Asia Pacific Pocketguide

8/16/2019 Asia Pacific Pocketguide

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GUEST EDITORS

Professor Stephen A. LocarniniVictorian Infectious Diseases Reference Laboratory Victoria, Australia

Professor Masao OmataUniversity of Tokyo, Tokyo, Japan

Professor Dong Jin Suh Asan Medical Center, Seoul, Korea

EDUCATIONAL REVIEWER

Adnan Said, MDUniversity of WisconsinSchool of Medicine

and Public HealthMadison, 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

Asia-Pacific

Pocket Guide to

HEPATITIS B


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iAsia-Pacific Pocket Guide to Hepatitis B

NEEDS ASSESSMENTNowhere 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 AUDIENCEThis 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 OBJECTIVESAt 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

CME INFORMATION


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ii Asia-Pacific Pocket Guide to Hepatitis B

ACCREDITATIONThis activity has been planned and implemented in accordance with theEssential Areas and Policies of the Accreditation Council for ContinuingMedical Education (ACCME) through the joint sponsorship of the University ofWisconsin School of Medicine and Public Health and MDG DevelopmentGroup. The University of Wisconsin School of Medicine and Public Health isaccredited by the ACCME to provide continuing medical education for physicians.

All materials were reviewed by Adnan Said, MD, Assistant Professor ofMedicine in the Unit of Gastroenterology at the University of Wisconsin Schoolof Medicine and Public Health.

CREDIT

The University of Wisconsin School of Medicine and Public Health designatesthis educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)TM.Physicians should only claim credit commensurate with the extent of theirparticipation in the activity.

There are no prerequisites for this pocket guide and this activity will take 1hour to complete.

POLICY ON FACULTY AND SPONSOR DISCLOSUREAs 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 ofthe existence of any significant financial interest or any other relationship thesponsor or participating faculty members have with the manufacturer(s) ofany commercial product(s) discussed in this pocket guide. The participatingfaculty reported the following:

Professor Stephen A. Locarnini• 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

ACKNOWLEDGMENTThe University of Wisconsin School of Medicine and Public Health and MDGDevelopment Group gratefully acknowledge the independent educationalgrant provided by Novartis Pharmaceuticals AG.

Release Date: October 2008Expiration 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 writtenpermission of the publisher. The opinions expressed in the report are those

of the author and not to be construed as the opinions or recommendationsof the sponsor or the publisher. Readers are encouraged to check thecurrent prescribing information for all drugs and devices mentioned in thetext of this publication.

CME INFORMATION


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iiiAsia-Pacific Pocket Guide to Hepatitis B

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 haveresponded 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.

Professor Stephen A. LocarniniChairman, Asia-Pacific Steering Committee

of the ACT-HBV® InitiativeHead, 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.

INTRODUCTION


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OVERVIEW

OF HEPATITIS B

O v e r v i e w

O f H e p a t i t i s B


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1Asia-Pacific Pocket Guide to Hepatitis B

EPIDEMIOLOGY

• Chronic HBV infection is a serious public health problemaffecting ~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

PREVALENCE

• Varies greatly by geography and population subgroups

High >8% Asia, Southeast Asia, Sub-SaharanAfrica, Pacific Islands

Intermediate 2%–8% India, Pakistan, Korea, Malaysia,Singapore, Indonesia, Thailand

Low


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2 Asia-Pacific Pocket Guide to Hepatitis B

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 2.6–5.1Malaysia 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 Horizontal

• 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 chronicallyinfected but at a much lower rate

• Child-to-child• Household members• Healthcare settings

– Needle sticks– Infected workers(transmission risk higherthan for HIV or HCV)

• Injection of illicit drugs• Sexual contact• Blood products• Transplantation* (solid organ, bone marrow)

*Possible, but largely eliminated by HBsAg testing

OVERVIEW OF HEPATITIS B


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COINFECTION/SUPERINFECTION

• Concurrent infection with HCV, HDV, or HIV in HBV-infected 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, andmortality

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.

