: deoxyribonucleic acid
» b-DNA:
branched chain dna
» (ccc) DNA:
covalently closed circular dna
FBC: full blood count
FCSW: female commercial sex workers
Fibrosis, stage of disease:
Methods to score the level of scar formation in the liver. Scoring systems include: histological activity
inflammation (HAI); Ishak modified system, METAVIR and Scheuer classifications
Genotype:
The specific genetic structure of the virus. Currently, there are eight recognised HBV genotypes (A–
H), the prevalence of which varies geographically. The most common HBV genotypes are A–D. HBV
genotype may be related to clinical outcome by predicting disease progression and treatment response
to pegylated interferon
GGT: Gamma-glutamyl transferase
An enzyme found mainly in the liver. When the liver is injured or obstructed, the GGT level rises
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 115

Glossary and abbreviations
GP: General practitioner
HAART: Highly active antiretroviral therapy
HBcAg: Hepatitis b core antigen
» Anti-HBc:
antibody to hepatitis b core
» antigen (HBcAb)
Anti-HBc IgM indicates recent exposure to HBV and anti-HBc IgG indicates past exposure to HBV
HBeAg: Hepatitis b e antigen
Anti-HBe: antibody to hepatitis b e antigen (Hbeab)
HBIG: Hepatitis b immunoglobulin
HBsAg: Hepatitis b surface antigen
Anti-HBs: antibody to hepatitis b surface antigen (Hbsab)
HCC: Hepatocellular carcinoma
Histological markers of liver disease:
An assessment of fibrosis (stage of disease) and necroinflammation (grade of disease) from liver biopsy.
Histological evaluation of liver biopsy is a more accurate indicator of liver disease than ALT levels. Tests
for the non-invasive assessment of hepatic fibrosis are becoming available
HIV: Human immunodeficiency Virus
IDU: injecting drug use
IFN: interferon
Ig: immunoglobulin
IgM: Immunoglobin M
IgG: Immunoglubin G
IM: intramuscular
INR: international normalised ratio (a test of blood clotting)
Can be elevated in liver failure or as a result of taking anticoagulant medications
IV: intravenous
IU: International units (measurement of HbV dna replication).
The previous unit of measurement (copies/mL) has been standardised internationally to IU/mL. The
conversion factor is 5–6 genome copies/mL = 1 IU/mL
LFT: Liver function test
µL: Microlitre
mL: Millilitre
mmol: Millimole
MRI: Magnetic resonance imaging
MSM: Men who have sex with men
NA: nucleoside and nucleotide analogues
NAAT: nucleic acid amplification techniques
116 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

Notification:
Medical practitioners and laboratories have a legal duty to notify their state health department of
diseases listed as notifiable. Notifiable diseases can differ from state to state. Acute viral hepatitis B is
notifiable by all doctors in all Australian states and territories. HBsAg-positive results must be notified by
laboratories in NSW. Notification does not legally breach a patient’s right to privacy
Occupational exposure:
An injury or incident occurring in the workplace, where blood or body substances come into contact
with non-intact skin or membranes, with the potential for the transmission of infection
Partner notification: see contact tracing
Patient confidentiality:
The legal duty of confidentiality obliges health care practitioners to protect their patients against
inappropriate disclosure of personal (health) information
PCR: Polymerase chain reaction
A laboratory technique that amplifies the genetic material of a virus to a level that can be detected
PEG-IFN: Pegylated interferon
PEP: Post-exposure prophylaxis
Percutaneous ablation:
Method of destroying tumour cells using chemicals, such as ethanol or acetic acid
pg/mL: Picogram per millilitre
RCT: randomised controlled trial
RNA: ribonucleic acid
(pg) RNA: Pregenomic rna
rt: reverse transcriptase
Screening:
Testing for the presence of an asymptomatic condition in an apparently healthy individual
Section 100:
A section of the Pharmaceutical Benefits Scheme (PBS), which provides access to highly specialised
drugs
Seroconversion:
Process whereby a serological test for a given microbiological or virological agent changes from nonreactive
to reactive, coinciding with recent infection
» HBeAg seroconversion:
Loss of HBeAg and detection of anti-HBe in a person who was previously HBeAg positive and anti
HBe negative
Serological markers of hepatitis B infection:
HBsAg persistence for more than 6 months indicates chronic HBV; anti-HBs indicates recovery, or
