Asia-Pacific Pocket Guide to HEPATITIS B - Hepatitis B Foundation

Asia-Pacific 

Pocket Guide to 

HEPATITIS B 

Guest Editors 

Professor Stephen A. Locarnini 

Victorian Infectious Diseases Reference Laboratory 

Victoria, Australia 

Professor Masao Omata 

University of Tokyo, Tokyo, Japan 

Professor Dong Jin Suh 

Asan Medical Center, Seoul, Korea 

Educational Reviewer 

Adnan Said, MD 

University of Wisconsin 

School of Medicine 

and Public Health 

Madison, Wisconsin, USA 

A CME activity jointly sponsored by the University of Wisconsin School 

of Medicine and Public Health and MDG Development Group 

A CME-accredited activity developed by 

the members of the ACT-HBV ® Initiative 

Supported through an independent educational 

grant from Novartis Pharmaceuticals AG

cme information 

Needs Assessment 

Nowhere in the world is chronic HBV infection a greater health 

problem than in the Asia-Pacific region. Of the more than 2 billion 

people infected worldwide with HBV, more than 400 million have 

chronic infection, and 75% of these are found in Asia, with 50% from 

China and India alone. 

Disease prevention activities, including screening and vaccination 

programs, have been implemented successfully in some Asia-Pacific 

countries. Individuals with chronic HBV infection and individuals at 

risk for infection need to be identified and managed appropriately. 

Chronic hepatitis B is a complex viral illness. HBV infection remains 

one of the primary causes of liver disease, including cirrhosis and 

HCC. Appropriate pharmacotherapy is critical to altering the course 

of the disease, since sustained viral suppression is the key to reducing 

hepatic injury. 

There remains a significant unmet need for effective education about 

HBV infection in the Asia-Pacific healthcare community. Since the 

publication of the last pocket guide, new data regarding the 

relationship between HBV DNA levels and risk of liver disease and 

response to treatment have emerged. Additionally, new antiviral 

agents have become available and the guidelines for the management 

of CHB in the Asia-Pacific region have been updated. However, 

practitioners may not be aware of these guidelines or of the recent 

updates. This pocket guide will make useful information readily 

available to community-based physicians. 

Target Audience 

This educational resource has been designed to meet the needs 

of hepatologists, gastroenterologists, infectious disease specialists, 

primary care physicians, and other medical care providers who see 

patients who have hepatitis B or who are at risk for HBV infection. 

Learning Objectives 

At the conclusion of this activity, participants should be able to 

• Describe the epidemiology of HBV infection in the Asia-Pacific 

region 

• Explain the virology of HBV as it relates to the natural history of 

HBV infection and its stages 

• Describe the vaccination schedules for infants and adults 

• Describe newly licensed antiviral agents and agents under clinical 

investigation for the treatment of CHB 

• Implement the new guidelines for the treatment and monitoring of 

HBV-infected individuals 

• Employ appropriate treatment strategies for special patient 

populations 

Asia-Pacific Pocket Guide to Hepatitis B 

i

cme information 

Accreditation 

This activity has been planned and implemented in accordance with the 

Essential Areas and Policies of the Accreditation Council for Continuing 

Medical Education (ACCME) through the joint sponsorship of the University of 

Wisconsin School of Medicine and Public Health and MDG Development 

Group. The University of Wisconsin School of Medicine and Public Health is 

accredited by the ACCME to provide continuing medical education for physicians. 

All materials were reviewed by Adnan Said, MD, Assistant Professor of 

Medicine in the Unit of Gastroenterology at the University of Wisconsin School 

of Medicine and Public Health. 

Credit 

The University of Wisconsin School of Medicine and Public Health designates 

this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s) TM . 

Physicians should only claim credit commensurate with the extent of their 

participation in the activity. 

There are no prerequisites for this pocket guide and this activity will take 1 

hour to complete. 

Policy on Faculty and Sponsor Disclosure 

As a provider accredited by the ACCME, it is the policy of the University of 

Wisconsin School of Medicine and Public Health to require the disclosure of 

the existence of any significant financial interest or any other relationship the 

sponsor or participating faculty members have with the manufacturer(s) of 

any commercial product(s) discussed in this pocket guide. The participating 

faculty reported the following: 


• Has received grants/research support from Evivar Medical Pty. Ltd and 

Gilead Sciences, Inc 

• Has acted as a consultant for Bristol-Myers Squibb Company, Evivar 

Medical Pty. Ltd, Gilead Sciences, Inc, and Pharmasset, Inc 

• Has received honoraria from Bristol-Myers Squibb Company 

Professor Masao Omata 

• Has acted as a consultant for Boehringer Ingelheim, Bristol-Myers Squibb 

Company, and Roche Laboratories, Inc. 

• Has received honoraria from Bristol-Myers Squibb Company, Merck & Co, 

Pfizer Inc, and Roche Laboratories, Inc. 

Professor Dong Jin Suh 

• Has acted as a consultant for GlaxoSmithKline 

• Has received honoraria from Roche Laboratories, Inc. and Schering-Plough 

Corporation 

Adnan Said, MD 

• Has no relevant financial relationships to disclose 

Acknowledgment 

The University of Wisconsin School of Medicine and Public Health and MDG 

Development Group gratefully acknowledge the independent educational 

grant provided by Novartis Pharmaceuticals AG. 

Release Date: October 2008 

Expiration Date: October 2009 

©2008 University of Wisconsin Board of Regents and MDG Development Group 

All rights reserved. This material may not be reproduced without the written 

permission of the publisher. The opinions expressed in the report are those 

of the author and not to be construed as the opinions or recommendations 

of the sponsor or the publisher. Readers are encouraged to check the 

current prescribing information for all drugs and devices mentioned in the 

text of this publication. 

ii 

Asia-Pacific Pocket Guide to Hepatitis B

introduction 

Hepatitis B virus infection is particularly prevalent in the Asia-Pacific 

region, where it is most often acquired at birth or in early childhood. 

They thus face a lifelong interaction with a virus that can lead to 

chronic illness, progressing to cirrhosis, hepatic decompensation, 

and HCC. These sequelae usually occur at an earlier age than in 

persons from other, nonendemic regions, where the infection is 

generally contracted in adulthood and less often becomes chronic. 

The Asia-Pacific region accounts for 75% of the world’s 400 million 

persons who have chronic HBV infection; 50% of these come from 

China and India alone. Many of the Asia-Pacific countries have 

responded to the call to action to halt the spread of HBV disease by 

implementing widespread screening and vaccination programs, with 

remarkable success. In some cases, however, concerted action is 

lacking, a consequence of the unique barriers existing in each country. 

A scarcity of resources and trained medical personnel are obvious 

obstacles, as are socioeconomic restrictions and patient compliance 

issues related to a poor understanding of the nature of the disease. 

But even among medical practitioners, a lack of consensus on how 

best to treat and monitor patients has often fragmented the most 

well-intentioned efforts to manage HBV infection. This is changing, 

however, with a better understanding of the disease course and the 

availability of new medications that can more effectively suppress 

viral replication. Such therapies represent a real potential to alter the 

outcome of the disease. 

To help clinicians in the care of their patients, this pocket guide 

provides a compendium of the most recent information on HBV 

infection in the Asia-Pacific region. Most importantly, it includes the 

2008 updates to the Consensus Statement on the Management 

of Chronic Hepatitis B issued by the Asia-Pacific Association for the 

Study of the Liver. 1 We hope you will find it helpful in your practice. 


Chairman, Asia-Pacific Steering Committee 

of the ACT-HBV® Initiative 

Head, Research and Molecular Development 

Victorian Infectious Diseases Reference Laboratory 

Victoria, Australia 

1. Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management 

of chronic hepatitis B: a 2008 update. Hepatol Int. 2008. Available at: http://www. 

springerlink.com/content/du475u12q655175j/fulltext.pdf. Accessed August 22, 2008. 


iii

overview 

of hepatitis b 

Overview Of Hepatitis B

overview of hepatitis b 

EPIDEMIOLOGY 

• Chronic HBV infection is a serious public health problem 

affecting ~400 million individuals worldwide 

• The Asia-Pacific region suffers disproportionately from 

chronic HBV infection, accounting for 75% of all infected 

individuals; the Western-Pacific region alone accounts for 

45% of all HBV infections 

• HBV-related liver disease is the cause of >200,000 deaths 

in the Asia-Pacific region 

Low 8% 

Source: Lesmana LA, et al. Liver Int. 2006;26(suppl 1):3–114. 

PREVALENCE 

• Varies greatly by geography and population subgroups 

High >8% Asia, Southeast Asia, Sub-Saharan 

Africa, Pacific Islands 

Intermediate 2%–8% India, Pakistan, Korea, Malaysia, 

Singapore, Indonesia, Thailand 

Low


Country Number HBsAg+ (%) 

Australia 170,000 0.9 

China 112,600,000 5.3–12.0 

Hong Kong 600,000 4.5–12.0 

India 37,300,000 2.4–4.7 

Indonesia 8,700,000 4.0 

Japan 3,700,000 N/A 

Korea (South) 1,800,000 2.6–5.1 

Malaysia 1,700,000 5.2 

New Zealand 60,000 6.0–8.0 

Pakistan 6,000,000 5.0 

The Philippines 8,300,000 5.0–16.0 

Singapore 160,000 4.0–6.0 

Taiwan 2,700,000 10.0–13.8 

Thailand 3,900,000 4.6–8.0 

Vietnam 6,300,000 5.7–10.0 

Source: Mohamed R, et al. J Gastroenterol Hepatol. 2004;19:958–969. 

