hepatitis B

all you wanted to know about

a guide for primary care providers

hepatitis B
a guide for primary care providers
Editors Gail Matthews and Monica Robotin

all you wanted to know about

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) Locked Mail Bag 5057, Darlinghurst, NSW 1300 Telephone (61) (0) 804 0700 Facsimile (61) (0) 91 38 Email ashm@ashm.org.au Website http://www.ashm.org.au First published 008 Editors: Gail Matthews and Monica Robotin Copy Editor: Mary Sinclair Printed by: Paragon Print Australasia B Positive - all you wanted to know about hepatitis B: a guide for primary care providers ISBN: 978-1-90773-56-4 Includes index. Copyright in this publication is jointly held by ASHM and The Cancer Council NSW © Australasian Society for HIV Medicine Inc. 008 ABN 48 64 545 457 CFN 17788 © The Cancer Council NSW 008 ABN 51 116 463 846 CFN 1851 Apart from any fair dealing for the purpose of research or study, criticism or review, as permitted under the Copyright Act 1968, no part of this book may be reproduced by any process without written permission. Primary health care providers are granted a non-exclusive licence to copy patient information. Direct enquiries to the Australasian Society for HIV Medicine (ASHM). Effort has been made to get permission from copyright owners for use of copyright material. We apologise for any omissions or oversight and invite copyright owners to draw our attention to them so that we may give appropriate acknowledgment in subsequent reprints or editions. The statements or opinions that are expressed in this book reflect the views of the contributing authors and do not necessarily represent the views of the editors or publisher. Every care has been taken to reproduce articles as accurately as possible, but the publisher accepts no responsibility for errors, omissions or inaccuracies contained therein or for the consequences of any action taken by any person as a result of anything contained in this publication. All terms mentioned in the book that are known to be trademarks have been appropriately capitalised. ASHM cannot attest to the accuracy of this information. Use of a term in this book should not be regarded as affecting the validity of any trademark. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing clinician. For detailed prescribing information or instructions on the use of any product described herein, please consult the prescribing information issued by the manufacturer. 

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

Contents
Acknowledgments .................................................................................................................... Foreword ...................................................................................................................................... Executive Summary .................................................................................................................. Chapter 1 Chapter  Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 1 Chapter 13 Appendix 1 Appendix 2 Prevalence and epidemiology of hepatitis B ........................................ Van TT Nguyen, Gregory J Dore Virology: viral replication and drug resistance ..................................... Stephen Locarnini Hepatitis B virus testing and interpreting test results ....................... Mark Danta Natural history of chronic hepatitis B virus infection ......................... Marianne Guirgis, Amany Zekry Primary prevention of hepatitis B virus infection ................................ Nghi Phung, Nicholas Wood Clinical assessment of patients with hepatitis B virus infection ...... Darrell HG Crawford, Rebecca J Ryan, Nghi Phung Treatment of chronic hepatitis B virus infection .................................. Rebecca J Ryan, Miriam T Levy, Darrell HG Crawford Managing patients with advanced liver disease .................................. Robert Batey Hepatitis B virus-related hepatocellular carcinoma ............................ Monica Robotin Managing hepatitis B virus infection in complex situations ............ Benjamin Cowie Infection control and occupational health ............................................ Jacqui Richmond Privacy, confidentiality and other legal responsibilities .................... Sally Cameron The role of complementary medicine in hepatitis B ........................... Ses J Salmond, Robert Batey Patient fact sheet........................................................................................... Useful resources.............................................................................................. 5 6 8 13 24 31 40 46 51 57 65 69 75 82 90 96 102 106 114 119

Glossary and abbreviations .................................................................................................... Index .............................................................................................................................................

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

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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

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Foreword
in nsW, just seven cancers—those of prostate, breast, bowel, lung, melanoma and nonHodgkin’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

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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 Zhang bH, yang bH, tang Zy. randomized controlled trial of screening for hepatocellular carcinoma. J cancer res clin oncol 2004;130(7):417-22. 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.

2. 3.

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

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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
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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

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

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

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
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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

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

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

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

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

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

PREVALENCE AND EPIDEMIOLOGY OF HEPATITIS B
Van TT Nguyen Gregory J Dore

1

School of Public Health and Community Medicine, The University of New South Wales, Kensington, New South Wales. 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

the prevalence of chronic HbV infection in australia has increased, predominantly Hepatitis b virus (HbV) infection remains a related to the increase in immigration major global public health problem, despite from highly endemic regions.4,5 based on the availability of a highly effective vaccine a national laboratory-based serosurvey, and improvements in antiviral therapy. Globally, of the two billion people previouslyl refs Mthec number of chronic HbV infection cases Ch 1 Fina S.do 13/02/08 was estimated to be between 90,000 and infected, more than 350 million people have 160,000, representing a 0.5–0.8% population 5 Figures developed chronic HbV infection, causingand 2 Tables prevalence.6 a hospital-based study found 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

HBV prevalence in Australia and the impact on its health system

20

Figure 1.1.

figure 1.1: Geographical distribution of hepatitis b virus endemicity3 Geographical distribution of hepatitis B virus endemicity[3]

b Positive – all you wanted to know about hepatitis b: a guide for primary care providers
10000 9000 8000

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C h 1 F i nal ref s M S . doc 13/02/08

2

5 Figures and 2 Tables

1 Prevalence and epidemiology of hepatitis B

HBV prevalence

6,000 4,000 2,000 0

45 30 15 0

10000 9000 8000 7000 6000 5000 4000 3000 2000 1000 0 1992 1998 2002 2004 C h 1 F i na1994s M S1996 13/02/08 2000 l ref . doc figure 1.2: notifications of chronic hepatitis b to the national 8 notifiable diseases system 2006

1960

1964

1968

1972

1976

1980

1984

1996

2000

2004

2012

2016

2020

1988

HBV

figure 1.4: estimated chronic hepatitis b virus prevalence and hepatitis b Figure 1.4. Estimated chronic hepatitis B virus prevalence and HBV-related5 virus-related Hcc incidence among residents of australia born in china hepatocellular carcinoma incidence among China-born residents in Australia

1992

HCC

2008

2024

HCC incidence

Hbsag prevalence of 2.1%, with 70% of patients inOther 22% new south Wales, the incidence rate of liver cancer in males per 100,000 increased from 2.0 with HbV infection born overseas.7 Hepatitis in 1972 to 7.4 in 2004, and in females from 0.5 b diagnosis requires mandatory notification in 1972 to 2.9 in 2004.14 despite the availability in all australian states and territories. the and annual number of hepatitis b cases reported IDU 5% efficacy of the HbV vaccine, the prevalence South-East Asian 33% of chronic HbV infection and HbV-related Hcc to the national notifiable diseases surveillance MSM 8% among australian residents born in the asiasystem varies from around 5000 in 1992 and North-EastPacific region has been projected to increase Asian 16% 1993 to peaks of close to 9000 cases in 1994 and in the next two decades. this is owed primarily 1996, and around 6000 cases since 2003 (figure to the continued of total prevalence 1.2).8 the majority of people with chronic HbV Figure 1.3. Estimates of proportionsimmigration from highly endemic countries and the long latency of Hcc infection come from four high-risk groups: development (figure 1.4).5 immigrants from highly endemic countries 14,000 105 (particularly north-east and south-east asia); 12,000 90 injecting drug users (idus); men who have sex Figure 1.1. Geographical distribution of hepatitis B virus endemicity[3] 10,000 75 with men (MsM); and indigenous australians 8,000 60 (figure 1.3).6
6

Indigenous 16%

5

Indigenous 16% Other 22%

the economic burden related to chronic HbV infection is substantial. the average annual 21 direct cost per patient for managing HbVrelated liver disease has been estimated at $1778 for active hepatitis, $1394 for compensated cirrhosis and $11,753 for Hcc (year 2001, a$).15