immunity to HBV after successful vaccination; HBeAg indicates active replication of HBV; anti-HBe
generally indicates HBeAg seroconversion, the goal of HBV therapy for HBeAg-positive HBV; anti-HBc
IgM indicates recent exposure to HBV and anti-HBc IgG indicates past exposure to HBV
Serology:
(Usually) Diagnostic identification of antibodies, sometimes antigens, in serum
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 117

Glossary and abbreviations
Standard infection control precautions:
Work practices required for the basic level of infection control; are recommended for the treatment
and care of all patients. Standard precautions are designed to reduce the risk of transmission of microorganisms
from both recognised and unrecognised sources of infection to a susceptible host
STI: sexually transmitted (or transmissible) infection
An infection that can be transmitted from one person to another by sexual activity (oral, anal and
vaginal intercourse)
STD: sexually transmitted disease
The more accurate term, sexually transmissible infection (STI) is now in current use
SVR: Sustained virological response
The elimination of the hepatitis C virus following treatment
TAE: transcatheter arterial embolisation
TACE: transarterial chemoembolisation
T-cell: White blood cell or lymphocyte
TMA: transcription mediated assay, a naat
Transmission:
» Horizontal:
Transmission of an infection from person to person in the community
» Vertical:
Transmission of an infection from mother to child, during pregnancy, delivery or breastfeeding
Vaccination:
Australian vaccination policy to control hepatitis B began in 1988. In 1997, a universal hepatitis B
vaccination program for adolescents was implemented, followed in 000 by a universal program for
infants
Viraemia:
Presence of a virus in the bloodstream
Viral load:
The amount of virus circulating in the blood, usually measured by a quantitative PCR test
Virological markers of hepatitis B infection:
The amount of HBV DNA in serum is a measure of the level of viral replication and a strong predictor
of the development of cirrhosis and hepatocellular carcinoma. HBV DNA testing is now approved in
Australia to evaluate a patient for treatment and to monitor treatment efficacy. The threshold HBV DNA
level associated with progressive liver disease is unknown; 0,000 IU/mL has been arbitrarily selected to
indicate less hepatic damage
WHO: World Health organization
118 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

INDEX
a
Aboriginal also see Indigenous Australians
• high risk group...........................................................18–19, 40
• liver cancer............................................................................15–16
• prevalence.............................................................14–16, 35, 47
• vaccination....................................................................15, 47, 50
Acquired Immune Deficiency Syndrome (AIDS)....... 6, 78
Actitest®............................................................................................................34
acute infection..............................................................41, 43, 51, 53–4
adefovir dipivoxil (ADV)....10, 5, 7–8, 55, 57, 59–6 , 78, 103
advanced liver disease.......11–1 , 18, 41–3, 65–8, 75, 78–9
alanine aminotransferase (ALT).............................................................
.... 7, 31, 33–6, 41–3, 5 –3, 57–60, 65, 77–8, 80, 97, 99, 103
alpha fetoprotein estimation.............................53–5, 69–71, 77
American Association of the Study of Liver Diseases
(AASLD)......................................................................................................35, 41
andrographis paniculata (green chiretta; Chuan Xin Lian)
.................................................................................................................................98
andrographolide........................................................................................98
anti-HBc...................................................15, 17, 3 , 34, 36, 5 , 54, 80
anti-HBc IgG...........................................................................................3 , 43
anti-HBc IgM...................................................................3 , 34, 43, 5 –3
anti-HBe.....................................................3 , 34, 36, 4 –3, 5 , 54, 58
anti-HBs...................................................................................................................