OVERVIEW OF HEPATITIS B


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VIROLOGY/

NATURAL HISTORY

V i r o l o

g y / N a t u r a l H i s t o r

y


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THE VIRUS

• HBV is a small enveloped DNA virus, partially doublestranded

• 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 theentire 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 animportant 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

VIROLOGY


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HBV LIFE CYCLE

1. HBV enters the hepatocyte via a cell surface receptor2. 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 theHBV 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 theability to produce cirrhosis

VIROLOGY


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GENERAL FEATURES

• The natural history of chronic HBV infection is a dynamicstate 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 infectedpatients 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 ofALT elevation andliver inflammationand fibrosis

• HBV DNA levels≥2,000−20,000IU/mL (≥104–5 copies/mL)

• Genotype C>B;D>A

• HBV mutations − T1762/A1764

in HBV corepromoter gene

− Precore mutation

• Habitual alcoholconsumption

• Habitual cigarettesmoking

• Aatoxin 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


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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 × 106 to

2 × 107 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 DNAlevels, 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

NATURAL HISTORY


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REACTIVATION

• Reactivation of HBV infection is defined as a reappearanceof 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 acutereactivations 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% ofHBsAg-positive patients, and as many as 6% of HBsAg-

negative 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 (


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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 104–5

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

NATURAL HISTORY


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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 develop-ment 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

NATURAL HISTORY


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REFERENCES

VirologyKramvis 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.

NATURAL HISTORY


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VACCINATION

V a c c i n a t i o n


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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 ORGANIZATIONIMMUNIZATION SCHEDULES AND DOSING

AgeHBV 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) HepB–dose 2(m) DTP-HepB–dose1(c)

10 weeks HepB–dose 2(m or c)

DTP-HepB–dose2(c)

14 weeks HepB–dose 3(m or c)

HepB–dose 3(m)

DTP-HepB–dose3(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 infectionsacquired 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


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DOSAGE

• Standard dose for INFANTS and CHILDREN (aged


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POSTVACCINATION TESTING

• Not routinely recommended following vaccination ofinfants, children, adolescents, or most adults with low-

risk 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 hepatitisB vaccine

– Nonresponder is a person who, despite correct

administration of a full course of hepatitis B vaccine,

has an anti-HBV titer of


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BOOSTERS

• Because vaccination efficacy lasts >15 years in personswith 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 abooster 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 InfectDis. 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.

VACCINATION


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DIAGNOSIS

D i a g n o s i s


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VIROLOGIC DIAGNOSTIC TOOLS

• The primary diagnostic tools are serologic markers ofHBV and antibodies to HBV

HBV Marker Antibodies to HBV

• HBV DNA• HBsAg• HBeAg

• 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

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

1 10 102 103 104 105 106 107 108 109 1010

AbbottMolecular

Diagnostics

Digene Corp.

RocheMolecularSystems

Artus-Biotech

Bayer Corp.

Abbott Realtime PCR

HBV Digene Hybrid-Capture I

HBV Digene Hybrid-Capture II

Ultra-Sensitive Digene

Hybrid-Capture II

Amplicor HBV Monitor

Cobas Amplicor HBV Monitor

Cobas Taqman 48 HBV

Real Art HBV PCR Assay

Versant HBV DNA 1.0

Versant HBV DNA 3.0

HBV DNA IU/mL

Available HBV DNA Assays:Dynamic Range

DIAGNOSIS


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HBV ANTIGENS

HBsAg • Protein expressed on surface of HBV• First serologic marker to appear after infection• General marker of infection

HBcAg • Nucleocapsid that encloses the viral DNA

HBeAg • Soluble viral protein secreted from infected cellswhen HBV replication is high

• Some variants of HBV do not produce HBeAg

(eg, precore mutant)

HBV ANTIBODIES

Anti-HBs • Produced in response to the envelope antigen• Confers protective immunity