TRANSMISSION 

• Perinatal (vertical) transmission is the predominant mode 

of HBV transmission in the Asia-Pacific region 

−Approximately 30% to 50% of all chronic infections are 

acquired perinatally from HBeAg-positive mothers 

• Horizontal transmission, particularly, child-to-child and 

that among household members, is also a significant 

mode of transmission in the Asia-Pacific region 

Vertical 

• Perinatal (mother-to-infant) 

• 70% to 96% of infants of 

HBeAg-positive mothers 

become infected and >90% 

become chronically infected 

• Infants of HBeAg-negative 

mothers may become chronically 

infected but at a much lower rate 

Horizontal 

• Child-to-child 

• Household members 

• Healthcare settings 

– Needle sticks 

– Infected workers 

(transmission risk higher 

than for HIV or HCV) 

• Injection of illicit drugs 

• Sexual contact 

• Blood products 

• Transplantation* 

(solid organ, bone marrow) 

*Possible, but largely eliminated by HBsAg testing 

2 Asia-Pacific Pocket Guide to Hepatitis B


COINFECTION/SUPERINFECTION 

• Concurrent infection with HCV, HDV, or HIV in HBVinfected 

individuals is relatively common because of 

shared routes of transmission for these viruses 

• 90% of patients with HIV have serologic markers of past 

or current HBV infection, and up to 10% have chronic 

HBV infection 

• Patients with concurrent infection, such as HCV, HDV, 

and HIV, tend to have higher rates of cirrhosis, HCC, and 

mortality 

REFERENCES 

Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and 

current and emerging prevention and control measures. J Viral Hepat. 2004; 

11:97–107. 

Lesmana LA, Leung N, Mahachai V, et al. Hepatitis B: Overview of the burden 

of disease in the Asia-Pacific region. Liver Int. 2006;26(suppl 2):3–10. 

Liaw YF. Role of hepatitis C virus in dual and triple hepatitis virus infection. 

Hepatology. 1995; 22:1101–1108. 

Liaw YF, Chen YC, Sheen IS, et al. Impact of acute hepatitis C virus superinfection 

in patients with chronic hepatitis B virus infection. Gastroenterology. 2004;126: 

1024–1029. 

Thio CL, Locarnini S. Treatment of HIV/HBV coinfection: clinical and virologic 

issues. AIDS Rev. 2007;9:40–53. 

World Health Organization. Fact sheet 2002. Hepatitis B. Available at: 

http://www.who.int/mediacentre/factsheets/fs204/en. Accessed June 5, 2008. 


3

virology/ 

natural history 

Virology/Natural History

virology 

THE VIRUS 

• HBV is a small enveloped DNA virus, partially double 

stranded 

• HBV is not, in itself, directly cytopathic 

• HBV infection represents a dynamic interaction between 

host and virus 

• Liver disease is the result of an ineffective or inappropriate 

immune response to HBV-infected hepatocytes 

GENOTYPES 

• Eight genotypes of HBV (A-H) are currently recognized 

that are differentiated by a >8% sequence divergence in 

the entire genome 

– Several subgenotypes of HBV have been described 

which differ by at least 4% sequence divergence in the 

entire genome: Aa (A1: Asia/Africa), Ae (A2: Europe), Bj 

(B1: Japan), Ba (B2: Asia), Ce (C2: east), and Cs 

(C1,C3,C4,C5: south) 

• The genotypes show a distinct geographical distribution 

between and even within regions 

• Genotypes B and C are prevalent in the Asia-Pacific region 

where perinatal or vertical transmission plays an 

important role in spreading the virus 

• In contrast, genotypes A and D are prevalent in Europe 

and the Mediterranean region 

• Genotype B is associated with less progressive liver 

disease than is genotype C, and genotype D has a less 

favorable prognosis than does genotype A 

• Patients with genotypes A and B appear to respond better 

to IFN and PEG-IFN than do patients with genotypes C 

and D 

• Patients with genotype C have higher HBV DNA levels, a 

higher frequency of mutations (pre-S deletion and core 

promoter), and a higher risk of developing HCC than do 

patients with genotype B 


5

virology 

HBV LIFE CYCLE 

1. HBV enters the hepatocyte via a cell surface receptor 

2. HBV envelope is removed; HBV genomic DNA is transported 

to the nucleus 

3. In the nucleus, genomic DNA is converted to a cccDNA 

form or minichromosomes 

4. cccDNA acts as a template for RNA transcription during 

viral replication 

5. Core virus particles are enveloped with HBsAg, and the 

HBV virion is released 

IMMUNE RESPONSE 

• Cell injury occurs via T-cell lysis of virus-containing 

hepatocytes 

• The immune response to HBV antigens both clears the 

virus and contributes to hepatocellular injury. Humoral 

response to HBsAg clears the virus; cell-mediated response 

to HBsAg and HBcAg helps to eliminate infected cells 

• Weaker immune responses in patients who develop CHB 

are strong enough to continue to destroy HBV-infected 

hepatocytes, producing chronic inflammation with the 

ability to produce cirrhosis 


Natural history 

GENERAL FEATURES 

• The natural history of chronic HBV infection is a dynamic 

state of interactions among HBV, hepatocytes, and 

immune cells of the host 

• Chronic inflammation and liver cell regeneration contribute 

to hepatic cell DNA damage and the development of HCC 

• Pathology associated with HBV infection ranges from 

mild to severe liver disease 

• 15% (females) and 40% (males) of chronically infected 

patients are at risk for developing cirrhosis, liver failure, 

or HCC in their lifetime 

• In the Asia-Pacific region, HBV disease is marked 

by infection early in life and a long latency period 

(seroconversion occurs between ages 25 and 35) 

• Disease course is influenced by host, viral, and other 

environmental factors such as alcohol use 

Host Factors Viral Factors Other Factors 

• Age: >40 years 

• Gender 

(male > female) 

• Immune status 

• Severity, extent, 

and frequency of 

ALT elevation and 

liver inflammation 

and fibrosis 

• HBV DNA levels 

≥2,000−20,000 

IU/mL (≥10 4–5 

copies/mL) 

• Genotype C>B; 

D>A 

• HBV mutations 

− T1762/A1764 

in HBV core 

promoter gene 

− Precore mutation 

• Habitual alcohol 

consumption 

• Habitual cigarette 

smoking 

• Aflatoxin exposure 

• Coinfection (HCV, 

HDV, HIV) 

INFANTS AND CHILDREN 

• Infants born to HBeAg-positive mothers and children of 

HBeAg-positive mothers have the highest risk (90%) of 

chronicity after infection 

• Children tend to have mild, asymptomatic disease 

• ~25% of infected children develop cirrhosis or HCC 

as adults 

ADULTS 

• Most adults who acquire infections (>98%) and have a 

functioning immune system recover from acute infection 

(chronicity in adults is


PHASES OF CHRONIC INFECTION 

• The natural course of chronic HBV infection in the Asia- 

Pacific region can be divided into several phases: 

– Immune tolerant 

– Immune clearance 

– Residual or inactive 

– Reactivation 

IMMUNE TOLERANT PHASE 

• Occurs in young, HBsAg- and HBeAg-seropositive 

individuals 

• Characterized by high serum HBV DNA levels (>2 × 10 6 to 

2 × 10 7 IU/mL) 

• ALT is persistently normal; no or minimal clinicopathologic 

changes 

IMMUNE CLEARANCE PHASE 

• Characterized by increased ALT levels and decreased HBV 

DNA levels 

– Acute flares with serum ALT > 5 × ULN can occur and 

be complicated by hepatic decompensation in some 

patients 

• Higher ALT levels reflect more vigorous immune response 

to HBV and histologic activity (ie, necroinflammation) 

• Eventually followed by seroconversion from HBeAg to 

anti-HBe and/or undetectable HBV DNA 

– Spontaneous HBeAg seroconversion occurs annually 

in approximately 2% to 15% of patients per year, 

depending on age, ALT levels, and HBV genotype 

RESIDUAL OR INACTIVE PHASE 

• Occurs after seroconversion from HBeAg to anti-HBe 

• Preceded by a marked reduction of serum HBV DNA 

levels, normalization of serum ALT levels, and resolution 

of liver necroinflammation 

• Most individuals who are chronically infected and who 

seroconvert remain HBeAg negative and anti-HBe positive 

for their lifetime 



REACTIVATION 

• Reactivation of HBV infection is defined as a reappearance 

of active necroinflammatory disease of the liver in 

individuals known to have an inactive HBsAg phase or 

those who have undergone HBeAg seroconversion 

• Reactivation of HBV is characterized as a rise in serum 

ALT levels accompanied by detection of HBV DNA 

using hybridization assays, with or without HBeAg 

seroreversion 

• Genotype C and male gender have been shown to be 

independent factors predictive of reactivation of hepatitis B 

• Additionally, the likelihood of reactivation of hepatitis 

B is increased if more rigorous immune-mediated 

hepatocytolysis or a more prolonged immune clearance 

phase is necessary to eliminate the virus 

• Approximately 50% of patients will experience acute 

reactivations during the natural history of their disease 

• HBV reactivations may present as an acute event, may be 

asymptomatic, and are often spontaneous 

• Patients with a history of hepatitis B who receive cancer 

chemotherapy or immunosuppressive therapy are at risk 

for HBV reactivation 

• HBV reactivation occurs in approximately 50% of 

HBsAg-positive patients, and as many as 6% of HBsAgnegative 

but core-positive (HBcAb) patients undergoing 

chemotherapy 

SEROCONVERSION 

HBeAg 

• Loss of HBeAg and detection of anti-HBe in a person who 

was previously HBeAg positive and anti-HBe negative 

• Most patients ultimately clear (lose) HBeAg and undergo 

seroconversion to anti-HBe (90% before age 40) 

• Seroconversion represents a transition from chronic 

hepatitis B to the inactive HBsAg phase 

• HBV DNA falls to low (


HBsAg 

• Loss of serum HBsAg; may occur in the inactive HBsAg 

phase 

• HBsAg seroclearance occurs at a low rate (1.2% per year) 

• HBsAg seroconversion is associated with an excellent 

prognosis; however, HCC can still occur, although at a 

very low rate, if cirrhosis has already developed before 

HBsAg seroconversion 

CHRONIC HEPATITIS B 

• Caused by persistent infection with HBV for ≥6 months 

(HBsAg positive) 

• The disease is marked by the presence of HBV in 

serum and variable degrees of chronic inflammation, 

hepatocellular necrosis, and fibrosis of the liver 

HBeAg Positive 

• The continued presence of HBsAg and HBeAg, high HBV 

DNA levels, and elevation of ALT levels signals the onset 

of CHB 

• The presence of HBeAg and HBV DNA is associated with 

an enhanced risk for developing cirrhosis and HCC 

HBeAg Negative 

• HBeAg negativity occurs in seroconverted patients who 

do not have sustained remission but have 

– Elevated HBV DNA (>2,000 to 20,000 IU/mL or 10 4–5 

copies/mL) and 

– ALT persistently or intermittently elevated 

• Caused by a variant of HBV that does not produce 

HBeAg 

• Does not occur de novo but emerges during the course of 

infection 

• This is a more severe and progressive form of chronic 

hepatitis B than that occurring in patients with sustained 

remission 

• Long-term prognosis is poor versus HBeAg-positive 

patients, possibly due to older age at presentation 



COINFECTIONS 

HBV/HCV 

• Concurrent HBV and HCV infection is not uncommon 

• In patients with chronic HBV infection acquired perinatally 

or during early childhood, HCV may suppress the 

pre-existing HBV, but it may also increase the risk of 

hepatic decompensation or failure, the severity of liver 

disease, and disease progression, including HCC 

HBV/HDV 

• HDV coinfection or superinfection is relatively rare in the 

Asia-Pacific region, except among injection drug users 

and persons practicing unsafe sex 

• HDV superinfection may increase the risk of hepatic 

decompensation or failure, the severity of liver disease, 

and disease progression 

HBV/HCV/HDV 

• Triple infection occurs rarely 

• Mutual suppression among the viruses exists (HCV is the 

strongest) 

HBV/HIV 

• HIV coinfection with HBV, versus HIV infection alone, is 

associated with 

– Higher HBV DNA levels 

– Lower ALT levels 

– Slower clearance of HBeAg 

• HIV-related immunosuppression (especially the development 

of AIDS) may reactivate HBV infection in patients 

who previously lost HBsAg or HBeAg 

• Conversely, HBV infection does not appreciably alter the 

natural history of HIV infection 

• IRD 


11


REFERENCES 

Virology 

Kramvis A, Kew M, Francois G. Hepatitis B virus genotypes. Vaccine. 2005;23: 

2409–2423. 

Locarnini S. Molecular virology of hepatitis B virus. Semin Liver Dis. 2004;24:3–10. 

Miyakawa Y, Mizokami M. Classifying hepatitis B virus genotypes. Intervirology. 

2003;46:329–338. 

Norder H, Courouce AM, Coursaget P, et al. Genetic diversity of hepatitis B 

virus strains derived worldwide: genotypes, subgenotypes, and HBsAg 

subtypes. Intervirology. 2004;47:289-309. 

Natural History 

Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B: 

special emphasis on disease progression and prognostic factors. J Hepatol. 

2008;48:335–352. 

Chu CM, Liaw YF. Predictive factors for reactivation of hepatitis B following 

hepatitis B e antigen seroconversion in chronic hepatitis B. Gastroenterology. 

2007;133:1458–1465. 

Hui CK, Leung N, Yuen ST, et al. Natural history and disease progression in 

Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 

2007;46:395–401. 

Lai M, Hyatt BJ, Nasser I, et al. The clinical significance of persistently normal ALT in 

chronic hepatitis B infection. J Hepatol. 2007;47:760–767. 

Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the 

management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008; Available 

at: http://www.springerlink.com/content/du475u12q655175j/fulltext.pdf. Accessed 

August 22,2008. 


vaccination 

Vaccination

Vaccination 

TYPES OF HBV VACCINE 

• HBV vaccine is available in different formulations 

– Monovalent vaccine—protects only against hepatitis B 

– Combination vaccine—protects against hepatitis B and 

other infectious diseases (diphtheria, tetanus, pertussis, 

Haemophilus influenzae type B, and hepatitis A) 

HBV Vaccination Coverage in Asia-Pacific Region 

• WHO recommended integration of HBV vaccine into 

national immunization programs 

• All countries complied 

• WHO implemented a strategic plan to reduce HBsAg 

seroprevalence to 5 million people each year are 

not receiving full HBV immunization 

EFFICACY 

• Vaccination prevents up to 95% of chronic infections if 

combined with HBIG 

• Vaccination alone prevents up to 75% of chronic 

infections 

• Protection is long term: anti-HBs lasts up to 15 years 

• Broad (universal) vaccination is more effective in reducing 

transmission than vaccination of high-risk groups only 

• Introduction of universal HBV vaccination has reduced 

HBsAg prevalence rates among children and adolescents 

to

Vaccination 

CANDIDATES FOR HEPATITIS B VACCINATION 

• Newborns of HBsAg-positive mothers 

• Children under the age of 10 in regions of high endemicity 

• Household contact of acute and chronically infected 

individuals 

• Injection drug users 

• Individuals at risk of sexual transmission 

• Hemodialysis patients 

• Blood concentrate recipients 

• Individuals coinfected with HIV or HCV 

• Adults at increased risk for HBV (ie, healthcare workers, 

prison inmates, and staff of correctional facilities) 

CURRENT WORLD HEALTH ORGANIZATION 

IMMUNIZATION SCHEDULES AND DOSING 

Age 

HBV Vaccination 

Without Birth 

Dose* 

HBV Vaccination Schedule 

With Birth Dose † 

Option I Option II Option III 

Birth HepB(m) HepB(m) 

4 weeks HepB–dose 1 

(m or c) 


(m or c) 


(m or c) 

HepB–dose 2 

(m) 

HepB–dose 3 

(m) 

DTP-HepB–dose 

1(c) 


2(c) 


3(c) 

(m) = Monovalent vaccine only; (c) = combination vaccine. 

*This schedule does not prevent perinatal hepatitis B infections 

† In addition to vaccine, children of HBeAg-positive mothers should receive 100 

IU of HBIG intramuscularly into the lateral thigh within 12 hours of birth 

• Schedule option I is usually easiest if the three doses of 

hepatitis B vaccine are given at the same time as the three 

doses of DTP vaccine. This schedule prevents infections 

acquired during early childhood, but does not prevent 

perinatal HBV infections because it does not include a 

dose of hepatitis B vaccine at birth. 

• Schedule options II and III can be used to prevent perinatal 

HBV infections; the four-dose schedule (option III) is easier 

to administer programmatically but is more costly 


Vaccination 

DOSAGE 

• Standard dose for INFANTS and CHILDREN (aged

Vaccination 

POSTVACCINATION TESTING 

• Not routinely recommended following vaccination of 

infants, children, adolescents, or most adults with lowrisk 

exposure 

• Most individuals develop antibody titers >100 IU/mL 

within 6 to 8 weeks of completion of full course of hepatitis 

B vaccine 

• Approximately 5% to 15% of healthy immunocompetent 

individuals do not mount an antibody response to hepatitis 

B vaccine 

– Nonresponder is a person who, despite correct 

administration of a full course of hepatitis B vaccine, 

has an anti-HBV titer of

Vaccination 

BOOSTERS 

• Because vaccination efficacy lasts >15 years in persons 

with functioning immune systems who have responded 

(anti-HBs seroconverted), booster doses are not currently 

recommended for any group 

• However, Lu et al reported that ≥10% of vaccinated 

adolescents may lose immune memory conferred by a 

plasma-derived HBV vaccine 15 to 18 years later. This decay 

of immune memory may raise concerns about the need for a 

booster vaccine for high-risk groups in the long term. 

REFERENCES 

Chang MH. Impact of hepatitis B vaccination on hepatitis B disease and nucleic 

acid testing in high-prevalence populations. J Clin Virol. 2006;36(suppl 1): 

S45-S50. 

Chang MH, Chen CJ, Lai MS, et al, for the Taiwan Childhood Hepatoma Study 

Group. Universal hepatitis B vaccination in Taiwan and the incidence of 

hepatocellular carcinoma in children. N Engl J Med. 1997;336:1855–1859. 

Chen DS. Hepatocellular carcinoma in Taiwan. Hepatol Res. 2007;37(suppl 2): 

S101-S105. 

Chien YC, Jan CF, Kuo HS, Chen CJ. Nationwide hepatitis B vaccination program 

in Taiwan: effectiveness in the 20 years after it was launched. Epidemiol Rev. 

2006;28:126-135. 

Lu CY, Ni YH, Chiang BL, et al. Humoral and cellular immune responses to a 

hepatitis B vaccine booster 15-18 years after neonatal immunization. J Infect 

Dis. 2008;197:1419-1426. 

Ni YH, Huang LM, Chang MH, et al. Two decades of universal hepatitis B 

vaccination in Taiwan: impact and implication for future strategies. 

Gastroenterology. 2007;132:1287-1293. 

Yu AS, Cheung RC, Keeffe EB. Hepatitis B vaccines. Clin Liver Dis. 2004;8: 

283–300. 

World Health Organization. Fact sheet. Hepatitis B vaccine. Core information 

for the development of immunization policy, 2002 update, vaccines and 

biologicals. Available at http://www.who.int/immunization_delivery/new_ 

vaccines/4.Coreinformation_Hepatitis%20B.pdf. Accessed July 9, 2008. 


17

diagnosis 

Diagnosis

diagnosis 

VIROLOGIC DIAGNOSTIC TOOLS 

• The primary diagnostic tools are serologic markers of 

HBV and antibodies to HBV 

HBV Marker 

• HBV DNA 

• HBsAg 

• HBeAg 

Antibodies to HBV 

• Anti-HBc 

• Anti-HBs 

• Anti-HBe 

– Other components of the HBV, such as the nucleocapsid 

or core protein HBcAg, are also the target of the immune 

response (eg, anti-HBc) 

HBV DNA 

• Serum HBV DNA level is used to determine indications for 

antiviral therapy and to monitor response to therapy 

Available HBV DNA Assays: 

Dynamic Range 

Abbott 

Molecular 

Diagnostics 

Digene Corp. 

Abbott Realtime PCR 

HBV Digene Hybrid-Capture I 

HBV Digene Hybrid-Capture II 

Ultra-Sensitive Digene 

Hybrid-Capture II 

Roche 

Molecular 

Systems 

Amplicor HBV Monitor 

Cobas Amplicor HBV Monitor 

Cobas Taqman 48 HBV 

Artus-Biotech 

Real Art HBV PCR Assay 

Bayer Corp. 

Versant HBV DNA 1.0 

Versant HBV DNA 3.0 

1 10 10 2 10 3 10 4 10 5 10 6 10 7 10 8 10 9 10 10 

HBV DNA IU/mL 

Source: Hoofnagle JH, et al. Hepatology. 2007;45:1056–1075. 

• Currently available HBV DNA assays differ considerably 

in their lower limits of detection and quantitation 

• Standardization of units to IU/mL has been recommended 

– 1 IU/mL = 5.26 copies/mL 

• Undetectable serum HBV DNA is defined as HBV DNA 

levels below detection limit of a PCR-based assay 


19

diagnosis 

HBV ANTIGENS 

HBsAg 

HBcAg 

HBeAg 

• Protein expressed on surface of HBV 

• First serologic marker to appear after infection 

• General marker of infection 

• Nucleocapsid that encloses the viral DNA 

• Soluble viral protein secreted from infected cells 

when HBV replication is high 

• Some variants of HBV do not produce HBeAg 

(eg, precore mutant) 

HBV ANTIBODIES 

Anti-HBs 

Anti-HBe 

Anti-HBc (IgM) 

Anti-HBc (IgG) 

• Produced in response to the envelope antigen 

• Confers protective immunity 

• Detectable in patients who have recovered 

from natural infection or who have gained 

immunity from vaccination 

• Produced in response to HBeAg 

• Appears after HBeAg has been cleared 

• Marker of reduced level of replication 

• Marker of acute or recent infection 

• Appears with low titer in 15% to 20% of acute 

flares of chronic HBV infection 

• Marker of current or past infection 

• Found in recovery 

• Low-level carrier 


diagnosis 

INTERPRETATION OF THE HEPATITIS B PANEL 

Test Result 

HBsAg 

Total anti-HBc 

Anti-HBs 

HBsAg 

Anti-HBc 

Anti-HBs 

HBsAg 

Anti-HBc 

Anti-HBs 

HBsAg 

Anti-HBc 

IgM anti-HBc 

Anti-HBs 

HBsAg 

Anti-HBc 

IgM anti-HBc 

Anti-HBs 

HBsAg 

Anti-HBc 

Anti-HBs 

– 

– 

– 

– 

+ 

+ 

– 

– 

+ 

+ 

+ 

+ 

– 

+ 

+ 

– 

– 

– 

+ 

– 

Susceptible 

Interpretation 

Immune due to natural infection 

Immune due to hepatitis B vaccination 

Acutely infected 

(chronic hepatitis B with acute exacerbation, 

low-titer IgM anti-HBc) 

Chronically infected 

Three possible interpretations: 

1. May be recovering from acute infection 

(IgM anti-HBc+) 

2. May be distantly immune; test not sensitive 

enough to detect very low level of anti-HBs 

in serum 

3. Undetectable level of HBsAg may be 

present in serum, and person is actually 

chronically infected 

Source: Liaw YF, Tsai N. Gastroenterol Hepatol. 2007;3(suppl 31):6–14. 


21

diagnosis 

WHO SHOULD BE TESTED? 

• Candidates for diagnostic testing include 

– Individuals living or born in areas of intermediate to 

high HBV prevalence 

– Persons likely exposed to HBV via the common modes 

of transmission 

• Serologic HBV markers are highly prevalent in these 

groups 

Prevalence of HBV 

Serologic Markers (%) 

Population HBsAg All Markers 

Persons born in endemic areas* 13 70–85 

Men who have sex with men 6 35–80 

IV drug users 7 60–80 

Dialysis patients 3–10 20–80 

HIV-infected patients 8–11 89–90 

Pregnant women (USA) 0.4–1.5 

Family/household and sexual contacts 3–6 30–60 

*Endemic areas include the Far East except Japan, Africa, South Pacific 

Islands, Middle East, Eastern Europe, Amazon Basin, and Greenland. 

Source: Lok ASF, McMahon BJ. Hepatology. 2001;34:1225–1241. 

BIOCHEMICAL DIAGNOSTIC TOOLS 

Definitions of serum ALT levels 

• High normal: serum ALT level between 0.5 and 1 × ULN 

• Low normal: serum ALT level

diagnosis 

HISTOLOGIC DIAGNOSTIC TOOLS 

Liver Biopsy 

• Liver biopsy is not mandatory but may be helpful in 

selected cases to clarify the activity and severity of 

disease and assist in the determination of the need for 

antiviral therapy 

−HBV DNA levels >2,000 IU/mL (10 4 copies/mL) 

increases the risk for progression to cirrhosis or HCC 

• The role of liver biopsy in evaluation of chronic HBV 

infection is to 

– Confirm the diagnosis of CHB 

– Grade the severity of necroinflammation 

– Stage the amount of fibrosis 

• Liver biopsy can also help clarify the diagnosis and 

need for therapy when ALT and HBV DNA levels are 

discordant 

High HBV DNA, Normal ALT 

Some patients may have 

significant liver disease 

Low HBV DNA, High ALT 

Some patients (small number) 

may have either active chronic 

HBV infection or (more often) 

other causes of liver disease 

• Liver biopsy should be considered for individuals with 

detectable HBV DNA (>1,000 IU/mL) and normal ALT 

levels, particularly if they are >35 to 40 years of age and 

thus less likely to be immune tolerant 

• Liver biopsy is also useful when ALT is between 1 and 

2 × ULN as many patients may have mild inflammation 

and no or mild fibrosis and may not need immediate 

antiviral therapy 

SCORING SYSTEMS—LIVER DISEASE 

• Liver disease is generally assessed through histologic 

evaluation of liver biopsies 

• Three semiquantitative scoring systems are used to rate 

the degree of hepatic injury and fibrosis or disease severity 

on liver biopsy 

1. Knodell HAI 

2. Ishak scoring system (modification of Knodell) 

3. METAVIR scoring system 


23

diagnosis 

Knodell HAI 

• Scores three categories of necroinflammation (18 points) 

and one category of fibrosis (4 points) 

• Maximum HAI score is 22 

• Change of 2 points is usually considered improvement 

(in clinical trials) 

Ishak Scoring System 

• Modification of the Knodell scoring system (Ishak modified 

HAI) 

• Fibrosis stage is scored continuously from 0 to 6 (rather 

than 0 to 4) 

• Ishak score adds more detail to the fibrosis score 

– Gives a more accurate assessment of fibrosis 

– Gives a better assessment of the effect of therapy on 

fibrosis 

METAVIR Scoring System 

• An easier grading system than either the Knodell or Ishak 

scoring systems; more commonly used in clinical 

practice 

• Grading of disease activity is based on 

– Severity of periportal inflammation or injury to the 

portal zones between the lobules of the liver 

– Degree of focal parenchymal necrosis 

• Activity is graded on a scale from A0 (no activity) to A3 

(severe activity) 

• Fibrosis is graded continuously from F0 (no fibrosis) to F4 

(presence of cirrhosis) 

CTP Classification (Clinical Assessment of Cirrhosis) 

• CTP score is an assessment of cirrhosis based on laboratory 

and clinical markers of liver function. It was originally 

developed to assess the need for shunt surgery. 

• The composite score from the five markers determines the 

Child’s classification (class A, B, or C) or CTP score from 

5 to 15; CTP score 5 or 6 = class A; CTP score 7–9 = 

class B; CTP score 10–15 = class C 


diagnosis 

NONINVASIVE TESTING 

Ultrasound 

• 80% accuracy for cirrhosis 

• Reliability improves if clinical findings are present 

(thrombocytopenia, esophageal or gastric varices, history of 

ascites, spontaneous bacterial peritonitis, encephalopathy) 

Serum Markers 

• Blood tests that reflect hepatic fibrogenesis or fibrolysis 

are undergoing validation studies 

FibroTest 

• A noninvasive diagnostic test for assessing fibrosis that 

uses an algorithm to combine the results of serum tests of 

b 2 

-macroglobulin, haptoglobulin, apolipoprotein A1, total 

bilirubin, GGT, and ALT to assess the level of fibrosis and 

necroinflammatory activity 

Transient Elastography (FibroScan ® ) 

• A new, noninvasive, rapid, reproducible, bedside method, 

allowing assessment of liver fibrosis by measuring liver 

rigidity under clinical evaluation 

• FibroScan and biochemical markers may be reliable 

noninvasive methods for detecting liver fibrosis in patients 

with hemochromatosis 

• FibroScan should not be used on patients with ascites, 

patients who are pregnant, or patients under the age of 

18 years 

Chronic HBV and Categories of Disease 

• Chronic HBV infection is defined as the presence of HBsAg 

seropositivity for ≥6 months 

Mild 

• Mild necroinflammation with no fibrosis 

• Normal or slightly elevated ALT levels 

Moderate to Severe 

• Moderate to severe necroinflammation, with fibrosis or 

cirrhosis 

• Elevated ALT levels 


25

diagnosis 

Compensated Cirrhosis 

• Knodell or METAVIR stage 4 fibrosis or Ishak fibrosis 

score 5 and 6 

• CTP score: 5–6 (Child’s class A) 

Decompensated Cirrhosis 

• NAFLD 

• Knodell or METAVIR stage 4 fibrosis or Ishak fibrosis 

score 5 and 6 

• CTP score: ≥7 (Child’s class B or C) 

• Ascites, variceal bleeding, overt jaundice, and/or 

encephalopathy 

Diagnostic Criteria for Phases 

of Chronic HBV Infection 

Definition 

HBsAg 

Chronic 

Hepatitis B 

(HBeAg positive) 

Chronic 

Hepatitis B 

(HBeAg negative) 

Chronic inflammatory disease of the 

liver caused by persistent infection 

with HBV 

Positive for 

>6 months 

Positive for 

>6 months 

Low Replicative 

Phase 

Persistent HBV 

infection of the 

liver without 

significant ongoing 

necroinflammatory 

disease 

Positive for 

>6 months 

HBeAg Positive Negative Negative 

Anti-HBe Negative Positive * Positive 

ALT/AST 

Persistent or 

intermittent 

increase 

Persistent or 

intermittent 

increase 

Persistently normal 

Serum 

HBV DNA 

>20,000 IU/mL 

(10 5 copies/mL) 

>2,000 IU/mL 

(10 4 copies/mL) 

diagnosis 

REFERENCES 

Bedossa P, Poynard T. The METAVIR Cooperative Study Group. An algorithm for 

the grading of activity in chronic hepatitis C. Hepatology. 1996;24:289–293. 

Child CG III, Turcotte JG. Surgery in portal hypertension. In: Child CG III, ed. 

The Liver and Portal Hypertension. Philadelphia: WB Saunders, 1964;50–64. 

de Franchis R, Hadengue A, Lau G, et al. The EASL Jury. EASL International 

Consensus Conference on Hepatitis B. J Hepatol. 2003;39(suppl):S3–S25. 

Hoofnagle JH, Doo E, Liang TJ, et al. Management of hepatitis B: summary of a 

clinical research workshop. Hepatology. 2007;45:1056-1075. 

Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic 

hepatitis. J Hepatol. 1995;22:696–699. 

Knodell RG, Ishak KC, Black WC, et al. Formulation and application of a 

numerical scoring system for assessing histological activity in asymptomatic 

chronic active hepatitis. Hepatology. 1981;1:431–435. 

Liaw YF, Tsai N. Natural history of chronic hepatitis B: implications for 

diagnostic testing and patient monitoring. Gastroenterol Hepatol. 2007; 

3(suppl 31):6–14. 

Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225–1241. 

Pugh RNH, Murray-Lyon IM, Dawson JL, et al. Transection of the esophagus in 

bleeding oesophageal varices. Br J Surg. 1973;60:648–652. 


27

management 

Management

management 

GENERAL PRINCIPLES 

• Chronic HBV infection can run a fluctuating disease course 

• Serial testing is often required to accurately categorize 

the stage of disease 

• Patient management is dictated by the severity of the 

hepatitis, the presence of cirrhosis, and whether it is 

compensated or decompensated 

• Thorough evaluation and counseling are mandatory 

before considering drug therapy 

• HCC surveillance should be performed in appropriate 

patients 

• Due to the limited sustained long-term efficacy of drugs 

currently approved for the treatment of chronic HBV, 

careful consideration should be given to the likelihood of 

sustained response, patient age, severity of liver disease, 

likelihood of drug resistance, adverse events, and 

complications when selecting antiviral therapy 

• Patients receiving oral antiviral therapy should be 

monitored for virologic response and resistance, and their 

therapy adjusted accordingly 

INITIAL EVALUATION 

• Comprehensive history and physical examination 

– Family history of HBV infection, liver disease, and HCC 

– Excessive alcohol consumption 

– Physical findings of advanced disease 

– Risk factors (including coinfection with HIV and/or 

other hepatitis viruses) 

• Diagnostic tests 

– Liver disease activity (AST, ALT, bilirubin) 

– Serologic and virologic markers of HBV replication (HBV 

DNA level, HBsAg, HBeAg, HBcAg) and coinfections 

(HCV, HAV, HDV, HIV) 

– Evaluation for disease stage (platelet, albumin, prothrombin 

time, ultrasound), HCC 


29

management 

COUNSELING 

• All patients require counseling about lifestyle modifications 

and ways to prevent transmission to others 

Lifestyle Contacts Alcohol 

• Prevention of 

transmission 

– Sexual 

– Perinatal 

– Blood spill 

• Sexual and household 

contacts 

– HBV testing 

recommended 

– Vaccination if test 

negative 

DISCUSSION OF TREATMENT OPTIONS 

• Heavy alcohol 

discouraged 

• Abstinence if cirrhosis 

present 

• Patients need to be fully informed 

• Explain the objectives of antiviral therapy (eg, prevent 

cirrhosis and HCC) 

• Discuss practical issues, including route of administration, 

efficacy, and potential adverse events 

• Explain how the following factors may affect treatment 

success 

– Severity of the liver disease present 

– Patient’s age 

– HBV DNA levels 

– Potential development of resistance 

– Presence of comorbidities 

• Expected length of treatment 

– Biochemical, virologic, or histologic end points used to 

define treatment response 

GENERAL MONITORING 

• All HBV carriers should be monitored 

• Monitoring is essential to assess 

– Progression of liver disease 

– Development of HCC 

– Need for treatment 

– Response to treatment (see On-Treatment Monitoring) 

• Patients with a rising trend in ALT (from normal or 

minimally elevated levels) or with ALT 5 × ULN should be 

monitored closely for weekly or biweekly serum bilirubin 

levels and prothrombin time measurement, particularly 

patients with increasing serum HBV DNA levels (10 8 

copies/mL) or advanced fibrosis 


management 

HCC Surveillance 

• Persons with chronic HBV infection at high risk for HCC 

include 

– Men aged >40 years 

– Persons with cirrhosis 

– Persons with a family history of HCC 

• HCC surveillance should usually be performed every 3 to 

6 months using both AFP and hepatic ultrasound or CT 

scan of liver 

Who to Treat: Candidates for Antiviral Therapy 

• Patients with HBeAg-positive or -negative CHB who have 

viral replication but persistently normal or minimally elevated 

ALT levels (40 years with detectable HBV DNA and elevated 

ALT levels, or those with high normal ALT levels 

HBeAg Positive (Figure 1) 

• HBeAg-positive patients who have persistently elevated 

ALT levels 2 to 5 × ULN and HBV DNA levels ≥20,000 

IU/mL (10 5 copies/mL) over 3 to 6 months or are at risk for 

hepatic decompensation should be considered for antiviral 

treatment 

• Treatment should be started as early as possible in case 

of impending or overt hepatic decompensation 

• HBeAg-positive patients who have elevated ALT levels 

>5 × ULN and HBV DNA levels ≥20,000 IU/mL 

(10 5 copies/mL) are candidates for antiviral therapy 


31

management 

Figure 1: Treatment Recommendations for 

HBeAg-Positive Patients 

• Treat if disease is 

persistent (3-6 months) 

or there are concerns 

about hepatic 

decompensation 

• IFN-based therapy, 

entecavir, tenofovir, 

telbivudine, lamivudine, 

and adefovir are all 

firstline options 

Patients at risk: HCC surveillance 

• AFP and ultrasonography every 6 months 

Adapted from: Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. 

Hepatol Int. 2008. Available at: http://www.springerlink.com/content/du475u12q655175j/fulltext.pdf. Accessed August 22, 2008. 

tenofovir, telbivudine, and 

entecavir, 


management 

HBeAg Negative (Figure 2) 

• HBeAg-negative patients who have persistently elevated 

ALT levels >2 × ULN and HBV DNA levels ≥2,000 IU/mL 

(10 4 copies/mL) over 3 to 6 months should be considered 

for treatment 

• HBeAg-negative patients who have ALT 1 to 2 × ULN and 

HBV DNA levels ≥2,000 IU/mL (10 4 copies/mL) should be 

closely monitored, and a liver biopsy is recommended for 

patients ≥40 years of age. Antiviral therapy should be 

considered if significant necroinflammation or fibrosis is 

present on biopsy. 

Cirrhosis (Compensated and Decompensated) (Figure 3) 

• As shown on page 35, patients with compensated cirrhosis 

who have HBV DNA levels >2000 IU/mL should be 

considered for antiviral treatment 

• Patients with decompensated cirrhosis and any HBV DNA 

level should receive antiviral therapy and be considered 

for liver transplantation 

GENERAL CONSIDERATIONS 

• Conventional IFN or PEG-IFN a-2a, lamivudine, adefovir, 

entecavir, tenofovir and telbivudine can all be considered 

for initial therapy in patients without liver decompensation 

– Compared with direct antiviral therapy, higher rates of 

sustained response can be achieved with IFN-based 

therapy, but IFN-based therapy has more side effects 

and requires closer monitoring 

• For viremic patients with elevated ALT levels (>5 × ULN), 

entecavir, telbivudine, or lamivudine is recommended if 

there is a concern about hepatic decompensation because 

of the rapid and profound reduction of HBV DNA levels 

achieved with these agents 

• For HBeAg-positive patients with an ALT level of 2 to 

5 × ULN, the choice between IFN-based therapy and 

direct antiviral agents is less clear and either agent may 

be used 

• Corticosteroid priming before IFN or lamivudine therapy 

is generally not recommended and should be used 

cautiously and only in expert centers and not in patients 

with advanced disease 


33

management 

Figure 2: Treatment Recommendations for 

HBeAg-Negative Patients 






management 

Figure 3: Treatment Recommendations for Patients With 

Cirrhosis (Compensated and Decompensated) 



IFN-based 

Entecavir 

Adefovir dipivoxil 

Tenofovir 

Telbivudine 

Lamivudine 



Entecavir 

Tenofovir 

Telbivudine 

Lamivudine 

Adefovir dipivoxil 


35

management 

DEFINITIONS OF VIROLOGIC RESPONSE 

• Maintained virologic response: undetectable serum 

HBV DNA and HBeAg seroconversion, if applicable, during 

therapy 

• Primary treatment failure: failure to reduce serum 

HBV DNA by 1 log 10 

IU/mL at 12 weeks of oral antiviral 

therapy in a compliant patient 

• Sustained virologic response: serum HBV DNA ≤2,000 

IU/mL (10 4 copies/mL) and HBeAg seroconversion, if 

applicable, for at ≥6 months after stopping therapy 

• Complete response: sustained virologic response with 

HBsAg seroclearance 

ON-TREATMENT AND POST-TREATMENT MONITORING 

On-Treatment 

• During therapy, ALT HBeAg and/or HBV DNA level should 

be monitored at least every 3 months 

• Renal function should be monitored if adefovir is used 

• During IFN therapy, monitoring of adverse effects is 

mandatory 

• High residual HBV DNA levels after the first 6 to 12 months 

of therapy is associated with an increased risk of viral 

resistance 

End of Therapy 

• A 6- to 12-month observation period after the end of IFN 

therapy is recommended to both detect delayed response 

and establish whether a response is sustained, and thus 

whether retreatment or other therapy is required 

• A 12-month observation period is recommended after the 

end of thymosin α-1 therapy 

• ALT and HBV DNA levels should be monitored monthly 

for the first 3 months to assess durability of response and 

detect early relapse, and then 

– Every 3 months for cirrhotic patients and those who 

remain HBeAg/HBV DNA positive 

– Every 6 months for patients who have PCR-undetectable 

HBV DNA 


management 

WHEN TO STOP OR CHANGE ANTIVIRAL THERAPY 

Reasons for stopping or changing antiviral therapy 

• Treatment end points are achieved 

• Inadequate response to therapy 

• Development of resistance 

STOPPING ANTIVIRAL THERAPY: 

TREATMENT END POINTS 

• Duration of IFN-based therapy is finite 

– Conventional IFN: 4 to 6 months for HBeAg-positive 

patients and ≥1 year for HBeAg-negative patients 

– PEG-IFN: ≥6 months for HBeAg-positive patients and 

12 months for HBeAg-negative patients 

• Thymosin α-1: 6 months for both HBeAg-positive and 

-negative patients 

• Traditional end points for stopping direct antiviral agents 

– For HBeAg-positive patients: HBeAg seroconversion 

with undetectable HBV DNA by PCR documented on 

2 separate occasions ≥6 months apart 

– For HBeAg-negative patients: the optimal duration of 

treatment is unknown and the decision to stop therapy 

should be determined by clinical response and severity 

of the underlying liver disease 

CHANGING ANTIVIRAL THERAPY 

• Modification of antiviral therapy should be considered for 

individuals who experience a primary nonresponse or 

viral breakthrough during treatment 

– Patients with primary nonresponse to antiviral therapy 

should be considered for alternate antiviral therapy to 

facilitate clinical response and minimize viral resistance 

• Viral breakthrough: defined as >1 log 10 

IU/mL increase of 

HBV DNA from nadir of initial response during therapy as 

confirmed 1 month later 

– Patients with viral breakthrough should be questioned 

regarding compliance and undergo testing for presence 

of HBV resistance mutations 


37

management 

ANTIVIRAL DRUG RESISTANCE 

• As shown in the following figure, a number of mutations 

in the reverse transcriptase region of the Pol gene are 

involved in conferring resistance and cross-resistance to 

specific antiviral agents 

– Primary resistance mutations, rtA181V/T and rtM204V/I, 

confer reduced susceptibility to most of the available 

oral nucleos(t)ide analogs 

– Additionally, broad clusters of compensatory mutations 

frequently arise during lamivudine therapy (rtV214A, 

rtQ215S vs rtI169T + rtV173L vs rtT184S). These 

mutations compromise future salvage therapy options 

with more potent NAs such as adefovir, tenofovir, 

and entecavir. 

Adapted from Locarnini S, et al. Antivir Ther. 2004;9:679-693. 


MANAGEMENT 

DRUG RESISTANCE: RESCUE STRATEGIES 

• Once viral breakthrough occurs, rescue therapy should be 

instituted as early as possible with a non–cross resistant 

drug 

• Current APASL recommendations for rescue therapy are 

as follows: 

Resistant Drug 

Lamivudine 

Adefovir in lamivudinenaive 

patient 

Entecavir 

Telbivudine 

Rescue Therapy 

Add on adefovir therapy 

or switch to entecavir (1 mg/day) 

Add on or switch to lamivudine, 

telbivudine, or entecavir 

Add on or switch to adefovir or tenofovir 

Add on adefovir therapy or switch to 

IFN-based therapy 

REFERENCES 

Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the 

management of chronic hepatitis B virus infection in the United States: an 

update. Clin Gastroenterol Hepatol. 2006;4:936–962. 

Keeffe EB, Dieterich DT, Pawlotsky JM, Benhamou Y. Chronic hepatitis B: 

preventing, detecting, and managing viral resistance. Clin Gastroenterol Hepatol. 

2008;6:268–274. 

Keeffe EB, Zeuzem S, Koff RS, et al. Report of an international workshop: 

roadmap for management of patients receiving oral therapy for chronic 

hepatitis B. Clin Gastroenterol Hepatol. 2007;5:890–897. 

Liaw YF, Leung N, Guan R, et al. Asian-Pacific consensus statement on the 

management of chronic hepatitis B: a 2005 update. Liver Int. 2005;25:472–489. 

Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on 

the management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008. 

Available at: http://www.springerlink.com/content/du475u12g655175j/fulltext. 

pdf. Accessed August 22, 2008. 

Locarnini S, Hatzakis A, Heathcote J, et al. Management of antiviral resistance 

in patients with chronic hepatitis B. Antivir Ther. 2004;9:679-693. 

Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–539. 

Lok AS, Zoulim F, Locarnini S, et al. Hepatitis B Virus Drug Resistance Working 

Group. Antiviral drug-resistant HBV: standardization of nomenclature and 

assays and recommendations for management. Hepatology. 2007;46:254–265. 


39

pharmacotherapy 

Pharmacotherapy


GOALS OF TREATMENT 

• Achievement of HBeAg seroconversion and/or sustained 

suppression of HBV DNA to levels below the level 

of detection using PCR-based methods and ALT 

normalization 

• Achievement of a durable response to prevent hepatic 

decompensation, reduce or prevent progression to 

cirrhosis and HCC, and prolong survival 

GENERAL CONSIDERATIONS 

• Thorough evaluation and counseling are mandatory 

before considering drug therapy 

• Selection of pharmacotherapy should include consideration 

of individual needs, likelihood of response, and economic 

factors of individual patients 

• The advantages of IFN-based therapy include finite 

duration of treatment with modest response, long-term 

benefit, and no resistance 

• PEG-IFN may eventually replace conventional IFN because 

of higher efficacy and more convenient once-weekly 

administration 

• Patients infected with HBV genotype C or D may require 

longer-term treatment with IFN-based therapy than may 

patients with genotype A or B 

• When choosing a direct oral antiviral agent, the resistance 

profile of the agents should be considered 

TREATMENT OPTIONS 

Commonly used for treatment of patients with CHB 

• Immunomodulatory therapy 

– IFN α-2b 

– PEG-IFN α-2a 

– Thymosin α-1* 

• Direct oral antiviral therapy 

– Lamivudine 

– Adefovir dipivoxil 

– Entecavir 

– Telbivudine 

– Clevudine † 

– Tenofovir 

*Approved for management of CHB in some Asian countries 

† Approved for management of CHB in Korea 


41


RESPONSE TO THERAPY 

Biochemical Virologic Histologic 

• Normalization of 

serum ALT 

• HBV DNA undetectable 

by unamplified 

assay 

• Loss of HBeAg ± 

development of anti-HBe 

• Loss of HBsAg ± 

development of anti-HBs 

• HAI decrease by 

≥2 points vs 

pretreatment liver 

biopsy 

DOSING 

Drug Adults Children 

IFN α-2b 

PEG-IFN α-2a 

Thymosin α-1 

Subcutaneous injection 

5–10 MU 3 times/week 

for 16–24 weeks 


180 µg/week for 

24–48 weeks 


1.6 mg twice weekly 


6 MU/m 2 3 times/week, 

to a maximum of 10 MU 

Not evaluated 

Not evaluated 

Lamivudine 

Oral 

100 mg/day* † Oral 

3 mg/kg per day, to a 

maximum of 100 mg/day 

Adefovir 

Entecavir 

Telbivudine 

Tenofovir 

Oral 

10 mg/day* 

Oral 

0.5 mg/day 

(nucleoside-naive) ‡ 

1.0 mg/day 

(lamivudine-refractory) ‡ 

Oral 

600 mg/day 

Oral 

300 mg/day 

Not evaluated 

Not evaluated 

Not evaluated 

Not evaluated 

*Normal renal function, no HIV coinfection 

† With HIV coinfection, 150 mg two times per day 

‡ Dosage adjustment recommended for patients with renal impairment 



COMPARISON OF TREATMENT OPTIONS 

General Considerations 

• Twelve-month IFN or PEG-IFN a-2a induces higher sustained 

response rates than direct antiviral agents in HBeAg-negative 

patients with intermittent or persistent ALT elevation, 

moderate to severe inflammation, fibrosis on biopsy, and 

serum HBV DNA levels of >2000 IU/mL (>10 4 copies/mL) 

• A rapid and profound reduction of HBV DNA levels can be 

achieved with direct antiviral agents, but long-term therapy is 

required and therefore the drug resistance profile of the drug 

to be used should be considered (see Resistance section) 

• Although PEG-IFN a-2b has been approved for the treatment 

of HBV infection in a few countries, the clinical experience 

with this agent in HBeAg-negative patients is limited 

Immunomodulatory Therapy: HBeAg–Positive Patients 

Parameter 

IFN 

(vs Untreated) 

12–24 

Weeks 

PEG-IFN α-2a 

(vs Lamivudine) 

48 Weeks 

Thymosin α-1 

(vs Untreated) 

24 Weeks 

HBV DNA loss* 37% (17%) 25% (40%) 30%–56% (7%) 

HBV DNA 

Log 10 

reduction 

Not reported 4.5 log 10 

(5.8) Not reported 

HBeAg loss 33% (12%) 30% (22%) 

at week 48 

34% (21%) 

at week 72 

HBeAg 

seroconversion 

HBsAg loss 11%–25% 

at 5 years in 

Caucasian 

patients 

ALT 

normalization 

Histologic 

improvement 

18% 27% (20%) 

at week 48 

32% (19%) 

at week 72 

23% (not 

reported) 

3% (0%) 

at week 72 

(HBsAg 

seroconversion) 

Poor data 38% (34%) 

at week 72 

23% 

Not reported 

Not reported 

39% (62%) 34%–39% 

(17%) 

Resistance No No No 

Durability of 

response after 

HBeAg 


80%–90% at 

4–8 years 

Not reported 

In responders 

Not reported 

Side effects Many Better than IFN Minimal 

Cost/year ++ +++ +++ 

All data are at 1 year unless otherwise stated. 

*Assays 


43


Drug Assay Used Lower Limit Undetectable 

IFN, lamivudine Hybridization 10 5 copies/mL — 

PEG-IFN α-2a 

PCR 

(Roche COBAS) 

— 


DIRECT ANTIVIRAL THERAPY WITH 

NUCLEOSIDES/NUCLEOTIDES IN HBeAg-POSITIVE PATIENTS 

Parameter 

Lamivudine 

(vs Placebo) 

48–52 Weeks 

Adefovir Dipivoxil 

(vs Placebo) 

48 Weeks 

Entecavir 

48 Weeks 

Telbivudine 

52 Weeks 

Tenofovir 

48 Weeks 

HBV DNA loss* 44% (16%) 21% (0%) 67% 60% 76% 

HBV DNA log 10 

reduction 5.39 log 10 

3.52 log 10 

(0.55) 6.86 log 10 

6.45 log 10 

— 

HBeAg loss 

17%–32% 

(6%–11%) 

24% (11%) 

46% at 96 weeks 


22% 26% 22% 

HBeAg 


16%–18% 

(4%–6%) 

50% at 5 years 

12% (6%) 



21% 22% 21% 

HBsAg loss


DIRECT ANTIVIRAL THERAPY WITH 

NUCLEOSIDES/NUCLEOTIDES IN HBeAg-NEGATIVE PATIENTS 

Parameter 

Lamivudine 

(vs Placebo) 

52 Weeks 

Adefovir Dipivoxil 

(vs Placebo) 

48 Weeks 

Entecavir 

48 Weeks 

Telbivudine 

52 Weeks 

Tenofovir 

48 Weeks 

HBV DNA loss* 63% (6%) 

at week 24 † 51% (0%) 90% 88% 93% 

HBV DNA 

log 10 

reduction 

3.00–4.00 log 10 

(1.50) 

3.91 log 10 

(1.35) 5.00 log 10 

5.23 log 10 

— 

HBsAg loss 0% (1.5%) 

at week 24 

Not reported


REFERENCES 

Bonino F, Marcellin P, Lau GK, et al. Predicting response to peginterferon 

alpha-2a, lamivudine and the two combined for HBeAg-negative chronic 

hepatitis B. Gut. 2007;56:699–705. 

Chan HL, Tang JL, Tam W, Sung JJ. The efficacy of thymosin in the treatment of 

chronic hepatitis B virus infection: a meta-analysis. Aliment Pharmacol Ther. 

2001;15:1899–1905. 

Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine 

for HBeAg-positive chronic hepatitis B. N Engl J Med. 2006;354:1001–1010. 

Chien RN, Liaw YF, Chen TC, et al. Efficacy of thymosin α1 in patients with 

chronic type B hepatitis: a randomized controlled trial. Hepatology. 1998;27: 

1383–1387. 

Cooksley WG. Treatment with interferons (including pegylated interferons) in 

patients with hepatitis B. Semin Liver Dis. 2004;24(suppl 1):45–53. 

Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in 

patients with HBeAg-positive chronic hepatitis B. Gastroenterology. 2007;133: 

1437–1444. 

Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with 

adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. 

Gastroenterology. 2006;131:1743–1751. 

Heathcote EJ, Gane E, DeMan R, et al. A randomized, double-blind, comparison 

of tenofovir (TDF) versus adefovir dipivoxil (ADV) for the treatment of HBeAg 

positive chronic hepatitis B (CHB): study GS-US-174-0103 [Abstract LB6]. 

Hepatology. 2007;46(4 suppl 1):861. 

Iino S, Toyota J, Kumada H, et al. The efficacy and safety of thymosin alpha-1 

in Japanese patients with chronic hepatitis B: results from a randomized 

clinical trial. J Viral Hepat. 2005;12:300–306. 

Keeffe EB, Dieterich DT, Han S-HB, et al. A treatment algorithm for the 

management of chronic hepatitis B virus infection in the United States: 2008 

Update. Clin Gastroenterol Hepatol. 2008;26 August 2008 (10.1016/j.cgh. 2008. 

08.021). 

Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with 

chronic hepatitis B. N Engl J Med. 2007;357:2576–2588. 

Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with 

HBeAg-negative chronic hepatitis B. N Engl J Med. 2006;354:1011–1020. 

Lai C-L, Gane E, Hsu CW, et al. Two-year results from the GLOBE trial in 

patients with hepatitis B: greater clinical and antiviral efficacy for telbivudine 

(LDT) vs lamivudine [Abstract 91]. Hepatology. 2006;44(4 suppl 1):22A. 

Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivudine, and the 

combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352: 

2682–2695. 

Lim SG, Wai CT, Lee YM, et al. A randomized, placebo-controlled trial of 

thymosin-alpha1 and lymphoblastoid interferon for HBeAg-positive chronic 

hepatitis B. Antivir Ther. 2006;11:245–253. 


47

PHARMACOTHERAPY 

Marcellin P, Buti M, Krastev Z, et al. A randomized, double-blind comparison 

of tenofovir DF (TDF) versus adefovir dipivoxil (ADV) for the treatment of 

HBeAg-negative chronic hepatitis B (CHB): study GS-US-174-0102 [Abstract 

LB2]. Hepatology. 2007;46(4 suppl 1):290A–291A. 

Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine 

alone, and the two in combination in patients with HBeAg-negative chronic 

hepatitis B. N Engl J Med. 2004;351:1206–1217. 

Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudinerefractory, 

HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130: 

2039–2049. 

You J, Zhuang L, Cheng HY, et al. A randomized, controlled, clinical study of 

thymosin alpha-1 versus interferon-alpha in [corrected] patients with chronic 

hepatitis B lacking HBeAg in China [corrected]. J Chin Med Assoc. 2005;68:65–72. 


special 

populations 

Special Populations

Special Populations 

HBV/HIV COINFECTION 

• Antiretroviral therapy should be initiated in HIV-infected 

patients coinfected with HBV when treatment for HBV 

infection is indicated regardless of CD4 cell count 

TREATMENT OF HBV ONLY 

• All HIV-infected patients with active HBV replication and 

elevated serum ALT levels may be considered for treatment, 

particularly those patients with low CD4 counts (


IMMEDIATE HIV TREATMENT NEEDED 

Treatment 

• Use combination therapy 

to avoid or delay the 

development of antiviral 

resistance 

• Use two active anti-HBV 

drugs and at least three 

anti-HIV agents 

• If lamivudine resistance is not 

present, use HAART including 

tenofovir plus lamivudine or 

emtricitabine 

• If lamivudine resistance 

present, use HAART including 

tenofovir 

• Use IFN for young patients 

who have low HBV DNA and 

high ALT levels, CD4 levels 

>350 cells/mm 3 , and are 

naive to antiretroviral therapy 

Monitoring 

• Evaluate and monitor HBV 

DNA, HBeAg, and ALT levels 

• Aim for HBV DNA levels 


PATIENTS WITH CONCURRENT HCV 

OR HDV INFECTION 

• The dominant virus should be identified before designing 

therapeutic strategy 

• Once the dominant viral infection has been determined 

treat the patient accordingly 

– If HBV is dominant, treatment should be aimed toward 

this virus 

– If HCV is dominant, standard IFN or PEG-IFN therapy in 

combination with ribavirin can achieve a sustained 

HCV clearance rate comparable to that in patients with 

HCV monoinfection 

– Lamivudine is ineffective in patients with chronic HDV 

infection 

NORMAL ALT LEVELS 

• Most Asian patients are diagnosed during the immune 

tolerant phase, when ALT is normal despite high HBV 

DNA levels 

• Age >40 years is an independent predictor of significant 

histologic disease in such patients 

• Significant HBV replication may be present if a patient has 

−Precore or core promoter mutant HBV 

−HBeAg negativity 

−Detectable anti-HBe 

Young patient, 

minimal liver disease 

Patient aged >35 to 40 years 

• Treatment not recommended 

for immune tolerant phase 

• Monitor the patient 

• Candidate for therapy if ALT 

level increases 

• Liver biopsy 

• Treat with antiviral therapy if 

– Liver disease present on 

biopsy 

– Active HBV replication 

(≥20,000 IU/mL for HBeAgpositive 

patients or ≥2,000 

IU/mL for HBeAg-negative 

patients) 


51


IMMUNOSUPPRESSION/CHEMOTHERAPY 

• Reactivation of HBV replication with decompensation 

occurs in 20% to 50% of CHB patients undergoing cancer 

chemotherapy or immunosuppressive therapy, especially 

that containing a high-dose steroid regimen 

– Reactivation commonly occurs after the first 2 to 3 

cycles of chemotherapy 

– High viral load at baseline is the most important risk 

factor for HBV reactivation 

• Lamivudine prophylaxis administered 1 week before the 

start and continued for ≥12 weeks after the end of 

chemotherapy can reduce HBV reactivation frequency 

and severity of flares and improve survival 

• HBsAg-negative patients, especially those receiving 

rituximab plus a steroid-containing regimen, should be 

closely monitored 

Chemotherapy Patients 

Prophylaxis 

Post-chemotherapy 

Lamivudine 100 mg orally daily 

within 1 week before beginning 

chemotherapy 

Lamivudine for ≥12 weeks after 

the end of chemotherapy 

Patients With Decompensated Liver Disease 

• Direct antiviral therapy is associated with improved clinical 

status and may reduce the need for liver transplantation 

– Lamivudine is the agent of choice for treatmentnaive 

patients with obvious or impending hepatic 

decompensation 

– Adefovir can be added to lamivudine therapy in patients 

with lamivudine-resistant HBV, but renal dysfunction is 

a potential problem in these patients and close 

monitoring of renal function is required 

– Entecavir, telbivudine, and tenofovir can also be 

considered. IFN-based therapy is contradicted in patients 

with Child’s B or C cirrhosis; due to lack of efficacy, risk 

for serious bacterial infections, and possible exacerbation 

of liver disease 



LIVER TRANSPLANTATION 

• Transplantation has become routine for patients with 

chronic hepatitis B and end-stage liver disease 

• Success has been enhanced by advances in antiviral therapy 

and in prophylaxis against reinfection (reinfection


Pediatric Patients 

• Perinatal infection is followed by a prolonged immune 

tolerant phase 

−Characterized by HBeAg, high HBV DNA, and normal 

ALT levels 

• Usually asymptomatic and histologically mild 

• Monitor children regularly with liver ultrasound and AFP 

• Antiviral therapy is usually not recommended in pediatric 

patients because of the apparent lack of long-term benefits 

and attendant risks of starting drug therapy 

• However, antiviral therapy is recommended in children 

with ensuing or overt hepatic decompensation 

Children >2 Years, ALT ≥2 × ULN 

IFN a (preferred) 

6 MU/m 2 SC 3 times/week for 

6 months 

Lamivudine 3 mg/kg per day PO, up to 100 

mg/day for 12 months 

REFERENCES 

Broderick A, Jonas MM. Management of hepatitis B in children. Clin Liver Dis. 

2004;8:387–401. 

Chien RN, Lin CH, Liaw YF. The effect of lamivudine therapy in hepatic 

decompensation during acute exacerbation of chronic hepatitis B. J Hepatol. 

2003;38:322–327. 

Farci P, Chessa C, Balestrieri C, et al. Treatment of chronic hepatitis D. J Viral 

Hepat. 2007;14(suppl 1):58–63. 

Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality in 

patients with decompensated chronic hepatitis B treated with antiviral therapy. 


Gane EJ, Angus PW, Strasser S, et al. Lamivudine plus low-dose hepatitis B 

immunoglobulin to prevent recurrent hepatitis B following liver transplantation. 


Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on the 

management of chronic hepatitis B: a 2008 update. Hepatol Int. 2008; Available 

at: http://www.springerlink.com/content/du475u12q655175j/fulltext.pdf. Accessed 

August 22,2008. 

Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant 

hepatitis B in pre- and post-liver transplantation. Hepatology. 2003; 38:1419–1427. 

Sokal E, Kelly D, Wirth S, et al. The pharmacokinetics (PK) and safety of a 

single dose of adefovir dipivoxil (ADV) in children and adolescents aged 2–17 

with chronic hepatitis B. J Hepatol. 2004;40(suppl 1):132. 

Terrault NA, Jacobson IM. Treating chronic hepatitis B infection in patients 

who are pregnant or are undergoing immunosuppressive chemotherapy. Semin 

Liver Dis. 2007;27(suppl 1):18-24. 

Thio CL, Locarnini S. Treatment of HIV/HBV coinfection: clinical and virologic 

issues. AIDS Rev. 2007;9:40–53. 


glossary 

AFP α-Fetoprotein 

AIDS Acquire immune deficiency syndrome 

ALD Alcoholic liver disease 

ALT Alanine aminotransferase 

AMA American Medical Association 

APASL Asian Pacific Association for the Study of the Liver 

AST Aspartate aminotransferase 

Anti-HBc Antibody to hepatitis B core antigen 

Anti-HBe Antibody to hepatitis B e antigen 

Anti-HBs Antibody to hepatitis B surface antigen 

BCG Bacille Calmette Guerin (vaccine) 

cccDNA Covalently closed circular deoxyribonucleic acid 

CHB Chronic hepatitis B 

CT Computed tomography 

CTP Child-Turcotte-Pugh 

DTP Diphtheria-tetanus-pertussis 

GGT γ-Glutamyltranspeptidase 

HAART Highly active antiretroviral therapy 

HAI Histology Activity Index 

HBcAb Hepatitis B core antibody 

HBcAg Hepatitis B core antigen 

HBeAg Hepatitis B e antigen 

HBIG Hepatitis B immune globulin 

HBsAg Hepatitis B surface antigen 

HBV Hepatitis B virus 

HCC Hepatocellular carcinoma 

HCV Hepatitis C virus 

HDV Hepatitis D virus 

HepB Hepatitis B (vaccine) 

HIV Human immunodeficiency virus 

IFN Interferon 

IgG Immunoglobulin G 

IgM Immunoglobulin M 

IM Intramuscular 

IRD Immune reconstitution disease 

IU International units 

IV Intravenous 

LT Liver transplantation 

MU Million units 

NA Nucleos(t)ide analog 

NAFLD Nonalcoholic fatty liver disease 

NRTI Nucleoside reverse transcriptase inhibitor 

PCR Polymerase chain reaction 

PEG-IFN Pegylated interferon 

PO Per os (by mouth) 

SC Subcutaneously 

ULN Upper limit of normal 

WHO World Health Organization 


55

cme activity: 

quiz 

Cme Activity: Quiz

cme activity: quiz 

University of Wisconsin 

School of Medicine and Public Health 

Office of Continuing Professional Development 

in Medicine and Public Health 

Post Test and evaluation 

To obtain AMA PRA category 1 Credit TM , participants must correctly answer 

7 of the 10 questions (70%). Please complete the CME answer sheet and 

evaluation form. 

1. Which of the following would be appropriate in patients who are HBsAgpositive 

upon initial screening? 

a. Determination of HBeAg status and HBV genotype 

b. Assessment for coinfection (eg, anti-HIV, anti-HCV, anti-HAV, 

anti-HDV) 

c. Administration of hepatitis A vaccine 

d. Monitoring of AST/ALT and HBV DNA levels for 6 months 

e. All of the above 

2. Which of the following is an indication that a patient has CHB? 

a. Persistence of HBsAg in the serum for ≥3 months 

b. Persistence of HBsAg in the serum for ≥6 months 

c. Persistence of HBeAg in the serum for ≥6 months 

3. What is the primary mode of transmission of hepatitis B in the Asia- 

Pacific region? 

a. Sexual contact 

b. Blood products 

c. Transplantation (eg, bone marrow, non-liver solid organ) 

d. Mother-to-infant 

e. Child-to-child 

4. Which of the following statements best relates to hepatitis B vaccination? 

a. Vaccination prevents 95% of CHB infections 

b. Universal vaccination for all infants and children, and selective 

vaccination for persons at risk, is the recommended standard of care 

c. Hepatitis B vaccination provides lifetime immunity 

d. Vaccination is very safe; common reactions include local pain and 

mild and transient fever 

e. All of the above 

5. Which phase of chronic HBV infection is characterized by high HBV DNA 

levels (>2 × 10 6 IU/mL), normal ALT levels, and no or minimal 

clinicopathologic changes? 

a. Residual or inactive phase 

b. Immune clearance phase 

c. Immune tolerant phase 

6. Patients who are aged >40 years with HBeAg-positive or -negative CHB 

who have high HBV DNA levels (≥20,000 IU/mL for HBeAg-positive and 

≥2,000 IU/mL for HBeAg-negative patients) but persistently normal or 

minimally elevated ALT levels (


7. Which of the following is considered a primary goal of treatment for 

patients with HBeAg-positive CHB infection? 

a. HBeAg seroconversion 

b. Sustained suppression of HBV DNA to levels below the level of 

detection using PCR-based methods 

c. ALT normalization 

d. All of the above 

8. Monitoring patients who are receiving antiviral therapy is essential to 

assess which of the following? 

a. Progression of liver disease 

b. Response to treatment 

c. HBV genotype 


e. a and b 

9. Which of the following statements is false regarding the treatment of 

patients with decompensated liver disease? 

a. Initiation of antiviral therapy should be considered only for patients with 

HBV DNA levels >20,000 IU/mL 

b. Lamivudine is the agent of choice for treatment-naive patients with 

obvious or impending hepatic decompensation 

c. Adefovir can be added to lamivudine therapy in patients with 

lamivudine-resistant HBV with close monitoring of renal function 

d. IFN-based therapy is contradicted in patients with Child’s B or C 

cirrhosis due to lack of efficacy and risk for serious bacterial infections 

and possible exacerbation of liver disease 

10. Which of the following statements is true regarding the treatment of 

HBV-HIV coinfection? 

a. All HIV-infected patients with active HBV replication and elevated serum 

ALT levels may be considered for treatment, particularly those patients 

with low CD4 cell counts and active liver disease 

b. Patients who require both anti-HBV and anti-HIV therapies should be 

treated with a fully suppressive antiretroviral regimen containing NRTIs 

with activity against both viruses as part of HAART 

c. The use of tenofovir, lamivudine, and entecavir is not recommended in 

patients who require treatment of their HBV infection only as these 

agents are active against HIV and their use may compromise future 

treatment options for HIV 




Did you find the information presented in the educational activity to be fair, 

balanced, and free of commercial bias? 

£ Yes £ No 

If no, please state reasons: 

Were the activity objectives met? 

£ Yes £ No 


Is the information presented useful in your practice? 

£ Yes £ No 


ANSWER FORM 

On the answer form below, please circle the letter that represents your answer 

for each question. You must answer at least 70% of the questions correctly to 

receive credit. 

1. a b c d e 6. a b 

2. a b c 7. a b c d 

3. a b c d e 8. a b c d e 

4. a b c d e 9. a b c d 

5. a b c 10. a b c d 

Please mail or fax your answer and evaluation form to: 

University of Wisconsin School of Medicine 

and Public Health, OCME 

2701 International Lane #208 

Madison, WI 53704 

USA 

Fax: (608) 240-2151 

Please type or print clearly: 

First Name 

Last Name 

Address 

City State ZIP 

Country 

Phone 

E-mail 

Degree: (select one) 

£MD £DO £Other 

I claim AMA PRA Category 1 Credit TM (up to 1) 

Signature 

Expiration Date: October 2009 


59

Asia-Pacific Pocket Guide to HEPATITIS B - Hepatitis B Foundation

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?