..... 6, 8, 3 , 34, 36, 41, 46, 48–9, 5 –4, 77–8, 80, 86–7, 103
antiviral agents .................................................................................................
.................10, 4, 6–7, 44, 55, 57–6 , 65–6, 75–80, 97–8, 103
• see also adefovir dipivoxil (ADV); clevudine;
complementary and alternative medicine (CAM);
emtricitabine (FTC); entecavir (ETV); lamivudine
(LMV); telbivudine (L-dT); tenofovir disoproxil
fumarate (TDF) antiviral resistance see drug resistance
apigenin (Ocinum basilicum)...........................................................96
Artemisia annua (Chinese wormwood; Qing Hao)...........98
artesunate.......................................................................................................98
ascites..........................................................................11, 33, 5 , 54, 67–8
Asian-American Hepatitis B Program [New York]...............7
aspartate aminotransferase (AST).................................35, 53, 99
Astragalus membranaceus (milk-vetch root; Huang Qi).....97–8
Atractylis gummifera (pine thistle).........................................96, 98
Australian Acupuncture and Chinese Medicine
Association (AACMA)......................................................................96, 99
Australian Immunisation Handbook.............................50, 85–6
Australian Medical Association (AMA)........................................90
b
bilirubin.............................................................................................34, 54, 99
black cohosh (Actea racemosa and Cimicifuga
racemosa).......................................................................................................99
blood product recipients.....................................................40, 46, 85
body piercing............................................................................47, 85, 10
Bupleurum chinensis (Chai Hu)......................................................97
c
Cancer Council NSW............................................................................6–7
Cancer Incidence in New South Wales Migrants 1991- 001
(Cancer Council NSW).................................................................................6
Carlina gummifera....................................................................................96
cART see Combination Antiretroviral Therapy
CD4 T-cells....................................................................................................... 4
CD8 T-cells....................................................................................................... 4
Centers for Disease Control and Prevention [USA]............83
chemotherapy.................................................................... 6, 69, 71, 80
Chinese.............................................................................................15, 18, 70
Chinese medicine................................................................................96–9
chronic HBV
• age factors.......................................................................41, 46, 51
• clinical assessment.............................................................51–6
• definition.................................................................................9, 10
• drug resistance...................................................................... 6–9
• immune active phase......................................................9–10
• immune clearance phase......................................34, 41–3
• immune control phase...................................34, 41–3, 53
• immune escape phase............................................34, 41–3
• immune tolerant phase.........................10, 34, 41–3, 59
• liver damage........................................ 4, 4 , 54–5, 58, 103
• management in complex situations..................75–80
• mortality..........................................................................................44
• natural history........................................................................40–4
• paediatric management................................................77–8
• referral guidelines......................................................................54
• treatment...............................................................................57–63
chronic liver disease........................15, 47, 49, 5 , 66, 7 , 85, 96
cirrhosis
• compensated.......................................................................11, 14
• complementary medicine...................................96, 98–9
• decompensated..........................10–11, 44, 60, 65–6, 71
• definition..........................................................................................65
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 119

Index
• HBV DNA level.......................................................................31–
• HBV/HCV co-infection............................................................79
• HBV/HIV co-infection..............................................................78
• HCC screening.....................................................................56, 7
• hepatocellular carcinoma (HCC)....................................70
• liver biopsy results.....................................................................33
• monitoring.............................................................................6 , 67
• mortality..........................................................................................44
• prediction of development...............................33, 43, 53
• pregnancy......................................................................................76
• risk factors................................................................................44, 51
clevudine......................................................................................................... 7
clinical assessment.............................................................................51–6
• see also test results; testing
clotting disorder patients..............................................................46–7
coinfection
• HBV- hepatitis D...................................................44, 66, 78–9
• HBV-HCV....................................................................17, 44, 78–9
• HBV-HIV........................................................ 7–8, 44, 63, 78–9