Figure 1.2. Notifications of chronic hepatitis B to National Notifiable Diseases System 8
IDU 5% MSM 8% North-East Asian 16% South-East Asian 33%

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

Figure 1.3. Estimates of proportions of total prevalence

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figure 1.3: estimates of proportions of total prevalence6

chronic HbV infection in australia is contributing 12,000 90 to an increasing burden of advanced liver 10,000 75 disease, 8,000 including hepatocellular carcinoma 60 9-11 Hcc incidence and mortality rates (Hcc). 6,000 45 have been increasing over the last three 4,000 30 decades, 2,000 particularly among overseas-born 15 9,12,13 males. between 1978 and 1997, age0 0 standardised Hcc mortality rates increased HBV from 2.4 to 4.4 per 100,000 HCC overseas-born for Figure 1.4. Estimated 1.4 hepatitis B virus prevalence overseasmales, and 0.6 to chronic per 100,000 forand HBV-related born hepatocellular carcinoma incidence among China-born residents in Australia females.12
HBV prevalence 1960 1964 1968 1972 1976 1980 1984 1996 2000 2004 2012 2016 2020 1988 1992 2008 2024

14,000

105

HCC incidence
5

14

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

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.

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
15

Aboriginal and Torres Strait Islander peoples

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

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

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 burrell cJ et al. 198359 barrett eJ, 197260 study population (n) aboriginal (327) aboriginal adults (160) aboriginal children (731) torres strait islander adults (79) aboriginal (2193) study setting Prevalence of Hbsag+ (%) south australia 26.0 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

barrett eJ, 197661

6.1

Moore et al. 1987

51

aboriginal women (816) aboriginal population aged 12 or older (1150) aboriginal (375)

3.6 7.0 (3.0-22.0) 19.2

Holman et al. 198752 campbell et al. 198954

Gill et al. 199056 campbell et al. 199153 Gardner et al. 199257 Patterson et al. 199355

aboriginal children (277) aboriginal children aged 0-16 years (408) aboriginal children (439) aboriginal (98) indigenous teenagers (132 incomplete vaccination)

6.1 14.0 8.2 16.9 (1983-1984) 6.0 (1987-1988) 26.0

Malcolm et al. 200058

16

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

People who inject drugs are at high risk of HbV infection. an estimated 200,000 people inject drugs in australia6 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

Injecting drug users

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

table 1.2: Prevalence and incidence of hepatitis b virus infection in injecting drug users and prisoners68-70, 72-76
references crofts n et al. 199468 crofts n et al. 199769 cook Pa et al. 2001 Maher L et al. 2004
76

study population idus idus idus idus Prisoners Prisoners Prisoners

Prevalence of anti-Hbc (%) 47.0 52.4 26.6 28.0 32.5 31.0 35.0 31.0

Prevalence of Hbsag+ (%) 1.8

HbV infection incidence (per 100 person years) 1.8

72

2.7 2.6 3.2
22

crofts n et al. 199573 butler tG et al. 1997 butler tG et al. 2005
Other/unknown 19%
74 70 75

12.6

butler tGnetreal.MS.doc 13/02/08 Prisoners Ch 1 Fi al fs 1999

3.0

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 MSM 7% IDU 44% national survey found that only a third of drug and alcohol agencies in australia routinely provide HbV testing and vaccination onsite, figure 1.5: risk factors among newly acquired HbV (2002-2003) Figure 1.5. Risk factors among groups with newly acquired hepatitis B virus (2002- a quarter of the agencies did not offer and 2003) this service at all.79 in addition, the high stigma relating to injecting drug use often precludes
Heterosexual 28%
71

71

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.

rates of HbV vaccination as outlined in recent studies91 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.

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 behaviour99,100 and low
18

Men who have sex with men

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.

Increasing the burden of HBV-related liver disease

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.

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

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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References
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1 Prevalence and epidemiology of hepatitis B

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75. butler t, boonwaat L, Hailstone s. national prison entrants’ bloodborne virus survey report, 2004. centre for Health research in criminal Justice, national centre in HiV epidemiology and clinical research, university of new south Wales, 2005. report no.: cHrcJ research report no. 1. 76. cook Pa, McVeigh J, syed Q, Mutton K, bellis Ma. Predictors of hepatitis b and c infection in injecting drug users both in and out of drug treatment. addiction 2001;96:1787-97. 77. Maher L, sargent P, Higgs P, crofts n, Kelsall J, Le tt. risk behaviours of young indochinese injecting drug users in sydney and Melbourne. aust nZ J Public Health 2001;25:50-4. 78. Macdonald V, dore GJ, amin J, van beek i. Predictors of completion of a hepatitis b vaccination schedule in attendees at a primary health care centre. sexual Health 2007;4:27-30. 79. Winstock ar, anderson cM, sheridan J. national survey of HiV and hepatitis testing and vaccination services provided by drug and alcohol agencies in australia. Med J aust 2006;184:560-2. 80. dietzman de, Harnisch JP, ray cG, alexander er, Holmes KK. Hepatitis b surface antigen (Hbsag) and antibody to Hbsag. Prevalence in homosexual and heterosexual men. J am Med assoc 1977;238 2625-6. 81. bleeker a, coutinho ra, bakker-Kok J, tio d, de Koning Ga. Prevalence of syphilis and hepatitis b among homosexual men in two saunas in amsterdam. br J Vener dis 1981;57:196-9. 82. coutinho ra, schut bJ, albrecht-Van Lent na, reerink-brongers ee, Jesdijk Ls. Hepatitis b among homosexual men in the netherlands. sex transm dis 1981;8:333-5. 83. schreeder Mt, thompson se, Hadler sc, berquist Kr, Zaidi a, Maynard Je, et al. Hepatitis b in homosexual men: prevalence of infection and factors related to transmission. J infect di. 1982;146:7-15. 84. coester cH, bienzle u, Hoffmann HG, Koehn e, Guggenmoos-Holzmann i. syphilis, hepatitis a and hepatitis b seromarkers in homosexual men. Klin. Wochenschr. 1984; 62: 810-3. 85. coester cH, avonts d, colaert J, desmyter J, Piot P. syphilis, hepatitis a, hepatitis b, and cytomegalovirus infection in homosexual men in antwerp. br J Vener dis 1984;60:48-51. 

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

86. shah n, ostrow d, altman n, baker aL. evolution of acute hepatitis b in homosexual men to chronic hepatitis b. Prospective study of placebo recipients in a hepatitis b vaccine trial. arch intern Med 1985;145:881-2. 87. Keeffe eb. clinical approach to viral hepatitis in homosexual men. Med clin north am 1986;70:567-86. 88. us department of Health and Human services. centers for disease control and Prevention. Hepatitis b prevention for men who have sex with men. 2006 [Last accessed June 2007]; available from: http://www.cdc. gov/ncidod/diseases/hepatitis/msm/hbv_ msm_fact.htm 89. Gilson rJ, de ruiter a, Waite J, ross e, Loveday c, Howell dr, et al. Hepatitis b virus infection in patients attending a genitourinary medicine clinic: risk factors and vaccine coverage. sex transm infect 1998;74:110-5. 90. MacKellar da, Valleroy La, secura GM, Mcfarland W, shehan d, ford W, et al. two decades after vaccine license: hepatitis b immunization and infection among young men who have sex with men. am J Public Health 2001;91:965-71. 91. Jin f, Prestage GP, Pell cM, donovan b, Van de Ven PG, Kippax sc, et al. Hepatitis a and b infection and vaccination in a cohort of homosexual men in sydney. sexual Health 2004;1:227-37. 92. diamond c, thiede H, Perdue t, secura GM, Valleroy L, Mackellar d, et al. Viral hepatitis among young men who have sex with men: prevalence of infection, risk behaviors, and vaccination. sex transm dis 2003;30:425-32. 93. anderson b, bodsworth nJ, rohrsheim ra, donovan bJ. Hepatitis b virus infection and vaccination status of high risk people in sydney: 1982 and 1991. Med J aust 1994;161:368-71. 94. yee LJ, rhodes sd. understanding correlates of hepatitis b virus vaccination in men who have sex with men: what have we learned? sex transm infect 2002;78:374-7. 95. rhodes sd, Hergenrather Kc. exploring hepatitis b vaccination acceptance among young men who have sex with men: facilitators and barriers. Prev Med 2002;35:128-34.