• Detectable in patients who have recoveredfrom natural infection or who have gainedimmunity from vaccination

Anti-HBe • Produced in response to HBeAg• Appears after HBeAg has been cleared• Marker of reduced level of replication

Anti-HBc (IgM) • Marker of acute or recent infection• Appears with low titer in 15% to 20% of acute

flares of chronic HBV infection

Anti-HBc (IgG) • Marker of current or past infection• Found in recovery• Low-level carrier

DIAGNOSIS


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INTERPRETATION OF THE HEPATITIS B PANEL

Test Result Interpretation

HBsAgTotal anti-HBcAnti-HBs

–––

Susceptible

HBsAgAnti-HBcAnti-HBs

–++

Immune due to natural infection


––+

Immune due to hepatitis B vaccination

HBsAgAnti-HBcIgM anti-HBcAnti-HBs

+++–

Acutely infected(chronic hepatitis B with acute exacerbation,low-titer IgM anti-HBc)

HBsAgAnti-HBcIgM anti-HBcAnti-HBs

++––

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-HBsin serum

3. Undetectable level of HBsAg may bepresent in serum, and person is actuallychronically infected

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

DIAGNOSIS


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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


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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 (104 copies/mL)

increases the risk for progression to cirrhosis or HCC

• The role of liver biopsy in evaluation of chronic HBVinfection 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 Low HBV DNA, High ALT

Some patients may havesignificant liver disease

Some patients (small number)may have either active chronicHBV 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

DIAGNOSIS


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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


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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

b2-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 reliablenoninvasive 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

DIAGNOSIS


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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 PHASESOF CHRONIC HBV INFECTION

ChronicHepatitis B

(HBeAg positive)

ChronicHepatitis B

(HBeAg negative)Low Replicative

Phase

Definition Chronic inflammatory disease of theliver caused by persistent infectionwith HBV

Persistent HBVinfection of theliver withoutsignificant ongoingnecroinflammatory

diseaseHBsAg Positive for

>6 monthsPositive for>6 months

Positive for>6 months

HBeAg Positive Negative Negative

Anti-HBe Negative Positive* Positive

ALT/AST Persistent orintermittent

increase

Persistent orintermittent

increase

Persistently normal

SerumHBV DNA

>20,000 IU/mL(105 copies/mL)

>2,000 IU/mL(104 copies/mL)


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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 fordiagnostic 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.

DIAGNOSIS


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MANAGEMENT

M a n a g e m e n t


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MANAGEMENT

Figure 1: Treatment Recommendations forHBeAg-Positive Patients

P at i ent s at r i s k : H C C s ur v ei l l an c e

•A F P

an

d ul t r a

s on

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ph

y

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: L i a

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un

g N ,K a

o J H , et al .A

s i an- P a

ci f i c

c on

s en s u s s t at em

ent ont h

em

an

a g

em ent of ch r oni ch

e p at i t i s B

: a

2 0 0 8 u p d at e

.

H

e p at ol I nt .2

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v ai l a

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at

: h t t p : / / w w w . s pr i n

g er l i nk . c

om

/ c ont ent /

d u4

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t en

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or t h er e

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s


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MANAGEMENT

HBeAg Negative (Figure 2)• HBeAg-negative patients who have persistently elevated

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

(104 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 (104 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 ispresent 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 DNAlevel 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 consideredfor 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 ifthere 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


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MANAGEMENT

Figure 2: Treatment Recommendations forHBeAg-Negative Patients

P at i ent s at r i s k : H C C s ur v ei l l an c e

•A F P

an

d ul t r a

s on

o gr a

ph

y

e v er y

6 m

ont h

s

A

d a pt e

d f r om

: L i a

wY F ,L e

un

g N

,K a o J H , et al .A

s i an- P a

ci f i c

c on

s en s u s s t at em

ent ont h

em

an

a g

em ent of ch r oni ch

e p at i t i s B

: a

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.

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e p at ol I nt .2

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at

: h t t p : / / w w w . s pr i n

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om

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7 5 j /

f ul l t ex t . p

d f .A

c c e s s e d A

u g u s t 2 2 ,2

0 0 8 .


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MANAGEMENT

Figure 3: Treatment Recommendations for Patients WithCirrhosis (Compensated and Decompensated)

P a t i e n t s a t r i s k : H C C

s u r v e i l l a n c e

• A F P a n d u l t r a s o n o g r a p h y e v e r y 6

m o n t h s

A d a p t e d f r o m : L i a w Y F , L e u n g N , K a o J H ,

e t a l . A s i a n - P a c i f i c c o n s e n s u s s t a t e m e n t o n t h e m a n a g e m e n t o f c h r o n i c h e p a t i t i s B : a 2 0 0 8 u p

d a t e .

H e p a t o l I n t . 2 0 0 8 . A v a i l a b l e a t : h t t p : / / w

w w . s p r i n g e r l i n k . c o m / c o n t e n t /

d u 4 7 5 u 1 2 q 6 5 5 1 7 5 j / f u l l t e x t . p d f . A c c e s s e d A u g u s t 2

2 , 2 0 0 8

. I F N - b a s e d

E n t e c a v i r

A d e

f o v i r d i p i v o x i l

T e n o f o v i r

T e l b i v u d i n e

L a m i v u d i n e

E n t e c a v i r

T e n o f o v i r

T e l b i v u d i n e

L a m i v u d i n e

A d e f o v i r d i p i v o x i l


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DEFINITIONS OF VIROLOGIC RESPONSE

• Maintained virologic response: undetectable serumHBV DNA and HBeAg seroconversion, if applicable, during

therapy

• Primary treatment failure: failure to reduce serum

HBV DNA by 1 log10

IU/mL at 12 weeks of oral antiviral

therapy in a compliant patient

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

IU/mL (104 copies/mL) and HBeAg seroconversion, ifapplicable, 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 thuswhether retreatment or other therapy is required

• A 12-month observation period is recommended after the

end of thymosin a-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 whoremain HBeAg/HBV DNA positive

– Every 6 months for patients who have PCR-undetectable

HBV DNA

MANAGEMENT


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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 a-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 severityof 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 log10

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

MANAGEMENT


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ANTIVIRAL DRUG RESISTANCE

• As shown in the following figure, a number of mutationsin 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 mutationsfrequently 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


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DRUG RESISTANCE: RESCUE STRATEGIES

• Once viral breakthrough occurs, rescue therapy should beinstituted as early as possible with a non–cross resistant

drug

• Current APASL recommendations for rescue therapy are

as follows:

Resistant Drug Rescue Therapy

Lamivudine Add on adefovir therapyor switch to entecavir (1 mg/day)

Adefovir in lamivudine-naive patient

Add on or switch to lamivudine,telbivudine, or entecavir

Entecavir Add on or switch to adefovir or tenofovir

Telbivudine 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 themanagement 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.

MANAGEMENT


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PHARMACOTHERAPY

P

h a r m a c o t h e r a p y


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GOALS OF TREATMENT

• Achievement of HBeAg seroconversion and/or sustainedsuppression 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 requirelonger-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 OPTIONSCommonly used for treatment of patients with CHB

• Immunomodulatory therapy

– IFN a-2b

– PEG-IFN a-2a

– Thymosin a-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

PHARMACOTHERAPY


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RESPONSE TO THERAPY

Biochemical Virologic Histologic

• Normalization of serum ALT

• HBV DNA undetectableby unamplifiedassay

• Loss of HBeAg ±development of anti-HBe

• Loss of HBsAg ±development of anti-HBs

• HAI decrease by ≥2 points vspretreatment liverbiopsy

DOSING

Drug Adults Children

IFN a-2b Subcutaneous injection5–10 MU 3 times/weekfor 16–24 weeks

Subcutaneous injection6 MU/m2 3 times/week,to a maximum of 10 MU

PEG-IFN a-2a Subcutaneous injection180 µg/week for24–48 weeks

Not evaluated

Thymosin a-1 Subcutaneous injection1.6 mg twice weekly

Not evaluated

Lamivudine Oral 100 mg/day*†

Oral3 mg/kg per day, to amaximum of 100 mg/day

Adefovir Oral 10 mg/day*

Not evaluated

Entecavir Oral 0.5 mg/day(nucleoside-naive)‡

1.0 mg/day(lamivudine-refractory)‡

Not evaluated

Telbivudine Oral

600 mg/day

Not evaluated

Tenofovir Oral 300 mg/day

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

PHARMACOTHERAPY


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PHARMACOTHERAPY

COMPARISON OF TREATMENT OPTIONS

General Considerations• Twelve-month IFN or PEG-IFNa-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 (>104 copies/mL)

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

achieved with direct antiviral agents, but long-term therapy isrequired and therefore the drug resistance profile of the drug

to be used should be considered (see Resistance section)

• Although PEG-IFNa-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 a-2a(vs Lamivudine)

48 Weeks

Thymosin a-1(vs Untreated)24 Weeks

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

HBV DNA

Log10 reduction

Not reported 4.5 log10

(5.8) Not reported

HBeAg loss 33% (12%) 30% (22%)at week 4834% (21%)at week 72

23%

HBeAgseroconversion

18% 27% (20%)at week 4832% (19%)

at week 72

Not reported

HBsAg loss 11%–25%at 5 years inCaucasianpatients

3% (0%)at week 72(HBsAgseroconversion)

Not reported

ALTnormalization

23% (notreported)

39% (62%) 34%–39%(17%)

Histologicimprovement

Poor data 38% (34%)at week 72

In responders

Resistance No No No

Durability ofresponse afterHBeAgseroconversion

80%–90% at4–8 years

Not reported Not reported

Side effects Many Better than IFN Minimal

Cost/year ++ +++ +++

All data are at 1 year unless otherwise stated.

*Assays


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PHARMACOTHERAPY

DIRECT ANTIVIRAL THERAPY WITHNUCLEOSIDES/NUCLEOTIDES IN HBeAg-POSITIVE PATIENTS

All data are at 1 year unless otherwise stated. Duration of treatment has not

been established.*Assays

Drug Assay UsedLowerLimit

Undetectable

Lamivudine Hybridization 105 copies/mL —

Adefovir PCR(Roche AMPLICOR

MONITOR)

400 copies/mL —

Entecavir, telbivudine,and tenofovir

PCR(Roche COBAS)

—


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PHARMACOTHERAPY

DIRECT ANTIVIRAL THERAPY WITHNUCLEOSIDES/NUCLEOTIDES IN HBeAg-NEGATIVE PATIENTS

All data are at 1 year unless otherwise stated. Duration of treatment has not

been established.*Assays†Combined efficacy end point of loss of serum HBV DNA and normalization of ALT.

Drug Assay Used Lower Limit Undetectable

Lamivudine Hybridization 105 copies/mL —

Adefovir PCR (RocheAMPLICOR MONI-

TOR)400 copies/mL —

Entecavir, Telbivudine,and Tenofovir

PCR (Roche COBAS) —


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REFERENCES

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

alpha-2a, lamivudine and the two combined for HBeAg-negative chronichepatitis 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 a1 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 inpatients 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 chronichepatitis B. Antivir Ther. 2006;11:245–253.

PHARMACOTHERAPY


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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 lamivudine-

refractory, 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.

PHARMACOTHERAPY


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SPECIAL

POPULATIONS

S p e c i a l P o p u l a t i o n s


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IMMEDIATE HIV TREATMENT NEEDED

Treatment Monitoring

• Use combination therapyto avoid or delay thedevelopment of antiviralresistance

• Use two active anti-HBVdrugs and at least threeanti-HIV agents

• If lamivudine resistance is notpresent, use HAART includingtenofovir plus lamivudine oremtricitabine

• If lamivudine resistancepresent, use HAART includingtenofovir

• Use IFN for young patients

who have low HBV DNA andhigh ALT levels, CD4 levels>350 cells/mm3, and arenaive to antiretroviral therapy

• Evaluate and monitor HBVDNA, HBeAg, and ALT levels

• Aim for HBV DNA levels


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IMMUNOSUPPRESSION/CHEMOTHERAPY

• Reactivation of HBV replication with decompensationoccurs 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 Lamivudine 100 mg orally dailywithin 1 week before beginningchemotherapy

Post-chemotherapy Lamivudine for ≥12 weeks afterthe 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 treatment-

naive 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 beconsidered. 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

SPECIAL POPULATIONS


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LIVER TRANSPLANTATION

• Transplantation has become routine for patients withchronic hepatitis B and end-stage liver disease

• Success has been enhanced by advances in antiviral therapy

and in prophylaxis against reinfection (reinfection


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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/m2 SC 3 times/week for6 months

Lamivudine 3 mg/kg per day PO, up to 100mg/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 hepaticdecompensation 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 ViralHepat . 2007;14(suppl 1):58–63.

Fontana RJ, Hann HW, Perrillo RP, et al. Determinants of early mortality inpatients with decompensated chronic hepatitis B treated with antiviral therapy.

Gastroenterology . 2002;123:719–727.

Gane EJ, Angus PW, Strasser S, et al. Lamivudine plus low-dose hepatitis Bimmunoglobulin to prevent recurrent hepatitis B following liver transplantation.Gastroenterology . 2007;132:931–937.

Liaw YF, Leung N, Kao JH, et al. Asian-Pacific consensus statement on themanagement of chronic hepatitis B: a 2008 update. Hepatol Int. 2008; Availableat: 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-resistanthepatitis 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 asingle dose of adefovir dipivoxil (ADV) in children and adolescents aged 2–17with 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. SeminLiver Dis. 2007;27(suppl 1):18-24.

Thio CL, Locarnini S. Treatment of HIV/HBV coinfection: clinical and virologicissues. AIDS Rev . 2007;9:40–53.

SPECIAL POPULATIONS


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AFP a-Fetoprotein

AIDS Acquire immune deficiency syndrome

ALD Alcoholic liver disease

ALT Alanine aminotransferase

AMA American Medical Association

APASL Asian Pacic 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 therapyHAI 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 virusHCC Hepatocellular carcinoma

HCV Hepatitis C virus

HDV Hepatitis D virus

HepB Hepatitis B (vaccine)

HIV Human immunodeficiency virus

IFN Interferon

IgG Immunoglobulin GIgM Immunoglobulin M

IM Intramuscular

IRD Immune reconstitution disease

IU International units

IV Intravenous

LT Liver transplantation

MU Million unitsNA 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 SubcutaneouslyULN Upper limit of normal

WHO World Health Organization

GLOSSARY


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CME ACTIVITY:

QUIZ

C m e

A c t i v i t y : Q u i z


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University of WisconsinSchool 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 answer7 of the 10 questions (70%). Please complete the CME answer sheet andevaluation form.

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

positive 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 monthsc. 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 DNAlevels (>2 × 106 IU/mL), normal ALT levels, and no or minimalclinicopathologic 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 orminimally elevated ALT levels (


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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 FORMOn 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 b2. a b c 7. a b c d3. a b c d e 8. a b c d e4. a b c d e 9. a b c d5. a b c 10. a b c d

Please mail or fax your answer and evaluation form to:University of Wisconsin School of Medicineand Public Health, OCME2701 International Lane #208Madison, WI 53704

USAFax: (608) 240-2151

Please type or print clearly:

First Name

Last Name

Address

City State ZIP

Country

Phone

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Degree: (select one)

£MD £DO £Other

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

Expiration Date: October 2009

CME ACTIVITY: QUIZ


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