combination Antiretroviral Therapy (cART)........... 6, 78–80
combination therapy................................................. 9, 61– , 78–9
complementary and alternative medicine (CAM)....11, 96–9
compound 861 (Cpd 861).............................................................97–9
computed tomography (CT) scanning.............................66, 70
Comvax.............................................................................................................48
confidentiality.........................................................................................90–5
contact tracing..............................................................................37, 94–5
covalently closed circular (ccc) DNA.............................. 4–5, 43
criminal law....................................................................................................95
Culturally and Linguistically Diverse (CALD) communities
• prevalence.............................................................................14–15
• vaccination.............................................................................47, 50
d
depression..............................................................................................59, 63
discrimination......................................................................19, 84, 91, 95
drug resistance......................10, 4–9, 33, 55, 57–6 , 77–8, 80
duty of care to third parties................................................................95
e
emtricitabine (FTC)...........................................................10, 7, 61, 78
Engerix-B....................................................................................................48–9
entecavir (ETV)........10, 5, 7–9, 55, 57, 59–6 , 65, 78, 80, 103
epidemiology......................................................................................13–19
ethics...................................................................................................................90
exposure-prone procedures.......................................5 , 8 , 86–7
1 0 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
f
Fibroscan®.......................................................................................................35
• fibrosis see hepatic fibrosis
Fibrotest®....................................................................................................34–5
flares..............................................4 –3, 5 , 55, 57–8, 60, 76, 79–80
flavonoids..................................................................................................96–8
fluid and electrolyte balance problems..............................66–7
fulminant hepatitis.............................................43, 46, 54, 76–7, 79
G
genotypes.............................................................................33, 44, 59–60
genotyping....................................................................................................33
glomerulonephritis..................................................................................5
gloves.................................................................................................................84
glycyrrhiza root (liquorice; Gan Cao) root.................................97
H
H-B-VAX II.........................................................................................................48
haemodialysis patients..........................................35, 40, 47, 49, 85
hand hygiene...............................................................................................84
HBcAg.................................................................................................. 5–6, 5
HBeAg.....................................................................................................10–11,
6, 31–4, 36, 41–3, 51–5, 57–60, 6 , 76–80, 83, 97–8, 103
• HBeAg-negative patients ....10, 43, 5 –3, 58–60, 76
• HBeAg-positive patients ............................................................
..............................................10, 3 , 43, 51, 53, 55, 57–60, 6 , 76
• HBeAg seroconversion....10, 6, 3 –3, 4 , 55, 58–60, 98
HBIG......................................................... 6, 46–7, 49–50, 76–7, 86–7
HBsAg................................................................................14–18, 4–6, 8,
31– , 34, 36, 41–3, 46–9, 5 –4, 58, 60, 76–80, 87, 97, 103
• HBsAg-negative patients............................43, 76, 78–80
• HBsAg-positive patients..................................................9, 11,
15–18, 35–6, 40–1, 43, 46–7, 49, 5 , 54–5, 57, 78, 80
• HBsAg seroconversion...........................................10, 58, 60
HBV antigens................................................................................. 4, 6, 31
HBV DNA.................................................................................................... 4–6
• genome.............................................................................. 5, 3 –3
• level........................................................10, 7, 31–4, 37, 4 –4,
5 –5, 57–9, 6 , 65, 76, 78, 80, 83, 96–7, 99, 103
• HBV DNA testing see testing
HBV-HCV coinfection........................................................17, 44, 78–9
HBV-hepatitis D coinfection.........................................44, 66, 78–9
HBV-HIV coinfection............................................ 7–8, 44, 63, 78–9
HBV Pol................................................................................................ 5, 7–8
HBV-related liver disease projections..........................................18
• HCC see hepatocellular carcinoma health care
workers
• HBV infected.................................................................................87
• occupational exposure...................................47, 5 , 8 –8
• vaccination..........................................49, 8 , 85, 87, 89, 104

Health Records and Information Privacy Act 2002 (NSW) .....9
‘healthy carrier’.............................................................................................41
Hepadnaviridae.......................................................................................... 4
hepatic decompensation.....................................10, 51, 6 , 65–6
hepatic encephalopathy.....................................................11, 5 , 54
hepatic fibrosis...................................................................................................