96. rudy et, detels r, douglas W, Greenland s. factors affecting hepatitis vaccination refusal at a sexually transmitted disease clinic among men who have sex with men. sex transm dis 2003;30:411-8. 97. brook MG. sexual transmission and prevention of the hepatitis viruses a-e and G. sex transm infect 1998;74:395-8. 98. Pitts MK, couch Ma, smith aMa. Men who have sex with men (MsM): how much to assume and what to ask? Med J aust 2006;185:450-2. 99. Van de Ven P, Prestage G, french J, Knox s, Kippax s. increase in unprotected anal intercourse with casual partners among sydney gay men in 1996-98. aust nZ J Public Health 1998;22:814-8. 100. Van de Ven P, Prestage G, crawford J, Grulich a, Kippax s. sexual risk behaviour increases and is associted with HiV optimism among HiV-negative and HiV-positive gay men in sydney over the 4 year period to february 2000. aids 2000;14:2951-3.

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

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

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

b core antigen [Hbcag]) with the viral Figure 2.2 reverse transcriptase/dna polymerase. B: HBV polymerase-HBsAg link Telbivudine Entecavir this core structure is then surrounded Adefovir Lamivudine X XX X X by its envelope, the hepatitis b surface antigen (Hbsag). the life cycle of HbV begins when its envelope protein attaches X X X 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 A: HBV genome 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] figure 2.2 a: Hepatitis b virus (HbV) dna genome showing the circular and surface [Hbsag]) are made, as well arrangement of the four overlapping but frame-shifted reading frames as the replication protein, HbV reverse the hepatitis b virus polymerase–Hbsag link, demonstrating transcriptase/dna polymerase. the HbV figure 2.2 b: the changes observed in the HbV Pol due to the emergence reverse transcriptase (rt) then copies the of drug-resistance, affect the Hbsag directly for all four nucleos(t)ide analogues approved for chronic hepatitis b HbV pregenomic (pg) rna to dna inside treatment the core particle. the viral envelope proteins now coat those replicating core the life cycle of HbV revolves around two key complexes, and mature virions are made and processes (figure 2.3): then released from the cell, completing the  Generation of HbV ccc dna from genomic life cycle (figure 2.1). the only viral enzyme dna and its subsequent processing by host
Polymerase Terminal Protein Spacer

G FA

B C DE

RNAse H

Surface

PreS1

Pre S2

S

HBV rt

HBV HBsAg HBV RC DNA

Figure 2.1

HBcAg

HBV cccDNA

HB

CD VR

NA

RNA

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).
Figure 2.3
Intrahepatic Covalently Closed Circular (ccc) DNA [Viral Minichromosomes] Host DNA Repair Enzymes

HBsAg RNA
HBV DNA

HBcAg HBV rt HBcAg

RNA

Genomic DNA [HBV RC DNA]

REVERSE TRANSCRIPTION

Replicating Cores

HBV RNA

HBV rt

(-)

(+)

HBV Virions

figure 2.1:

Life-cycle of the hepatitis b virus from entry (at the top) to exiting the cell (shown at the bottom)

HBV Pol HBV DNA Polymerase/ Reverse Transcriptase [HBV Pol]

Host RNA Polymerase II

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).

(-)

AAAA Pregenomic HBV (pg) RNA

HBV Minus (-) DNA [Inside Viral Nucleocapsids]

[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 minichromosome2,3

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

5

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]).

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

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

Common mutants of HBV 1. Mutations affecting HBeAg

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 vaccination9 and following treatment of liver transplant recipients with hepatitis b immune globulin (Hbig) prophylaxis.10 Most vaccineHbig 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 failure9 and has been shown to be transmitted and cause disease.

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

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.

3. Polymerase mutations: antiviral drug resistance

Figure 2.4

HBV Pol: primary resistance mutations
1

Terminal Protein

Spacer
183 349 (rt1)

POL/RT

RNaseH
692 (rt 344) 845 a.a.

F__V__LLAQ__ YMDD

I(G)

II(F)

A

B

C

D

E

LMV Resistance L-dT Resistance ADV Resistance TDF Resistance ETV Resistance

rtA181T/V rtM204V/I rtA181T/V rtM204I rtA181T/V rtN236T rtL180M rtA181T/V rtA194T/rtM204V/I rtN236T 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 LMV-r adV-r Ldt-r etV-r LMV ftc adV tdf X X √ X X = lamivudine = emtricitabine = adefovir = tenofovir = resistant

adV/tdf √ X √ √

L-dt X √ X X

etV reduced √ √ X

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

(a) Lamivudine and other L-nucleoside analogue resistance

L-dt = telbivudine etV = entecavir r = 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. resistance to adefovir dipivoxil (adV) was initially associated with changes in the b 
7

(b) Adefovir dipivoxil resistance

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

2 Virology: viral replication and drug resistance

(rta181t/V) and d (n236t)-domains of the reverse transcriptase17 (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 LMV17 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 etVresistance 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

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-infection14 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.

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

(d) Multi-drug resistance

(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

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.

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4

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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References
1 chisari f, ferrari c. Hepatitis b virus immunopathogenesis. ann rev immunol 1995;13:29-60.

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bock ct, schranz P, schroder cH, Zentgraf H. Hepatitis b virus genome is organized into nucleosomes in the nucleus of the infected cell. Virus Genes 1994;8:215-29. newbold Je, Xin H, tencza M, sherman G, dean J, bowden s, Locarnini s. the covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minochromosomes. J Virol1995;69:3350-7. Milich dr, Jones Je, Hughes JL, Price J, raney aK, McLachlan a. is a function of the secreted hepatitis b e antigen to induce immunologic tolerance in utero? Proc natl acad sci usa 1990;87:6599-603. Hunt cM, McGill JM, allen Mi, condreay Ld. clinical relevance of hepatitis b viral mutations. Hepatology 2000;31:1037-44. 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;91:407781. bartholomeusz a, schaefer s. Hepatitis b virus genotypes: comparison of genotyping methods. rev Med Virol 2004;14:3-16. Gunther s, fischer L, Pult i, sterneck M, Will H. naturally occurring variants of hepatitis b virus. adv Virus res 1999;52:25-137. 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. 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. shaw t, Locarnini s. entecavir for the treatment of chronic hepatitis b. expert rev anti infect ther 2004;2:853-71. 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. 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. 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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Leung n. clinical experience with lamivudine. semin Liver dis 2002;22(suppl 1):s15-s21. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. yim HJ, Hussain M, Liu y, Wong sn, fung sK, Lok as. evolution of multi-drug resistant hepatitis b virus during sequential therapy. Hepatology 2006;44:703-12.

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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;34:398402. 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. 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. 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. 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. 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. 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. carman Wf. the clinical significance of surface antigen variants of hepatitis b virus. J Viral Hepat 1997;4:11-20. thibault V, aubron-olivier c, agut H, Katlama c. Primary infection with a lamivudineresistant hepatitis b virus. aids 2002;16:131-3. besisik f, Karaca c, akyuz f, Horosanli s, onel d, badur s, et al. occult HbV infection and yMdd variants in hemodialysis patients with chronic HcV infection. J Hepatol 2003;38:506-10. richman dd. the impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis b. Hepatology 2000;32:866-7.

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

HEPATITIS B VIRUS TESTING AND INTERPRETING TEST RESULTS
Mark Danta St Vincent’s Clinical School, The University of New South Wales, Darlinghurst, NSW.

3

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 Serum HBeAg
% Maximum E levation

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
100

50

% Maximum E levation

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).

100

Serum HBsAg Serum HBV DNA Serum ALT Activity

anti HBc anti HBe anti HBs

Serum HBeAg Serum HBsAg Serum HBV DNA

anti HBc anti HBe

50

Serum ALT activity

0 0 1 2 3 4 5 Months after Infection 6 7 8

0 0 10 20 21 Immunotolerance 30 31 Years after Infection 40 41 Reactivation phase 50

Incubation Acute Disease, References Clinical Symptoms phase

Recovery Protective Immunity

Immunoactive phase

Low replicative phase

figure 3.1: temporal changes in serological, virological and biochemical parameters in HbV. (a) acute HbV and (b) chronic HbV infection1

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

H

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.

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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.

dna replication (<105 copies/mL or 20,000 iu/ ml). the loss of Hbeag and the development of anti-Hbe is termed Hbeag seroconversion, and has been used as an end-point for treatment in Hbeag-positive people, as it has been shown that seroconversion is associated with a lower risk of disease progression.2

Virological markers HBV DNA

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 (antiHbc) 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 antiHbc igG, but test for total anti-Hbc antibody.

Antibody to core antigen (anti-HBc)

With the advent of molecular amplification technology, such as the polymerase chain reaction (Pcr), it has become possible to directly quantify the level of HbV replication. this is now an integral part of HbV management, especially with the development of effective antiviral treatment. Pcr-based assays (target amplification assays) involve a process of lysing the virion and purifying the dna, which is then amplified and quantified. alternatively, signal amplification assays can quantify the level of HbV dna from serum and require no purification step. currently, the Pcr-based assays for HbV dna detection have the best range of quantification.3 initially, the unit of measurement was copies/mL, which is now being standardised to international units (iu)/mL, using a conversion factor of between 5–6 genome copies/mL = 1 iu/mL, depending on the assay. the introduction of real-time Pcr has allowed for sensitivities ranging from 5–10 iu/mL up to 8–9 log10 iu/mL.4 the level of 20,000 iu/mL (around 105 copies/ml) has been arbitrarily selected as the level below which there is a relatively low likelihood of hepatic damage, although this can still occur.5 the serum level of HbV dna is a dynamic parameter in chronic HbV. the level of circulating HbV has recently been shown to be the strongest predictor of the development of cirrhosis and hepatocellular carcinoma (Hcc).6,7 in a large prospective taiwanese cohort (n=3653) followed over 11 years, the incidence of cirrhosis and Hcc ranged from 4.5% and 1.3% respectively, in those with low HbV dna (<300 copies/mL), to 36.2% and 14.9% respectively, in those with high HbV dna (106 copies/mL). the incidence of both cirrhosis and Hcc followed

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

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 104 copies/mL, 1 log lower than the current level used to signify a low risk of progression (105 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

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.

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

Biochemical markers Alanine aminotransferase (ALT)

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

HBV genotyping

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.
33

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

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.

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®).

Non-invasive assessment of hepatic fibrosis

table 3.1: serological, virological and biochemical profiles of hepatitis b virus
Hbsag Acute HBV Natural HBV immunity (resolved infection) Vaccination Chronic HBeAg positive immune tolerance phase immune clearance phase Chronic HBeAg negative immune control phase immune escape phase Occult HBV Reactivation of HBV + + + + + + + +/+ + + +/+/<2, 000 iu/mL* >2 000 iu/mL* Very low >20,000 iu/mL n  n  + + + >20,000 iu/mL >20,000 iu/mL (fluctuating) n + anti-Hbs + + anti-Hbc (total) + + anti-Hbc igM + Hbeag + anti-Hbe +/+/HbV dna (iu/mL) High absent absent aLt  n n

+

-

+

-

+

-/+

+=positive, -=negative, n=normal, =elevated. * HbV dna cut-off levels may change in the future.
34 b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

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.

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.

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.

2. Clinical interpretation

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

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

Who should be tested?

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 antiHbc, 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.

table 3.3 discussion

summary of HbV pre-test

 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

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

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

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

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

Milich d, Liang tJ. exploring the biological basis of hepatitis b e antigen in hepatitis b virus infection. Hepatology 2003;38(5):107586. 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 (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). 10. 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):9981002. 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.

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

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 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. 25. 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(rr16):1-33; quiz ce31-34. 26. 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 Amany Zekry Gastroenterology and Hepatology Department, St George Hospital, Kogarah, NSW. Hepatology Unit, St George Hospital, Kogarah, NSW.

4

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
 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).

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.

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.

40

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

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).

the american association of the study of Liver diseases (aasLd) practice guidelines define chronic hepatitis b as chronic necroinflammatory disease of the liver caused by persistent infection with HbV. diagnostically, chronic hepatitis b is defined as Hbsag positivity for more than six months.4 the terminology used to describe the different phases in the natural history of chronic hepatitis b infection varies considerably and has been the subject of much debate (refer to table 4.2). in particular, the phase of immune control is, or has been, referred to as the ‘healthy carrier’ state, the ‘inactive carrier’ state and the ‘nonreplicative’ state of chronic hepatitis b. Many of these terms may be potentially misleading and fail to reflect the fluctuating nature of cHb over time. the terms used below to describe the phases of cHb reflect the importance of the immune system in controlling this infection.

Definition and preferred terminology

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% respectively3 (table 4.1). table 4.1: risk of development of chronic hepatitis b infection by the patient’s age at infection
Perinatal development of chronic infection risk of advanced liver disease immunotolerant phase 80–90% childhood 30% adult <5%

the natural history of chronic HbV infection is characterised by four distinct phases (table 4.2). table 4. 2: terminology of chronic hepatitis b
Preferred term Phase i Phase ii immune tolerant immune clearance immune control immune escape also known as replicative state immune competence phase immunoactive phase non-replicative state inactive carrier ‘Healthy’ carrier Hbeag negative cHb Pre-core mutant disease reactivation phase

The natural history of chronic hepatitis B infection

Phase iii

20–30%

5–10%

1–2%

Phase iV

Prolonged

Variable

short

the host immune responses determine the outcome of infection and the severity of liver injury.

these phases are dependent on a complex interaction between host, viral and environmental factors, and the age at infection particularly (table 4.3).
41

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

4 Natural history of chronic hepatitis B virus infection

table 4.3: Phases of chronic hepatitis b infection
Phase
immune tolerance

Liver histology
Minimal inflammation

HbV dna
>20 000 iu/mL

aLt

Hbeag

antiHbe
-

duration

natural history
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

normal

Present

20-30 years

Variable immune inflammation clearance +/- fibrosis

>20 000 elevated iu/mL (fluctuating) (fluctuating)

Present

+/-

can be protracted

immune control

Minimal inflammation and liver damage

< 2000 iu/mL

normal

absent

+

years

immune escape (Hbeagnegative cHb)

inflammation and often significant fibrosis

2000– 20,000 iu/mL

elevated

absent

+

-

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.

1. Immune tolerance phase

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).

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
4

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 (<2000 iu/mL) and liver function tests (Lfts) are normal. these patients are at low risk of developing advanced liver disease and its related complications.5 in

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

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 Older age Male

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

High HBV DNA level this phase is characterised by Alcohol consumption negative Hbeag, Genotype C14 Co-infection with hepatitis positive anti-Hbe and detectable viral load C, human (HbV dna > 2000 iu/mL). itimmunodeficiency virus is often termed precore mutant HbV because a hepatitis D (HIV), mutation in Obesity, the precore region of the dna results in a lack diabetes15 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 Figure 4.1 The four phases of hepatitis B 6 hepatitis (10-30%) infection 4.1). (figure

4. Immune escape phase (HBeAgViral factors Other factors negative chronic hepatitis B)

Immune toleranance phase

Immune clearance phase

Immune control phase 10-30%

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).

Reactivation of HBV following immunosuppression

10-20%
Immune escape phase

Occult HBV

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.

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
43

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

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.

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

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 factors older age Viral factors other factors

Complications of 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.

Impact of antiviral therapy on the natural course of chronic hepatitis B virus infection

Conclusion

High HbV dna alcohol level consumption co-infection with hepatitis c, human immunodeficiency virus (HiV), hepatitis d

Male

Genotype c14

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.

obesity, diabetes15

References
in a large prospective cohort study of cHb from taiwan (the reVeaL study), elevated HbV dna level (>104 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

1

2

Villeneuve JP. the natural history of chronic hepatitis b virus infection. J clin Virol 2005;34 (suppl 1):s139-42. 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.

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

3

4

5

6

7

8

9

10

11

12

13

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. Lok as, McMahon bJ. american association for the study of Liver diseases Practice Guidelines. chronic Hepatitis b. Hepatology 2007;45(2):507-39. 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. Zacharakis GH, Koskinas J, Kotsiou s, 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/ecProject). 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. 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. 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. 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. yeo W, Johnson PJ. diagnosis, prevention and management of hepatitis b virus reactivation during anticancer therapy. Hepatology 2006;43(2):209-20. fattovich G, Giustina G, schalm sW, et al. occurrence of hepatocellular carcinoma 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

15

16

17

18

19

20

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. 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. 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. 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. bosch fX, ribes J, cleries r, diaz M. epidemiology of hepatocellular carcinoma. clin Liver dis 2005;9:191-211. Liaw yf, sung JJ, chow Wc, farrell G, Lee cZ, yuen H, et al. cirrhosis asian Lamivudine Multicentre study Group. Lamivudine 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 Nicholas Wood Department of Drug and Alcohol, Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, NSW. National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The Children’s Hospital at Westmead, Westmead, NSW.

5

KEY POINTS
 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.

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

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.

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

Target groups for vaccination in Australia

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

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 blood donors MsM indigenous communities Hbsag prevalence in risk group (%) 0.1 3.3 2.3 (urban) 8.2 (rural) 12 (prisoners) 0.9 (Middle east/ africa) 3.7 (Pacific islands) 4.9 (ne asia) 5.4 (se asia) 1.6 1.6-3.0 Proportion of cHb in australia (%) n/a 8 16

caLd communities

16 (ne asia) 33 (se asia) 5

idu Prison inmates

Modified from o’sullivan et al. 20045 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.
47

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

5 Primary prevention of hepatitis B virus infection

Vaccines available
1. Monovalent vaccines
Hepatitis b surface antigen (Hbsag) engerix-b (adult formulation) engerix-b (paediatric formulation) H-b-VaX ii (paediatric formulation) H-b-VaX ii (dialysis formulation) 20 µg per 1 mL 10 µg per 0.5 mL

table 5.2: the national immunisation Program for Hepatitis b11
age
birth

antigen
Hep b

nsW, act, Wa, tas
monovalent

Vic, QLd, sa
monovalent

nt
monovalent

2 mth 4 mth 6 mth 12 mth

Hep b Hep b Hep b Hep b

dtPa-HibiPV- Hep b dtPa-HibiPV- Hep b dtPa-HibiPV- Hep b

Hib-Hep b Hib-Hep b

dtPa- iPVHep b dtPa- iPVHep b dtPaiPV- Hep b

H-b-VaX ii (adult formulation) 10 µg per 1 mL 5 µg per 0.5 mL 40 µg per 1 mL

Hib- Hep b

dtPa: diphtheria-tetanus-acellular pertussis Hib: Haemophilus influenzae type b iPV: oral inactivated poliomyelitis vaccine

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).

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

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

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).

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

table 5.3: accelerated hepatitis b vaccination schedules
Vaccine age dose (Hbsag protein) 10 µg Volume 0.5 mL schedule

 those expected to have a poor response to hepatitis b vaccine (e.g. haemodialysis patients).

engerix-b up to 20 (paediatric) years engerix-b (adult) *

0, 1, 2, 12 months

Adverse events following hepatitis B vaccination

>20 years

20 µg

0, 7, 21 days; 1.0 mL booster at 12 months 0, 7, 21 days; 1.0 mL booster at 12 months

twinrix (720/20) *

>15 years

20 µg

* 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.

 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)

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.

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)  400 iu (>30kg weight)

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)

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

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

References
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. 1.

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

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

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.

6

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

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.

HbV replication status1 (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 clearance2,3 (table 6.1). table 6.1: Hepatitis b serology
serological marker HBsAg Anti-HBs Anti-HBc HBeAg Anti-HBe HBV DNA interpretation Hepatitis b infection immunity to HbV infection Previous exposure Viral replication and infectivity* immune control phase (if HbV dna negative)* Viral replication

Transmission risk

*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

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.

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

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

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

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.

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.

Managing patients with chronic HBV infection

table 6.2: referral guidelines for specialist review of patients with hepatitis b virus infection
Investigations to be performed before referral 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)

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

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

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.

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

Screening for hepatocellular carcinoma

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

References
1. 2. Lok asf, McMahon bJ. chronic hepatitis b. Hepatology 2007;45(2):507-39. 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. McMahon bJ. epidemiology and natural history of hepatitis b. semin Liver dis 2005;25(suppl 1):3-8. 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. 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. sherman M. Pathogenesis and screening for hepatocellular carcinoma. clin Liver dis 2004;8:419-43, viii.

3.

Conclusion

4.

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.

5.

6.

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

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.

7

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
 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 >105 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
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b Positive – all you wanted to know about hepatitis b: a guide for primary care providers

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

the rates of resistance vary with the chosen antiviral agent.

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 antiHbV 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.

Indications for antiviral therapy

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

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

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

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.

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

HBeAg-negative patients

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

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.

Pegylated interferon

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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

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

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

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 treatmentnaïve patients with HbV infection. entecavir has

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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

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.

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

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,
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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

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.

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

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.

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7 Treatment of chronic hepatitis B virus infection

References
1 2 Lok asf, McMahon bJ. chronic Hepatitis b. Hepatology 2007;45(2):507-39. 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. 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. 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. 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. schiff er. treatment algorithms for hepatitis b and c. Gut 1993;34(suppl 2):s148-s149. 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. 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. 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. 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.

11

12

3

13

4

14

5

15

6 7

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Locarnini s. Molecular virology and the development of resistant mutants: 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. 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. tenney dJ, Leine sM, rose re, Walsh aW, Weinheimer sP, discotto L, et al. clinical emergence of entecavir-resistant HbV 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 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.

8

9

10

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

MANAGING PATIENTS WITH ADVANCED LIVER DISEASE
Robert Batey Links to: University of New South Wales, Bankstown Hospital, Bankstown, NSW. Chapter 7: Treatment of chronic hepatitis B virus infection Chapter 9: Hepatitis B virus-related hepatocellular carcinoma

8

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,

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
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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

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

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

 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.

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.

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

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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. schiff er, sorrell Mf, Maddrey Wc. schiff’s diseases of the Liver (10th edition); Vol 1 and 2. Philadelphia: Lippincott Williams & Wilkins; 2007. sherlock s, summerfield Ja. a colour atlas of liver disease. London: Wolfe Medical Publications Ltd; 1979.

2.

3.

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

HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA
Monica Robotin

9

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

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
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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

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

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
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Screening assays for HCC

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

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
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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 cancer48 (see table 6.4, chapter 6: clinical assessment of patients with hepatitis b virus infection).
7

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.

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

REFERENCES
1. 2. bosch fX, ribes J, borras J. epidemiology of primary liver cancer. semin Liver dis 1999;19(3):271-85. amin J, dore GJ, o’connell d L, bartlett M, tracey e, Kaldor JM, et al. cancer incidence in people with hepatitis b or c infection: a large community-based linkage study. J Hepatol 2006;45(2):197-203. chu cM. natural history of chronic hepatitis b virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol 2000;15(suppl):e25-30. Parkin dM, bray f, ferlay J, Pisani P. Global cancer statistics, 2002. ca cancer J clin 2005;55(2):74-108. Liu J, fan d. Hepatitis b in china. Lancet 2007;369(9573):1582-3. coates M, tracey e. cancer in new south Wales: incidence and mortality 1997. nsW Public Health bull 2001;12(2):40-2. tracey e, chen s, baker d, bishop J, Jelfs P. cancer in new south Wales: incidence and Mortality 2004. sydney: cancer institute nsW, 2006. seeff Lb, Hoofnagle JH. epidemiology of hepatocellular carcinoma in areas of low hepatitis b and hepatitis c endemicity. oncogene 2006;25(27):3771-7. Visser o, van Leeuwen fe. cancer risk in first generation migrants in north-Holland/ flevoland, the netherlands, 1995-2004. eur J cancer 2007;43(5):901-8. schiff er. Prevention of mortality from hepatitis b and hepatitis c. Lancet 2006;368(9539):896-7. de Masi s, tosti Me, Mele a. screening for hepatocellular carcinoma. dig Liver dis 2005;37(4):260-8. bolondi L. screening for hepatocellular carcinoma in cirrhosis. J Hepatol 2003;39(6):1076-84. chen ds, sung JL, sheu Jc, Lai My, How sW, Hsu Hc, et al. serum alphafetoprotein in the early stage of human hepatocellular carcinoma. Gastroenterology 1984;86(6):1404-9. bruix J, Hessheimer aJ, forner a, boix L, Vilana r, Llovet JM. new aspects of diagnosis and therapy of hepatocellular carcinoma. oncogene 2006;25(27):3848-56.

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15. sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. semin Liver dis 2005;25(2):143-54. 16. Zhang bH, yang bH, tang Zy. randomized controlled trial of screening for hepatocellular carcinoma. J cancer res clin oncol 2004;130(7):417-22. 17. Plesch fn, Kubicka s, Manns MP. Prevention of hepatocellular carcinoma in chronic liver disease: molecular markers and clinical implications. dig dis 2001;19(4):338-44. 18. rugge Jb, Lochner J, Judkins d. What is the best surveillance for hepatocellular carcinoma in chronic carriers of hepatitis b? J fam Pract 2006;55(2):155-6; 19. tanaka H, nouso K, Kobashi H, Kobayashi y, nakamura s, Miyake y, et al. surveillance of hepatocellular carcinoma in patients with hepatitis c virus infection may improve patient survival. Liver int 2006;26(5):543-51. 20. chalasani n, said a, ness r, Hoen H, Lumeng L. screening for hepatocellular carcinoma in patients with cirrhosis in the united states: results of a national survey. am J Gastroenterol 1999;94(8):2224-9. 21. Mann cd, neal cP, Garcea G, Manson MM, dennison ar, berry dP. Prognostic molecular markers in hepatocellular carcinoma: a systematic review. eur J cancer 2007;43(6):979-92. 22. arii s, tanaka J, yamazoe y, Minematsu s, Morino t, fujita K, et al. Predictive factors for intrahepatic recurrence of hepatocellular carcinoma after partial hepatectomy. cancer 1992;69(4):913-9. 23. nagao t, inoue s, Goto s, Mizuta t, omori y, Kawano n, et al. Hepatic resection for hepatocellular carcinoma. clinical features and long-term prognosis. ann surg 1987;205(1):33-40. 24. Pompili M, rapaccini GL, covino M, Pignataro G, caturelli e, siena da, et al. Prognostic factors for survival in patients with compensated cirrhosis and small hepatocellular carcinoma after percutaneous ethanol injection therapy. cancer 2001;92(1):126-35. 25. nagasue n, Kohno H, chang yc, taniura H, yamanoi a, uchida M, et al. Liver resection for hepatocellular carcinoma. results of 229 consecutive patients during 11 years. ann surg 1993;217(4):375-84. 26. Qin LX, tang Zy. the prognostic significance of clinical and pathological features in hepatocellular carcinoma. World J Gastroenterol 2002;8(2):193-9.
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27. bruix J, sherman M. Management of hepatocellular carcinoma. Hepatology 2005;42(5):1208-36. 28. Perry Jf, Poustchi H, George J, farrell Gc, Mccaughan GW, strasser si. current approaches to the diagnosis and management of hepatocellular carcinoma. clin exp Med 2005;5(1):1-13. 29. Kawano n, ohmori y, inoue s, nagao t, Morioka y. Long-term prognosis of surgical patients with hepatocellular carcinoma. cancer chemother Pharmacol 1989;23(suppl):s129-32. 30. Llovet JM, schwartz M, Mazzaferro V. resection and liver transplantation for hepatocellular carcinoma. semin Liver dis 2005;25(2):181-200. 31. cha c, fong y, Jarnagin Wr, blumgart LH, deMatteo rP. Predictors and patterns of recurrence after resection of hepatocellular carcinoma. J am coll surg 2003;197(5):753-8. 32. belghiti J. transplantation for liver tumors. semin oncol 2005;32(6 suppl 8):s29-s32. 33. Mazzaferro V, regalia e, doci r, andreola s, Pulvirenti a, bozzetti f, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. n engl J Med 1996;334(11):693700. 34. Hemming aW, cattral Ms, reed ai, Van der Werf WJ, Greig Pd, Howard rJ. Liver transplantation for hepatocellular carcinoma. ann surg 2001;233(5):652-9. 35. Llovet JM, fuster J, bruix J. intention-totreat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology 1999;30(6):143440. 36. Kawamoto c, ido K, isoda n, nagamine n, Hozumi M, ono K, et al. Prognosis of small hepatocellular carcinoma after laparoscopic ethanol injection. Gastrointest endosc 1999;50(2):214-20. 37. ohnishi K, nomura f, ito s, fujiwara K. Prognosis of small hepatocellular carcinoma (less than 3 cm) after percutaneous acetic acid injection: study of 91 cases. Hepatology 1996;23(5):994-1002. 38. bruix J, castells a, Montanya X, calvet X, bru c, ayuso c, et al. Phase ii study of transarterial embolization in european patients with hepatocellular carcinoma: need for controlled trials. Hepatology 1994;20(3):643-50.

39. ando e, tanaka M, yamashita f, Kuromatsu r, yutani s, fukumori K, et al. Hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis: analysis of 48 cases. cancer 2002;95(3):588-95. 40. ni yH, chang MH, Huang LM, chen HL, Hsu Hy, chiu ty, et al. Hepatitis b virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis b vaccination. ann intern Med 2001;135(9):796800. 41. chang MH, chen cJ, Lai Ms, Hsu HM, Wu tc, Kong Ms, et al. universal hepatitis b vaccination in taiwan and the incidence of hepatocellular carcinoma in children. taiwan childhood Hepatoma study Group. n engl J Med 1997;336(26):1855-9. 42. Kao J, chen d. overview of hepatitis b and c viruses. in: Goedert J, editor. infectious causes of cancer. totowa, nJ, usa: Humana Press inc, 2006:313-30. 43. craxi a, camma c. Prevention of hepatocellular carcinoma. clin Liver dis 2005;9(2):329-46, viii. 44. fung sK, Lok as. treatment of chronic hepatitis b: who to treat, what to use, and for how long? clin Gastroenterol Hepatol 2004;2(10):839-48. 45. Lai cJ, terrault na. antiviral therapy in patients with chronic hepatitis b and cirrhosis. Gastroenterol clin north am 2004;33(3):62954, x-xi. 46. Lok as, McMahon bJ. american association for the study of Liver diseases Practice Guidelines. chronic Hepatitis b. Hepatology 2007;45(2):507-39. 47. Hache c, Villeneuve JP. Lamivudine treatment in patients with chronic hepatitis b and cirrhosis. expert opin Pharmacother 2006;7(13):1835-43. 48. sherman M. Pathogenesis and screening for hepatocellular carcinoma. clin Liver dis 2004;8(2):419-43, viii. 49. 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. 50. centers for disease control and Prevention (cdc). screening for chronic hepatitis b among asian/Pacific islander populationsnew york city, 2005.MMWr Morb Mortal Wkly rep 2006;55(18):505-509.

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

MANAGING HEPATITIS B VIRUS INFECTION IN COMPLEX SITUATIONS
Benjamin Cowie

10

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
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.

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

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.
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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
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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 >108 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.

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

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.
1. HBIG* 100 iu, iM, single dose

Paediatric management

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
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

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.

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
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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

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.

Co-infections

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 antiHbV drug, entecavir, had no anti-HiV activity, however, recent reports indicate that entecavir can induce resistance mutations in HiV12 and its use as HbV monotherapy in the context of HiV co-infection is being re-evaluated. Pegylated

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 liver78

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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 load11, 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.

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 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

HBV/HCV 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 year7, 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.
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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.

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 antiHbc-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.

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References
1 national Health and Medical research council. the australian immunisation handbook. 9th edition. canberra: commonwealth department of Health and ageing, 2007. 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. Mast ee, Margolis Hs, fiore ae, brink eW, Goldstein st, Wang sa, 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 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 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. broderick a, Jonas MM. Management 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. 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.

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shukla nb, Poles Ma. Hepatitis b virus infection: co-infection with hepatitis c virus, hepatitis d virus, and human immunodeficiency virus. clin Liver dis 2004;8(2):445-60, viii. 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 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 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. 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 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):699712.

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81

INFECTION CONTROL AND OCCUPATIONAL HEALTH
Jacqui Richmond St Vincent’s Hospital, Melbourne, VIC.

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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
 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.

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

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.
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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.

dressing. alcohol-based hand rubs can be used in the absence of appropriate washing facilities.

Gloves

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
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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.

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

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.

 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.

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

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)
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Hepatitis B vaccination regime

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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 <10 iu/mL following the third dose of vaccine, he or she is classified as a non-responder and should be offered further doses of HbV vaccine. a dose of HbV vaccine can be given as either a fourth double dose or a further three doses at monthly intervals, with further serological testing four weeks later. tabLe 11.1: exposure-prone procedures1
High-risk or ‘exposure-prone’ procedures

the mandatory testing of clinicians and other health care workers for HbV, HcV and HiV is not warranted, due to the low risk of transmission if standard precautions are followed. testing for blood-borne viruses should only be undertaken on the basis of clinical assessment or where testing is in the interests of patients and health care workers (e.g. a needlestick injury).1 clinicians and other health care workers who regularly perform exposure prone procedures have a responsibility to be regularly tested for HiV, HcV and HbV if they are not immune (table 11.1). the provision of confidentiality, privacy and consent for testing should be applied.

Testing

 any submucosal invasion with sharp, hand-held instruments or procedures dealing with sharp pathology and bone spicules, usually in confined spaces or where visibility is poor (e.g. orthopaedic surgery, trauma, internal cavity surgery) Variable-risk procedures  Minor dental procedures (excluding examination) and routine dental extractions  internal and instrument examination; biopsy (e.g. endoscopy, vaginal examination, laparoscopy)  Minor skin surgery Low-risk procedures     interview consultation and dental examination non-invasive examinations or procedures (aural testing, electrocardiogram, abdominal ultrasound) intact skin palpation (gloves not required) injections and venepuncture (gloves required)

Persistent non-responders should be informed about the need for hepatitis b immunoglobulin (HbiG) within 72 hours of a potential exposure to HbV. booster doses are no longer recommended in immunocompetent individuals after a primary course of HbV vaccine, as the evidence suggests that a completed course of HbV vaccination provides long-lasting protection. this applies to children and adults, including health care workers.6 for further information about the HbV vaccine, please refer to The Australian Immunisation Handbook, 9th edition (2007),6 and chapter 5: Primary prevention of hepatitis b virus infection.
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Occupational exposures

all clinicians and health care workers should have access to infection control guidelines that advise about the management of an occupational injury, including clear written instructions on the appropriate action to take in the event of a needlestick and other blood or body substance exposures involving either patients or other health care workers. clinicians and health care workers are encouraged to report occupational exposures immediately and all testing procedures and follow-up treatment should be fully documented. confidentiality should be maintained.

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

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.

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

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.

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.
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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.

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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.

 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.

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:

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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.

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 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. 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. 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. Perry JL, Pearson rd, Jagger J. infected health care workers and patient safety: a double standard. am J infect control 2006;34:313–9. national Health and Medical research council (nHMrc). the australian immunisation Handbook – 9th edition. canberra: commonwealth department of Health and ageing; 2007.

2.

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.

3.

4.

5.

6.

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PRIVACY, CONFIDENTIALITY AND OTHER LEGAL RESPONSIBILITIES
Sally Cameron Australian Federation of AIDS Organisations, NSW.

1

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
 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.

Why is privacy and confidentiality important?

the australian Medical association (aMa) code of ethics requires medical practitioners to maintain a patient’s confidentiality. ‘exceptions
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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.’

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

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.

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
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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

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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:

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

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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.

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.

 Notification

 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/).

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.
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 Accessing personal records

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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.

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

 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
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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

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

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.

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

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/ .

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

THE ROLE OF COMPLEMENTARY MEDICINE IN HEPATITIS B
Ses J Salmond Robert Batey

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Drug and Alcohol Clinical Services, Hunter New England Area Health Service, Arkana Therapy Centre and Leichhardt Women’s Community Health Centre, NSW. 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
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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

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

be targeting different aspects of the disease process such as: altered viral replication4,5 antiinflammatory actions6 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

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.

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

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 levels16 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

Anti-inflammatory activity

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
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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

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.

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.

Herbal medicines with well documented evidence of hepatotoxicity are: teucrium chamaedrys (wall germander) and teucrium polium, both cause zonal necrosis, hepatitis and fibrosis29–31; Mentha pulgeium (pennyroyal) causes necrosis and microvesicular steatosis30; atractylis gummifera (pine thistle) leads to panlobular hepatic necrosis and renal failure29–34; certain pyrrolizidine alkaloids can cause veno-occlusive disease29,30,32–34 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.

Hepatotoxicity

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

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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

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.

References
1. batey rG, salmond sJ, bensoussan a. complementary and alternative medicine in chronic liver disease. curr Gastroenterol rep 2005;7(1):63-70. MacLennan aH, Wilson dH, taylor aW. the escalating costs and prevalence of alternative medicine. Prev Med 2002;35:166-73. MacLennan aH, Myers sP, taylor aW. the continuing use of complementary and alternative medicines in south australia: costs and beliefs in 2004. Med J aust 2006;184(1):27-31. chen J, chen M, Zhao b, Wang y. effects of acupuncture on the immunological functions in hepatitis b virus carriers. J tradit chin Med, 1999;19(4):268-272. Wu Xn, Wang GJ. experimental studies of oxymatrine and its mechanisms of action in hepatitis b and c viral infections. chin J dig dis, 2004;5:12-6.

2.

3.

4.

Conclusion

5.

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

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13 The role of complementary medicine in hepatitis B

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yin ss, Wang be, Wang tL. Jia Jd, Qian LX. the effect of cpd 861 on chronic hepatitis b related fibrosis and early cirrhosis: a randomized, double-blind, placebo controlled clinical trial [article in chinese] Zhonghua Gan Zang bing Za Zhi 2004;12(8):467-70. tu H, Zhang J, cheng WZ, et al. traditional chinese medicine intervention for development of hepatocellular carcinoma in patients with chronic hepatitis b: an analysis of 17 cases [article in chinese]. World chin J digestol 2005;13(19):2389–91. Wang be. treatment of chronic liver diseases with traditional chinese medicine (Management of chronic Hepatitis b). J Gastroenterol Hepatol 2000;15(suppl):e67– e70. Li W, Wei W. chinese materia medica: combinations and applications. donica Publishing Ltd, st albans: 2002. bartram t. bartram’s encyclopedia of Herbal Medicine. robinson Publishing, London: 1998. Mills s, bone K. Principles and Practice of Phytotherapy – Modern Herbal Medicine. churchill Livingstone, edinburgh: 2000. Guo Q, Zhao L, you Q. et al. anti-hepatitis b virus activity of wogonin in vitro and in vivo. antiviral research 2007;74:16–24. chiang Lc, ng Lt, cheng PW, chiang W, Lin cc. antiviral activities of extracts and selected pure constituents of ocium basilicum. clin exp Pharmacol Physiol 2005;32:811–6. Lu LG, Zeng Md, Mao yM, Li JQ, Wan Mb, Li cZ, et al. oxymatrine therapy for chronic hepatitis b: a randomized double-blind and placebo controlled multicentre trial. World J Gastroenterol 2003;9(11):2480–3. chen c, Guo sM, Liu b. a randomized controlled trial of kurorinone versus interferon α2a treatment in patients with chronic hepatitis b. J Viral Hepat 2000;7:225– 9. Hirayama c, okumura M, tanikawa K, yano M, Mizuta M, ogawa n. a multicentre randomized controlled trial of sho saiko to in chronic active hepatitis. Gastroenterol Jpn 1989;24(6):715–9. shimizu i, Ma yr, Mizobuchi y, Liu f, Miura t, nakai y, et al. effects of sho-saiko-to, a Japanese herbal medicine on hepatic fibrosis in rats. Hepatology 1999;29(1):149–60.

18. sakaida i, Hironaka K, Kimura t, terai s, yamasaki t, okita K. Herbal medicine sho saiko to (tJ-9) increases expression matrix metalloproteinases (MMPs) with reduced expression of tissue inhibitor of metalloproteinases (tiMPs) in rat stellate cell. Life sci 2004;74(18):2251–63. 19. Kusunose M, Qiu b, cui t, Hamada a, yoshioka s, ono M, et al. effect of sho saiko to extract on hepatic inflammation and fibrosis in dimethylnitrosamine induced liver injury rats. biol Pharm bull 2002;25(11):1417–21. 20. chang Js, Wang Kc, Liu HW, chen Mc, chiang Lc, Lin cc. sho saiko to (Xiao-chai-Hu-tang) and crude saikosaponins inhibit hepatitis b virus in a stable HbV-producing cell line. am J chin Med 2007;35(2):341–51. 21. suzuki t, Higa M, takahashi M, saito s, Kikuchi n, yamamuro W. a case of shoseiryu-to induced pneumonia with a marked increase in peripheral eosinophils (article in Japanese). nihon Kokyuki Gakkai Zasshi 2006;44(8):578–82. 22. Hatakeyama s, tachibana a, Morita M, suzuki K, okano H. five cases of pneumonitis induced by sho-saiko-to (article in Japanese). nihon Kyobu skikkan Gakkai Zasshi 1997;35(5):505– 10. 23. ishizaki t, sasaki f, ameshima s, shiozaki K, takahashi H, y. abe y, et al. Pneumonitis during interferon and/or herbal drug therapy in patients with chronic active hepatitis. eur respir J 1996;9(12):2691–6. 24. Wang L, Wang J, Wang be, Xiao PG, Qiao yJ, tan XH. effects of the herbal compound 861 on human hepatic stellate cell proliferation and activation. World J Gastroenterol 2004;10(19):2831–5. 25. Ji L, Liu t, Liu J, chen y, Wang Z. andrographolide inhibits human-hepatoma derived Hep3b growth through activation of c-Jun n-terminal kinase. Planta Med 2007;73:1397–401. 26. Varghese L, agarwal c, tyagi a, singh rP, agarwal r. silibinin efficacy against human hepatocellular carcinoma. clin cancer res 2005;11(23):8441–8. 27. Mcculloch M, broffman M, Gao J, colford JM Jr. chinese herbal medicine and interferon in the treatment of chronic hepatitis b: a metaanalysis of randomized controlled trials. am J Public Health 2002;92:1619–28.

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28. romero Mr, effereth t, serrano Ma, castaño b, Macias ri, briz o, et al. effect of artemsinin/ artesunate as inhibitors of hepatitis b virus production in an ‘in vitro’ replicative system. antiviral res 2005;68:75–83. 29. Gunawan b, Kaplowitz n. clinical perspectives on xenobiotic-induced hepatoxicity. drug Metab rev 2004;36(2):301–2. 30. schiano td. Hepatotoxicity and complementary and alternative medicines. clin Liver dis 2003;7:453–73. 31. stedman c. Herbal hepatotoxicity. sem Liver dis 2002;22:195–206. 32. seeff Lb, Lindsay KL, bacon br, Kresina tf, Hoofnagle JH. complementary and alternative medicine in chronic liver disease. Hepatology 2001;34(3):595–603. 33. stewart MJ, steenkamp V. Pyrrolizidine poisoning: a neglected area in human toxicology. ther drug Monit 2001;23:698– 708. 34. Pittler MH, ernst e. systematic review: hepatotoxic events associated with herbal medicinal products. aliment Pharmacol ther 2003;18(5):451–71. 35. australian Government department of Health and ageing, therapeutic Goods administration http://www.tga.gov.au/docs/ html/kavaspon.htm (cited on 02/12/07) 36. australian Government department of Health and ageing, therapeutic Goods administration new labelling requirements and consumer information for medicines containing cimicifuga racemosa. http:// www.tga.au/cm/0705blkcohosh.htm (cited on 02/12/07) 37. yeun Mf, tam s, fung J, Wong dK, Wong bc, Lai cL. traditional chinese Medicine causing hepatotoxicity in patients with chronic hepatitis b infection: a 1-year prospective study. aliment Pharmacol ther 2006;24:1179– 1186. 38. Liu JP, Mcintosh a, Lin H. chinese medicinal herbs for chronic hepatitis b. cochrane database syst rev. 2001;(2):cd002231. 39. Modi aa, Wright ec, seeff Lb. complementary and alternative medicine (caM) for the treatment of chronic hepatitis b and c: a review. antivir ther 2007;12:285–95.

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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

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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
Hepatitis b surface antigen Hepatitis b e antigen Hepatitis b virus dna alanine aminotransferase

abbreviation
Hbsag Hbeag HbV dna aLt

What it means
Hepatitis b infection immunity to hepatitis b infection Viral replication and infectivity Viral replication estimates liver inflammation or damage

anti-hepatitis b surface antibody anti-Hbs

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.

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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.

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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

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Appendix 2
ORGANISATIONS:

List of useful organisations and resources on hepatitis B
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

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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

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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

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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

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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

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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

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GLOSSARY AND ABBREVIATIONS
Viral hepatitides HAV: HBV: HCV: HEV: hepatitis a virus hepatitis b virus hepatitis c virus hepatitis e virus

HDV: hepatitis d (delta) 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

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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

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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

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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
119

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

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

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

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

10

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

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
11

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

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

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

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

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

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

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

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

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

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

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Notes

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

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