...............9–11, 31, 33–5, 37–8, 4 , 44, 53, 59–60, 6 , 65, 96–8
hepatic synthetic function..................................................................53
hepatitis A...............................................................................37, 48, 5 , 77
Hepatitis Australia...................................................................................105
Hepatitis B immunoglobulin (HBIG) see HBIG
hepatitis C.............................................................................................17–18,
35, 47, 51, 53–4, 63, 65–6, 68, 78–9, 8 –3, 85–7, 104–5
• see also HBV-HCV coinfection
hepatitis D..........................................................43–4, 5 , 54, 66, 78–9
hepatocellular carcinoma (HCC.............................................69–7
• chronic hepatitis B.....................................................................51
• cirrhosis.....................................................................................44, 70
• epidemiology...................................................................................11
• ethnicity...........................................................................15, 18, 69
• HBV DNA level.............................................................31, 44, 53
• high-risk communities..................................................69–70
• incidence........................................................................14, 69–70
• Indigenous Australians..........................................................16
• lamivudine....................................................................................60
• mortality...................................................................................14, 69
• prediction of development....3 –3, 43–4, 53, 65, 69
• prevention................................................................................71–
• risk factors.......................................................................................44
• screening.................................................................55, 68, 70, 7
• treatment options..............................................................11, 71
• vaccination.....................................................................................46
hepatocytes............................................................ 4–5, 43, 54, 80, 98
hepatoma see liver cancer
high-risk behaviours.......................................................17–19, 40, 47
• see also exposure-prone procedures
high-risk communities.......................6, 9, 14–18, 35, 40, 47, 7
highly active antiretroviral therapy (HAART) see cART
Histological Activity Index (HAI)......................................................34
histology....................................................................................4 –3, 60, 97
HIV......................................................................................................... 6–9, 35,
47, 55, 61, 66, 75–6, 80, 8 –3, 85–7, 89–90, 104
• HBV-HIV coinfection ....................... 7, 44, 5 , 63, 78–9
HIV Observational Database............................................................78
Hong Kong immigrants........................................................................15
household contacts...................................................................................
..............................35, 40, 46–7, 5 , 75, 77, 83, 85, 10 , 104–5
i
immunosuppression..............................35, 43, 47, 49, 54, 75, 80
‘inactive carrier’......................................................................................41–
incubation...............................................................................................31, 41
Indigenous Australians
• high risk group ..........................................................18–19, 40
• liver cancer ...........................................................................15–16
• prevalence ............................................................14–16, 35, 47
• vaccination .................................................................. 15, 47, 50
Infanrix HepB.................................................................................................48
Infanrix Hexa..................................................................................................48
Infanrix Penta................................................................................................48
infant vaccination programs......9, 18, 46–9, 71, 76–7, 85, 104
infection control...................................................................................8 –9
Infection Control Guidelines for the Prevention of
Transmission of Infectious Diseases in the Health Care
Setting.................................................................................................8 –4, 87
informed consent......................................................................36, 90, 93
injecting drug users
• disease pattern............................................................................17
• HBV-HCV coinfection......................................................17, 79
• HBV-HDV coinfection.............................................................79
• HBV transmission.........................................40, 46, 10 , 104
• prevalence............................................................13–14, 17–18
• vaccination..................................................................47, 85, 104
intellectually disabled people...........................................................47
interferon based-therapy...........................................................................
.......................10, 33, 55, 57, 59–63, 65–6, 7 , 77–80, 97–8, 103
Ishak modified HAI...................................................................................34
J
jaundice.........................................................................11, 41, 53, 66, 10
K
kava................................................................................................................98–9
kurorinone................................................................................................97–9
L
lamivudine (LMV)...........................................................................................
.......................10, 5, 7–9, 44, 55, 57, 59–6 , 76–80, 97–8, 103
Larrea tridenta (chaparral)...........................................................96, 98
lifestyle issues.............................................................................................103
liver biopsy.................................9, 33–5, 43, 53, 55, 57–9, 70, 103
• liver cancer see hepatocellular carcinoma (HCC)
liver enzymes................................................................................................53
liver function tests...............................................................4 , 53–4, 6
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 1 1

Index
liver transplantation................................11, 58, 6 , 65, 69–7 , 85
liver ultrasound.................................................53–5, 69–70, 77, 103
M
magnetic resonance imaging (MRI).............................................70
mandatory notification.........................................................................14
medical records.....................................................................................93–5
Medical Services Advisory Committee......................................33
men who have sex with men (MSM)
• high-risk behaviour .........................................................19, 40
• HIV-HBV coinfection ...............................................................78
• prevalence ....................................................................14, 18, 47
• vaccination ................................................................18, 47, 104
Mentha pulgeium (pennyroyal).............................................96, 98
METAVIR system....................................................................................34–5
Models of Care database..............................................................91, 93
monitoring treatment.....19, 33, 35, 54, 57–8, 61– , 67–8, 77
multi-drug resistance.............................................................................. 8
multidisciplinary teams.........................................................................94
mutations................. 4, 6–9, 33, 43, 50, 53, 55, 6 , 76, 78, 80
n
National Herbalists Association of Australia (NHAA)....96, 99
National Notifiable Diseases Surveillance System............8, 14
needlestick injury..............................................................85–7, 94, 10
New Zealand National Hepatitis B Programme.............7, 7
non-invasive assessment...............................................................34–5
notifiable disease.........................................................................90–1, 93
NSW Needlestick Injury Hotline......................................................87
nucleoside and nucleotide analogues (NA).................................
................................................................ 4–5, 7–9, 54–5, 58, 61–3, 65
o
occult HBV.................................................................. 9, 34, 43–4, 78–9
occupational health..................................................................47, 8 –9
Ocium basilicum (sweet basil)..........................................................97
Office of the Privacy Commissioner..............................91–3, 95
overlapping open reading frames (ORF).................................. 5
oxymatrine.......................................................................................96–7, 99
P
paediatric management................................................................77–8
Passiflora incarnata (passionflower).............................................98
pegylated interferon.....................10, 55, 57, 59–65, 77–9, 103
percutaneous ablation...........................................................11, 69, 71
peripheral oedema...................................................................................5
Pharmaceutical Benefits Advisory Committee............55, 59
Pharmaceutical Benefits Scheme.................55, 58–6 , 76, 78
phyllanthus...............................................................................................98–9
1 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
Piper methysticum (kava)....................................................................98
pol-env overlap.......................................................................................... 8
• Pol ORF see reverse transcriptase/DNA polymerase
(Pol ORF)
polyarteritis nodosa.................................................................................5
polymerase chain reaction (PCR) assays......9, 3 , 43, 53, 83
polymerase mutations.................................................................... 7–9
portal hypertension...................................................................11, 66–8
portal systemic encephalopathy.............................................66–8
post-exposure prophylaxis (PEP)....................................................87
precautions against transmission...............................................104
‘precore mutant’ HBV................................................ 6, 33, 4 –3, 53
preferred terminology............................................................................41
pregnancy................................................................................55, 63, 75–6
premature infants......................................................................................48
prevalence.............................................................................13–19, 35, 47
prevention.............................................................................................46–50
prisoners...............................................................................17, 19, 47, 104
privacy..........................................................................................................90–5
Privacy Act 1988 (Commonwealth)...............................90–1, 94
prophylaxis
• health care workers..................................................................87
• during immunosuppressive therapy..........................80
• pregnancy................................................................................76–7
protective equipment............................................................................84
prothrombin time...............................................................................53–4
Public Health Act 1991 (NSW)..........................................................93
public health programs..........................................................18, 71–
pyrrolizidine alkaloids.............................................................................98
r
reactivation............................10–11, 3 , 34, 41–3, 57, 75, 78–80
rescue therapy............................................................................................. 8
REVEAL study................................................................................................44
reverse transcriptase.................................................................. 4–6, 8
reverse transcriptase/DNA polymerase (Pol ORF).............. 5
risk factors...............................................................................17–19, 40, 51
rituximab ........................................................................................................ 10
s
safe sex...........................................................................................................104
Salvia miltiorrhiza (scarlet root; Dan Shen)..............................97
screening..........................................................11, 35, 46–7, 69, 71, 85
• antenatal..........................................................................................76
• effectiveness....................................................................................7
• HCC screening....................................................55, 68–7 , 77
Scutellaria baicalensis (baical skullcap).......................................97
Scutellaria laterifolia (skullcap)...........................................................98
sex workers.................................................................................40, 47, 104

sexual contacts.................18, 35, 37, 46–7, 5 , 85, 10 , 104–5
sharps injury............................................................................................85–7
shosaiko-to.....................................................................................................97
side effects of treatment.......................................................................63
silibinin...............................................................................................................98
Silybum marianum (Saint Mary’s thistle)...................................98
Sophora flavescens...................................................................................97
splenomegaly.......................................................................................5 , 66
surgical resection................................................................................69, 71
t
tattoos......................................................................40, 46–7, 50, 85, 10
telbivudine (L-dT)........................................................10, 5, 7–9, 61
tenofovir disoproxil fumarate (TDF).......10, 7–8, 61, 63, 78
test results.....................................................................31–7, 5 –3, 58–9
testing.................................................................31–7, 5 –4, 6 , 86, 103
• see also clinical assessment
Teucrium chamaedrys (wall germander).........................96, 98
Teucrium polium................................................................................96, 98
Therapeutic Goods Administration (TGA)...............................59
TJ-9.......................................................................................................................97
transarterial chemoembolisation (TACE)..........................11, 71
transcatheter arterial embolisation (TAE)..................................71
transmission..........................40, 46, 50, 5 , 75–6, 83, 87–8, 10
• vertical.....................................................................40, 75–6, 10
transmission offences............................................................................95
transmission risk.........................................................................................5
transplant recipients........................................................ 6, 47, 50, 85
travellers........................................................................................47, 85, 104
treatment.....................................................................................57–63, 103
• see also antiviral agents; drug resistance; side effects
Twinrix.........................................................................................................48–9
V
vaccination programs...................................................................46–50
• accelerated schedules........................................................48–9
• adolescents and adults..................................................9, 47–8
• booster doses................................................................................49
• catch-up schedules....................................................................49
• effectiveness...................................................................................1
• health care workers...........................49, 8 , 85, 87, 89, 104
• Indigenous Australians.....................................15–16, 47, 50
• infants................................................................................9, 46–9, 77
• National Immunisation Program: 007..........................48
• non-response........................................................................49–50
• pregnancy........................................................................................76
• recommended recipients....................................................104
• regime...........................................................................................85–6
vaccine failure...................................................................................... 6, 50
vaccines............................................................................................................48
vertical transmission .................................................... 40, 75–6, 10
Vietnamese immigrants.........................................8, 13–15, 18, 70
viral load.................................................. 6, 9, 43, 60, 76, 79–80, 83
virology....................................................................................................... 4–9
W
wogonin (Scutellaria baicalensis)...................................................96
World Health Organization (WHO)...................................8–9, 46
b Positive – all you wanted to know about hepatitis b: a guide for primary care providers 1 3

Notes
1 4 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers