CME Information

CME MONOGRAPH ARTICLE You have requested to view an article that is part of a CME monograph. In keeping with ACCME standards, you have been directed to a file that contains all the articles published in this monograph. Before reading any of the articles (and certainly before taking the CME Posttest), please read the required CME Information, which may be found in this file before the articles.

THE AMERICAN JOURNAL of MEDICINE

December 2008

®

Volume 121 Number 12A

Optimizing Management Strategies in Patients with Chronic Hepatitis B GUEST EDITOR Eugene R. Schiff, MD Schiff Liver Institute Director, Center for Liver Disease University of Miami School of Medicine Miami, Florida

This CME-certified activity is jointly sponsored by Postgraduate Institute for Medicine and Strategic Consultants International. This supplement was supported by an educational grant from Bristol-Myers Squibb. Medical writing and editorial assistance was provided by Strategic Consultants International, Hemel Hempstead, United Kingdom. Statement of Peer Review: All supplement manuscripts submitted to The American Journal of Medicine for publication are reviewed by the Guest Editor(s) of the supplement, by an outside peer reviewer who is independent of the supplement project, and by the Journal’s Supplement Editor (who ensures that questions raised in peer review have been addressed appropriately and that the supplement has an educational focus that is of interest to our readership). Author Disclosure Policy: All authors contributing to supplements in The American Journal of Medicine are required to fully disclose any primary financial relationship with a company that has a direct fiscal or financial interest in the subject matter or products discussed in the submitted manuscripts, or with a company that produces a competing product. These relationships (e.g., ownership of stock or significant honoraria or consulting fees) and any direct support of research by a commercial company must be indicated on the title page of each manuscript. This information will be published in the frontmatter of each supplement.

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THE AMERICAN JOURNAL of MEDICINE ®

December 2008 Volume 121 Number 12A

Optimizing Management Strategies in Patients With Chronic Hepatitis B S1

Introduction Eugene R. Schiff

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Demography and Presentation of Chronic Hepatitis B Virus Infection E. Jenny Heathcote

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Diagnosis of Chronic Hepatitis B and the Implications of Viral Variants and Mutations Robert G. Gish

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Assessment of the Newly Diagnosed Patient with Chronic Hepatitis B Virus Infection Robert J. Fontana

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Therapeutic Strategies for Chronic Hepatitis B Virus Infection in 2008 Asim Khokhar and Nezam H. Afdhal

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Implementing Evidenced-Based Practice Guidelines for the Management of Chronic Hepatitis B Virus Infection Brian J. McMahon

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CME Section

CME INFORMATION Optimizing Management Strategies in Patients with Chronic Hepatitis B Statement of Need/Program Overview The management of CHB infection is evolving as new data and novel agents become available. The revised guidelines from the AASLD highlight many of the ongoing changes. Physicians are required to implement evidence-based guidelines in their clinical practice. However, clinical practice is often far-removed from the trial setting and many patients do not fit neatly into the categories defined within the guidelines. Consequently, physicians rely on educational activities which provide expert opinion on how the guidelines can be implemented in clinical practice and how patients who fall outside the recommendations should be managed. The purpose of the activity is to provide an update on the current data in hepatitis B management and its application in clinical practice and to share expert opinion on application of the revised AASLD Practice Guidelines.

Target Audience This activity has been designed to meet the educational needs of internists, infectious disease specialists and gastroenterologists involved in the management of patients with chronic hepatitis B.

Educational Objectives After completing this activity, the participant should be better able to: ● Identify patients at high risk of hepatitis B infection. ● Identify the serological markers that can be used to distinguish different sub-types of chronic hepatitis B infection. ● Outline appropriate follow-up strategies in patients with chronic hepatitis B infection. ● Describe the eligibility criteria for treatment for HBeAg-positive and HBeAg-negative disease. ● Describe the effect of various options for the long-term virological control of chronic hepatitis B and the potential impact on clinical outcomes. ● Outline the clinical application of the latest guidelines for treatment of chronic hepatitis B

Method of Participation There are no fees for participating and receiving CME credit for this activity. During the period December 2008 through December 31, 2009 participants must 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the posttest by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. A statement of credit will be issued only upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better. Your statement of credit will be mailed to you within three weeks.

Media Journal Supplement

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Accreditation Statement 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 Postgraduate Institute for Medicine (PIM) and Strategic Consultants International. PIM is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement Postgraduate Institute for Medicine designates this educational activity for a maximum of 3.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine (PIM), Strategic Consultants International and Bristol-Myers Squibb do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of PIM, Strategic Consultants International and Bristol-Myers Squibb. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. This activity is jointly sponsored by Postgraduate Institute for Medicine and Strategic Consultants International

This activity is supported by an educational grant from Bristol-Myers Squibb Company Release Date: December 2008 Expiration Date: December 31, 2009 Estimated time to complete activity: 3 hours

Optimizing Management Strategies in Patients with Chronic Hepatitis B Infection

Guest Editor Eugene R. Schiff, MD Schiff Liver Institute Director, Center for Liver Disease University of Miami School of Medicine Miami, Florida

Faculty Nezam H. Afdhal, MD Associate Professor of Medicine Harvard School of Medicine Beth Israel Deaconess Medical Center Boston, Massachusetts

E. Jenny Heathcote, MD Professor of Medicine Toronto Western Hospital University of Toronto Toronto, Ontario, Canada

Robert J. Fontana, MD Associate Professor of Medicine Medical Director of Liver Transplantation Division of Gastroenterology University of Michigan Ann Arbor, Michigan

Asim Kohkar, MD Beth Isreal Deaconess Medical Center Boston, Massachusetts

Robert G. Gish, MD Medical Director, Liver Transplant Program California Pacific Medical Center San Francisco, California

Brian J. McMahon, MD Scientific Program & Clinical Director Liver Disease and Hepatitis Program Alaska Native Medical Center Anchorage, Alaska

Faculty Disclosures Postgraduate Institute for Medicine (PIM) assesses conflict of interest with its instructors, planners, managers and other individuals who are in a position to control the content of CME activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CME activity:

Nezam H. Afdhal, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb, Gilead Sciences, Inc., Idenix/ Novartis, and Schering-Plough; has received research/grant support from Bristol-Myers Squibb, Cooley Pharmaceuticals, Echosens, GlaxoSmithKline, Gilead Sciences, Inc., Idenix Pharmaceuticals, Inc., Idun Pharmaceuticals, Inc., Intermune Pharmaceuticals, Inc., Isis Pharmaceuticals, Inc., Novartis, Ortho Biotech Products, Prometheus Laboratories Inc., Quest Diagnostics Inc., Schering-Plough, Salix Pharmaceuticals Inc., United Therapeutics Corporation, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Inc.; serves as a consultant to Arrow Pharmaceuticals Pty, Ltd., Atlas Pharmaceuticals Inc., BioCryst Pharmaceuticals Inc., Biogen Idec, Echosens, Gilead Sciences, Inc., GlaxoSmithKline, Idenix Pharmaceuticals Inc., Idera Pharmaceuticals Inc., Isis Pharmaceuticals Inc., Intermune Pharmaceuticals Inc., Novartis, Ortho Biotech Products, Prometheus Laboratories Inc., Salix Pharmaceuticals, Inc., Schering-Plough, Sirtris Pharmaceuticals, Inc., Stromedix, Valeant Pharmaceuticals International, Vertex Pharmaceuticals Inc., Wyeth/ViroPharma, and XTL Pharmaceuticals. Robert J. Fontana, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb, and Roche Laboratories; and serves as a consultant to Bristol-Myers Squibb. Robert G Gish, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb, F. Hoffman-LaRoche Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Ortho Biotech Products, L.P., Salix, Schering-Plough Corporation, and Valeant Pharmaceuticals International; serves as a consultant to Amgen Inc., Anadys Pharmaceuticals, Inc., Bayer AG, Bristol-Myers Squibb, Chiron Corporation, Corixa Corporation, Eximias Pharmaceutical Corporation, F. Hoffman-LaRoche Ltd., Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., HepaHope, Inc., Human Genome Sciences, Idenix Pharmaceuticals, Inc., Innogenetics NV, InterMune Pharmaceuticals, Inc., Merck & Co., Metabasis Therapeutics, Inc., Nucleonics, Inc., Ortho Biotech Products, L.P., Salix, Schering-Plough Corporation, SciClone Pharmaceuticals, Inc., and Valeant Pharmaceuticals International; and has received research/grant support from Bristol-Myers Squibb, F. Hoffman LaRoche Ltd., Gilead Sciences, Inc., GlobeImmune Idenix/Novartis, InterMune Pharmaceuticals, Inc., Ortho Biotech Products, L.P., Pfizer Inc, Salix, Schering-Plough Corporation, SciClone Pharmaceuticals, Inc., and Valeant Pharmaceuticals International. E. Jenny Heathcote, MD, is a member of the Speakers’ Bureau for Hoffman-La Roche, Inc., has received research/grant support from Axcan Pharma, Boehringer-Ingelheim, Bristol-Myers Squibb, Debiopharma, Human Genome Sciences, Gilead Sciences, Inc., GlaxoSmithKline, Novartis, Pharmasett, Schering-Plough and Vertex; and serves as an advisor to Gilead Sciences, Inc, Schering-Plough, and Hoffman-LaRoche, Inc. Asim Khokhar, MD, reports no relationships to a manufacturer of a product or device discussed in this supplement. Brian J McMahon, MD, reports no relationships to a manufacturer of a product or device discussed in this supplement. Eugene R. Schiff, MD, is a member of the Speakers’ Bureau for Gilead Sciences, Inc., Ortho Biotech Products, L.P., and Schering Plough; has received research/grant support from Abbott Laboratories, Bayer, Bristol-Myers Squibb, Coley Pharmaceutical Group, Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., Idenix Pharmaceuticals, Inc., LabCorp, Merck & Co., Novartis/Idenix, Pfizer Inc., Prometheus, Roche Diagnostics, Roche Molecular, Roche Pharmaceuticals, Salix Pharmaceuticals, Ltd., Schering-Plough, and Vertex Pharmaceuticals; and serves as a consultant to Abbott Laboratories, Achillion Pharmaceuticals, Inc., Bayer, Bristol-Myers Squibb, Cadence Pharmaceuticals, Inc. Daiichi-Sankyo, Dynavax Technologies Corporation, Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., Idenix Pharmaceuticals, Inc., Merck

& Co., Novartis/Idenix, Ortho Biotech Products, L.P., Pfizer Inc., Prometheus, Roche Molecular, Salix Pharmaceuticals, Ltd., and Schering Plough. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Ian Morgan, MSc (Strategic Consultants International) has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. Kate Ackrill, PhD (Strategic Consultants International) has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement. Trace Hutchison, PharmD (Postgraduate Institute for Medicine) has no real or apparent financial relationships to disclose related to the topic of this activity. Jan Hixon, RN, BSN, MA (Postgraduate Institute for Medicine) has no real or apparent financial relationships to disclose related to the topic of this activity. Linda Graham, RN, BSN, BA (Postgraduate Institute for Medicine) - has no real or apparent financial relationships to disclose related to the topic of this activity.

Editorial

Introduction Worldwide, hepatitis B remains significant: 2 billion individuals have been infected with the hepatitis B virus (HBV). Of these, 350 million have chronic hepatitis B (CHB).1 Even in areas with overall low prevalence significant numbers of people may be affected: in the United States up to 2 million patients may have CHB.2–5 In certain indigenous populations in the United States, Canada, New Zealand, and Australia, the prevalence of seropositivity may be ⬎5%.6 In addition, in countries in which prevalence is low among those born in the country, high prevalence rates may be found in communities of immigrants from areas with high endemicity.7 Approximately 25% of individuals infected with HBV in childhood will go on to develop cirrhosis or primary liver cancer (hepatocellular carcinoma [HCC]) as adults.8 Infection with HBV accounts for up to 1.2 million deaths per year.8 Vaccination is fundamental to the elimination of transmission of HBV infection,3,9,10 but vaccination is effective only in uninfected individuals, and the growing reservoir of existing carriers remains an issue that has been inadequately addressed. Extended diagnostic screening services, coupled with vaccination or referral of tested individuals and their contacts, have the potential to prevent serious disease and reduce HBV transmission. To this end, an understanding of the natural history of infection and epidemiology, and the appropriate use and interpretation of laboratory tests is required.10 Although treatment of CHB usually takes place under the supervision of a specialist in hepatology or gastroenterology, effective identification of patients at risk for infection and the implementation of appropriate screening and assessment strategies requires the expertise of all healthcare professionals. Initial assessment should include a complete history and physical examination and serum liver biochemistry tests; laboratory markers of HBV replication including hepatitis B e-antigen, hepatitis B e-antibody, and a quantitative HBV DNA level also should be obtained in all patients with newly diagnosed CHB.11,12 Patients with CHB and elevated alanine aminotransferase and HBV DNA levStatement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Eugene R. Schiff, MD, Schiff Liver Institute, Center for Liver Diseases, University of Miami School of Medicine 1500 NW 12 Avenue, Jackson Medical Tower E-1101, Miami, Florida 33136.

0002-9343/$ -see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjmed.2008.09.023

els (⬎2,000 IU/mL) should be referred to a specialist for evaluation for possible treatment, which may include oral antiviral therapy with nucleoside/nucleotide analogs, or interferon/peginterferon.11,12 This supplement to The American Journal of Medicine draws together a series of articles that review the natural history of hepatitis B and key management steps for patients with chronic HBV infection. In the first article, Dr. E. Jenny Heathcote reviews the natural history of HBV infection and the burden of disease resulting from chronic infection. Next, Dr. Robert G. Gish considers the diagnosis of infection with HBV, and the role of serologic markers, and Dr. Robert J. Fontana discusses the assessment of the newly diagnosed patient with CHB. Drs. Asim Khokhar and Nezam Afdhal provide a concise review of the therapeutic options for the management of patients with CHB. In the final article, Dr. Brian J. McMahon describes the implementation of effective strategies to manage patients and the role of treatment guidelines in optimizing outcomes. We hope that the reviews in this supplement provide a helpful, clinically relevant summary of current best-practice management of HBV infection to reduce the risk of serious sequelae. Eugene R. Schiff, MD Schiff Liver Institute Center for Liver Diseases University of Miami School of Medicine Miami, Florida, USA E-mail address: [email protected].

AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Eugene R. Schiff, MD, is a member of the Speakers’ Bureau for Gilead Sciences, Inc., Ortho Biotech Products, L.P., and Schering-Plough; receives research grant support from Abbott Laboratories, Bayer, Bristol-Myers Squibb, Coley Pharmaceutical Group, Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., Idenix Pharmaceuticals, Inc., LabCorp, Merck & Co., Novartis/ Idenix, Pfizer Inc, Prometheus, Roche Diagnostics, Roche Molecular, Roche Pharmaceuticals, Salix Pharmaceuticals, Ltd., Schering-Plough, and Vertex Pharmaceuticals; and serves as a consultant to Abbott Laboratories, Achillion Phar-

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The American Journal of Medicine, Vol 121, No 12A, December 2008 maceuticals, Inc., Bayer, Bristol-Myers Squibb, Cadence Pharmaceuticals, Inc., Daiichi-Sankyo, Dynavax Technologies Corporation, Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., Idenix Pharmaceuticals, Inc., Merck & Co., Novartis/Idenix, Ortho Biotech Products, L.P., Pfizer Inc, Prometheus, Roche Molecular, Salix Pharmaceuticals, Ltd., and Schering-Plough.

References 1. World Health Organization. Hepatitis B. WHO Fact Sheet No. 2004, revised October 2000. [WHO Web site.] Available at: http://www. who.int/mediacentre/factsheets/fs204/en/. Accessed July 18, 2008. 2. Centers for Disease Control and Prevention (CDC). Incidence of acute hepatitis B—United States, 1990 –2002. MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254. 3. Gish RG, Locarnini SA. Chronic hepatitis B: current testing strategies. Clin Gastroenterol Hepatol. 2006;4:666-676. 4. McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination surveys, 1976 through 1994. Am J Pub Health. 1999;89:14-18. 5. Cohen C, Evans AA, London WT, Block J, Conti M, Block T. Underestimation of chronic hepatitis B virus infection in the United States of America. J Viral Hepat. 2008;15:12-13. 6. Department of Vaccines and Biologicals, World Health Organization. Introduction of Hepatitis B Vaccine into Childhood Immuni-

7.

8.

9.

10.

11. 12.

zation Services. Geneva: WHO, 2001. Available at: http://www. who.int/vaccines-documents/DocsPDF01/www613.pdf. Accessed July 18, 2008. Centers for Disease Control and Prevention (CDC). Screening for chronic hepatitis B among Asian/Pacific Islander populations—New York City, 2005. MMWR Morb Mortal Wkly Rep. 2006;55:505-509. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. Mast EE, Margolis HS, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16): 1-31. Mast EE, Weinbaum CM, Fiore AE, et al. For the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45: 507-539. Keeffe EB, Dieterich DT, Han SB, 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.

Supplement issue

Demography and Presentation of Chronic Hepatitis B Virus Infection E. Jenny Heathcote, MD Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada

ABSTRACT Currently, ⬎350 million people worldwide are affected by chronic infection with the hepatitis B virus (HBV). Chronic infection may cause cirrhosis and hepatocellular carcinoma; HBV infection is responsible for 328,000 cancer deaths per year. In areas of high HBV endemicity, most infections occur early in life; infected children do not mount an effective immune response and exhibit immune tolerance, so that the risk of chronic infection is high. In areas of low endemicity, infections tend to be in adults within defined risk groups, and the risk of chronicity is much lower. Population migration from areas of high endemicity to areas of low endemicity is creating pockets of HBV infection in areas of low general prevalence, necessitating improved efforts to screen, vaccinate, and treat. Chronic HBV infection is a complicated, nonlinear disease with a variable course of progression; predictors of progression include the duration of time in the immunoactive phase of disease that follows the immune tolerant phase when hepatocytes are attacked. Additionally, the duration of a high viremic state, with ongoing clinical hepatitis and possibly concurrent infections (e.g., hepatitis C, human immunodeficiency virus), influence outcome. Targeted vaccination of high-risk groups has many limitations. Universal childhood vaccination to prevent chronic infection and its sequelae is the only approach that will lead to the global elimination of chronic HBV infection. © 2008 Published by Elsevier Inc. • The American Journal of Medicine (2008) 121, S3–S11 KEYWORDS: Chronic hepatitis B; Hepatitis B vaccine; Hepatocellular carcinoma

Of the 2 billion individuals who have been infected with the hepatitis B virus (HBV), ⬎350 million are affected by chronic hepatitis B (CHB).1 Prevalence of CHB, as identified by hepatitis B surface antigen (HBsAg) positivity, varies geographically (Figure 1).2 Approximately 45% of the world’s population lives in areas of high endemicity, where the prevalence of CHB is ⬎8%, and 12% live where the prevalence of CHB is ⬍2%3 (i.e., areas of low endemicity). Areas of high endemicity include Southeast Asia and the Pacific Basin (excluding Japan, Australia, and New Zealand), China, sub-Saharan Africa, the Amazon Basin, parts of the Middle East, the Arctic, and the central Asian Republics (Table 1)2-4: Up to 1 in 5 people in these areas may be HBsAg positive; there are an estimated 100 million HBV Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to E. Jenny Heathcote, MD, Toronto Western Hospital, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada. E-mail address: [email protected].

0002-9343/$ -see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjmed.2008.09.024

carriers in China.5 Areas of intermediate endemicity include the Mediterranean and Eastern Europe; prevalence is low in North America and Western and Northern Europe. Even in areas with overall low prevalence, however, significant numbers may be affected, including 1.1 to 2 million individuals in the United States.6 In certain indigenous populations in the United States, Canada, New Zealand, and Australia, the prevalence of seropositivity may be ⬎5%.4 In countries in which prevalence is low among those born in the country, high prevalence rates may be found in communities of immigrants from areas with high endemicity.7 Prevalence rates of CHB are associated with differences in the age at transmission of the virus. In areas of high endemicity, where the lifetime risk of HBV infection is 60%, most infections are acquired perinatally or in early infancy via child-to-child transmission.3 Infection early in life is associated with the highest risk for development of chronic infection; children do not mount an effective immune response to infection particularly if their mother is positive for hepatitis B e antigen (HBeAg). It is postulated

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Figure 1 Prevalence of chronic infection with hepatitis B virus, by country, 2006. (Reprinted from Travelers’ Health: Yellow Book, Centers for Disease Control and Prevention.2)

Table 1 Region

Geographic regions and countries with high hepatitis B virus endemicity (ⱖ8% hepatitis B surface antigen seroprevalence) Countries

Africa

All Countries Except Algeria, Djibouti, Egypt, Libya, Morocco, Tunisia Malaysia

Southeast Asia East Asia China, Hong Kong, Mongolia, North Korea, South Korea, Taiwan Australia and South Pacific Australia, Guam, New Zealand Middle East Jordan, Saudi Arabia Eastern Europe and Albania, Armenia, Azerbaijan, Bulgaria, Croatia, Georgia, Northern Asia Kazakhstan, Kyrgystan, Moldova, Tajikstan, Turkmenistan, Uzbekistan Western Europe Malta and indigenous populations in Greenland North America Alaskan Natives and indigenous populations in Northern Canada South America Amazonian areas of Bolivia, Brazil, Columbia, Peru, Venezuela Caribbean Turks and Caicos Adapted from World Health Organization (WHO).3

that HBeAg, a protein that crosses the placenta, “tolerizes” infants to their infection with HBV. By contrast, if the mother is HBeAg negative but nevertheless has replicating virus, the infant can be infected in childbirth and develop an acute hepatitis that may be very severe but the child is able to clear HBV. Indeed, 20% to 90% of infants who are infected before the age of 1 year develop CHB; the wide range is owing to different degrees of viral replication in the mother. Of those children infected between the ages of 1 and 4 years, 30% to 50% will develop CHB.3 In areas of

low prevalence the lifetime risk of HBV infection is ⬍20%, and most infections occur via percutaneous or sexual transmission in adults in particular risk groups such as healthcare workers, intravenous drug users, and men who have sex with men.3 Transmission of HBV in adults is more often associated with symptomatic acute HBV and an effective immune response, resulting in clearance of the virus; only 2% to 5% of adult HBV infections develop into CHB.3 Immunosuppressed adults are also at increased risk for developing CHB as a result of acute HBV infection.

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Evolution and Presentation of CHB Infection

BURDEN OF DISEASE CHB infection can cause serious liver disease and as such is a major public health problem. HBV infection accounts for up to 1 million deaths per year.8 Approximately 25% of individuals infected with HBV in childhood will go on to develop cirrhosis and/or primary liver cancer (hepatocellular carcinoma [HCC]) in adulthood.8 Cirrhosis develops as a result of recurrent bouts of immune activity directed against infected hepatocytes stimulated by the virus. Once established, although progress can be halted by viral suppression (spontaneous or drug induced), cirrhosis rarely resolves and the virus remains in the liver lifelong. Without treatment, patients with an ongoing hepatitis infection are likely to progress through compensated cirrhosis to decompensated cirrhosis with serious clinical complications such as ascites, variceal hemorrhage, and hepatic encephalopathy; in the absence of transplantation, death from liver failure ensues. Data from 2002 indicate cirrhosis resulting from HBV infection is responsible for 235,000 deaths from liver failure worldwide per year.9 The rate of progression to cirrhosis in patients with CHB depends on several factors, notably age and repeated acute exacerbations and an inability to maintain viral suppression, and occurs at a rate of approximately 2% per year.10,11 It is estimated that at any given time about 40% of patients chronically infected with HBV have an ongoing hepatitis. Liver cancer is the sixth most common cancer worldwide, but, because of its poor prognosis, it represents the third most common cause of death from cancer: there were an estimated 598,000 deaths from liver cancer in 2002.12 The global pattern of distribution of HCC mirrors that of CHB, with HBV causing ⬎50% of cases of HCC worldwide: HBV infection is responsible for an estimated 328,000 deaths from HCC each year.9 Individuals with CHB infection have a risk of developing HCC that is 100fold greater than the risk in persons who are not infected.13 The annual incidence of HCC is 0.1% in all chronically infected HBsAg-positive individuals, 1% in patients with CHB, and 3% to 10% in patients with cirrhosis.10 Although the incidence of HBV infection is declining in the United States as a result of vaccination programs, the overall incidence of HCC has increased rapidly over recent years, doubling between 1976 and 2000.14 This is in part because of the reservoir of individuals infected before the implementation of vaccination8 as well as the presence of cirrhosis in those who acquired hepatitis C in the 1960s and 1970s. This burden of disease is associated with substantial economic costs. The average annual cost per patient with CHB in the United States in 2000 was estimated at US$761; for those with compensated cirrhosis the costs were US$227. This increased in patients with decompensated cirrhosis (US$11,459) and increased yet further in those who needed liver transplantation (US$86,552) and posttransplantation care (US$12,560). The annual costs for patients with HCC (US$7,533) were lower than those for patients with decompensation; however only direct medical

S5 costs were included in this analysis. When indirect costs and nonmedical direct costs are also considered, coupled with the poor life expectancy of patients with HCC, these data may have underestimated the true total cost.15

IMPACT OF POPULATION MIGRATION Although universal childhood vaccination against HBV has been recommended by the World Health Organization (WHO) since 1991, this strategy is not employed in all countries (Figure 2).16 The global coverage of infant vaccination was estimated at 55% in 2005.17 As of August 2006, 158 of the 192 member states of the WHO had introduced a national infant immunization strategy; of these, 119 countries (62%) had achieved infant immunization coverage rates of ⱖ80%.17 Several Northern European countries (e.g., United Kingdom, Ireland, the Netherlands, and the Nordic countries) have chosen not to implement universal childhood vaccination against HBV.18 Universal childhood vaccination is also lacking in Japan and several southern African states.17 Although some of these countries have low endemicity and consider that an “at-risk” immunization strategy is sufficient, travel and integration of immigrant communities is increasing the number of at-risk individuals.18 Furthermore, a large pool of individuals with chronic infection originating before the instigation of vaccination will remain in many countries. As alluded to above, population migration from areas of relatively high prevalence to areas of lower prevalence can cause pockets of CHB in countries with low general HBV endemicity. A voluntary screening study in New York City carried out by the Asian American Hepatitis B Program found that approximately 21% of untested individuals in the Asian/Pacific Islander community had chronic infection with HBV, and similarly a high prevalence of HBsAg positivity has been found among such immigrants in other areas of the United States, such as Atlanta, Chicago, Philadelphia, and California.7 A study of consecutive patients with HBV attending a liver center in Canada found that the vast majority, 88%, were Asian, with virological and clinical characteristics reflecting their country of origin.19 Increasing immigration to Australia from Asian/Pacific countries has been associated with a rapid rise in the number of CHB cases in this growing population group, from a 5-year average of 208 in 1960 to a peak of 4,182 in 1990; the number of cases of HBV-related HCC among Asian/Pacific-born Australians rose 140-fold between 1960 and 2005, and projections to 2025 suggest universal vaccination programs in the immigrants’ countries of origin will have limited impact on HBV-related HCC in this population group (with the exception of those with origin in Taiwan, where universal vaccination was introduced in 1986).20 Estimates of the prevalence of HBV infection in France between 1993 and 2004 suggest prevalence had risen from 0.2% to 0.4% in the early 1990s to 0.65% in the early part of this century; prevalence was substantially higher among those born in sub-Saharan Africa (5.25%) and the Middle East (2.45%).21

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Figure 2

Global hepatitis B immunization.

Aliens arriving at US ports seeking admission as immigrants into the country can be deemed inadmissible if they have not been vaccinated against HBV.22 US guidelines recommend that all individuals born in countries in which HBV infection is highly endemic (ⱖ8%) be screened for HBsAg, irrespective of their vaccination status; this includes immigrants, refugees, asylum seekers, and internationally adopted children.23 The guidelines also recommend that all those from areas of high endemicity applying for permanent US residence should be screened as part of premigration medical examinations. HBsAg-positive individuals are not necessarily considered ineligible for immigration but should be counseled and recommended for follow-up medical evaluation and management in the United States.4 Unless these screening efforts are followed by ready access to appropriate therapy, the efforts are wasted and, worse, the level of anxiety in patients found to be infected is heightened. Because individuals infected at birth or in early childhood (i.e., mainly those originating from areas of high HBV endemicity, such as Asians and Pacific Islanders) are at a disproportionately high risk for HBV-related chronic liver disease and HCC, public health agencies and medical providers in the United States who serve such populations are advised to promote educational campaigns, which also need to address the stigma attached to this infection, as well as targeted HBV screening and follow-up programs.4,7 Screening programs enable identification of people with CHB so that they can receive appropriate counseling and medical management to prevent cirrhosis and liver cancer, and their

contacts can also be screened and, if necessary, given treatment, counseling, or—if this approach identifies unprotected individuals—vaccination. There are good examples of such comprehensive, community-based screening and evaluation programs that have been demonstrated to reach at-risk individuals effectively.7 Local health departments in New York City and San Francisco, for instance, 2 cities with large numbers of individuals of Asian/Pacific Islands origin, carry out surveillance for both acute and chronic HBV infection, and the Asian Liver Center of Stanford University has developed educational programs for both youths of Asian/Pacific Islands origin and practitioners of traditional Chinese medicine. Additionally, to target perinatal HBV infection, routine screening for HBsAg is recommended for all pregnant women,23 and those found to be infected will have their babies vaccinated at birth. Unless viral load in the mother is ⬎108 copies/mL, vaccination is highly effective in preventing transmission to the infant.

NATURAL HISTORY The natural history of CHB falls into 4 phases (Figure 3).16 The first, the immune-tolerant phase, is characterized by active viral replication, i.e., high serum HBV DNA, HBeAg positivity, normal liver biochemistry (i.e., alanine aminotransferase [ALT]), and little histologic activity. This phase only exists in persons infected neonatally or in early childhood24 and may last for up to several decades. This phase is followed by an immune clearance or “immunoactive” phase

Heathcote

Evolution and Presentation of CHB Infection

S7

Figure 3 Dynamics of the different phases of chronic hepatitis B virus (HBV) infection. The solid gray horizontal line represents the normal alanine aminotransferase (ALT) level and an HBV DNA value ⬍5 log10 copies/mL. The immune-tolerant phase is usually characterized by high HBV DNA (thin black line) and low ALT levels (thick black line), while the immune clearance and reactivation phases are characterized by persistently elevated ALT levels and high HBV DNA values or by fluctuating ALT (dashed black line) and/or HBV DNA levels (dotted gray line). Anti-HBe ⫽ HBe antigen antibody; HBeAg ⫽ hepatitis Be antigen. (Reprinted with permission from Arch Intern Med.16)

during which the immune system attempts to remove the virus by attacking infected hepatocytes. In this phase, HBV replication gradually declines, although HBeAg is still secreted. The immunoactive phase may last only a few weeks in persons with an apparent acute, symptomatic infection, but may persist for ⱖ10 years in individuals with a less robust immune response. In individuals infected in early childhood, the immune clearance phase usually starts between 15 and 50 years of age (mean, 35 years).10 In the third, “nonreplicative,” phase, although HBsAg persists, patients undergo seroconversion from HBeAg to anti-HBe, and HBV DNA decreases to undetectable levels: serum ALT normalizes and liver disease becomes inactive and some degree of histologic regression may take place. The fourth phase occurs in persons who, despite testing negative for HBeAg, have elevated HBV DNA levels and ongoing intermittent hepatitis. HBeAg-negative hepatitis, which is now the predominant cause of CHB, results from mutations in the core gene that prevent or reduce secretion of HBeAg. Liver damage in CHB requires an immune response. Disease is usually mild in the immune-tolerant phase, during which patients may have very high HBV DNA levels while ALT remains normal.25,26 Patients who progress to the immunoactive phase and develop high ALT levels experience greater disease progression.26 A small study in patients mainly of Asian origin found that the end of the immune-tolerant phase, which occurred at a mean age of 30 years, was characterized by a rapid transition to the inactive state in the majority of patients, while a third of patients

developed chronic active disease requiring treatment.25 In patients with active CHB, whether HBeAg positive or HBeAg negative, serum ALT may be raised persistently or intermittently: periods of raised serum ALT are associated with inflammatory activity and liver damage (and regeneration) and progressive hepatic fibrosis with greater frequency of flares being associated with increased rates of progressive liver disease.27 The ALT values that are followed by the most severe progression are those that fluctuate between 0.5 and 2 times the upper limit of normal (ULN)—not in those with very high ALT levels who are HBeAg positive, because this is often short lived and most often heralds HBeAg seroconversion. Periods of disease activity during which serum ALT is raised represent the major opportunity for treatment. Antiviral agents are inappropriate, however, when serum ALT values are within the normal range, the patient is HBeAg positive, and the level of HBV DNA is very high, because this situation (the immune-tolerant state) is not associated with significant liver disease. If treatment were given, the very high titers of HBV DNA (sometimes ⬎1010 IU/mL) would provide fertile ground for the development of drug resistance, because currently no antiviral agent can reduce HBV DNA by ⬎7 logs.28,29 The inactive HBsAg-positive, anti-HBeAg–positive phase generally carries a good prognosis, particularly in women, and may last for years or even lifelong. Spontaneous HBsAg seroconversion occurs in only approximately 1% to 2% of cases per year in Western countries, and even

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less frequently (0.05% to 0.8% of cases per year) in persons living in areas of high endemicity where infection has usually been acquired during childhood.30 However, two recent studies have indicated that in those who are inactive carriers, 50% lose HBsAg over 25 years of follow-up and this is associated with significantly less risk of HCC.30a,30b Approximately 20% of 30% of patients at any time during the inactive phase may develop reactivation of hepatitis—with raised serum ALT, a high HBV DNA level, moderate-tosevere histological activity, just occasionally with HBeAg seroreversion—thus all those infected with HBV should receive regular lifelong monitoring. Recurrent episodes of HBeAg-negative hepatitis contribute to progressive liver disease.30 Immunosuppressive therapy (IST) and cytotoxic chemotherapy are associated with reactivation of HBV replication in 20% to 50% of those with CHB infection.30 Once the immune suppression is withdrawn, this may precipitate a severe flare of hepatitis. Hence all “at risk” of being chronically infected should be screened for HBsAg before the introduction of IST. It is evident that CHB is a complicated, nonlinear, disease with a variable course of progression. Patients may progress from an immune-tolerant phase, through an active phase, to an inactive phase, but they may also alternate among these phases, meaning that all individuals chronically infected with HBV need lifelong monitoring. A variety of factors are predictive of disease progression, predominantly duration of viral replication, viral genotype, and sex. Several HBV genotypes may be associated with more severe disease; for example, genotype C, may be associated with greater risk for cirrhosis and HCC than genotype A and B, although studies have provided conflicting results.30 There is evidence that genotype B is associated with HBeAg seroconversion at a younger age,30 while a prospective study in Alaskan natives found HBeAg was less likely to clear in patients infected with the HBV genotype C.31 The ratio of males to females with HBV-related cirrhosis is around 2:1, and the incidence of HCC is 3- to 6-fold higher in men than women.32 Older age (⬎45 years) is a risk factor for development of cirrhosis and HCC, although this may be a reflection of longer duration of viral replication. Coinfection with hepatitis C or D virus or human immunodeficiency virus (HIV) also increases risk. There are little data on the effect of regular intake of alcohol.30 Persistently high HBV DNA levels may also be associated with increased likelihood of progression to active disease and HCC. A prospective study in a cohort of Taiwanese men with CHB infection who were mostly HBeAg-negative suggested that the incidence of cirrhosis and HCC increases in relation to HBV DNA level on entry to the study cohort, whose median age was the mid-30s at baseline. A serum HBV DNA ⬎10,000 copies/mL was found to be a predictor of risk for HCC independent of HBeAg status, serum ALT level, and cirrhosis, although the presence of elevated ALT and alcohol intake were contributory factors.33,34 It is, however, important to note that these findings are based on a single HBV DNA level in this particular cohort, and also to remember

that prolonged low-level viremia, such as that seen in patients with HBeAg-negative hepatitis, also poses a risk for progression. Liver damage in patients with prolonged lowlevel viremia, with serum ALT levels around or just over the ULN range may be insidious and continual, whereas the injury associated with acute exacerbations and high serum ALT (⬎2⫻ ULN) may not be permanent.35 It has been recently recognized that a normal ALT is ⬍19 IU/L for women and for ⬍30 IU/L men.36

VACCINATION STRATEGIES The principal objective of vaccination against HBV is to prevent HBV infection, thus avoiding the development of CHB and thence HCC. This approach has been effective in Taiwanese children all of whom have been vaccinated at birth as of 1986.37 HBV vaccination therefore represents the first vaccine shown to be effective against a major human cancer. Vaccination strategies include routine infant vaccination, prevention of perinatal HBV transmission, and catch-up vaccination of older age groups. In 1991, the WHO recommended universal vaccination in childhood or adolescence, according to endemicity, on the basis that where carrier prevalence is ⱖ2%, the most effective strategy is to incorporate HBV vaccination into routine childhood immunization schedules.38 The WHO now recommends universal infant vaccination as the correct strategy in all countries for the long-term control of CHB and its sequelae.39,40 However, this has not been adopted by all countries (Figure 2). In countries with high endemicity of HBV infection, routine infant vaccination is a high priority because the majority of chronic infections are acquired during childhood, such that infant vaccination has the potential to reduce transmission rapidly.39 Even in areas of intermediate and low endemicity, an important proportion of CHB is acquired through infection in childhood.40 One advantage of universal infant vaccination in such areas is that it would prevent chronic infections acquired during childhood in children born to mothers not infected with HBV; these infections would not all be prevented via an antenatal screening and perinatal immunization strategy. This is significant, given that most HBV infections acquired during childhood in areas of intermediate or low endemicity are due to horizontal, not perinatal, infection and occur in children whose mothers are not HBsAg positive.39 Universal vaccination has been proved to reduce the incidence and prevalence of HBV infection and is the most effective means by which to reduce the global burden of CHB.18 Although the effects may not be evident for several years, during which time targeted vaccination of those at most risk of infection would need to continue, a wellimplemented universal vaccination program would interrupt transmission of the virus, resulting in a decline in HBV prevalence in the entire population rather than only in specific groups. Immunization of the majority of individuals would also provide protection, through herd immunity, to

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Evolution and Presentation of CHB Infection

the small minority of unvaccinated individuals. In areas of low endemicity, universal infant vaccination provides lifelong protection for children before they reach an age at which they might become engaged in risk-related behavior, can be integrated easily and conveniently into existing immunization schedules, and is likely to be associated with high adherence and coverage rates. There may be an issue in rural areas with making sure parents follow through with all 3 vaccinations required by their baby over a time period of 6 months (coverage from 1 injection would therefore be optimal). Infant vaccination is also preferred because immune responses to vaccination decline with age.18,39 Decision-makers in countries with low endemicity that have not introduced universal vaccination argue that CHB is not sufficiently significant to justify the expense of universal vaccination, and provide vaccination only to at-risk groups and in conjunction with antenatal screening. However, although results of cost-effectiveness studies in countries with low endemicity have provided conflicting results, several have demonstrated universal vaccination to be an economically attractive proposition, particularly if the indirect costs of productivity in those chronically infected with HBV are taken into consideration.18,39,41,42 Decision-makers in the United Kingdom acknowledge that a selective vaccination program, even if improved, will not eliminate HBV infection and its substantial associated human and economic costs, but maintain that universal infant immunization, although the most practicable strategy, should not be introduced until a suitable combination vaccine that will limit cost becomes available.43 Another argument leveled against universal childhood vaccination is that it may raise parental concerns about unnecessary and “overvaccination” of young children, which may have a detrimental effect on prevention of other diseases, particularly those covered by a combination vaccine; it is of note, however, that pneumococcal vaccination has recently been added to the childhood immunization schedule in the United Kingdom without apparent difficultly.18 A study of the acceptability of universal HBV vaccination, albeit in older children (aged 12 to13 years), has suggested acceptability would be high among children and parents, provided sufficient information is made available.44 However, to prevent chronic infection with HBV, vaccination must take place in early childhood, teenagers and adults ⬍50 years of age old almost always clear the virus when infected. Although targeted vaccination strategies have the potential for low cost coupled with an immediate impact in those at high risk for infection, they also have many shortcomings. Targeting infants born to mothers who are HBsAg positive through antenatal screening is likely to be only partially effective, because women at highest risk for HBV infection often fail to attend prenatal clinics, and, as outlined above, HBV infections acquired during childhood—the most important in terms of development of chronic disease— occur most often in children whose mothers are not HBsAg positive.39 There is evidence from the United Kingdom of failures in the antenatal

S9 screening program, with low uptake rates among mothers, leaving many at-risk babies without the recommended vaccination.43 Other limitations of targeted vaccination strategies include the difficultly of identifying and accessing high-risk groups, in part because in certain populations there is a tremendous social stigma that goes with chronic HBV infection. Additionally, there is a likelihood that persons at risk may be infected with HBV before they are identified for vaccination, resulting in a lack of perceived risk among these individuals. In the general population, ⬎30% of individuals at risk do not have identifiable risk factors.18,42 Targeted vaccination will have limited impact on the epidemiology of CHB and leaves the general population still at risk of exposure and infection. Ultimately, global eradication of HBV transmission and CHB relies on universal vaccination in early childhood, and every country in the world has an ethical responsibility to play its part.

CURRENT RECOMMENDATIONS The WHO recommends universal infant vaccination against HBV regardless of endemicity. The vaccine can be incorporated into national immunization programs in a variety of ways: 3 doses given intramuscularly at minimum intervals of 4 weeks are recommended.39 The WHO recommends the vaccine should be given to all children aged ⬍18 years who have not previously been vaccinated and, particularly in areas of low endemicity, as part of a catch-up strategy to adults at high risk of infection, including those with highrisk sexual behavior, partners and contacts of HBsAg-positive individuals, intravenous drug users, people who require frequent blood products, recipients of solid organ transplantation, healthcare workers, and travelers to areas with high HBV endemicity. In the United States, the Advisory Committee on Immunization Practices (ACIP) recommends universal vaccination of newborns, coupled with vaccination of previously unvaccinated children and adolescents, with the intention of eliminating HBV transmission.23 Their recommendations are summarized in Table 2.3,23 Vaccination of at-risk adults (Table 3) is also recommended.3,4

SUMMARY Despite the introduction of universal vaccination programs in many countries, CHB remains a huge burden and a cause of substantial disease and death. Globally, CHB is responsible for up to 1 million deaths annually, a scale similar to that caused by HIV/acquired immunodeficiency syndrome (currently 2.8 to 3 million).45 Population movement is increasing the prevalence in areas with low endemicity, necessitating active measures to screen, identify, monitor, and treat those affected when appropriate. Targeted vaccination strategies have many limitations and, ultimately, worldwide eradication of HBV transmission and the burden of CHB depends on global universal vaccination. Every country

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Table 2

Summary of hepatitis B virus (HBV) vaccination recommendations in the USA

Group

Recommended Vaccination Series

Infants born to HBsAg-positive mothers Infants born to mothers of unknown HBsAg status

HBV vaccine (dose 1) and HBIG ⱕ12 hr of birth HBV vaccine (dose 1) ⱕ12 hr of birth; HBIG within 1 wk if mother found to be HBsAg positive HBV vaccine (dose 1) before hospital discharge

Medically stable full-term infants ⱖ2 kg born to HBsAg-negative mothers Preterm infants ⱕ2 kg born to HBsAg-negative mothers HBV vaccine (dose 1) 1 month after birth or at hospital discharge Infants who have received a birth dose Completion of the series; single-antigen vaccine at 1–2 mo and 6–18 mo, or combination vaccine at 2 mo, 4 mo, 6 mo, or 12–15 mo Unvaccinated children and adolescents ⬍19 yr HBV vaccine series (3 doses, various schedules, select to optimize adherence) Unvaccinated adults at risk of HBV infection HBV vaccine series (3 doses, various schedules, select to optimize adherence) Adults requesting protection from HBV infection HBV vaccine series (3 doses, various schedules, select to optimize adherence) HBIG ⫽ hepatitis B immune globulin; HBsAg ⫽ hepatitis B surface antigen. Adapted from World Health Organization (WHO)3 and MMWR Recomm Rep.23

Table 3

Adults at risk for hepatitis B virus (HBV) infection for whom vaccination is recommended in the USA

Risk Group

Stratification

Individuals at risk by sexual exposure

Sex partners of HBsAg-positive individuals Sexually active individuals not in a long-term, mutually monogamous relationship Individuals seeking evaluation or treatment for a sexually transmitted disease Men who have sex with men Current or recent intravenous drug users Household contacts of HBsAg-positive individuals Residents and staff of facilities for developmentally disabled people Healthcare and public safety workers with reasonably anticipated risk for exposure to blood or blood-contaminated body fluids Individuals with end-stage renal disease International travelers to regions with high or intermediate of endemic HBV infection Individuals with chronic liver disease Individuals with HIV infection

Individuals at risk by percutaneous or mucosal exposure to blood

Others

HBsAg ⫽ hepatitis B surface antigen; HIV ⫽ human immunodeficiency virus.

should conform to WHO recommendations and implement universal childhood vaccination.

AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: E. Jenny Heathcote, MD, is a member of the Speakers’ Bureau for Hoffman-LaRoche Inc; has received research/grant support from Axcan Pharma, BoehringerIngelheim, Bristol-Myers Squibb, Debiopharma, Human Genome Sciences, Gilead Sciences, GlaxoSmithKline, Novartis, Pharmasett, Schering-Plough, Vertex; and serves as on advisor to Gilead, Schering-Plough, and Hoffman-LaRoche.

References 1. World Health Organization. Hepatitis B. WHO Fact Sheet No. 2004, revised October 2000. [WHO Web site.] Available at: http:// www.who.int/mediacentre/factsheets/fs204/en/. Accessed November 5, 2008.

2. Centers for Disease Control and Prevention. Travelers’ Health: Yellow Book. CDC health information for international travel 2008. Chapter 4, prevention of specific infectious diseases: Hepatitis, viral, type B. [CDC Web site.] Available at: http://wwwn.cdc.gov/travel/ yellowBookCh4-HepB.aspx. Accessed July 17, 2008. 3. Department of Vaccines and Biologicals, World Health Organization. Introduction of Hepatitis B Vaccine into Childhood Immunization Services. Geneva: WHO, 2001. Available at: http://www.who.int/ vaccines-documents/DocsPDF01/www613.pdf. Accessed November 5, 2008. 4. Mast EE, Weinbaum CM, Fiore AE, et al, for of the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep. 2006; 55(RR-16):1-33. 5. Department of Communicable Diseases Surveillance and Response, World Health Organization. Hepatitis B. Geneva: WHO, 2002. Available at: http://www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo 2002_2.pdf. Accessed September 19, 2007. 6. Centers for Disease Control and Prevention. Incidence of acute hepatitis B—United States, 1990-2002. MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254.

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Evolution and Presentation of CHB Infection

7. Centers for Disease Control and Prevention. Screening for chronic hepatitis B among Asian/Pacific Islander populations—New York City, 2005. MMWR Morb Mortal Wkly Rep. 2006;55:505-509. 8. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. 9. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45:529538. 10. Chu CM. Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 2000;15(suppl):E25-E30. 11. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol. 2002;36:263-270. 12. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108. 13. Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus: a prospective study of 22 707 men in Taiwan. Lancet. 1981;2:1129-1133. 14. McGlynn KA, Tarone RE, El-Serag HB. A comparison of trends in the incidence of hepatocellular carcinoma and intrahepatic cholangiocarcinoma in the United States. Cancer Epidemiol Biomarkers Prev. 2006;15:1198-1203. 15. Lee TA, Veenstra DL, Iloeje UH, Sullivan SD. Cost of chronic hepatitis B infection in the United States. J Clin Gastroenterol. 2004; 38(suppl 10):S144-S147. 16. Wong SN, Lok AS. Treatment of hepatitis B: who, when and how? Arch Intern Med. 2006;166:9-12. 17. World Health Organization. WHO 2006. Progress Towards Global Immunization Goals—2006: Summary Presentation of Key Indicators [slide kit presentation]. Updated September 2007. [WHO Web site.] Available at: http://www.who.int/immunization_monitoring/data/Slides GlobalImmunization.pdf. Accessed July 18, 2008. 18. Zuckerman J, van Hattum J, Cafferkey M, et al. Should hepatitis B vaccination be introduced into childhood immunisation programmes in northern Europe? Lancet Infect Dis. 2007;7:410-419. 19. Fung SK, Wong FS, Wong DK, Hussain MT, Lok AS. Hepatitis B virus genotypes, precore and core promoter variants among predominantly Asian patients with chronic HBV infection in a Canadian center. Liver Int. 2006;26:796-804. 20. Nguyen VT, Razali K, Amin J, Law MG, Dore GJ. Estimates and projections of hepatitis B-related hepatocellular carcinoma in Australia among people born in Asia-Pacific countries. J Gastroenterol Hepatol. 2008;23:922-929. 21. Maffre C, Le Strat Y, Delarocque-Astagneau E, et al. Prevalence of hepatitis B in France, 2003-2004 [abstract]. J Hepatol. 2006;44(suppl 2):S22. Abstract 46. 22. Centers for Disease Control and Prevention. Public Health Screening at US Ports of Entry: A Guide for Federal Inspectors. Atlanta, GA: CDC, July 2007. Available at: http://www.cdc.gov/ncidod/dq/pdf/ hguide.pdf. Accessed July 18, 2008. 23. Mast EE, Margolis HS, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1-33. 24. Lee WM. Hepatitis B infection. N Engl J Med. 1997;337:1733-1745. 25. Andreani T, Serfaty L, Mohand D, et al. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histological findings and outcome. Clin Gastroenterol Hepatol. 2007;5:636-641.

S11 26. Hui C-K, Leung N, Yuen S-T, et al, for the Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46:395-401. 27. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long-term cohort study. J Hepatol. 2002;36:263-270. 28. Heathcote J. Treatment of HBe antigen-positive chronic hepatitis B. Semin Liver Dis. 2003;23:69-80. 29. Lok ASF, McMahon BJ. Chronic hepatitis B [AASLD Practice Guideline] [published correction appears in Hepatology. 2007;45:1347]. Hepatology. 2007;45:507-539. 30. Pan CQ, Zhang JX. Natural history and clinical consequences of hepatitis B virus infection. Int J Med Sci. 2005;2:36-40. 30a. Fattovich G, Olivari N, Pasino M, D’Onofrio M, Martone E, Donato F. Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years. Gut. 2008;57:84-90. 30b. Yuen MF, Wong DK, Fung J, et al. HBsAg seroclearance in chronic hepatitis B in Asian patients: replicative level and risk of hepatocellular carcinoma. Gastroenterology. 2008;135:1192-1199. 31. Livingston SE, Simonetti JP, McMahon BJ, et al. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis. 2007;195:5-11. 32. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liver Dis. 2003;23:47-58. 33. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, for the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/ Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686. 34. Chen CJ, Yang HI, Jen CL, et al, for the REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. 35. Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54: 1610-1614. 36. Kim HC, Nam CN, Jee SH, Han KH, Oh DK, Suh I. Normal serum aminotransferase concentration and risk of mortality from liver disease: prospective cohort study. BMJ. 2004;328:983. 37. World Health Organization. Expanded programme on immunization. Global Advisory Group–Part I. Wkly Epidemiol Rec. 1992;67:11-15. 38. Lo KJ, Lee SD, Tsai YT, et al. Long-term immunogenicity and efficacy of hepatitis B vaccination in infants born to HBeAg-positive HBsAg-carrier mothers. Hepatology. 1988;8:1647-1650. 39. World Health Organization. Introduction of hepatitis B vaccine into childhood immunization services. http://whqlibdoc.who.int/hq/2001/ who-V&B-01.31.pdf. 40. World Health Organization. WHO position paper on the use of hepatitis B vaccines. Wkly Epidemiol Rec. 2004;79:255-263. 41. Williams JR, Nokes DJ, Anderson RM. Targeted hepatitis B vaccination—a cost effective immunisation strategy for the UK? J Epidemiol Community Health. 1996;50:667-673. 42. Van Damme P, Kane M, Meheus A. Integration of hepatitis B vaccination into national immunisation programmes. BMJ. 1997;314:10331036. 43. Joint Committee on Vaccination and Immunisation, Hepatitis B Subgroup. Minutes of the meeting held on Monday 31 January 2005. [UK Department of Health Web site.] Available at: http://www.advisorybodies. doh.gov.uk/jcvi/mins-hepb-310105.htm. Accessed November 5, 2008. 44. Hinds A, Cameron JC. Acceptability of universal hepatitis B vaccination among school pupils and parents. Commun Dis Public Health. 2004;7:278-282. 45. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3:e442.

Supplement issue

Diagnosis of Chronic Hepatitis B and the Implications of Viral Variants and Mutations Robert G. Gish, MD Liver Transplant Program, California Pacific Medical Center, San Francisco, California, USA

ABSTRACT Chronic infection with the hepatitis B virus (HBV) is a major cause of morbidity and mortality worldwide, necessitating accurate and timely diagnosis of infected patients coupled with optimal treatment strategies. Although the prevalence of HBV infection in the United States is low owing to the implementation of universal vaccination, growing immigration from areas where infection is more endemic means that prevalence is forecast to increase. Healthcare providers must be active in providing low-cost screening (hepatitis B surface antigen identification) and vaccination programs for high-risk communities, such as Asian Americans, with linked specialist referral schemes for patients found to carry the virus. Serologic technologies and improved nucleic acid testing techniques generate important information about the stage of disease, viral load, and disease subtype, including the presence of precore and core promoter variants that provide prognostic indicators and can guide patient management. Serial DNA monitoring is playing the major role in the assessment of therapeutic response and steering treatment approaches. More research is needed to further clarify the significance of HBV variants and their relation to therapeutic agents and strategies. © 2008 Published by Elsevier Inc. • The American Journal of Medicine (2008) 121, S12–S21 KEYWORDS: Chronic hepatitis B; Screening mutations; Genotype; HBV DNA; Nucleic acid test

Chronic infection with the hepatitis B virus (HBV) affects 350 to 400 million people worldwide.1 The prevalence of HBV infection varies geographically: it is no higher than 1% in most of Western Europe and North America, while in Southeast Asia and Africa the prevalence may be as high as 20% of the population. About 33% of patients with chronic hepatitis B (CHB) develop cirrhosis and hepatocellular carcinoma (HCC), and approximately 1 million people are estimated to die annually from HBV-related chronic active hepatitis, cirrhosis, or HCC.2 This burden of disease necessitates accurate and timely diagnosis of infected patients coupled with best-practice treatment to reduce progression of disease and mortality. Although the United States has a low overall prevalence of HBV infection, prevalence rates can be high among immigrants from areas of the world where HBV infection is

Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Robert G. Gish, MD, Liver Transplant Program, California Pacific Medical Center, 2340 Clay Street, San Francisco, California 94115. E-mail address: [email protected].

0002-9343/$ -see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjmed.2008.09.025

highly endemic. The annual number of new cases of HBV, which had declined substantially from ⬎430,000 in the 1980s to 78,000 in the early 2000s as a result of vaccination programs, is forecast to rise again over the next 10 to 15 years owing to recently increased rates of immigration from countries with a high prevalence of HBV3,4; the current prevalence of HBV infection in the United States is believed to be up to 2 million.5 Many of these immigrants will have been infected early in life and therefore have a higher likelihood of developing CHB and its sequelae. Despite the enormous burden of HBV infection, many infected individuals are asymptomatic and therefore unaware that they are carrying the virus and of the implications for their health. A survey of Chinese and Southeast Asian Canadians in British Columbia found that although 68% were aware of HBV, ⬎60% were unaware that it could cause cirrhosis or HCC.6 Similarly, ⬍50% of a sample of Chinese American women in Seattle, Washington, knew that HBV could cause liver cancer, and only 35% reported having been tested for infection with HBV.7 A recent study in the San Francisco Bay area of California indicated that, despite being at higher risk for HBV infection than non– Asian Americans, Asian Americans had significantly poorer

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Diagnosis of CHB and Implications of Viral Variants and Mutations

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Figure 1 An algorithm for cost-effective screening of subjects to assess prevalence of hepatitis B virus surface antigen (HBsAg). Anti-HBe ⫽ anti-hepatitis B e antibody; Anti-HBs ⫽ anti-hepatitis B surface antibody; HAV ⫽ hepatitis A virus; HBeAg ⫽ hepatitis B e antigen; HBV ⫽ hepatitis B virus; HDV ⫽ hepatitis D virus; HIV ⫽ human immunodeficiency virus; PCR ⫽ polymerase chain reaction; TMA ⫽ transcription-mediated amplification; ⫹ve ⫽ positive; –ve ⫽ negative.

knowledge of HBV and its association with liver cancer; ⬍60% had been tested for HBV, only 31% reported being vaccinated against HBV, and ⬍50% had had their children vaccinated.8 Given this lack of awareness, screening programs are vital for the identification of infected individuals. A screening program in a predominantly immigrant Asian population in New York City found that around 15% of previously untested individuals, all of them born outside of the United States, had chronic HBV infection.9 Such screening programs, which are encouraged by Centers for Disease Control and Prevention (CDC), provide an effective means of identifying people with CHB and motivating them to seek medical care. Screening of all adults of Asian ethnic origin, regardless of reported vaccination status, is recommended. Another study of Asian American volunteers in San Francisco found that among the 12% who reported having been vaccinated against HBV,

5% were chronically infected, and 20% lacked protective antibodies.10 Screening of all pregnant women, as recommended in the United States, is another vital component of the strategy to reduce HBV transmission and HBV-associated morbidity.9 Vaccination is fundamental to the elimination of transmission of HBV infection,11,12 but vaccination is effective only in uninfected individuals, and the growing reservoir of existing carriers remains an issue that has been inadequately addressed. Extended diagnostic screening services, coupled with vaccination or referral of tested individuals and their contacts, have the potential to prevent serious disease and reduce HBV transmission. To this end, accurate diagnosis of HBV infection, an understanding of the infection’s natural history and epidemiology, and optimal patient management require the appropriate use and interpretation of serologic and nucleic acid testing.4

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The American Journal of Medicine, Vol 121, No 12A, December 2008 Hepatitis B virus (HBV) screening protocol

Stage

Personnel

Function

Time

Check-in

1-2 staff members/volunteers

⬍5 min per patient

Intake form/survey

In-language volunteers (students, community volunteers)

Educational workshop

1 MD

Blood draw

1 phlebotomist per 25 patients; 1 phlebotomist responsible for spinning down blood

1. Verify patient appointment 2. Make chart for patient 3. All patient forms to have patient bar code sticker 4. Include bar code stickers specific for patient in chart 5. Include lab requisition form 6. Give patient intake form and survey 1. Ensure patient completes intake form and survey individually 2. Answer patient questions without assisting in survey responses 3. Add completed form to patient’s chart 1. Provide HBV education to patients in a group setting 2. Question and answer session 1. Receive patient chart from staff member/volunteer 2. Call out patient name (in order of arrival/checkin at screening site) 3. Draw blood 4. Ensure tube and specimen bag are bar-coded 5. Place tube in specimen bag with corresponding lab requisition form 6. Spin down tubes (1 phlebotomist) and refrigerate/freeze samples

SCREENING IN PRACTICE The diagnosis of HBV infection is made using a combination of serologic, virologic, biochemical, and histologic tests. The main screening assay for acute and chronic HBV infection is the hepatitis B surface antigen (HBsAg). An algorithm for screening for prevalence of disease via HBsAg detection is shown in Figure 1. The basic screening cassette in this strategy tests for HBsAg, HBsAg antibody (anti-HBs), total antibody to hepatitis A virus, and anti– hepatitis C virus (HCV) antibodies. Patients positive for HBsAg (which defines HBV carrier status) or anti-HCV (which indicates HCV exposure) should be referred for further testing procedures such as liver tests, quantification of HBV replication by HBV DNA quantitative real-time polymerase chain reaction (RT-PCR) methodology, HCV RNA quantification, and viral genotyping. Patients who are HBsAg negative and anti-HBs seropositive require no further follow-up. Patients who are HBsAg negative but not anti-HBs seropositive should be vaccinated against HBV. There are 2 possible strategies for vaccination: Either initiate the vaccination series in all subjects at the first point of contact, with subsequent doses to be given only if serologic testing reveals that the individual is both HBsAg negative and anti-HBs seronegative; or, delay initiation of vaccination until serologic results are available, and commence the

20-25 min

20-25 min

Will vary according to number of subjects screened

vaccination series only in HBsAg-negative and anti-HBsseronegative individuals. A possible protocol for an HBV screening program is shown in Table 1. The aim of such a program would be to screen all individuals at risk for HBV infection in a defined area. Such a testing program has been initiated by the San Francisco Department of Health, which is providing convenient free or low-cost testing opportunities at partnering health facilities and events, with the aim of screening every citizen born in Asia or the Pacific Islands (an estimated 200,000 individuals or around 25% of the city’s population) for HBV and vaccinating all those found to be uninfected and not already protected.13 Data collected in San Francisco suggest that, in 2006, almost 85% of individuals with confirmed HBV infection were Asian/Pacific Islanders, 80% of whom were born outside the United States; ⬍50% of those with CHB had been referred to a gastroenterologist or hepatologist for evaluation or had undergone treatment at the time of reporting.13 In addition to identifying uninfected and unprotected individuals who can benefit from vaccination, such screening programs can identify individuals with CHB and encourage them to seek appropriate medical care, including treatment for CHB and urge their contacts to come forward for testing. Inclusion in the screening program of culturally appropriate health education, with

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Diagnosis of CHB and Implications of Viral Variants and Mutations

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Figure 2 Phases of chronic hepatitis B virus (HBV) infection. Anti-HBe ⫽ HBe antigen antibody; HBeAg ⫽ hepatitis B e antigen; CH ⫽ chronic hepatitis.

suitable language support, is also important in a strategy to eliminate HBV transmission.

THE NATURAL HISTORY AND DISEASE STAGES OF CHRONIC HEPATITIS B INFECTION: SEROLOGIC TESTS The age at which an individual becomes infected with HBV is the main factor in determining the outcome of acute infection. Up to 90% of those infected before the age of 1 year, and up to 50% of those infected between the ages of 1 and 4 years, develop chronic disease, whereas ⬍5% of those infected as adults do so.14 There are 4 phases of CHB infection, characterized by different patterns of test results, although not all patients go through all phases (Figure 2).15,16 In the immune-tolerant phase, individuals are positive for hepatitis B e antigen (HBeAg) and have high blood levels of HBV DNA (⬎20,000 IU/mL), but serum levels of liver enzymes (e.g., alanine aminotransferase [ALT]) are persistently normal and liver histology is typically normal.17 Individuals in the immunoactive phase are HBeAg positive with initially high serum HBV DNA and moderate-to-severe necroinflammation. HBV DNA levels are reduced by the activity of the immune system; rarely, patients may eliminate HBV DNA and undergo HBsAg seroconversion. Precore and basal core promoter HBV mutations emerge during the immunoactive phase in some patients; such patients are HBeAg negative but resume a replicative state, although with serum HBV DNA levels lower than in HBeAg-positive cases, and are more likely to run a fluctuating disease course characterized by persistently raised or fluctuating serum

ALT.16 The nonreplicative phase is characterized by detectability of HBsAg in serum, HBeAg seroconversion and hence undetectable HBeAg, low serum HBV DNA, and serum ALT that remains persistently normal for periods of ⬎6 months. The clinical course in these patients will depend on the extent of liver damage before HBeAg seroconversion and the durability of the phase, as well as the extent of integration of HBV DNA into hepatocyte nuclear DNA with the associated risk for subsequent development of HCC. After HBeAg seroconversion, reactivation of disease can occur, either spontaneously or as a result of immunosuppressive therapy, with increases in serum liver enzymes and a significant rise in serum HBV DNA.16 Repeated exacerbations or periods of reactivation can lead to progressive fibrosis.15 Resolved HBV infection is evidenced by HBsAg negativity, HBV DNA negativity, and normal serum levels of liver enzymes in an individual with a history of CHB. More sensitive PCR testing will reveal HBV DNA in as many as 50% of these individuals,18 and HBV transmission may occur occasionally (e.g., via solid-organ tissue donation). Immunosuppressive therapy may lead to reactivation of liver disease in patients with resolved infection. Patients’ liver disease and viral disease movement in and out of the various phases of CHB can be tracked by monitoring serologic and virologic tests of the disease stage (Table 2). Testing for HBeAg and anti-HBeAg antibody is particularly important: HBeAg negativity may signify the emergence of mutated virus, with the associated risk of more severe disease, or, in the absence of viral replication,

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The American Journal of Medicine, Vol 121, No 12A, December 2008 Clinical profiles of the 4 phases of chronic hepatitis B infection (CHB) Phase

HBsAg HBeAg Anti-HBe ALT HBV DNA Histology

Immune Tolerant

HBeAg-positive CHB

Inactive HBsAg Carrier

HBeAg-negative CHB (Precore Mutant)

⫹ ⫹ ⫺ Normal* ⬎20,000 IU/mL (⬎105 copies/mL) Normal*/mild

⫹ ⫹ ⫺ 1 ⬎20,000 IU/mL (⬎105 copies/mL) Active

⫹ ⫺ ⫹ Normal* ⬍200 IU/mL (⬍103 copies/mL) Normal*

⫹ ⫺ ⫹ 1 ⬎2000 IU/mL (⬎104† copies/mL) Active

Anti-HBe ⫽ hepatitis B e antigen antibody; HBeAg ⫽ hepatitis B e antigen; HBsAg ⫽ hepatitis B surface antigen; HBV ⫽ hepatitis B virus; 1 ⫽ increased; ALT ⫽ alanine aminotransferase. *“Normal” values indicate ALT levels within the range reported for a “healthy” population (⬍20-30 IU/L); this indicates no liver disease, or only residual liver damage. †Expert opinions vary as to this value.

a reduced risk for disease progression. Additional serologic tests can also be of use in patient evaluation: Immunoglobulin (Ig) G against HBV core protein (HBc) is usually evident in patients with CHB and in infected individuals who have cleared the infection.4 Presence of HBc antibody (anti-HBc) IgM is generally diagnostic of acute HBV infection, but it can also be found in patients with CHB with high viral loads or, transiently, during a disease flare.4 Management of patients with isolated anti-HBc antibody remains an area for further investigation and refinement. These patients are at risk for reactivation of CHB, including flares and fulminant liver failure, in the setting of an altered immune system, and many experts advocate the use of oral antiviral therapy during periods of immune suppression.19

Identifying Disease Subtype HBV Genotype. Eight genetic variants of HBV, designated genotypes A through H, have been identified. The global distribution of these genotypes varies. Genotypes A and D are prevalent in Western Europe and North America, whereas genotypes B and C are prevalent in East Asia and Oceania.20 The varying biological properties and geographic distribution of these genotypes may underlie differences in the prevalence of HBV mutants in different areas, in clinical outcome, and in response to therapy.21,22 Several PCR-based and serologic techniques are available for ascertaining HBV genotype.22 In patients with measurable HBV DNA who are considered candidates for treatment, genotype testing can be helpful because HBV genotype may be predictive of response to a particular therapy.23,24 Published evidence suggests patients infected with HBV genotypes D or C respond less well to interferon/ peginteferon therapy than do patients infected with genotypes A or B.20,21,25 In Europe, at least, genotype A infection is associated with higher HBsAg clearance and a better outcome.26 In a study in the Netherlands of patients treated with peginterferon-␣2b, loss of HBsAg, the hallmark of a

complete response to therapy, was more frequent in patients infected with genotype A HBV.27 Patients with genotype A HBV infection are also more likely to experience HBsAg seroconversion without therapy.27,28 For this reason, in a patient with genotype A infection revealed by sequential testing to have a declining serum HBV DNA level, waiting to see if viral clearance occurs without initiating therapy may be a prudent approach. The response to nucleoside analogues also appears to vary according to genotype. Compared with genotype C, genotype B infection is associated with higher rates of sustained response to lamivudine therapy,29 suggesting that a longer period of consolidation therapy after HBeAg seroconversion may be required in patients with genotype C infection. In Japanese patients treated with lamivudine, resistant mutants and breakthrough hepatitis developed more often with genotype A infection than with genotypes B or C.30 Genotype D has been associated with development of resistance to adefovir.31,32 Genotype may also be predictive of disease progression. Although patients with genotype A infection are more likely to undergo spontaneous seroconversion for HBeAg and HBsAg than are patients with genotype B or C, among individuals who do not clear the virus and remain HBeAg positive, genotype A is associated with more severe disease.33 In a French study of 109 patients with genotypes A through E CHB from a variety of geographic regions, genotypes A, C, and D appeared to be associated with more severe hepatic disease than the other genotypes, while precore and core promoter mutations were associated with genotype D.34 In Asia, genotype B, especially the subtype Bj, is associated with higher HBeAg clearance and lower rates of cirrhosis and HCC.26 Genotype C infection is a risk factor for development of HCC,35,36 although this may be a result of the close association between HBV genotype C and core promoter mutation.37 In a prospective study in 1,158 Alaskan natives followed for a median of 20.5 years, clear-

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Diagnosis of CHB and Implications of Viral Variants and Mutations

ance of HBeAg was found to be less likely in patients infected with HBV genotype C, and after HBeAg loss, genotype C and F were more likely to revert to HBeAg positivity.38 Genotype F was linked to an increased risk for HCC in Alaskan natives.38 Precore and Core Promoter Mutations. A sizeable minority of patients who are HBsAg positive carry variants with precore (27% of patients) or core (44% of patients) mutations.39 Patients with measurable HBV DNA in their serum can be tested to determine whether they carry these HBV variants; however, precore mutants rarely develop in genotype A HBV,40 and patients infected with HBV genotype A do not need to undergo testing. Because patients may be HBeAg positive yet have characteristics of HBeAgnegative disease by the presence of these mutations (as defined by nucleic acid testing), some clinicians are treating patients as if the patient has HBeAg-negative disease on the basis of nucleic acid testing, not on serologic tests, and therefore are continuing therapy indefinitely. Sustained remission is rare in individuals with HBeAgnegative CHB, and the condition may follow a more severe and progressive course, such that patients with precore and core promoter variants are at increased risk for cirrhosis, HCC, and death compared with those with HBeAg-positive CHB.41-43 In addition, except for a small proportion of patients treated with interferon, patients with HBeAg-negative CHB rarely show a sustained response off therapy, so that oral antiviral therapy has to be continued indefinitely.43 Precore and core promoter mutations may arise due to interferon therapy in patients with HBeAg seroconversion and lead to HBeAg-negative CHB.44-46 Similarly, exacerbations of liver disease occurring after cessation of lamivudine therapy can be caused by the emergence of precore mutant.47 Therefore, patients experiencing such disease flares should be investigated for these HBV variants.

The Importance of HBV DNA Levels Quantification of serum HBV DNA provides information regarding infectivity, prognosis, and the need for therapy, and is a vital part of assessment of therapeutic response and deciding duration of therapy.24,48 There is accumulating evidence that high levels of serum HBV DNA are associated with increased risks for cirrhosis, HCC, and death.49-52 A prospective cohort study in Taiwan found that risk for HCC in HBsAg-positive patients was related to the level of serum HBV DNA at study entry, being lowest in patients with ⬍300 copies/mL and highest in patients with ⱖ106 copies/mL (Figure 349,50); patients with persistently elevated serum HBV DNA during follow-up had the greatest risk of developing HCC.49 For this reason, all HBsAg-positive patients should undergo quantitative HBV DNA testing. The American Association for the Study of Liver Disease (AASLD) guidelines recommended serum HBV DNA thresholds for therapy of ⱖ20,000 IU/mL (⬎105 copies/mL) for patients with HBsAg-positive CHB, or ⱖ2000 IU/mL (⬎104 copies/mL) for HBeAg-negative CHB,16

S17

although serial monitoring is more important than an arbitrary cutoff value, owing to the widely fluctuating HBV DNA levels found in some individuals. The new EASL Guidelines now suggest a threshold of 2000 IU/mL for both HBeAg-positive and HBeAg-negative CHB. It also should be remembered that persistent lower level viremia may be associated with progressive disease.16,48,53,54 Relative levels of HBV DNA reflect the degree of necroinflammatory activity in the liver, which itself reflects the host’s immune response to the virus.55 Serum HBV DNA quantification is thus beginning to replace histology as a test of disease activity. During therapy, serial quantification of serum HBV DNA allows response to be assessed and development of resistance to be identified, enabling therapy to be changed if necessary. The primary aim of therapy is a durable reduction of serum HBV DNA to as low a level as possible—ideally, to below the limit of quantification.48 Serum HBV DNA quantification at key time points is increasingly being used to inform decisions about therapy, in particular with regard to agents with intermediate to high resistance rates such as telbivudine.48 It has been proposed that primary treatment failure should be defined as a reduction in serum HBV DNA of ⬍1 log10 IU/mL from baseline level at week 12. Quantification at week 24 is considered essential to classifying the virologic response to therapy as complete (HBV DNA ⬍60 IU/mL by a sensitive assay), partial (HBV DNA ⬍2000 IU/mL), or inadequate (HBV DNA ⱖ2000 IU/mL).48 A variety of HBV DNA detection and quantification assays are commercially available, with different dynamic ranges and limits of detection (Figure 4)4; assays have in the past provided results in different units, but the World Health Organization (WHO) has now established international units per milliliter as the international reference standard.56 Because these assays overlap to some degree, a patient may be positive according to one test but negative on another. Signal Amplification Assays. Two types of signal amplification assays are available, the hybrid capture II assay and the Versant HBV 3.0 test (Bayer Healthcare, Tarrytown, NY, USA). The Versant 3.0 assay has an improved detection limit of 2 ⫻ 103 copies/mL (357 IU/mL); however these assays are rarely used, having generally been supplanted by newer PCR-based assays. Target Amplification Assays. The target amplification assays are PCR-based, with the newer “real-time’” assays measuring product during the early exponential phase of amplification when the reaction is most efficient, rather than at the end of amplification when plateau effects may introduce errors. The use of fluorimetric detection of PCR amplification products simplifies the assay, extends dynamic range, and reduces the risk of contamination.57 The range of detection of older, conventional PCR-based assay is 2 ⫻ 102 to 2 ⫻ 105 copies/mL. The newer COBAS TaqMan HBV Test (Roche Molecular Systems, Pleasanton, CA, USA), which uses RT-PCR technology has a greater dynamic

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The American Journal of Medicine, Vol 121, No 12A, December 2008

Figure 3 Cumulative incidence of cirrhosis (A) and hepatocellular carcinoma (B) by serum hepatitis B virus (HBV) DNA level at study entry. HCC ⫽ hepatocellular carcinoma. (Adapted from JAMA49 and Gastroenterology.50)

range (1.7 ⫻ 102 to 8.5 ⫻ 108 copies/mL, equating to 30 to 1.1 ⫻ 108 IU/mL), obviating the need for dilution of samples.

New Guidelines for Normal ALT Range Although quantification of HBV DNA is of growing use in monitoring patients with CHB, measurement of serum ALT

remains important in the diagnosis and assessment of liver disease. More recently, interest has been growing in the use of ALT as a test of insulin resistance and, in the context of obesity, the metabolic syndrome, and cardiovascular disease.58,59 Serum ALT can be viewed as a barometer of liver health, and the cause of a persistently raised serum ALT level should always be investigated.

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Diagnosis of CHB and Implications of Viral Variants and Mutations

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Figure 4 Dynamic ranges of commercially available quantitative hepatitis B virus (HBV) DNA assays. LLQ ⫽ lower limit of quantification; PCR ⫽ polymerase chain reaction; TMA ⫽ Transcription mediated amplification. (Clin Gastroenterol Hepatol.4)

Recently, however, what constitutes a normal and healthy serum ALT level has been a topic of considerable debate. The upper limit of the normal (ULN) range had been set typically at around 40 to 50 IU/L; such a level, based on assessments of “healthy” controls, is probably inflated by the unintentional inclusion in the reference population of individuals with subclinical liver disease, perhaps caused by undiagnosed viral hepatitis, heavy alcohol use, or nonalcoholic fatty liver disease. Serum ALT level may also depend on body mass index (BMI) and age.60-62 A study in 6,835 first-time blood donors (with negative hepatotropic viral serology and no behavioral contraindications for blood donation) carried out between 1995 and 1999 has suggested the ULN for serum ALT should be redefined as 30 IU/L for men and 19 IU/L for women.60 These limits were established by selecting the subpopulation at lowest risk for liver disease, with normal BMI and serum cholesterol, triglyceride, and glucose levels, and no current use of medication. There is a positive correlation between ALT concentration and mortality from liver disease, even within the level previously considered to be normal. A prospective cohort study in Korea found that the adjusted relative risk (compared with an ALT level of ⬍20 IU/L) of mortality from liver disease was 2.9 for ALT 20 to 29 IU/L and 9.5 for ALT 30 to 39 IU/L in men, and 3.8 and 6.6, respectively, in women.63 The authors of this study proposed that the best cutoff for the ULN ALT range for prediction of liver disease was 30 IU/mL, and recommended that individuals with slightly increased ALT, even within the normal range, should be observed and further investigated for liver dis-

ease. Liver biopsy of patients with elevated serum HBV DNA indicates that significant fibrosis is found in almost 25% of patients with “normal” ALT.64 Similarly, in a study of Asian patients with CHB, in which the ULN for ALT was defined as 53 IU/L in men and 31 IU/L in women, patients with ALT 0.5 to 1 times the ULN had a significantly higher risk of developing cirrhotic complications than did patients with ALT ⬍0.5 times the ULN.53 Findings such as these highlight the need for the normal range of serum ALT to be reassessed, such that guidelines restricting treatment to patient groups with a serum ALT concentration greater than twice the ULN do not exclude patients at risk for disease progression.16 The recently revised AALSD hepatitis B treatment guidelines acknowledge the call for revision of the normal range of serum ALT.16

SUMMARY CHB is a major healthcare problem worldwide. Elimination of CHB relies on effective screening and vaccination programs, coupled with optimal management of infected patients. Growing immigration to the United States from areas where infection with HBV is highly endemic means that healthcare providers must be active in providing low-cost screening opportunities and appropriate educational approaches. Screening technologies and improved nucleic acid testing techniques mean that infected patients, the stage of their disease, the viral load, and the subtype of disease can be identified, providing important prognostic information that can guide management decisions. Serial serum

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HBV DNA monitoring is playing an increasingly significant role in the assessment of therapeutic response and in informing decisions about therapy. Further research is needed to clarify the interplay between the various subtypes of disease and clinical outcome, and the role of different therapeutic agents and approaches in particular disease subtypes.

AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Robert G. Gish, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb, F. Hoffman-LaRoche Ltd., Gilead Sciences, Inc., GlaxoSmithKline, Ortho Biotech Products, L.P., Salix, Schering-Plough Corporation, and Valeant Pharmaceuticals International; serves as a consultant to Amgen Inc., Anadyls Pharmaceuticals, Inc., Bayer AG, Bristol-Myers Squibb, Chiron Corporation, Corixa Corporation, Eximias Pharmaceutical Corporation, F. Hoffman-LaRoche Ltd., Gilead Sciences, Inc., GlaxoSmithKline, GlobeImmune, Inc., HepaHope, Inc., Human Genome Sciences, Idenix Pharmaceuticals, Inc., Innogenetics NV, InterMune Pharmaceuticals, Inc., Merck & Co., Metabasis Therapeutics, Inc., Nucleonics, Inc., Ortho Biotech Products, L.P., Salix, Schering-Plough Corporation, SciClone Pharmaceuticals, Inc., and Valeant Pharmaceuticals International; and has received research/ grant support from Bristol-Myers Squibb, F. Hoffman LaRoche Ltd., Gilead Sciences, Inc., GlobeImmune Indenix/Novartis, InterMune Pharmaceuticals, Inc., Ortho Biotech Products, L.P., Pfizer Inc, Salix, ScheringPlough Corporation, SciClone Pharmaceuticals, Inc., and Valeant Pharmaceuticals International.

References 1. World Health Organization. Hepatitis B. WHO Fact Sheet No. 2004, revised October 2000. [WHO Web site.] Available at: http://www. who.int/mediacentre/factsheets/fs204/en/. Accessed July 17, 2008. 2. Department of Communicable Diseases Surveillance and Response, World Health Organization. Hepatitis B. Geneva: WHO, 2002. Available at: http:// www.who.int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf. Accessed July 17, 2008. 3. Centers for Disease Control and Prevention (CDC). Incidence of acute hepatitis B—United States, 1990-2002. MMWR Morb Mortal Wkly Rep. 2004;52:1252-1254. 4. Gish RG, Locarnini SA. Chronic hepatitis B: current testing strategies. Clin Gastroenterol Hepatol. 2006;4:666-676. 5. Gish RG, Gadano AC. Chronic hepatitis B: current epidemiology in the Americas and implications for management. J Viral Hepat. 2006; 13:787-798. 6. Cheung J, Lee TK, Teh CZ, Wang CY, Kwan WC, Yoshida EM. Cross-sectional study of hepatitis B awareness among Chinese and Southeast Asian Canadians in the Vancouver-Richmond community. Can J Gastroenterol. 2005;19:245-249. 7. Thompson MJ, Taylor VM, Jackson JC, et al. Hepatitis B knowledge and practices among Chinese American women in Seattle, Washington. J Cancer Educ. 2002;17:222-226. 8. Wu CA, Lin SY, So SK, Chang ET. Hepatitis B and liver cancer knowledge and preventive practices among Asian Americans in the San Francisco Bay Area, California. Asian Pac J Cancer Prev. 2007;8:127-134.

9. Centers for Disease Control and Prevention. Screening for chronic hepatitis B among Asian/Pacific Islander populations—New York City, 2005. MMWR Morb Mortal Wkly Rep. 2006;55:505-509. 10. Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. Hepatology. 2007;46:1034-1040. 11. Mast EE, Margolis HS, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1-31. 12. Mast EE, Weinbaum CM, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep 2006;55(RR-16):1-33. 13. Centers for Disease Control and Prevention (CDC). Characteristics of persons with chronic hepatitis B—San Francisco, California, 2006. MMWR Morb Mortal Wkly Rep. 2007;56:446-448. 14. Department of Vaccines and Biologicals, World Health Organization. Introduction of Hepatitis B Vaccine into Childhood Immunization Services. Geneva: WHO, 2001. Available at: http://www.who.int/ vaccines-documents/DocsPDF01/www613.pdf. Accessed July 17, 2008. 15. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B 2000, summary of a workshop. Gastroenterology. 2001;120:1828-1853. 16. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507539. 17. Chu CM. Natural history of chronic hepatitis B virus infection in adults with emphasis on the occurrence of cirrhosis and hepatocellular carcinoma. J Gastroenterol Hepatol. 2000;15(suppl):E25-E30. 18. Gandhi MJ, Yang GG, McMahon BJ, Vyas GN. Hepatitis B virions isolated with antibodies to the pre-S1 domain reveal occult viremia in Alaska Native HBV carriers who have seroconverted. Transfusion. 2000;40:910-916. 19. Benson CA, Kaplan JE, Masur H, Pau A, Holmes KK, for the Centers for Disease Control and Prevention, the National Institutes of Health, and the Infectious Diseases Society of America. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004;53(RR-15):1-112. 20. Enomoto M, Tamori A, Nishiguchi S. Hepatitis B virus genotypes and response to antiviral therapy. Clin Lab. 2006;52:43-47. 21. Palumbo E. Hepatitis B genotypes and response to antiviral therapy: a review. Am J Ther. 2007;14:306-309. 22. Bartholomeusz A, Schaefer S. Hepatitis B virus genotypes: comparison of genotyping methods. Rev Med Virol. 2004;14:3-16. 23. Bonino F, Marcellin P, Lau GK, et al for the Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Predicting response to peginterferon ␣-2a, lamivudine and the two combined for HBeAg-negative chronic hepatitis B. Gut. 2007;56:699-705. 24. Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B infection in the United States: an update. Clin Gastroenterol Hepatol. 2006;4:936-962. 25. Wiegand J, Hasenclever D, Tillman HL. Should treatment of hepatitis B depend on HBV genotypes? A hypothesis generated from an explorative analysis of published evidence. Antivir Ther. 2008; 13:211-20. 26. Verschuere V, Yap PS, Fevery J. Is HBV genotyping of clinical relevance? Acta Gastroenterol Belg. 2005;68:233-236. 27. Flink HJ, van Zonneveld M, Hansen BE, et al, for the HBV 99-01 Study Group. Treatment with peg-interferon ␣-2b for HBeAg-positive chronic hepatitis B: HBsAg loss is associated with HBV genotype. Am J Gastroenterol. 2006;101:297-303.

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28. Sánchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodés J. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology. 2002;123:1848-1856. 29. Chien RN, Yeh CT, Tsai SL, Chu CM, Liaw YF. Determinants for sustained HBeAg response to lamivudine therapy. Hepatology. 2003; 38:1267-1273. 30. Kobayashi M, Suzuki F, Akuta N, et al. Response to long-term lamivudine treatment in patients infected with hepatitis B virus genotypes A, B, and C. J Med Virol. 2006;78:1276-1283. 31. Schildgen O, Sirma H, Funk A, et al. Variant of hepatitis B virus with primary resistance to adefovir. N Engl J Med. 2006;354:1807-1812. 32. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006;44:283-290. 33. Kobayashi M, Akuta N, Suzuki F, et al. Virological outcomes in patients infected chronically with hepatitis B virus genotype A in comparison with genotypes B and C. J Med Virol. 2006;78:60-67. 34. Ganne-Carrié N, Williams V, Kaddouri H, et al. Significance of hepatitis B virus genotypes A to E in a cohort of patients with chronic hepatitis B in the Seine Saint Denis District of Paris (France). J Med Virol. 2006;78:335-340. 35. Chan HL, Hui AY, Wong ML, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut. 2004;53:1494-1498. 36. Yuen MF, Tanaka Y, Shinkai N, et al. Risk for hepatocellular carcinoma with respect to hepatitis B virus genotypes B/C, specific mutations of enhancer II/core promoter/precore regions and HBV DNA levels. Gut. 2008;57:98-102. 37. Yuen MF, Tanaka Y, Mizokami M, et al. Role of hepatitis B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study. Carcinogenesis. 2004;25:15931598. 38. Livingston SE, Simonetti JP, McMahon BJ, et al. Hepatitis B virus genotypes in Alaska Native people with hepatocellular carcinoma: preponderance of genotype F. J Infect Dis. 2007;195:5-11. 39. Chu CJ, Keeffe EB, Han SH, et al. Hepatitis virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003; 125:444-451. 40. Li JS, Tong SP, Wen YM, Vitvitski L, Zhang Q, Trepo C. Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region. J Virol. 1993;67:5402-5410. 41. Pan CQ, Zhang JX. Natural history and clinical consequences of hepatitis B virus infection. Int J Med Sci. 2005;2:36-40. 42. Liaw YF, Sollano JD. Factors influencing liver disease progression in chronic hepatitis B. Liver Int. 2006;26(suppl 2):23-29. 43. Hadziyannis SJ, Papatheodoridis GV. Hepatitis B e antigen-negative chronic hepatitis B: natural history and treatment. Semin Liver Dis. 2006;26:130-141. 44. Lau GK, Piratvisuth T, Luo KX, et al. Durability of response and occurrence of late response to peginterferon alfa-2a (40 kD) [Pegasys®] one year post-treatment in patients with HBeAg-positive chronic hepatitis B. [abstract]. J Hepatol 2006;44(suppl 2):S23. Abstract 50. 45. Carey, Giannattasio A, Bansal S, et al. Clearance of HBeAg is linked with emergence of mutations within pre-core and core regions of hepatitis B virus in paediatric patients. [abstract]. Hepatology 2006; 44(suppl 1):438A. Abstract 671. 46. Lim SG, Cheng Y, Guidon S, et al. Viral quasi-species evolution during hepatitis B e antigen seroconversion. Gastroenterology. 2007; 133:951-958.

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47. Yeh CT, Lin WP, Hsu CW, Chang ML, Lin SM, Sheen IS. Emergence and takeover of precore-stop mutant prior to exacerbation of e antigennegative chronic hepatitis B after withdrawal of lamivudine therapy. J Med Virol. 2006;78:906-910. 48. 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. 49. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. 50. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130: 678-686. 51. Ikeda K, Arase Y, Kobayashi M, et al. Hepatitis B virus-related hepatocellular carcinogenesis and its prevention. Intervirology. 2005; 48:29-38. 52. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265-272. 53. Yuen MF, Yuan HJ, Wong DK, et al. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications. Gut. 2005;54: 1610-1614. 54. Lai CL, Yuen MF. The natural history and treatment of chronic hepatitis B: a critical evaluation of standard treatment criteria end points. Ann Intern Med. 2007;147:58-61. 55. Mommeja-Marin HM, Mondou E, Blum MR, Rousseau F. Serum HBV DNA as a test of efficacy during therapy for chronic HBV infection: analysis and review of the literature. Hepatology. 2003; 37:1309-1319. 56. Saldanha J, Gerlich W, Lelie N, Dawson P, Heermann K, Heath A, for the WHO Collaborative Study Group. An international collaborative study to establish a World Health Organization international standard for hepatitis B virus DNA nucleic acid amplification techniques. Vox Sang. 2001;80:63-71. 57. Heid CA, Stevens J, Livak KJ, Williams PM. Real-time quantitative PCR. Genome Res. 1996;6:986-994. 58. Salazar MR, Carbajal HA, Curciarello JO, et al. Alanine-aminotransferase: an early test for insulin resistance? Medicine (B Aires). 2007; 67:125-130. 59. De Luis DA, Aller R, Izaola O, et al. Influence of insulin resistance in obese patients on elevated serum alanine aminotransferase. Eur Rev Med Pharmacol Sci. 2007;11:21-25. 60. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;137:1-9. 61. Piton A, Poynard T, Imbert-Bismut F, et al. Factors associated with serum alanine transaminase activity in healthy subjects: consequences for the definition of normal values, for selection of blood donors, and for patients with chronic hepatitis C. Hepatology. 1998;27:1213-1219. 62. Elinav E, Ben-Dov IZ, Ackerman E, et al. Correlation between serum alanine aminotransferase activity and age: an inverted U curve pattern. Am J Gastroenterol. 2005;100:2201-2204. 63. Kim HC, Nam CM, Jee SA, Han KW, Oh DK. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328:983-986. 64. Lai M, Hyatt B, Afdhal N. Role of liver biopsy in patients with normal ALT and high HBV DNA [abstract]. Hepatology. 2005;42(suppl 1): 720A. Abstract 1322.

Supplement issue

Assessment of the Newly Diagnosed Patient with Chronic Hepatitis B Virus Infection Robert J. Fontana, MD Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA

ABSTRACT An expanding population of patients with chronic hepatitis B (CHB) infection, including immigrants from endemic countries, are being identified in the United States. All newly diagnosed patients with CHB should be evaluated for initial disease severity and potential antiviral treatment options. Following a history and physical examination, routine laboratory measurements along with serum markers of hepatitis B virus (HBV) replication should be obtained. A liver biopsy provides important information regarding disease activity and stage and can help identify suitable candidates for antiviral therapy. Untreated patients with CHB should undergo periodic monitoring of serum aminotransferase and HBV DNA levels, as well as surveillance for hepatocellular carcinoma. Avoidance of hepatotoxic medications and immunosuppressants, as well as oral antiviral prophylaxis in selected clinical circumstances, is recommended for all patients with CHB. Behavioral modifications and education can help minimize the risk of inadvertent HBV transmission to close contacts. Although HBV is an entirely preventable disease via the use of a safe and highly effective vaccine, continued morbidity and mortality will likely be encountered due to the delay in diagnosis and treatment of the large number of patients with chronic HBV in the United States and worldwide. © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, S22–S32 KEYWORDS: Disease stage; Liver disease; Vaccination; Viral hepatitis

A diagnosis of acute hepatitis B virus (HBV) infection relies on the detection of circulating hepatitis B surface antigen (HBsAg) and/or anti-hepatitis B core antibody (anti-HBc IgM) along with a variably elevated serum alanine aminotransferase (ALT) and HBV DNA level.1 The Centers for Disease Control and Prevention (CDC) estimates that the incidence of acute infection with HBV declined 78% between 1990 and 2005, yet an estimated 51,000 cases continue to be reported each year.2 A diagnosis of chronic hepatitis B (CHB) relies on the persistence of serum HBsAg for ⱖ6 months after initial exposure. An estimated 0.4% of adult Americans, or 1.1 to 2.0 million individuals, have CHB.3-5 The CDC also estimates that the number of individuals with CHB is not decreasing; this is on account of the annual immigration of 40,000 patients with CHB from Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Robert J. Fontana, MD, Division of Gastroenterology, Department of Internal Medicine, University of Michigan, 3912 Taubman Center, Ann Arbor, Michigan 48109-0362. E-mail address: [email protected].

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.09.026

countries where the disease is endemic.2 Patients with CHB may have normal or intermittently elevated serum ALT or aspartate aminotransferase (AST) levels for many decades along with fluctuating serum HBV DNA levels.6,7 Because the majority of individuals with CHB have no signs or symptoms of liver disease, a high index of suspicion is required to diagnose this common condition.8-10 The natural history of chronic infection with HBV is highly variable and dependent on a number of host, viral, and environmental factors. The level of HBV replication and host immune response appear to be the key determinants of hepatic necroinflammation and disease progression.11,12 HBV is also capable of integration into the host genome, which can lead to a significantly increased lifetime risk for hepatocellular carcinoma (HCC) compared with uninfected individuals.13,14 In fact, CHB is a leading cause of liver failure and HCC throughout the world. In the United States, an estimated 5,000 deaths per year are attributed to infection with HBV along with substantial morbidity and healthcare expenditures.15 However, 7 approved medications for CHB have demonstrated improvement in 1-year

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Assessment of the Newly Diagnosed Patient with CHB

Table 1 Evaluation of patients with newly diagnosed chronic hepatitis B virus (HBV) infection Initial evaluation 1. History and physical examination a. Review alcohol and smoking history b. Review measures to reduce transmission c. Family history of liver disease, including HCC 2. Laboratory tests: CBC, liver biochemistries, INR, AFP 3. HBV replicative markers: HBeAg, anti-HBe, quantitative HBV DNA 4. Exclusion of cofactors a. Anti-HCV and anti-HIV in all patients b. Anti-HDV in injection drug users or if from endemic country c. Serum iron, iron-binding capacity, ferritin for iron overload 5. Screening for HCC* a. Serum AFP q6-12 mo b. Liver ultrasound q6-12 mo 6. Liver biopsy if grade and stage of disease would influence management decisions including use of antiviral medications General medical recommendations 1. Vaccines a. HAV for all patients b. Annual influenzae vaccine c. Pneumovax† q3-5 yr 2. Medications a. Acetaminophen-based analgesics are safe to use i. Preferred over aspirin/NSAIDs ii. Total daily dose ⬍4 g b. Other hepatotoxic drugs (e.g., isoniazid) i. Not contraindicated but serial ALT monitoring recommended ii. Review safety of frequently used herbal and OTC products c. If glucocorticoids, immunosuppresants, or chemotherapy are needed, recommend: i. Serial ALT and HBV DNA monitoring before, during, and after treatment ii. Prophylaxis with oral antiviral agent to prevent HBV reactivation during and after immunosuppression independent of ALT or HBV DNA level. 3. Surveillance for esophageal varices a. Upper endoscopy if advanced fibrosis on biopsy or clinical/radiologic evidence of portal hypertension b. Consider ␤-blockers/band ligation if medium/large varices are detected c. Repeat surveillance endoscopy q2-4 yr AFP ⫽ ␣-fetoprotein; ALT ⫽ alanine aminotransferase; Anti-HBe ⫽ HBeAg antibody; CBC ⫽ complete blood cell count; HAV ⫽ hepatitis A virus; HBeAg ⫽ hepatitis B e antigen; HCC ⫽ hepatocellular carcinoma; HDV ⫽ hepatitis D virus; HIV ⫽ human immunodeficiency virus; INR ⫽ international normalized ratio (for blood clotting time); NSAIDs ⫽ nonsteroidal anti-inflammatory drugs; OTC ⫽ over-the-counter. *See text for further details regarding high-risk individuals. †Pneumococcal vaccine polyvalent; Merck & Co., Inc., Whitehouse Station, NJ.

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studies, and hopefully these will translate into improved long-term outcomes with more prolonged treatment.1,6,7 Therefore, all newly diagnosed patients with CHB should be evaluated for disease severity and potential antiviral treatment options, as well as measures to prevent disease transmission.

EVALUATION OF THE NEWLY DIAGNOSED PATIENT HBV can survive for prolonged periods of time outside of the body and is readily transmitted by perinatal, percutaneous, and sexual exposure, as well as by close person-to-person contact.16 Newborns are at particularly high risk (90%) of developing chronic infection after exposure to HBV, whereas children are at intermediate risk (25% to 30%) and immunocompetent adults are at low risk (5%).17-19 Immunosuppressed individuals, including those with human immunodeficiency virus (HIV) coinfection, renal failure, and/or receiving immunosuppressant medications, are at increased risk for developing chronic infection after exposure.20,21 The recommended blood tests to screen for HBV are serum HBsAg, anti-HBc, and HBsAg antibody (anti-HBs). Patients who should be targeted for HBV screening include those born in countries with high and intermediate prevalence of HBV (e.g., southeast Asia, sub-Saharan Africa), household and sexual contacts of HBsAg-positive patients, injection drug users, male homosexuals, persons with multiple sex partners or sexually transmitted diseases, incarcerated individuals, all pregnant women, and subjects with unexplained serum ALT elevations.5,6 Screening all adults and children born in southeast Asia or the Pacific Islands, and vaccinating the nonimmune individuals is recommended, and will likely be cost-effective.22 Subjects with an isolated anti-HBc should undergo subsequent testing for anti-HBc (immunoglobulin M [IgM]) if acute HBV infection is suspected. Otherwise, it is presumed that these individuals experienced prior infection with HBV and have developed protective immunity.23 All subjects with newly diagnosed HBV infection should undergo a complete history and physical examination (Table 1). Stigmata of chronic liver disease such as gynecomastia, spider angiomata, and palmar erythema are usually observed only in subjects with advanced fibrosis or cirrhosis. Clinical evidence of advanced portal hypertension, such as ascites, edema, or hepatic encephalopathy, is associated with a poor short-term prognosis. Therefore, all patients with decompensated CHB should be referred for liver transplant evaluation and salvage antiviral therapy.24,25 Screening for hepatitis C virus (HCV) and HIV coinfection is advised in all newly diagnosed patients with CHB. Alcohol consumption should also be reviewed, as well as family history of HCC, which may influence subsequent surveillance strategies.26 Serum liver biochemistry tests should be obtained in all newly diagnosed patients with CHB.27,28 A complete blood cell count (CBC) with platelet count is useful to detect

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occult thrombocytopenia, which may be a sign of splenomegaly and underlying portal hypertension.29 The prothrombin time or international normalized ratio (INR) is also useful for detecting and monitoring disease severity. Newly diagnosed patients with CHB should undergo testing for hepatitis D virus (HDV) coinfection if they are injection drug users, or are from a high-risk area such as the Mediterranean or Amazon basins.30,31 Laboratory markers of HBV replication including hepatitis B e antigen (HBeAg), HBeAg antibody (anti-HBe), and a quantitative HBV DNA level also should be obtained in all patients with newly diagnosed chronic HBV. Extrahepatic manifestations such as polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis are rarely seen in patients with CHB and therefore routine screening for these conditions is not recommended in the absence of end-organ manifestations.32,33

HBV DNA Assays and Genotyping Most available HBV DNA assays are based on polymerase chain reaction (PCR) amplification.34 The lower limit of detection of these assays varies between 50 IU/mL and 200 IU/mL, with a dynamic range of 4 to 5 log10. However, HBV DNA assays that use real-time PCR technology with improved sensitivity (5 to 10 IU/mL) and a wider dynamic range of up to 9 log10 IU/mL have recently become available.35 Quantification of HBV DNA at initial diagnosis and periodically thereafter is recommended in light of its importance in categorizing disease stage, future prognosis, and potential need for antiviral therapy.1,6,7 Eight HBV genotypes that differ in the HBsAg region have been identified; they are labeled A through H.35-38 In the United States, the prevalence of HBV genotypes A, B, C, D, and E through G are 35%, 22%, 31%, 10%, and 2%, respectively.39 Recent data suggest that HBV genotypes may play an important role in disease progression and potential response to interferon therapy. For example, HBV genotype B is associated with earlier spontaneous and interferon-induced HBeAg seroconversion, less active hepatic necroinflammation, and a lower risk of HCC compared with genotype C.40,41 In addition, subjects infected with HBV genotype A appear to have the greatest likelihood of HBeAg seroconversion when treated with peginterferon compared with other genotypes.42 However, studies of the available oral antiviral agents have failed to show any relation between HBV genotype and treatment response.43 Therefore, most experts do not currently recommend testing for HBV genotype in clinical practice.1,36 Patients with HBeAg-negative chronic active HBV often harbor viral variants of HBV that lead to reduced expression of HBeAg.36,44,45 Because precore and core promoter variants are commonly detected during spontaneous and treatment-induced HBeAg seroconversion, they are believed to represent naturally occurring polymorphisms of HBV and they do not provide independent prognostic information. This is another reason that most experts do not

routinely recommend testing for HBV variants in clinical practice.1,6,36

Liver Biopsy The purpose of a liver biopsy in patients with chronic liver disease is to objectively assess disease severity and identify concomitant disease processes that may encourage/promote disease progression. Although the diagnosis of CHB is unequivocally established via serologic tests, liver biopsy can provide important prognostic and staging information that may influence treatment decisions.1,6 For example, up to one third of patients with CHB who have normal serum ALT levels and detectable HBV DNA may have significant inflammation or fibrosis on biopsy; conversely, some patients with abnormal ALT levels may be found to have only mild disease on biopsy.46 In addition, because the currently approved medications for CHB are frequently given for prolonged periods with a substantial risk of drug resistance, many experts recommend establishing disease severity via liver biopsy before initiating treatment.1,6 A liver biopsy in patients with chronic infection with HBV often demonstrates “ground- glass” hepatocytes indicative of retained cytoplasmic HBsAg particles and variable degrees of lymphocytic infiltration (Figure 1). The grade of necroinflammation can be characterized as mild, moderate, or severe.47,48 In contrast, the stage of liver disease is determined by the amount and pattern of collagen or scar tissue seen on special stains. Liver biopsies from subjects with viral hepatitis are most commonly staged using the Ishak or Metavir fibrosis scoring systems (Table 2).48-50 The Metavir scoring system ranges from 0 to 4 (4 ⫽ cirrhosis), while the Ishak scoring system ranges from 0 to 6 (6 ⫽ cirrhosis).48,49 With a larger range of values, it is not surprising that Ishak fibrosis scores are less reproducible than Metavir scores. In addition, the differences in fibrosis scores in either scoring system is not linear between individual stages as reflected by the amount of collagen seen using computerized morphometry,50-52 Unlike that reported in patients with chronic HCV, hepatic steatosis in patients with CHB is most commonly owing to metabolic syndrome factors rather than viral factors.53-55

Alternatives to Liver Biopsy Because a liver biopsy represents a small fraction of the total liver (i.e., ⬍1/50,000), sampling artifact may lead to inaccurate results. In particular, skinny needle biopsies (17 gauge) or short biopsies (⬍10 mm in length) with ⬍11 portal tracts may lead to an underestimation of fibrosis severity.56-58 In addition, many patients with CHB and their providers may be reluctant to undergo initial or serial liver biopsy because of potential complications, inconvenience, and costs. Minimally invasive means of assessing disease stage for CHB include laboratory, radiologic, and liver elasticity measurements. However, none of these methodologies has adequate accuracy and validation to replace liver

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Figure 1 Liver biopsy in a patient with chronic active hepatitis B virus (HBV). A 35-year old, HBeAg-positive Asian-American man had a persistently elevated serum alanine aminotransferase level (⬎2 ⫻ the upper limit of normal) for 12 months, with HBV DNA levels varying from 4 ⫻106 to 10 ⫻ 106 IU/mL. (A) A percutaneous liver biopsy demonstrates typical findings of chronic HBV infection with “ground-glass” hepatocyte cytoplasm (black arrow) and enlarged sanded nuclei (white arrow) (hematoxylin & eosin stain, 200⫻ magnification). (B) Staining for hepatic collagen demonstrates enlarged and scarred portal tracts connected by fibrous septae indicative of “bridging fibrosis” and an Ishak fibrosis score of 3 (Masson trichrome stains collagen blue, 100⫻ magnification). (Photomicrographs courtesy of Joel Greenson, MD, University of Michigan.)

biopsy. Laboratory indices that include routine laboratory tests such as the serum AST–platelet count ratio have reasonable positive predictive value for cirrhosis in subjects with chronic HCV,59 but these indices do not perform as well in subjects with CHB owing to the frequent spontaneous fluctuation in serum ALT/AST levels.29,60

Panels of serum fibrosis markers that more closely reflect liver fibrogenesis and fibrolysis have also been proposed, but few studies have been completed in patients with CHB.61-63 In the future, proteomic and glycoproteomic methods may prove useful in identifying serum biomarkers associated with liver disease severity.64,65

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Periodic imaging of the liver using ultrasound is recommended for HCC surveillance in many patients with chronic HBV infection. Liver imaging can also provide indirect evidence of advanced liver disease such as the presence of a nodular liver contour, caudate lobe hypertrophy, intraabdominal varices, and splenomegaly. However, routine liver imaging lacks adequate sensitivity and specificity for the full spectrum of histologic severity in CHB.66,67 Another promising technology for assessing disease severity in CHB is liver elastography.68-70 Ultrasound probes that assess the stiffness of a 1-cm core of tissue 3 to 4 cm from the skin surface have shown strong correlations with fibrosis severity in both patients with chronic HCV and patients

Table 3

Table 2 Staging of hepatic fibrosis severity in chronic hepatitis B virus Description

Metavir Score49

Ishak Score48

% Fibrosis* (range)

Absent Portal fibrosis (some) Portal fibrosis (most) Bridging fibrosis (few) Bridging fibrosis (many) Septal fibrosis Cirrhosis

0 1 1 2 3 4 4

0 1 2 3 4 5 6

3% 5% 7% 6% 12% 15% 28%

(1-10) (1-35) (1-32) (1-26) (2-28) (1-30) (5-65)

*Fibrosis percentage determined using computerized morphometry in patients with hepatitis C virus.50

Recommended frequency of laboratory and clinical assessment in untreated patients with chronic hepatitis B virus (HBV) Testing Frequency

Initial Status

ALT

Quantitative HBV DNA

Comments*

Inactive HBsAg carrier (Normal ALT, HBV DNA ⬍2,000 IU/mL, HBeAg⫺)

q3 mo ⫻ 1 yr then q6-12 mo

q12 mo

Immune-tolerant HBV (Normal ALT, HBV DNA ⬎105 IU/mL, HBeAg⫹)

q3-6 mo for 1 yr, then q6-12 mo

q6-12 mo; HBeAg q12 mo

HBeAg⫹ chronic active HBV (Variable ALT, HBV DNA ⬎2 ⫻ 104 IU/mL)

q1-3 mo for 1 yr, then q3-6 mon

q3-4 mo for 1 yr, then q6-12 mo; HBeAg q6 mo

HBeAg⫺ chronic active HBV (Variable ALT, HBV DNA ⬎2 ⫻ 103 IU/mL)

q1-3 mo for 1 yr, then q3-6 mo

q3-4 mo for 1 yr, then q6-12 mo

Decompensated HBV (Variable ALT, HBV DNA ⫹/⫺, HBeAg ⫹/⫺)

q1-2 mo

q1-3 mo

If ALT ⬎1-2 ⫻ ULN, check HBV DNA and exclude other etiologies; consider biopsy if 1 ALT or 1 HBV DNA persists ⬎12 mo If ALT ⬎1-2 ⫻ ULN, repeat q3 mo and exlcude other etiologies; consider biopsy if 1 ALT persists indicating HBeAg⫹ chronic active HBV Consider biopsy and treatment if ALT ⬎2 ⫻ ULN and HBeAg⫹ persists ⬎6 mo If ALT 1-2 ⫻ ULN intermittently ⬎12 mo, consider biopsy; otherwise, continue to monitor Consider biopsy and treatment if ALT ⬎2 ⫻ ULN and HBV DNA ⬎2,000 IU/mL If ALT 1-2 ⫻ ULN intermittently ⬎12 mo, consider biopsy; otherwise, continue to monitor Recommend immediate oral antiviral treatment and referral for liver transplantation

ALT ⫽ alanine aminotransferase; HBeAg ⫽ hepatitis B e antigen; ULN ⫽ upper limit of normal. *All untreated patients should be considered for prophylactic oral antiviral agent independent of serum ALT and HBV DNA level if placed on glucocorticoids, immunosuppressants, or chemotherapy.

with CHB.68-70 However, this technology is not currently licensed in the United States and its utility in distinguishing hepatic steatosis from inflammation and fibrosis requires additional refinement. Magnetic resonance elastography may also prove useful, but further research is needed.71 Therefore, disease staging in patients with compensated CHB continues to primarily rely on liver biopsy in combination with routine laboratory tests.

DISEASE STATES AND NATURAL HISTORY OF CHRONIC HEPATITIS B VIRUS Diagnostic criteria for the various states of chronic infection with HBV based on a combination of liver biochemistries,

HBV DNA levels, and liver histology have recently been published (Table 3).1,6

Immune-tolerant HBV During the initial phase of “vertically acquired” chronic infection with HBV, serum HBV DNA levels are high, HBeAg is typically present, and yet serum ALT levels are normal for prolonged periods.72 During the “immune-tolerant” phase of infection, biopsies tend to show minimal-tomild liver damage, despite the high levels of HBV replication. However, during follow-up many of these patients develop HBeAg-positive CHB with waxing and waning serum ALT levels in their adolescent or early adult years.72,73 Therefore, these patients should be monitored at

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3- to 6-month intervals and those with persistent ALT elevations and detectable HBeAg should be considered for potential liver biopsy and possible treatment.

Inactive HBsAg Carrier State The “inactive” HBsAg carrier state is defined as a patient who is either HBeAg positive or HBeAg negative with generally low or normal serum ALT/AST levels and a serum HBV DNA level ⬍2,000 IU/mL.1,6 In these patients, routine liver biopsy is not recommended, but if performed would likely identify minimal necroinflammation.74 The prognosis of inactive HBsAg carriers is generally good and there is a spontaneous rate of seroconversion to anti-HBs of 0.5% to 1.0% per year.75,76 Following initial diagnosis, serum ALT should be monitored every 3 months for the first year to verify that these patients are truly “inactive” carriers and then every 6 to 12 months because up to 20% may develop disease reactivation.77 Although inactive HBsAg carriers do not require antiviral therapy, they should receive a prophylactic oral antiviral agent if they receive chemotherapy or prolonged immunosuppression (i.e., anti-tumor necrosis factor-␣ therapy, steroids for ⬎6 weeks). Multiple studies have shown that oral antiviral agents given during and 1 year after immunosuppression or chemotherapy not only reduce the risk for HBV reactivation but also reduce liver-related morbidity and mortality in patients infected with HBV.78,79

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carriers. However, these inactive carriers may revert to an HBeAg-positive phenotype with ALT elevations and be at risk for developing progressive liver disease.84,85 Subjects with HBeAg-positive disease and a viral load ⬎20,000 IU/mL with a normal ALT and no significant disease on biopsy should have serum ALT levels checked every 3 to 6 months and more often if it becomes elevated. Host cofactors for disease progression include older age (indicative of longer duration of infection), chronic alcohol consumption, and HCV, HDV, or HIV coinfection.84 In addition, subjects with a family history of HCC, men, smokers, and those infected with HBV genotype C are at increased risk for HCC.86 After HBeAg seroconversion nearly 30% of patients will develop fluctuating serum HBV DNA and ALT levels.81 The natural history of patients with HBeAg-negative CHB is also highly variable. These subjects are generally older and have more advanced histology compared with HBeAgpositive patients owing to their more prolonged duration of infection.87 Patients with HBeAg-negative CHB with an HBV DNA ⬎2,000 IU/mL and a persistently abnormal ALT, or moderate to severe necroinflammation on biopsy, should be considered for antiviral therapy. Untreated HBeAg-negative subjects should have laboratory monitoring at least every 6 to 12 months, along with HCC surveillance.

SCREENING FOR HEPATOCELLULAR CARCINOMA Chronic Active HBV Subjects with chronic HBV infection are commonly divided into HBeAg-positive and HBeAg-negative (anti-HBe-positive) groups. By definition, both groups have persistent or intermittent serum ALT/AST elevations with variable HBV DNA levels. Liver biopsy in these patients demonstrates evidence of chronic inflammation that can vary from mild to severe. Patients with HBeAg-positive disease typically have fluctuating HBV DNA levels that are ⬎20,000 IU/mL, but bursts of HBV replication with concomitant increases in serum ALT/AST levels are commonly observed.73,80 In contrast, those with HBeAg-negative disease generally have lower HBV DNA levels, although these still are ⬎2,000 IU/mL, with intermittent bursts of viral replication and associated ALT/AST elevations.81 As a result, monitoring of serum ALT levels and HBV DNA levels at least every 3 to 6 months is warranted in subjects with chronic active infection with HBV not receiving antiviral therapy.1,6,7 Among HBeAg-positive patients with elevated serum ALT levels, the rate of spontaneous HBeAg clearance varies from 8% to 12% per year.82,83 Therefore, all newly diagnosed HBeAg-positive patients should be monitored for 6 to 12 months before considering antiviral therapy. Older age, higher ALT, and genotype B are associated with higher rates of spontaneous HBeAg clearance.1,14 Following spontaneous HBeAg seroconversion to anti-HBe, 70% to 80% of patients have low or undetectable HBV DNA with normal serum ALT levels and effectively become inactive HBsAg

Hepatitis B is only 1 of 2 viruses classified by the World Health Organization (WHO) as a known human carcinogen. Risk factors for HCC in patients with CHB include male sex, smoking, family history of HCC, older age, presence of cirrhosis, HBV genotype C, prolonged and high levels of HBV replication, and coinfection with HCV.88 Although cirrhosis is a strong risk factor for HCC, worldwide 30% to 50% of HCC develops in the absence of cirrhosis.89 Recently, large prospective cohort studies of untreated HBsAgpositive Asian patients showed the presence of HBeAg and high levels of HBV DNA to be independent risk factors for the development of both cirrhosis and HCC.84,86 Because these studies were carried out in countries where HBV is predominantly transmitted perinatally and the mean age at enrollment was 40 years, these data suggest that high levels of HBV replication over many decades is associated with an increased risk for HCC. Studies of prolonged suppression of HBV replication with effective antiviral therapy that are associated with a reduced lifetime risk for HCC have not yet been completed but are eagerly awaited. However, data in patients with compensated CHB with advanced fibrosis have confirmed that lamivudine decreases the risk for developing liver failure and clinical decompensaton.4,6 The principal screening methods for HCC are serum ␣-fetoprotein (AFP) testing and liver imaging. The recent American Association for the Study of Liver Diseases (AASLD) practice guideline concluded that the sensitivity, specificity, and accuracy of ultrasound imaging was supe-

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rior to that of periodic AFP measurement and that the latter was not routinely justified if ultrasound is available.90 They recommended that patients with chronic HBV infection at high risk for HCC should undergo ultrasound surveillance every 6 to 12 months. However, because ultrasound is operator dependent and has limited sensitivity, most clinicians rely on a combination of imaging and serum AFP every 6 to 12 months.7,91 Individuals considered to be at high risk for HCC include Asian men aged ⬎40 years, Asian women ⬎50 years of age, persons with cirrhosis, Africans ⬎20 years of age, and any patient with CHB with persistent or intermittent serum ALT elevations or HBV DNA levels ⬎2,000 IU/mL. These individuals should undergo AFP and liver imaging every 6 months if possible. Other patients with CHB at lower risk for HCC should undergo liver imaging and tumor marker assessment annually. Limitations of liver ultrasound include low sensitivity for tumors ⬍2 cm and inability to discern vascular enhancement. Limitations of serum AFP testing include low sensitivity in patients with biopsy-proven HCC (only ⬃60%) and lack of specificity, particularly in subjects with active necroinflammation and concomitant liver regeneration. Although other serum tumor markers such as des-␥-carboxyprothrombin appear promising, further validation studies are required before incorporation into clinical practice.92 If a new focal lesion or abnormality is noted in a patient with chronic HBV infection, follow-up contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the liver is recommended to differentiate benign from malignant lesions.90 Similarly, subjects with a persistently elevated or rising AFP or an absolute value ⬎500 ng/mL should undergo ultrasound imaging followed by contrast-enhanced CT or MRI. The need to biopsy focal masses identified on imaging modalities is controversial and usually reserved for atypical or small lesions before treatment. Patients with small tumors and minimal portal hypertension may be amenable to surgical resection, while others with early stage disease may be candidates for liver transplantation.93 However, many HBsAg-positive patients diagnosed with HCC have advanced-stage tumors at presentation and are only eligible for palliative chemoembolization or radiofrequency ablation. Recently, the orally administered tyrosine kinase inhibitor sorafenib has demonstrated survival benefit in subjects with advanced HCC and was approved by the US Food and Drug Administration (FDA).94

OTHER GENERAL MEDICAL RECOMMENDATIONS FOR PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION All patients with chronic HBV infection should receive vaccination against the hepatitis A virus (HAV) in light of the poor outcomes with acute HAV in patients with liver disease95 In addition, an annual flu shot and a Pneumovax (pneumococcal vaccine polyvalent; Merck & Co., Inc., Whitehouse Station, NJ) every 3 to 5 years is recommended for all patients with chronic liver disease.96 Excessive alco-

hol consumption has been associated with disease progression, but the threshold for liver injury is not known.97 Therefore, most experts advise abstinence from alcohol for all patients with chronic liver disease. Recent data suggest that long-term cigarette smoking is also a cofactor for fibrosis progression and HCC.98 Therefore, smoking cessation or reduction is advised. Although diabetes mellitus and obesity appear to be cofactors for fibrosis progression and HCC risk in HCV, their role in chronic HBV infection is less well established.99,100 However, insulin resistance and hepatic steatosis are associated with more severe liver disease in CHB.101,102 Therefore, aerobic exercise and avoidance of obesity is recommended by many experts for all patients with CHB. Patients with chronic HBV infection may be at a 2- to 3-fold increased risk for liver toxicity from some medications such as isoniazid, but the overall risk remains low.103,104 In addition, unregulated herbal products and natural remedies frequently taken by many patients with CHB can exacerbate liver injury.105,106 Use of immunomodulatory drugs such as hydroxychloroquine and leflunomide in patients with CHB may also lead to disease flares, emphasizing the need for periodic laboratory monitoring.107 However, subjects receiving glucocorticoids are at substantial risk for enhanced HBV replication, owing to the steroidresponsive element in the HBV genome, and should receive prophylactic antiviral therapy during and after treatment that exceeds 6 weeks.108 Acetaminophen-based analgesics are preferred for patients with CHB, particularly for those with advanced fibrosis, because of the significant risk of gastrointestinal bleeding with chronic aspirin or nonsteroidal anti-inflammatory drugs. However, the daily dose of acetaminophen should not exceed 4 g/day because of the risk of liver injury from higher doses.109 Subjects with histologic cirrhosis or bridging fibrosis should undergo periodic surveillance for esophageal varices and receive prophylactic ␤-blockers or band ligation as clinically indicated.110

COUNSELING AND PREVENTION OF HEPATITIS B VIRUS INFECTION Household members and sexual partners of HBsAg-positive patients are at increased risk for acquiring HBV compared with the general population. Therefore, if they test negative for HBV serologic markers they should be vaccinated. In addition, any adult requesting HBV vaccination should receive it independent of their underlying risk for acquisition of HBV as per updated CDC guidelines.96 Barrier contraception is also recommended to prevent HBV transmission to sexual partners of HBsAg-positive patients.2 Patients with CHB should not share toothbrushes or razors with others, and blood spots or spills in a home should be cleaned with bleach to sterilize the surface. In addition, patients with CHB should not donate blood, sperm, or organs because of the risk of inadvertent HBV transmission. However, awareness of the potential for stigmatization of these individuals

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is needed because excessive concern may lead to unnecessary anxiety and psychological distress.111 Therefore, adults and children with chronic HBV infection should be allowed to participate in contact sports, daycare, and other group and social activities, and sharing of food, utensils, and clothing items should not be restricted. All 3 doses of the HBV vaccine (given at 0, 1, and 6 months) are required to minimize the frequency of nonresponse amongst healthy seronegative individuals.2 Postvaccination assessment of anti-HBs levels is recommended only for individuals at ongoing risk for HBV acquisition, such as healthcare workers, infants of HBsAg-positive mothers, and sexual partners of HBsAg-positive individuals. For vaccine nonresponders, a repeat 3-dose series is advised and can lead to anti-HBs seroconversion in 50%. For persistent nonresponders, newer vaccines are under development but not yet available. Periodic booster vaccination is not recommended because of persistent immunologic reactivity in the circulating lymphocytes of successfully immunized individuals for up to 30 years.112 However, patients on hemodialysis are advised to receive periodic booster vaccination on account of their initial weak immune response and ongoing risk for acquiring HBV.110 Pregnant HBsAg-positive women should be counseled regarding measures to reduce the risk for HBV transmission to their newborns. At a minimum, all newborns of HBsAgpositive mothers should receive hepatitis B immunoglobulin immediately after birth, along with hepatitis B vaccine; this strategy is associated with a 95% efficacy rate in preventing HBV transmission.113 However, efficacy appears to be lower in mothers with very high levels of HBV DNA (i.e., ⬎108 IU/mL). There are few studies of the safety and efficacy of antiviral therapy during the third trimester of pregnancy in women with high serum HBV DNA levels.114-116 Therefore, antiviral therapy during pregnancy is not routinely recommended. In addition, there are no data to support the use of elective cesarean section over vaginal delivery to reduce the risk for HBV transmission. Finally, recent studies have demonstrated that HBsAg-positive mothers tend to have a reduction of serum ALT levels during pregnancy with a 40% risk for a mild disease flare within 6 months of delivery, highlighting the need for postpartum laboratory monitoring.117 Transmission of HBV from an HBsAg-positive healthcare worker to seronegative patients can occur in rare circumstances.118,119 Therefore, the CDC recommends that HBeAg-positive healthcare workers should not perform exposure-prone procedures without prior counseling and advice from an expert review panel regarding under what, if any, circumstances they should be allowed to perform these procedures.120

SUMMARY Although CHB is an entirely preventable disease, up to 0.4% of adult Americans harbor the virus and are at variable risk for disease progression and transmitting the infection to

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nonimmune household and sexual contacts. In general, Western inactive HBsAg carriers with normal ALT and low or undetectable HBV DNA levels have a favorable prognosis in the absence of chemotherapy or immunosuppression, which can precipitate a disease flare. Patients with chronic HBV infection in the immune-tolerant phase of vertically acquired infection should undergo frequent laboratory and clinical assessment for spontaneous anti-HBe seroconversion or the development of chronic, active HBV infection. Subjects with HBeAg-positive and anti-HBe-positive chronic active HBV infection typically have variably elevated serum ALT and HBV DNA levels as well as active necroinflammation on liver biopsy that can be improved and controlled with any of the 7 FDA-approved treatments. Untreated patients with CHB should undergo regular laboratory and clinical assessment for disease activity, as well as screening for HCC per AASLD guideline recommendations. Behavioral modifications and education are recommended to help minimize the risk for inadvertent HBV transmission to nonimmune individuals. Finally, greater use of HBV vaccination in newborns and catch-up vaccination of nonimmune adolescents and adults is recommended, both in the United States and worldwide, to further reduce the morbidity and mortality attributed to this preventable cause of acute and chronic liver disease.

AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Robert J. Fontana, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb and Roche Laboratories; and serves as a consultant to Bristol-Myers Squibb.

References 1. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45: 507-539. 2. Mast EE, Weinbaum CM, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendation of the Advisory Committee on Immunization Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33. 3. McQuillan GM, Coleman PJ, Kruszon-Moran D, Moyer LA, Lambert SB, Margolis HS. Prevalence of hepatitis B virus infection in the United States: the National Health and Nutrition Examination Surveys: 1976 through 1994. Am J Pub Health. 1999;89:14-18. 4. Centers for Disease Control and Prevention (CDC). Screening for chronic hepatitis B among Asian/Pacific Islander populations—New York City, 2005. MMWR Morb Mortal Wkly Rep. 2006;55:505-509. 5. Cohen C, Evans AA, London WT, Block J, Conti M, Block T. Underestimation of chronic hepatitis B virus infection in the United States of America. J Viral Hepat. 2008;15:12-13. 6. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056-1075. 7. Keeffe EB, Dieterich DT, Han SB, 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.

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8. Lin SY, Chang ET, So SK. Why we should routinely screen Asian American adults for hepatitis B: a cross-sectional study of Asians in California. Hepatology. 2007;46:1034-1040. 9. Spiegel BMR, Bolus R, Han S, et al. Development and validation of a disease targeted quality of life instrument in chronic hepatitis B: the hepatitis B quality of life instrument, version 1.0. Hepatology. 2007; 46:113-121. 10. Bondini S, Kallman J, Dan A, et al. Health-related quality of life in patients with chronic hepatitis B. Liver Int. 2007;27:1119-1125. 11. Chisari FV, Ferrari C. Hepatitis B virus immunopathogenesis. Annu Rev Immunol. 1995;13:29-60. 12. Fattovich G. Natural history and prognosis of hepatitis B. Semin Liv Dis. 2003;23:47-58. 13. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst. 2005;97:265-272. 14. Yim HJ, Lok AS. Natural history of chronic hepatitis B virus infection: when we knew in 1981 and what we know in 2005. Hepatology. 2006;43(suppl 1):S173-S181. 15. Kim WR, Benson JT, Therneau TM, Torgerson HA, Yawn BP, Melton LJ 3rd. Changing epidemiology of hepatitis B in a US community. Hepatology. 2004;39:811-816. 16. Bond WW, Favero MS, Petersen NJ, Gravelle CR, Ebert JW, Maynard JE. Survival of hepatitis B virus after drying and storage for one week. Lancet. 1981;1:550-551. 17. Beasley RP, Hwang LY, Lee GC, et al. Prevention of perinatally transmitted hepatitis B virus infections with hepatitis B immunoglobulin and hepatitis B vaccine. Lancet. 1983;2:1099-1102. 18. Beasley RP, Hwang LY, Lin CC, et al. Incidence of hepatitis B virus infections in preschool children in Taiwan. J Infect Dis. 1982;146: 198-204. 19. Coursaget P, Yvonnet B, Chotard J, et al. Age and sex-related study of chronic hepatitis B virus infections in preschool children in infants from an endemic area (Senegal). J Med Virol. 1987;22:1-5. 20. Horvath, Raffanti SP. Clinical aspects of the interactions between human immunodeficiency virus and the hepatotrophic viruses. Clin Infect Dis. 1994;18:339-347. 21. Bodsworth N, Donovan B, Nightingale BN. The effect of concurrent human immunodeficiency virus infection on chronic hepatitis B: a study of 150 homosexual men. J infect Dis. 1989;160:577-582. 22. Hutton DW, Tan D, So SK, Brandeau ML. Cost-effectiveness of screening and vaccinating Asian and Pacific Islander adults for hepatitis B. Ann Intern Med. 2007;147:460-469. 23. Lok AS, Lai CL, Wu PC. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implications in hepatitis B vaccination programs. Hepatology. 1988; 8:766-770. 24. De Jongh FE, Janssen HL, De Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic factors in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology. 1992; 103:1630-1635. 25. Fontana RJ. Management of patients with decompensated HBV cirrhosis. Semin Liv Dis. 2003;23:89-100. 26. Donato F, Tagger A, Chiesa R, et al. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a casecontrol study in Italy. Hepatology. 1997;26:579-584. 27. Borg FT, Kate FJW, Cuypers HTM, et al. Relation between laboratory test results and histological hepatitis activity in individuals positive for hepatitis B surface antigen and antibodies to hepatitis B e antigen. Lancet. 1998;351:1914-1918. 28. Myers RP, Tainturier MH, Ratziu V, et al. Predication of liver histological lesion with biochemical markers in patients with chronic hepatitis B. J Hepatol. 2003;39:222-230. 29. Hui AY, Chan HL, Wong VWS, et al. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple non-invasive predictive model. Am J Gastroenterol. 2005;100: 616-623.

30. Fattovich G, Giustina G, Christensen E, et al, for the European Concerted Action on Viral Hepatitis (Eurohep). Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. Gut. 2000;46:420-426. 31. Stroffolini T, Ferrigno L, Cialdea L, et al, for the SEIEVA Collaborating Group. Incidence and risk factors of acute Delta hepatitis in Italy: results from a national surveillance system. J Hepatol. 1994; 21:1123-1126. 32. Guillevin L, Lhote F, Cohen P, et al. Polyarteritis nodosa related to hepatitis B virus: a prospective study with long-term observation of 41 patients. Medicine. 1995;74:238-253. 33. Johnson RJ, Couser WB. Hepatitis B infection and renal disease: clinical, immunopathogenis and therapeutic considerations. Kidney Int. 1990;37:663-676. 34. Pawlotosky JM. Molecular diagnosis of viral hepatitis. Gastroenterology. 2002;122:1554-1568. 35. Weiss J, Wu H, Farrenkopf B, et al. Real-time TaqMan PCR detection and quantitation of HBV genotypes A-G with the use of an internal quantitation standard. J Clin Virol. 2004;30:86-93. 36. Wai CT, Fontana RJ. Clinical significance of hepatitis B virus genotypes, variants, and mutants. Clin Liv Dis. 2004;8:321-352. 37. Lindh M, Andersson AS, Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus—large-scale analysis using a new genotyping method. J Infect Dis. 1997;175:1285-1293. 38. Hussain M, Chu CJ, Sablon E, Lok AS. Rapid and sensitive assays for determination of hepatitis B virus (HBV) genotypes and detection of HBV precore and core promoter variants. J Clin Microbiol. 2003; 41:3699-3705. 39. Chu CJ, Keefe EB, Han SH, et al. Hepatitis B virus genotypes in the United States: results of a nationwide study. Gastroenterology. 2003; 125:444-451. 40. Chan HL, Hui AY, Wong ML, et al. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 2004;53:1494-1498. 41. Chu CJ, Hussain M, Lok ASF. Hepatitis B virus genotype B is associated with earlier HBeAg seronconversion compared with hepatitis B virus genotype C. Gastroenterology. 2002;122:1756-1762. 42. Erhardt A, Blondin D, Hauck K, et al. Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D. Gut. 2005;54:1009-1013. 43. Westland C, Delaney W, Yang H, et al. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil. Gastroenterology. 2003;125:107-116. 44. Lok AS, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proc Natl Acad Sci U S A. 1994;91:4077-4081. 45. Okamoto H, Tsuda F, Akahane Y, et al. Hepatitis B virus with mutations in the core promoter for an e antigen negative phenotype in carriers with antibody to e antigen. J Virol. 1994;68:8102-8110. 46. Zavaglia C, Mondazzi L, Maggi G, et al. Are alanine aminotransferase, hepatitis B virus DNA or IgM antibody to hepatitis B core antigen serum levels predictors of histological grading in chronic hepatitis B? Liver. 1997;17:83-87. 47. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Schever PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19:1513-1520. 48. Ishak K, Baptista A, Bianchi L, et al. Histologic grading and staging of chronic hepatitis. J Hepatol. 1995;22:696-699. 49. The French Metavir Cooperative Study Group. Intraobserver and interobserver variations in liver biopsy interpretation in patients with chronic hepatitis C. Hepatology. 1994;20:15-20. 50. O’Brien MJ, Keating NM, Elderiny S, et al. An assessment of digital image analysis to measure fibrosis in liver biopsy specimens of patients with chronic hepatitis C. Anat Pathol. 2000;114:712-718. 51. Pilette C, Rousselet MC, Bedossa P, et al. Histopathological evaluation of liver fibrosis: quantitative image analysis vs semi-quantitative scores. J Hepatol. 1998;28:439-446.

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52. Hui AY, Liew CT, Go MYY, et al. Quantitative assessment of fibrosis in liver biopsies from patients with chronic hepatitis B. Liver Int. 2004;24:611-618. 53. Altparmak E, Koklu S, Yalinkilic M, et al. Viral and host causes of fatty liver in chronic hepatitis B. World J Gastroenterol. 2005;11: 3056-3059. 54. Gordon A, McLean CA, Pedersen JS, Bailey HJ, Roberts SK. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution, and effect on fibrosis. J Hepatol. 2005;43:38-44. 55. Thomopoulos KC, Arvaniti V, Tsamantas AC, et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. Eur J Gastroenterol Hepatol. 2006;18:233-237. 56. Colloredo G, Guido M, Sonzongni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample the milder the disease. J Hepatol. 2003;39:239244. 57. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology. 2003;38:1449-1457. 58. Regev A, Berho M, Jeffers LT, et al. Sampling error and intraobserver variability in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol. 2002;97:2614-2618. 59. Wai CT, Greenson JK, Fontana RJ, et al. A simple non-invasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38:518-526. 60. Zeng MD, Lu LG, Mao YM, et al. Prediction of significant fibrosis in HBeAg-positive patients with chronic hepatitis B by a non-invasive model. Hepatology. 2005;42:1437-1445. 61. Giustina G, Fattovich G, De Paoli M, et al. Serum procollagen type III peptide in chronic hepatitis B: relationship to disease activity and response to interferon-alpha therapy. Int J Clin Lab Res. 1996;26: 33-36. 62. Pontinha N, Pessegueiro H, Barros H. Serum hyaluronan as a marker of liver fibrosis in asymptomatic chronic viral hepatitis B. Scand J Clinic Lab Invest. 1999;59:343-348. 63. Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (Fibrotest-Actiest) during lamivudine therapy in patients with chronic hepatitis B infection. Am J Gastroenterol. 2005;100:1970-1980. 64. He QY, Lau GKK, Zhou Y, et al. Serum biomarkers of hepatitis B virus infected liver inflammation: a proteomic study. Proteomics. 2003;3:666-674. 65. Callewaert N, Van Vlierberghe H, Van Hecke A, Laroy W, Delanghe J, Contreras R. Noninvasive diagnosis of liver cirrhosis using DNA sequencer-based total serum protein glycomics. Nat Med. 2004;10: 429-434. 66. Danet IM, Semelk RC, Braga L. MR imaging of diffuse liver disease. Radiol Clin North Am. 2003;41:67-87. 67. Iacobellis A, Fusilli S, Mangia A, et al. Ultrasonographic and biochemical parameters in the non-invasive evaluation of liver fibrosis in hepatitis C virus chronic hepatitis. Aliment Pharmacol Ther. 2005; 22:769-774. 68. Castera L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005; 128:343-350. 69. Kettaneh A, Marcellin P, Douvin C, et al. Features associated with success rate and performance of FibroScan measurements for the diagnosis of cirrhosis in HCV patients: a prospective study of 935 patients. J Hepatol. 2006;46:628-634. 70. Fung KP, Lai CL, Fong DY, Yuen JC, Wong DK, Yuen MF. Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of a predictive modes for liver fibrosis. Liver Int 2008 May 14 (epub ahead of print). 71. Yin M, Talwalka JA, Glaser KJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5:1207-1213.

S31 72. Lok AS, Lai CL. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children. Hepatology. 1988;8: 1130-1133. 73. Lee PI, Chang MH, Lee CY, et al. Changes of serum hepatitis B virus DNA and aminotransferase levels during the course of chronic hepatitis B in children. Hepatology. 1990;12:657-660. 74. Martinot-Peignoux M, Boyer N, Colombat M, et al. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers. J Hepatol. 2002;36:543-546. 75. McMahon BJ, Holck P, Bulkow L, Snowball H. Serologic and clinical outcomes in 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med. 2001;135:759-768. 76. Ahn SH, Park YN, Park JY, et al. Long-term clinical and histological outcomes in patients with spontaneous hepatitis B surface antigen seroclearance. J Hepatol. 2005;42:188-194. 77. Hsu YS, Chien RN, Yeh CT, et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002;35:1522-1527. 78. Yeo W, Johnson PJ. Diagnosis, prevention, and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209-220. 79. Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742-1749. 80. Lok AS, Lai CL. Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection: incidence, predisposing factors and etiology. J Hepatol. 1990;10:29-34. 81. Hadziyannis SJ, Vassilopoulos D. Hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2001;34:617-624. 82. Hoofnagle JH, Dusheiko GM, Seeff LB, Jones EA, Waggoner JG, Bales ZB. Seroconversion from hepatitis B e antigen to antibody in chronic type B hepatitis. Ann Intern Med. 1981;94:744-748. 83. Liaw YF, Chu CM, Su IJ, Huang MJ, Lin DY, Chang-Chien CS. Clinical and histological events preceding hepatitis B e antigen seroconversion in chronic type B hepatitis. Gastroenterology. 1983;84: 216-219. 84. Iloeje UH, Yang HI, Su J, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006; 130:678-686. 85. Yang HL, Lu SN, Liaw YF, et al. Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med. 2002;347:168-174. 86. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. 87. Brunetto MR, Oliveri F, Coco B, et al. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study. J Hepatol. 2002;36:263-270. 88. Donato F, Boffetta P, Puoti M. A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma. Int J Cancer. 1998;75:347-354. 89. Bosch FX, Ribes J, Cleres R, Diaz H. Epidemiology of hepatocellular carcinoma. Clin Liver Dis. 2005;9:191-211. 90. Bruix J, Sherman M, for the Practice Guidelines Committee of the American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236. 91. Chalasani N, Said A, Ness R, Hoen H, Lumeng L. Screening for hepatocellular carcinoma in patients with cirrhosis in the United States: results of a national survey. Am J Gastroenterol. 1999;94: 2224-2229. 92. Marrero JA, Su GL, Wei W, et al. Des-gamma carboxyprothrombin can differentiate hepatocellular carcinoma from nonmalignant chronic liver disease in American patients. Hepatology. 2003;37: 1114-1121. 93. Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999; 229:790-799. 94. Llovet J, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-390.

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95. Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998;338:286-290. 96. Advisory Committee on Immunization Practices. Recommended adult Immunization schedule: United States, October 2006-September 2007. Ann Intern Med. 2007;147:725-729. 97. Chevillotte G, Durbec JP, Gerolami A, Berthezene P, Bidart JM, Camatte R. Interaction between hepatitis B virus and alcohol consumption in liver cirrhosis: an epidemiologic study. Gastroenterology. 1983;85:141-145. 98. Marrero JA, Fontana RJ, Fu S, et al. Alcohol, tobacco, and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol. 2005; 42:218-224. 99. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology. 2003;125:1695-1704. 100. Kumar D, Farrell GC, Kench J, George J. Hepatic steatosis and the risk of hepatocellular carcinoma in chronic hepatitis C. J Gastrenterol Hepatol. 2005;20:1395-1400. 101. Bondini S, Kallman J, Wheeler A, et al. The impact of non-alcoholic fatty liver disease on chronic hepatitis B. Liver Int. 2007;27:1119-1125. 102. Gordon A, McLean CA, Pedersen JS, Bailey MJ, Roberts SK. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis. J Hepatol. 2005;43:38-44. 103. Patel PA, Voigt MD. Prevalence and interaction of hepatitis B and latent tuberculosis in Vietnamese immigrants to the United States. Am J Gastroenterol. 2002;97:1198-1203. 104. Wong WM, Wu PC, Yuen MF, et al. Antituberculosis drug-related liver dysfunction in chronic hepatitis B infection. Hepatology. 2000; 31:201-206. 105. Yuen MF, Tam S, Fung J, et al. Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study. Aliment Pharmacol Ther. 2006;24:1179-1186. 106. Wai CT, Tan BH, Chan CL, et al. Drug-induced liver injury at an Asian center: a prospective study. Liver Int. 2007;27:465-474. 107. Mok MY, Ng WL, Yuen MF, Wong RW, Lau CS. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol. 2000;18:363-368. 108. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocoricoid-responsive element. Proc Natl Acad Sci U S A. 1986;83:1627-1631.

109. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily. JAMA. 2006;296:87-93. 110. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology. 2007;46:922-938. 111. Fontana RJ, Kronfol Z. The patient’s perspective in hepatitis C. Hepatology. 2004;39:903-905. 112. Williams JL, Christensen CJ, McMahon BJ, et al. Evaluation of the response to a booster dose of hepatitis B vaccine in previously immunized healthcare workers. Vaccine. 2001;19:4081-4085. 113. Wong VC, Ip HM, Reesink HW, et al. Prevention of the HBsAg carrier state in newborn infants of mothers who are chronic carriers of HBsAg and HBeAg by administration of hepatitis B vaccine and hepatitis B immunoglobulin: double-blind, randomized, placebo-controlled study. Lancet. 1984;1:921-926. 114. van Zonneveld M, van Nunen AB, Niesters HG, de Man RA, Schalm SW, Janssen HL. Lamivudine treatment during pregnancy to prevent transmission of hepatitis B virus infection. J Viral Hepat. 2003;10:294297. 115. Su GG, Pan KH, Zhao NF, Fang SH, Yang DH, Zhou Y. Efficacy and safety of lamivudine treatment for chronic hepatitis B in pregnancy. World J Gastroenterol. 2004;10:910-912. 116. Xu WM, Cuit CYT, Wang L, et al. Efficacy and safety of lamivudine in late pregnancy for the prevention of child transmission of hepatitis B: a multicenter, randomised, double-blind, placebo-controlled study [abstract]. Hepatology. 2004;40:272A. 117. ter Borg MJ, Leemans WF, De Man RA, Janssen HL. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat. 2007; 15:37-41. 118. Harpaz R, Von Seidlein L, Averhoff FM, et al. Transmission of hepatitis B virus in multiple patients from a surgeon without evidence of inadequate infection control. N Engl J Med. 1996;334:549-554. 119. The Incident Investigation Teams and others. Transmission of hepatitis B to patients from four infected surgeons without hepatitis B e antigen. N Engl J Med. 1997;336:178-184. 120. Centers for Disease Control and Prevention. CDC recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures. MMWR Recomm Rep. 1991;40(RR-8):1-9.

Supplement issue

Therapeutic Strategies for Chronic Hepatitis B Virus Infection in 2008 Asim Khokhar, MD, and Nezam H. Afdhal, MD Liver Research Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

ABSTRACT Reducing progression of disease and preventing development of hepatocellular carcinoma in patients with chronic hepatitis B (CHB) is best achieved through durable suppression of viral replication without the development of resistance. Suitability of a patient for therapy depends on several factors, notably hepatitis B e antigen (HBeAg) status, serum alanine aminotransferase (ALT) level, and serum HBV DNA level. Interferon therapy can produce durable responses (HBeAg clearance) in approximately one third of patients with HBeAg-positive disease, but has limited use in HBeAg-negative patients owing to relapse after discontinuation of therapy. Oral antiviral agents have superior tolerability and ease of administration, but the long-term treatment that may be necessary can be associated with the development of resistance. The high propensity for development of resistance to lamivudine and telbivudine means that adefovir and entecavir, and where available tenofovir, are now considered the preferred oral agents. Monitoring patients during therapy enables assessment of response and adherence, such that treatment can be modified accordingly; genotypic testing in cases of virologic breakthrough is important to identify presence of resistant strains, which may be found months or years before elevation of serum ALT. In cases of confirmed antiviral resistance, treatment should be promptly adjusted either by switching to another agent, or more commonly, adding a second agent, depending on the circumstances. Long-term studies indicate that effective suppression of viral replication improves clinical outcome, with improvement of liver histology and, it is assumed, a decreased risk for development of hepatocellular carcinoma. © 2008 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2008) 121, S33–S44 KEYWORDS: Cirrhosis; Hepatitis B; Hepatocellular carcinoma; Interferon; Nucleoside; Nucleotide

Major advances in the therapy of hepatitis B virus (HBV) infection in the last 10 years have brought with them some controversy as to the best approach to its management.1 The major goals of therapy for patients with chronic hepatitis B (CHB) are to prevent cirrhosis, liver failure, and/or development of hepatocellular carcinoma (HCC). The consensus is that this can be best achieved by a durable suppression of HBV replication.2 The best way to achieve this durable suppression of HBV replication in an individual patient depends on multiple host factors, including hepatitis B e antigen (HBeAg) status, serum alanine aminotransferase

Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Nezam Afdhal, MD, Liver Research Center, Beth Israel Deaconess Medical Center, 110 Francis Street, Boston, Massachusetts 02215. E-mail address: [email protected].

0002-9343/$ -see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2008.09.027

(ALT) level, ethnicity, presence of advanced liver disease, and prior therapies. Our aim here is to define which patients represent treatment candidates, and to focus on the treatment recommendations for HBeAg-positive and HBeAg-negative patients, particularly with regard to durability of response and the development of resistance.

RECOMMENDATIONS REGARDING ELIGIBILITY FOR TREATMENT In assessing the benefits and risks of therapy, careful consideration is required before initiation of treatment, balancing the risk of HBV-related morbidity and mortality and the likelihood of achieving sustained viral suppression. The first issue in management is therefore to decide which patients should be treated and which should be followed up with no active therapy. There are several guidelines on chronic HBV infection, all of which include some directions

S34 Table 1

The American Journal of Medicine, Vol 121, No 12A, December 2008 American Association for the Study of Liver Disease (AASLD) 2007 treatment guidelines

HBeAg Status HBV DNA (PCR)

ALT

⫹

⬎20,000 IU/mL ⱕ2 ⫻ ULN

⫹

⬎20,000 IU/mL ⬎2 ⫻ ULN

⫺ ⫺

⬎20,000 IU/mL ⬎2 ⫻ ULN ⬎2,000 IU/mL 1-2 ⫻ ULN

⫺

ⱕ2,000 IU/mL

ⱕULN

⫾

Detectable

Cirrhosis

⫾

Undetectable

Cirrhosis

Eligibility for Treatment ● Low efficacy with current treatment, therefore observe only ● Consider treatment if ALT becomes elevated ● Consider biopsy in persons aged ⬎40 yr, ALT persistently high normal (2 ⫻ ULN), or with family history of HCC —Consider treatment if HBV DNA ⬎20,000 IU/mL and biopsy shows moderate–severe inflammation or significant fibrosis ● Observe for 3-6 mo and treat if no spontaneous HBeAg loss ● Consider liver biopsy before treatment if compensated ● Immediate treatment if icteric or clinical decompensation ● Treat ● Consider liver biopsy and treat if liver biopsy shows moderate–severe necroinflammation or significant fibrosis ● Observe ● Treat if HBV DNA or ALT become higher Compensated: ● HBV DNA ⬎2,000 IU/mL: Treat ● HBV DNA ⬍2,000 IU/mL: Consider treatment if ALT elevated Decompensated: ● Coordinate treatment with transplant center, refer for liver transplant Compensated: ● Observe Decompensated: ● Refer for liver transplant

ALT ⫽ alanine aminotransferase; HBeAg ⫽ hepatitis B e antigen; HBV ⫽ hepatitis B virus; HCC ⫽ hepatocellular carcinoma; PCR ⫽ polymerase chain reaction; ULN ⫽ upper limit of the normal range.

regarding the selection of patients for treatment.2– 4 These guidelines may, however, fail to identify all potential candidates for therapy.5 Taking the decision to treat with antiviral therapy is a multistep process, depending on several major variables (HBeAg status, serum ALT level, and serum HBV DNA level) considered sequentially, and thereafter less definitive variables such as histology, age, and family history of HCC. The American Association for the Study of Liver Disease (AASLD) guidelines regarding eligibility for treatment are summarized in Table 1.2 The primary determinant in these guidelines is HBeAg status.2 Perhaps the most controversial aspect is the ALT threshold level for therapy; the guidelines recommend observation rather than treatment for patients with a serum ALT level below twice the upper limit of the normal (ULN) range. An expert consensus has suggested that treatment should be individualized in patients with ALT less than this, with use of biopsy in those aged ⬎40 years to add information that may aid clinical decision-making.6 In a recent study of patients with HBV infection undergoing liver biopsy, 37% of those with persistently normal serum ALT were found to have significant fibrosis or inflammation; age and serum ALT ⬎25 IU/L were the best predictors of liver necroinflammation.7 Because the normal range of serum ALT levels was defined using populations that probably included individuals with subclinical liver disease, it has been suggested that the ULN

should be revised from 40 IU/L in men and 30 IU/L in women to 30 IU/L and 19 IU/L, respectively.8 In the patient with a serum ALT level greater than twice the ULN range and HBV DNA ⬎20,000 IU/mL, no liver biopsy is necessary because these patients have evidence of active disease and represent good treatment candidates. We are of the opinion that patients with lower ALT, 1 to 2 times the ULN range, should undergo biopsy so that the treatment decision can be guided by histology. In patients with more than moderate (grade 2) fibrosis, treatment should be initiated regardless of ALT and HBV DNA levels.6 Because patients may have widely fluctuating serum HBV DNA levels, serial monitoring of serum HBV DNA is more important than any particular cutoff level in predicting outcome and determining the need for treatment.2 The major differences between HBeAg-positive and HBeAg-negative disease are that in HBeAg-negative disease serum ALT levels can fluctuate and lower levels of viremia can be associated with significant disease.6 Therefore, in comparison with HBeAg-positive patients, HBeAgnegative patients have lower HBV DNA levels but may have more severe inflammation on biopsy.9 In HBeAgnegative patients the threshold for significant viremia warranting treatment is therefore reduced to 2,000 IU/mL rather than 20,000 IU/mL. The problem in HBeAg-negative patients is distinguishing active disease with low-level viral replication from the inactive, low-level carrier state, be-

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Therapeutic Strategies for CHB in 2008

cause there is no single cutoff HBV DNA level that is indicative of the inactive state. The potential for fluctuation means that monitoring of ALT and HBV DNA over time is critical to ensure that patients with the potential for significant disease are not missed.6 Biopsy is very useful in this population, particularly if ALT is elevated but still less than twice the ULN on consecutive readings. The utilization of genotyping with identification of the precore promoter mutation or core promoter gene mutations can confirm the exact diagnosis of HBeAg-negative individuals, but is not routinely undertaken in clinical practice.

THERAPEUTIC END POINTS End points in clinical trials have focused on the relatively short-term goals of improvement of liver histology, normalization of serum ALT, loss of HBeAg with development of anti-HBeAg antibody (HBeAg seroconversion), and reduction in serum HBV DNA at 1 year (see AASLD guidelines for key data from major clinical trials), although longer-term treatment durations have been assessed (e.g., in open-label extensions).2 Long-term end points/outcomes include clearance of hepatitis B surface antigen (HBsAg), development of HCC, and survival, although as yet the evidence for many agents is limited. Comparison between trials of different agents is difficult owing to differences in end point selection and use of different HBV DNA assays with differing limits of detection, and there have been few true comparative studies. In addition, the evolution of clinical care has outpaced many of the current clinical trials, resulting in recommendations that are often founded on clinical expert opinion as well as evidence-based medicine.10

EFFICACY OF LICENSED AGENTS IN HEPATITIS B E ANTIGEN–POSITIVE AND HEPATITIS B E ANTIGEN–NEGATIVE DISEASE AND THEIR ROLE IN MANAGEMENT Currently, in the United States, 7 agents are approved for treatment of CHB in adults: interferon (IFN) ␣-2b, pegintereferon ␣-2a, lamivudine, telbivudine, adefovir, entecavir, and tenofovir. The decision to use a particular agent depends on the category into which the patient falls as well as his or her clinical condition (e.g., presence of cirrhosis). Major considerations are efficacy and safety, resistance, cost, and side effects (including the risk in women of childbearing potential). The preferred options for treatment are adefovir, entecavir, tenofovir, and peginterferon ␣-2a (the only peginterferon approved for treatment of chronic HBV infection in the United States); telbivudine is less preferable, and lamivudine is falling out of favor owing to the high incidence of development of resistance.2 Peginterferon is preferred to standard interferon because it is more convenient to administer and produces a sustained viral suppression in a greater proportion of patients.2

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Standard IFN and Peginterferon IFN ␣-2a has antiviral, antiproliferative, and immunomodulatory effects.11 Pegylated IFN has activity similar to or slightly better than standard IFN, and, in clinical practice, has almost replaced it. A major contradiction is that trials with standard IFN suggested treatment for 16 to 24 weeks, but the more efficacious peginterferon requires 48 weeks of treatment. Peginterferon is most effective in the subset of patients with chronic HBV infection who are HBeAg positive and have evidence of active viral replication (HBV DNA positive) and active liver disease (elevated serum ALT concentration and chronic hepatitis on liver biopsy). Approximately one third of HBeAg-positive patients treated for 6 to 12 months with peginterferon can be expected to clear HBeAg.12 HBeAg-positive patients can be treated with standard IFN ␣-2b 5 mU daily or 10 mU thrice weekly for 16 to 24 weeks, or with peginterferon ␣-2a 180 ␮g/wk for 24 to 48 weeks. Durability of response to standard IFN, as evidenced by HBeAg seroconversion, is reported in 80% to 90% of patients who initially responded after a follow-up period of 4 to 8 years; however, HBV DNA remains detectable in most patients.2 The role of IFN therapy in HBeAg-negative patients is limited because, although 60% to 70% of patients respond to therapy (with loss of serum HBV DNA), relapse after discontinuation of therapy is usual. Responses may be more durable in patients who receive a longer duration of treatment,13 but keeping patients on IFN treatment indefinitely is not practical because of the parenteral mode of administration and side-effect profile. IFN therapy is associated with “flares” (elevations) in serum ALT in 30% to 40% of patients; this is considered to be an indicator of a favorable response,14 as flares may result from immune-mediated clearance of infected hepatocytes, but they can lead to hepatic decompensation, particularly in patients with underlying cirrhosis. Occasionally the flares are severe enough to require discontinuation of IFN treatment. As a result, there is controversy about the use of IFN in patients with cirrhosis; some studies have shown minimal benefit of therapy, risk of bacterial infection, and exacerbation of disease, whereas patients with compensated cirrhosis in clinical trials showed similar responses to patients precirrhosis, with ⬍1% developing decompensation.2

Lamivudine Lamivudine is an oral nucleoside analogue that becomes incorporated into growing DNA chains, causing premature chain termination. Once the first-line oral agent, its use is now decreasing because newer agents show better resistance profiles. Development of resistance to lamivudine is shown in up to 32% of patients after 1 year of treatment and in 60% to 70% after 5 years.2 Lamivudine is used at a dose of 100 mg once a day, or 150 mg daily in those with HIV coinfection. The effects of 1 year of lamivudine therapy in HBeAg-positive patients include normalization of serum

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ALT in 41% to 70%, HBeAg loss in 17% to 32%, HBeAg seroconversion in 16% to 21%, and histologic improvement in 49% to 56%.2 The rate of HBeAg seroconversion after 1 year of lamivudine therapy is thus similar to that associated with a 16-week course of standard IFN; after 5 years of therapy the seroconversion rate rises to 50%. Elevated pretreatment serum ALT is the best predictor of response to lamivudine in HBeAg-positive patients15; HBeAg seroconversion rates are lower in patients with serum ALT less than twice the ULN range—10% after 1 year and 19% after 3 years.2 In HBeAg-negative disease, HBV DNA is suppressed to undetectable levels in 60% to 70% of patients after 1 year of lamivudine therapy, and a similar proportion show histologic improvement and normalization of serum ALT. However, around 90% of patients relapse after stopping treatment. Although there are substantial clinical benefits in patients with HBeAg-negative CHB who maintain a virologic response, only about 39% of patients maintain this response after 4 years of therapy owing to the development of lamivudine-resistant mutant strains.16 Thus increasing the duration of treatment is not beneficial. In patients who have failed to respond to IFN, the response rate to lamivudine is similar to that in treatmentnaive patients.17 In patients with bridging fibrosis and compensated cirrhosis, lamivudine has shown benefits in terms of decrease in progression (Child-Pugh score or development of HCC); clinical benefit was mainly evident in patients with viral suppression.18 Similarly, in patients with decompensated cirrhosis, lamivudine is well tolerated and can stabilize or improve liver function, delaying the need for liver transplant.2 The clinical benefits are seen after 3 to 6 months of treatment, but screening for HCC needs to be continued, because it can still develop despite therapy. The durability of response to lamivudine in terms of HBeAg seroconversion appears to be less than that with IFN, although no good comparative studies are available.19 In HBeAg-negative patients the durability of viral suppression is ⬍10% after 1 year of treatment, but may be improved with 2 years of therapy.20 Hepatitis flares can develop in patients who become lamivudine resistant, whether or not treatment is continued. Flares associated with the emergence of lamivudine resistance may be associated with HBeAg seroconversion.21

Telbivudine Telbivudine is an oral L-nucleoside analogue, structurally related to, but more potent than, lamivudine in suppression of HBV in both HBeAg-positive and HBeAg-negative patients. Telbivudine also achieves higher rates of ALT normalization than lamivudine, but histologic improvement and HBeAg seroconversion rates are similar. Telbivudine is used at a dose of 600 mg/day orally (with dosage adjustment in patients with creatinine clearance ⬍0.83 mL/sec). Despite the advantages over lamivudine, telbivudine monotherapy has a limited role in the treatment of CHB because

of the high rate of development of resistance, which is also cross-resistant with lamivudine. As a result, the AASLD guidelines do not recommend its use as monotherapy.2 The rate of resistance to telbivudine increases rapidly after the first year of treatment, although undetectable HBV DNA at 24 weeks is predictive of a lower rate of resistance at 1 or 2 years.22,23 The use of telbivudine should include early monitoring of HBV DNA and failure to suppress virus at 24 weeks should lead to modification of therapy to avoid development of resistance.

Adefovir Adefovir is an oral adenosine monophosphate (nucleotide) analogue that inhibits both reverse transcriptase and DNA polymerase activity and causes chain termination by becoming incorporated into HBV DNA. It is used for suppressing both wild-type and lamivudine-resistant HBV strains, in the latter case usually being added to lamivudine rather than replacing it. The most commonly used dose is 10 mg/day, at which level adefovir is well tolerated. This dose may be inadequate in some patients,24 but higher doses are associated with renal toxicity.25 In HBeAg-positive patients, 48 weeks of treatment with adefovir 10 mg/day resulted in an HBeAg seroconversion rate of 12%, normalization of serum ALT in 48% of patients, loss of HBV DNA in 21%, and histologic improvement in 53%.2 The HBeAg seroconversion rate increased to 48% after 5 years of treatment.26 Durability of HBeAg seroconversion after cessation of therapy appears to be high, ⬎90% after 3 years, but this may be associated with a longer duration of treatment after HBeAg seroconversion.27 In HBeAg-negative patients, 48 weeks of adefovir has shown a favorable response, with normalization of ALT in 72% of patients and suppression of HBV DNA in 51%.28 The sustained virologic response rate is low (8%) if treatment is stopped after 1 year,29 but with 4 to 5 years of continued treatment, 67% of patients achieve sustained viral suppression.28 The end points and duration of treatment in HBeAg-negative patients are not clear, but the majority of patients who continue therapy for up to 5 years maintain their response, with around 5% clearing HBsAg.2 Up to 33% of HBeAg-positive patients show primary nonresponse to adefovir, which may result from the agent’s moderate antiviral action or presence of HBV variants with resistance to adefovir.25 At a dose of 10 mg/day for 48 weeks, adefovir produces a 3 to 4 log10 reduction in mean HBV DNA levels, which is less than that seen with entecavir or telbivudine (5 to 7 log10 reduction) or lamivudine (4 to 5 log10 reduction).30,31 Alternative therapies should be considered in patients with a suboptimal virologic response (residual HBV DNA ⬎4 log10 copies/mL) after 6 to 12 months of adefovir treatment. Because the optimal duration of therapy is uncertain, treatment should be continued in HBeAgpositive patients for 6 months after HBeAg seroconversion, and for at least 4 to 5 years in HBeAg-negative patients who have and maintain viral DNA suppression.

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Therapeutic Strategies for CHB in 2008

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Tenofovir

De Novo Combination Therapy

Tenofovir is an oral nucleotide analogue that inhibits reverse transcription and DNA polymerase activity and causes chain termination by becoming incorporated into HBV DNA. In the phase 3 study, GS-US-174-0103, 266 patients with HBeAg-positive CHB were randomized (2:1) to tenofovir 300 mg or adefovir 10 mg.32 After 48 weeks’ therapy significantly more patients treated with tenofovir achieved the primary composite end point (HBV DNA ⬍400 copies/mL and a 2-point improvement in Knodell inflammatory score) than those treated with adefovir (67% vs. 12%). In addition, significantly more patients had suppression of HBV DNA to below 300 copies/mL (74% vs. 12%), or below the limit of quantification (69% vs. 9%). In the companion trial (GS-US-174-0102) in 375 treatment-naive patients with HBeAg-negative CHB, similar results were reported, with significantly more patients achieving the primary composite end point (71% vs. 49%), and HBV DNA suppression to below 300 copies/mL (92% vs. 59%), or below the limit of quantification (91% vs. 56%).33 Despite surveillance, no cases of tenofovir resistance mutations were detected, and reported cases of virologic breakthrough were associated with treatment nonadherence.32,33

Combination therapy has been used successfully in the management of other difficult-to-treat viruses, such as hepatitis C and HIV, and is now showing promising results in the treatment of HBV. Combination therapy may offer additive or synergistic antiviral effects and decreased incidence of resistance, but raises costs and increases the potential for drug interactions and side effects. Various combinations have been tried; the more successful ones are discussed below.

Entecavir Entecavir is an orally administered cyclopentyl guanosine analogue that inhibits HBV replication at 3 different steps, and is the most potent licensed nucleoside agent in terms of its effect on serum HBV DNA.6 The recommended dose is 0.5 mg/day for nucleoside-naive patients and 1.0 mg/day for lamivudine-refractory/resistant patients, with adjustments in patients with creatinine clearance ⬍0.83 mL/sec or on dialysis. After 1 year of therapy, entecavir is associated with HBeAg seroconversion rates similar to those with lamivudine, but entecavir produces higher rates of biochemical, virologic, and histologic responses than lamivudine.2 Continued treatment for up to 3 years in virologic responders not initially achieving HBeAg seroconversion is associated with maintenance of virologic suppression, and incremental increases in the rate of HBeAg seroconversion.2 Of patients experiencing HBeAg seroconversion during the first year of therapy with entecavir and who stopped treatment at week 48, 70% remained HBeAg negative.2 As in HBeAg-positive infection, entecavir produces superior virologic, biochemical, and histologic responses compared with lamivudine in HBeAg-negative patients. Elevated ALT is the best predictor of response to entecavir, although it is less predictive than other oral antivirals. With long-term (ⱖ5 years) follow-up of patients receiving entecavir, resistance in lamivudine-naive patients was reported in 1.2%, indicating that long-term treatment with entecavir is feasible, and at least partially explaining the maintained virologic suppression with prolonged therapy.34,35

Interferon and lamivudine. Combination of IFN ␣-2a and lamivudine shows better on-treatment and sustained offtreatment viral suppression than lamivudine alone, but no benefit in sustained off-treatment suppression over IFN monotherapy.36 In the only published report of peginterferon ␣-2a in HBeAg-negative patients, HBV DNA suppression was greater with peginterferon-lamivudine combination therapy than with peginterferon or lamivudine alone at the end of treatment (48 weeks), but sustained response rates showed no advantage of the combination therapy over peginterferon monotherapy (though both were superior to lamivudine alone).37 Lamivudine and adefovir. In nucleoside-naive patients, treatment with a combination of lamivudine and adefovir has no synergistic or additive effects and does not completely prevent resistance to lamivudine. However, this combination has a greater role in cases of lamivudine resistance, where addition of adefovir to lamivudine rather than substitution appears to lead to a lower incidence of adefovir resistance, and avoids “sequential” drug resistance.2 Addition of adefovir to lamivudine as soon as genotypic resistance is detected is associated with persistently normal ALT levels and virologic response rates of 100%. Delaying the addition of adefovir until phenotypic resistance is identified is associated with ALT normalization which reaches 93% at 24 months and 78% virologic response.38 Three-year follow-up in lamivudine-resistant patients in whom adefovir has been added reported no evidence of development of adefovir resistance.39

Summary Each of the agents approved for the treatment of chronic hepatitis B in the United States has advantages and disadvantages. The oral nucleoside/nuceotide agents have the advantage of easier administration and favorable side-effect profiles, but involve long-term therapy and the potential for resistance. IFN offers therapy of a finite, short, duration without resistance issues, and in HBeAg-positive CHB, for highly durable HBeAg seroconversion and HBsAg loss, but less favorable tolerability and the potential for disease flares. Once the decision to treat a patient has been made, the choice of first-line agent will depend on the characteristics of the patient’s disease (HBeAg status, ALT level) and clinical condition, coupled with factors such as adherence,

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The American Journal of Medicine, Vol 121, No 12A, December 2008 Definitions of responses to antiviral therapy of chronic hepatitis B virus (HBV) infection

Response

Definition

Primary treatment failure Virologic breakthrough Inadequate virologic response Partial virologic response Complete virologic response Initial response Maintained on-therapy response On-therapy end-of-treatment response Off-therapy sustained response Complete response

Failure to reduce serum HBV DNA by 1 log10 IU/mL (10 IU/mL or 50 copies/mL) at 12 wk An increase in serum HBV DNA level ⱖ1 log10 greater than the lowest level Residual serum HBV DNA level ⬎2,000 IU/mL (⬎4 log copies/mL) at week 24 of treatment Residual serum HBV DNA level ⬍2,000 IU/mL (⬍4 log copies/mL) by week 24 of treatment Serum HBV DNA level ⬍60 IU/mL (⬍300 copies/mL) by week 24 of treatment Measured at 24–48 wk Response persisting throughout the course of treatment Response at the end of a defined course of therapy Response present (SR-6 SR-12) after stopping therapy Full biochemical and virologic response, coupled with loss of HBsAg and seroconversion to anti-HBsAg

Anti-HBsAg ⫽ HBsAg antigen antibody; HBsAg ⫽ hepatitis B s antigen; SR-6 ⫽ sustained response 6 months posttherapy; SR-12 ⫽ sustained response 12 weeks posttherapy. Adapted from Hepatology2,25 and Clin Gastroenterol Hepatol.10

patient and provider preference, technical issues, cost, and side effects including effects on fertility. IFN therapy is perhaps best suited to young patients with HBeAg-positive CHB and well-compensated liver disease, who wish not to be on long-term treatment or are planning to have children within the next few years, and who also need to avoid drug resistance so that their future treatment options are not limited. IFN is contraindicated during pregnancy because of its antiproliferative effects.25 There is some experience with lamivudine in pregnancy, and it has low acquisition costs. Although it can be a useful medication if the duration of treatment is short, such as in prophylaxis against reactivation of disease during chemotherapy, the high incidence of resistance and availability of superior oral agents now limit its use. Like lamivudine, telbivudine is only suitable for short-term therapy. Adefovir replaced lamivudine as the preferred agent for first-line therapy of CHB, but entecavir may be associated with greater suppression of HBV DNA and lower rates of resistance (although there have been no direct comparative studies). Tenofovir has been shown to be superior to adefovir in comparative trials, but has not been compared with lamivudine. The oral agents are generally preferred to IFN, but where IFN is used the pegylated form is recommended. Pending more data, combination therapy with licensed agents appears to hold promise, but is not currently a firstline approach.

ASSESSING RESPONSE TO THERAPY Favorable responses to antiviral therapy of CHB include normalization of serum ALT, decrease in serum HBV DNA level, loss of HBeAg with or without detection of antiHBeAg, and improvement in liver histology. It has been proposed that responses should be standardized, and characterized as biochemical (normalization of serum ALT), virologic (decrease in HBV DNA to levels undetectable by polymerase chain reaction [PCR] technology, with HBeAg seroconversion in patients who originally were HBeAg positive), or histologic (decrease in histology activity index of

at least 2 points, with no worsening of fibrosis score in comparison with pretreatment biopsy), and defined further as on-therapy, or sustained responses off-therapy.25,40 Some terms used to characterize responses to therapy are outlined in Table 2.2,10,25

Monitoring Parameters, Time Points, and Response-Based Alterations Monitoring patients during treatment enables assessment of treatment response, tolerability issues, and adherence; early responses may help to predict the outcome of continued therapy. An algorithm for treatment with IFN and monitoring response is shown in Figure 1.41 A “roadmap” concept has been proposed for on-treatment monitoring of patients taking oral antiviral therapy (Figure 2).10 The expert panel that drew up this roadmap considered the residual serum HBV DNA level a better marker of outcome of therapy and the emergence of resistance than the change from the baseline level; the longer viral replication continues unchecked despite antiviral therapy, the greater the chance of viral breakthrough and emergence of resistance. Primary treatment failure, defined as failure to reduce serum HBV DNA by 1 log10 IU/mL (10 IU/mL or 50 copies/mL) at 12 weeks [Table 2], was, however, considered a useful indicator in patient management: The occurrence of primary treatment failure in the face of established adherence signals the need to switch to a more potent or combination therapy. Virologic response, in terms of absolute serum HBV DNA levels, as defined in Table 2, should be assessed and characterized at 24 weeks, then again at 48 weeks, as shown in Figure 2. These time points were recommended on the basis of data indicating that a serum HBV DNA level at 24 weeks of oral antiviral (lamivudine) therapy ⬎103 copies/mL is associated with emergence of lamivudine resistance mutations,42 and that from 24 weeks onward, an HBV DNA load below the limit of detection by PCR is predictive of the loss of HBeAg.43 There is controversy over whether the roadmap concept has less

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Therapeutic Strategies for CHB in 2008

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Figure 1 Treatment of hepatitis B e antigen–positive (HBeAg⫹) chronic hepatitis B virus (HBV) infection with interferon. ALT ⫽ alanine aminotransferase. (Reprinted with permission from UpToDate.41)

Figure 2 The roadmap concept: on-treatment virologic responses and their management in patients receiving oral therapy for chronic hepatitis B virus. PCR ⫽ polymerase chain reaction. (Adapted from Clin Gastroenterol Hepatol.10)

relevance, or requires modification, for the use of agents with good efficacy and low levels of treatment-emergent resistance, such as entecavir and tenofovir. Assessment

of adefovir response at 48 weeks may be more appropriate, because adefovir appears to reduce serum HBV DNA more slowly than lamivudine and telbivudine.41

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Figure 3 Antiviral resistance after therapy for chronic hepatitis B in treatment-naive patients. (Adapted from Hepatology.25)

Reducing the Risk of, and Managing, Antiviral Resistance Development of drug resistance is a major problem in the management of CHB and is also an important consideration when choosing the modality of treatment. The error-prone nature of HBV replication means that resistance mutations continually appear in the viral population. Selection pressure during antiviral therapy leads to selection and consequent dominance of resistant strains. Resistance can be defined at several levels — genotypic, viral, or clinical. The first rule in prevention of resistance is to avoid unnecessary treatment, by carefully selecting which patients to treat, i.e., not treating patients, particularly young patients (aged ⬍30 years), with minimal disease who are unlikely to achieve a sustained response. The second rule is to initiate treatment with potent antiviral agents associated with a low rate of resistance (Figure 3)25 or with combination therapy (not routine clinical practice at this time), with reinforcement of adherence. The third rule is to switch to alternative therapy in cases of primary nonresponse. Patients should be monitored carefully during treatment, with serum HBV DNA quantification (by PCR assay) every 3 to 6 months; adherence should be evaluated in patients with virologic breakthrough, and antiviral resistance confirmed via genotypic testing. Emergence of resistant mutations can negate any original response to antiviral therapy and may result in flares and hepatic decompensation; early identification of resistant strains, i.e., when HBV DNA increases, may be successful months or even years before elevation of serum ALT, and is therefore important in prevention of disease progression. Lamivudine resistance. The most common problem with lamivudine therapy is development of genotypic mutation,

typically the YMDD mutation, which is a methionine-tovaline or methionine-to-isoleucine substitution in the YMDD motif of the catalytic domain of HBV polymerase at position 204 (M204V/I). Another mutation encountered is a leucine-to-methionine substitution located upstream of the YMDD motif, which is a compensatory mutation (allowing the resistant mutant to replicate at a higher rate) that is usually found in combination with one of the mutations in the YMDD motif.2,25 Factors associated with resistance to lamivudine include long duration of treatment, high pretreatment serum HBV DNA, and a high level of residual DNA after initiation of treatment. Although other L-nucleosides (telbivudine) are ineffective against lamivudine-resistant strains, the nucleotide analogue adefovir is effective. Adefovir is usually added to rather than replacing lamivudine therapy, because adefovir resistance is predominantly found in patients with lamivudine-resistant strains switched to adefovir monotherapy.2 In nucleoside-naive patients, combination therapy with lamivudine and adefovir lessens but does not completely prevent incidence of lamivudine resistance.2 Although lamivudineresistant strains are less susceptible in vitro to entecavir than wild-type HBV,44 entecavir has been shown to be effective against lamivudine-refractory HBeAg-positive disease.45 Adefovir resistance. Resistance to adefovir develops more slowly than lamivudine resistance; in phase 3 clinical trials in nucleoside-naive patients, no adefovir-resistant mutations were evident after 1 year of treatment.46 More recent studies with more sensitive detection methods suggest adefovirresistant mutations can arise after 1 year of treatment, but these were evident mainly in patients with lamivudineresistant mutations switched to adefovir monotherapy.2 The risk factors for development of adefovir resistance are sub-

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optimal DNA suppression, and sequential monotherapy with lamivudine and adefovir. Entecavir and lamivudine have been shown to be effective against adefovir-resistant strains in vitro and in preliminary clinical studies.47,48 In patients with prior lamivudine resistance who develop adefovir resistance after switching to adefovir monotherapy, reintroduction of lamivudine may lead to rapid reemergence of lamivudine resistance.49 There is evidence that telbivudine causes a sustained decrease in viral load in patients with a persistent suboptimal viral response to adefovir.50 Tenofovir resistance. During the phase 3 clinical trial program, routine surveillance did not detect any resistance mutations to tenofovir, including in those patients with virologic breakthrough through with 48 weeks’ treatment.32,33 However, follow-up of patients receiving tenofovir for longer periods will be required to confirm the low potential for resistance. Telbivudine resistance. Like lamivudine, telbivudine is associated with a high rate of resistance and, because it also causes YMDD mutations, cross-resistance with lamivudine. Telbivudine is therefore of limited use in long-term treatment. In a small study of patients with virologic breakthrough on telbivudine who were treated with adefovir, either as monotherapy or in addition to telbivudine, adefovir suppressed serum HBV DNA.51 Entecavir resistance. Resistance to entecavir is rare, and, interestingly, seems to require initial selection of the M204V/I YMDD mutation conferring resistance to lamivudine followed by subsequent mutations at positions 169, 184, 202, or 250. The effect is greatest when there is lamivudine resistance coupled with ⱖ2 additional mutations at these positions.35,52 Because preexisting lamivudine resistance (and presumably telbivudine resistance) predisposes the virus to entecavir resistance, unlike the situation with adefovir, therapy with entecavir should be switched to, not added to lamivudine (or telbivudine), to lessen the risk of emergence of entecavir resistance. In vitro studies have shown that adefovir can be used for entecavir-resistant strains, but clinical data are lacking.2

Summary In cases of confirmed antiviral resistance, treatment should be switched or added to as appropriate. For lamivudine resistance, adefovir should be added, or lamivudine stopped and the patient switched to entecavir. For adefovir or tenofovir resistance, lamivudine can be added, the patient can be switched to entecavir, or entecavir can be added. For patients developing entecavir resistance, patients may be switched to adefovir or adefovir may be added. Finally, for telbivudine resistance, strategies include adding adefovir or stopping telbivudine and switching to entecavir.

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EXPECTED OUTCOMES IN TREATED PATIENTS Clearance of HBsAg within 5 years of HBeAg loss has been reported in 12% to 65% of patients treated with IFN in European and US studies, but such delayed clearance of HBsAg was not found in Chinese patients.2 Approximately 20% of patients with HBeAg-negative infection showing a sustained response to IFN clear HBsAg after 5 years of follow-up.2 Long-term follow-up indicates that patients who receive IFN therapy have a higher cumulative survival and lower cumulative incidence of HCC than untreated control patients.53 Long-term outcome in HBeAg-positive patients treated with IFN is linked to HBeAg seroconversion: those experiencing HBeAg seroconversion show higher rates of HBsAg loss, decreased necroinflammatory activity in the liver, a lesser degree of fibrosis progression, a lower risk of developing HCC, and improved overall survival and survival without clinical complications.54,55 A retrospective study with 15 years of follow-up has indicated that while IFN therapy reduces cirrhosis and HCC development in patients experiencing HBeAg seroconversion in comparison with matched, untreated, HBeAg-positive controls, treatment not resulting in seroconversion was associated with a significant, but only marginal reduction in incidence of cirrhosis.56 Sustained virologic response to IFN therapy in patients with HBeAg-positive CHB is also associated with reduced rates of progression of cirrhosis and development of HCC compared with nonresponders and untreated controls.57 It has been estimated that IFN therapy in a 20-yearold patient with HBeAg-positive CHB increases life expectancy by 4.8 years.58 Therapy with IFN is also associated with improved longterm clinical outcome in HBeAg-negative patients who show sustained biochemical response; IFN therapy improves overall survival and complication-free survival, and reduces progression of fibrosis in this patient group.59,60 However, it should be remembered that the majority of HBeAg-negative patients will not develop a sustained response to therapy. The fact that even low serum HBV DNA levels are associated with worse long-term outcomes, with increased risk for cirrhosis, HCC, and mortality due to HCC or chronic liver disease, suggests that effective suppression of HBV DNA via oral nucleoside/nucleotide therapy should be associated with long-term clinical benefit.61 Clinical trials of lamivudine therapy for chronic HBV infection began in the early 1990s, so long-term data are now available from patients who have been treated for several years. Three years of lamivudine therapy for HBeAg-positive disease reduces necroinflammatory activity and reverses fibrosis (including cirrhosis) in the majority of patients, although the emergence of resistant strains results in blunted histologic responses.62 Similarly, liver histology improves in patients with HBeAg-negative disease treated for 3 years with lamivudine, with greatest benefit in patients without YMDD variants.63 A placebo-controlled study of treatment with

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lamivudine for up to 5 years in patients with HBeAgpositive or HBeAg-negative CHB with histologically confirmed cirrhosis or advanced fibrosis found that lamivudine therapy was associated with a 50% decrease in disease progression during a median treatment period of 32 months, with reduced risk of hepatic decompensation and HCC; therapy was less successful in patients who developed YMDD mutations, but was nevertheless more effective than placebo.18 Viral breakthrough after lamivudine therapy in HBeAg negative infection is related to mortality and development of HCC.16 It appears possible therefore to reverse fibrosis and even cirrhosis with nucleoside/nucleotide therapy, provided HBV replication is suppressed sufficiently and consistently. The problem with this is that long-term therapy is likely to be necessary in many patients, and this brings with it the risk of development of resistance. It is encouraging in this respect that long-term nucleoside/nucleotide therapy in HBeAg-negative disease commencing with lamivudine, with subsequent administration of adefovir to patients with virologic or biochemical breakthrough, has been associated with improved survival and reduced risk for major complications in comparison with historical cohorts of untreated patients.64 Similarly, the ability of 48 weeks of adefovir therapy in patients with lamivudine-resistant HBV awaiting liver transplantation (a situation associated with progression of liver disease and death) to suppress serum HBV DNA to an undetectable level in 81% of patients and improve liver functioning (to the extent that some patients were removed from the transplant waiting list) provides hope that good clinical outcomes can be achieved if viral replication is effectively suppressed.65 New agents, notably entecavir and tenofovir, demonstrate potent antiviral effects with lower resistance rates, and thus have the ability to offer long-term disease control, thereby preventing the development of complications. This potential for long-term viral suppression, coupled with the ability to switch to alternative drugs, means that it is possible to improve outcomes, and treatment should not be withheld until an individual’s CHB has progressed and significant liver disease developed.

SUMMARY Treatment guidelines such as those produced by the AASLD provide a framework for assessing which patients with CHB are eligible for treatment. Because of resistance concerns, treatment should be reserved for those likely to benefit and show a sustained response, but it is not necessary to delay initiation until patients have significantly advanced disease. There is, however, a role for clinical judgment in the implementation of such guidelines, an example being the greater use of biopsy to guide decision-making in patients in whom serum ALT is raised but not in excess of twice the ULN range. Selection of the best treatment for an individual patient will depend on several factors, including safety, efficacy

against the type of HBV the patient has (e.g., HBeAg negative or positive), prior therapy, whether resistant strains are present, age, stage of disease, and planned duration of treatment. The recommended first-line agents are now peginterferon ␣-2a, adefovir, entecavir, and tenofovir. Oral agents are generally preferred because of their superior tolerability and ease of administration, but short-term treatment with these nucleoside/nucleotide agents, particularly in HBeAg-negative disease, is generally inadequate to achieve durable response. The ideal agent, combination, or sequence of agents will need to produce profound, sustained suppression of HBV replication without the emergence of resistance. Monitoring of on-therapy responses is an important part of patient management that permits alterations to be made if necessary. Evidence from studies of long-term clinical outcomes provides hope that therapy for CHB can offer significant benefits in terms of reducing disease progression and improving survival.

AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Asim Khokhar, MD, reports no relationships to a manufacturer of a product or device discussed in this supplement. Nezam H. Afdhal, MD, is a member of the Speakers’ Bureau for Bristol-Myers Squibb, Gilead Sciences, Inc., Idenix/Novartis, and Schering-Plough; has received research/grant support from Bristol-Myers Squibb, Cooley Pharmaceuticals, EchoSens, GlaxoSmithKline, Gilead Sciences, Inc., Idenix Pharmaceuticals, Inc., Idun Pharmaceuticals, Inc., InterMune Pharmaceuticals, Inc., Isis Pharmaceuticals, Inc., Novartis, Ortho Biotech Products, Prometheus Laboratories Inc., Quest Diagnostics Inc., Schering-Plough, Salix Pharmaceuticals, Inc., United Therapeutics Corporation, Valeant Pharmaceuticals International, and Vertex Pharmaceuticals Inc.; serves as a consultant to Arrow Pharmaceuticals Pty. Ltd., Atlas Pharmaceuticals, Inc., BioCryst Pharmaceuticals Inc., Biogen Idec, EchoSens, Gilead Sciences, Inc., GlaxoSmithKline, Idenix Pharmaceuticals, Inc., Idera Pharmaceuticals, Inc., Isis Pharmaceuticals, Inc., InterMune Pharmaceuticals, Inc., Novartis, Ortho Biotech Products, Prometheus Laboratories Inc., Salix Pharmaceuticals, Inc., Schering-Plough, Sirtris Pharmaceuticals, Inc., Stromedix, Valeant Pharmaceuticals International, Vertex Pharmaceuticals Inc., Wyeth/ ViroPharma, and XTL Pharmaceuticals.

References 1. Perrillo RP, Gish RG, Peters M, et al. Chronic hepatitis B: a critical appraisal of current approaches to therapy. Clin Gastroenterol Hepatol. 2006;4:233-248. 2. Lok ASF, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45: 507-539.

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3. de Franchis R, Hadengue A, Lau G, et al, for the EASL Jury. EASL International Consensus Conference on Hepatitis B. 13-14 September, 2002 Geneva, Switzerland. Consensus statement (long version). J Hepatol. 2003;39(suppl 1):S3-S25. 4. Liaw YF, Leung N, Guan R, et al, for the Asian-Pacific Consensus Update Working Party on Chronic Hepatitis B. Asian–Pacific consensus update working party on chronic hepatitis B. Liver Int. 2005;25: 472-489. 5. McMahon BJ. Selecting appropriate management strategies for chronic hepatitis B: who to treat. Am J Gastroenterol. 2006;101(suppl 1):S7-S12. 6. 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. 7. Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007;47:760-767. 8. Prati D, Taioli E, Zanella A, et al. Updated definitions of healthy ranges for serum alanine aminotransferase levels. Ann Intern Med. 2002;237:1-10. 9. Peng J, Luo K, Zhu Y, Guo Y, Zhang L, Hou J. Clinical and histological characteristics of chronic hepatitis B with negative hepatitis B e antigen. Chin Med J (Engl). 2003;116:1312-1317. 10. Keefe 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. 11. Haria M, Benfield P. Interferon-alpha-2a: a review of its pharmacological properties and therapeutic use in the management of viral hepatitis. Drugs. 1995;50:873-896. 12. Thomas HC. Best practice in the treatment of chronic hepatitis B: a summary of the European Viral Hepatitis Educational Initiative (EVHEI). J Hepatol. 2007;47:588-597. 13. Manesis EK, Hadziyannis SJ. Interferon alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B. Gastroenterology. 2001;121:101-109. 14. Nair S, Perillo RP. Serum aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia? Hepatology. 2001;34: 1021-1026. 15. Perrillo RP, Lai CL, Liaw YF, et al. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B. Hepatology. 2002;36: 186-194. 16. Di Marco V, Marzano A, Lampertico P, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004;40:883-891. 17. Schiff ER, Dienstag JL, Karavalcin S, et al. Lamivudine and 24 weeks of lamivudine/interferon combination therapy for hepatitis B e antigenpositive chronic hepatitis B in interferon nonresponders. J Hepatol. 2003;38:818-826. 18. Liaw YF, Sung JJ, Chow WC, et al, for the Cirrhosis Asian Lamivudine Multicenter Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004;351:15211531. 19. van Nunen AB, Hansen BE, Suh DJ, et al. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase. Gut. 2003;52:420-424. 20. Fung SK, Wong F, Hussain M, Lok AS. Sustained response after a 2-year course of lamivudine treatment of hepatitis B e antigen-negative chronic hepatitis B. J Viral Hepat. 2004;11:432-438. 21. Liaw YF, Chien RN, Yeh CT, Tsai SL, Chu CM. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy. Hepatology. 1999;30:567-572. 22. Amarapurkar DN. Telbivudine: a new treatment for chronic hepatitis B. World J Gastroenterol. 2007;13:6150-6155. 23. DiBisceglie A, Lai CL, Gane E, et al. Telbivudine GLOBE trial: maximal early HBV suppression is predictive of optimal two-year

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24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42.

efficacy in nucleoside-treated hepatitis B patients. [abstract]. Hepatology. 2006;44(suppl 1):230A. Abstract 112. Hézode C, Chevaliez S, Bouvier-Alisa M, et al. Efficacy and safety of adefovir dipivoxil 20 mg daily in HBeAg-positive patients with lamivudine-resistant hepatitis B virus and a suboptimal virological response to adefovir dipivoxil 10 mg daily. J Hepatol. 2007;46:791-796. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056-1075. Marcellin P, Chang TT, Lim SG, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2008;48:750-758. Chang T, Shiffman ML, Tong M, et al. Durability of HBeAg seroconversion following adefovir dipivoxil treatment for chronic hepatitis B. Gastroenterology. 2006;130:A-846. Abstract T-1844. 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. Hadziyannis SJ, Tassapoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352:2673-2681. Dienstag JL, Wei LJ, Xu D, Kreter B. Cross-study analysis of the relative efficacies of oral antiviral therapies for chronic hepatitis B infection in nucleoside-naive patients. Clin Drug Investig. 2007;27: 35-49. Hou J, Yin YK, Tan D, et al. Telbivudine versus lamivudine in Chinese patients with chronic hepatitis B: results at 1 year of a randomized, double-blind trial. Hepatology. 2008;47:447-454. Heathcote EJ, Gane E, DeMan R, et al. A randomized double-blind, comparison of tenofovir DF versus adefovir dipivoxil for the treatment of HBeAg positive chronic hepatitis B: study GS-US-174-0103. [abstract]. J Hepatol. 2007;46(suppl 1):861. Abstract LB6. Marcellin P, Buti M, Krastev Z, et al. A randomized, double-blind comparison of tenofovir DF versus adefovir dipivoxil for the treatment of HBeAg-negative chronic hepatitis B: study GS-US-174-0102. [abstract]. J Hepatol. 2007;46(suppl 1):290A. Abstract LB2. Colonno RJ, Rose RE, Pokornowski K, et al. Four-year assessment of ETV resistance in nucleoside-naive and lamivudine-refractory patients. [abstract]. J Hepatol. 2007;43(suppl 1):S294. Abstract 781. Tenney DJ, Pokorowski KA, Rose RE, et al. Entecavir at five years shows long-term maintenance of high genetic barrier to hepatitis B virus resistance. Presented at the 18th Conference of the Asia-Pacific Association for the Study of the Liver (APASL); March 24, 2008; Seoul, Korea. Abstract PL02. 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. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAgnegative chronic hepatitis B. N Engl J Med. 2004;351:1206-1217. Lampertico P, Vigano M, Manenti E, Iavarone M, Lunghi G, Colombo M. Adefovir rapidly suppresses hepatitis B in HbeAg-negative patients developing genotypic resistance to lamivudine. Hepatology. 2005;42: 1414-1419. Rapti I, Deimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir in lamivudine-resistance HbeAg-negative chronic hepatitis B. Hepatology. 2007;45:307-313. Lok AS, Heathcote EJ, Hoofnagle JH. Management of hepatitis B: 2000 —summary of a workshop. Gastroenterology. 2001;120:18281853. Lok ASF. Patient information: hepatitis B. 2007. In Rose, BD, ed. UpToDate. Waltham, MA: UpToDate, 2008. [UpToDate Website.] Available at: www.uptodate.com/patients. Accessed November 6, 2008. Yuen MF, Sablon E, Hui CK, et al. Factors associated with hepatitis B virus DNA breakthrough in patients receiving prolonged lamivudine therapy. Hepatology. 2001;34:785-791.

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43. Zöllner B, Schafer P, Feucht HH, Schroter M, Petersen J, Laufs R. Correlation of hepatitis B virus load with loss of e antigen and emerging drug-resistant variants during lamivudine therapy. J Med Virol. 2001;65:659-663. 44. Ono SK, Kato N, Shiratori Y, et al. The polymerase L528M mutation cooperates with nucleotide binding-site mutations, increasing hepatitis B virus replication and drug resistance. J Clin Invest. 2001;107:449-455. 45. Sherman M, Yurdaydin C, Sollano J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039-2049. 46. Westland CE, Yang H, Delaney WE IV, et al, for the 437 and 438 Study Teams. Week 48 resistance surveillance in two phase 3 clinical studies of adefovir dipivoxil for chronic hepatitis B. Hepatology. 2003;38:96-103. 47. Qi X, Xiong S, Yang H, Miller M, Delaney WE IV. In vitro susceptibility of adefovir-associated hepatitis B virus polymerase mutations to other antiviral agents. Antivir Ther. 2007;12:355-362. 48. Fung SK, Chae HB, Fontana RJ, et al. Virologic response and resistance to adefovir in patients with chronic hepatitis B. J Hepatol. 2006;44:283-290. 49. Fung SK, Andreone P, Han SH, et al. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation. J Hepatol. 2005;43:937-943. 50. Marcellin P, Chan HLY, Lai CL, et al. 76 weeks’ follow-up of HBeAg-positive chronic hepatitis B patients treated with telbivudine, adefovir or switched from adefovir to telbivudine [abstract]. J Hepatol. 2007;46(suppl 1):S55. Abstract 124. 51. Gane E, Lai CL, Min A, et al. Adefovir salvage therapy for virologic breakthrough in telbivudine-treated patients from the GLOBE study [abstract]. J Hepatol. 2007;46(suppl 1):S187. Abstract 493. 52. Tenney DL, Levine SM, Rose RE, et al. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine. Antimicrob Agents Chemother. 2004;48:3498-3507. 53. Lin SM, Sheen IS, Chien RN, Chu CM, Liaw YF. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection. Hepatology. 1999;29:971-975.

54. Niederau C, Heintges T, Lange S, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422-1427. 55. van Zonneveld M, Honkoop P, Hansen BE, et al. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B. Hepatology. 2004;39:804-810. 56. Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol. 2007;46:45-52. 57. Tangkijvanich P, Thong-ngam D, Mahachai V, Kladchareon N, Suwangool P, Kullavanijaya P. Long-term effect of interferon therapy on incidence of cirrhosis and hepatocellular carcinoma in Thai patients with chronic hepatitis B. Southeast Asian J Trop Med Public Health. 2001;32:452-458. 58. Wong JB. Interferon treatment for chronic hepatitis B or C infection: costs and effectiveness. Acta Gastroenterol Belg. 1998;61:238-242. 59. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAgnegative chronic hepatitis B. J Hepatol. 2001;34:306-313. 60. Papatheodoridis GV, Petraki K, Cholongitas E, Kanta E, Ketikoglou I, Manesis EK. Impact of interferon-alpha therapy on liver fibrosis progression in patients with HBeAg-negative chronic hepatitis B. J Viral Hepat. 2005;12:199-206. 61. Gish RG. Improving outcomes for patients with chronic hepatitis B. Curr Gastroenterol Rep. 2007;9:14-22. 62. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124: 105-117. 63. Rizzetto M, Tassopoulos NC, Goldin RD, et al. Extended lamivudine treatment in patients with chronic HBeAg-negative chronic hepatitis B. J Hepatol. 2005;42:173-179. 64. Papatheodoridis GV, Dimou E, Dimakopoulos K, et al. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine. Hepatology. 2005; 42:121-129. 65. Schiff ER, Lai CL, Hadziyannis S, et al. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients. Hepatology. 2003;38:1419-1427.

Supplement issue

Implementing Evidenced-Based Practice Guidelines for the Management of Chronic Hepatitis B Virus Infection Brian J. McMahon, MD Liver Disease and Hepatitis Program, Alaska Native Medical Center, Anchorage, Alaska, USA

ABSTRACT In the past 2 years, evidenced-based guidelines and statements on screening, diagnosis, and management of hepatitis B virus (HBV) from several organizations and experts have been published. The purpose of this article is to take the recommendations from these documents and help guide clinicians—whether they are primary care providers, hepatologists, gastroenterologists, or public health workers—about how to incorporate these guidelines into practice. The first task is for all providers to be involved in identifying persons with chronic HBV infection (CHB). New recommendations from the Centers for Disease Control and Prevention (CDC) advocate screening for the HBV in those at highest risk, especially persons from countries where HBV is endemic. Using information from the clinical and laboratory evaluation of the patient infected with HBV, especially the hepatitis B e antigen/antibody status, clinicians can classify the patient into 1 of the 4 phases of HBV infection. Because CHB is a dynamic process and patients can move from inactive to active infection status, and vice versa, all patients must be followed with alanine aminotransferase (ALT) and aspartate aminotransferase monitoring every 3 to 12 months for life. Those with elevated ALT and HBV DNA levels (⬎2,000 IU/mL) should be referred to a specialist for evaluation for possible treatment. Patients selected for antiviral therapy with nucleoside analogues should be followed every 3 to 6 months to detect emergence of antiviral resistance to the agent chosen. In addition, ␣-fetoprotein should be tested and ultrasound performed on all men aged ⬎40 years and women ⬎50 years of age to detect any hepatocellular carcinoma (HCC) in an early stage. Algorithms are included for primary care providers providing information on initial evaluation and management and referral of persons with CHB, and for specialists evaluating and treating HBV. Implementing steps to identify, follow, refer, and treat appropriately persons with CHB infection by all primary care and specialist healthcare providers can have a major impact on reducing the occurrence of HCC and cirrhosis in infected persons. © 2008 Published by Elsevier Inc. • The American Journal of Medicine (2008) 121, S45–S52 KEYWORDS: Chronic hepatitis B; Management; Treatment

Chronic infection with the hepatitis B virus (HBV) afflicts between 350 and 400 million persons worldwide.1 This chronic viral disease has a complicated natural history, encompassing several different clinical “phases” that patients pass through during their lifetimes.2 Through the past decade our knowledge about the natural history of this disease has increased dramatically, but much is still unknown. In addition, several new antiviral agents have been Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Brian J. McMahon, MD, Liver Disease and Hepatitis Program, Alaska Native Medical Center, 4315 Diplomacy Drive, Anchorage, Alaska 99508. E-mail address: [email protected].

0002-9343/$ -see front matter © 2008 Published by Elsevier Inc. doi:10.1016/j.amjmed.2008.09.028

developed and licensed for the treatment of HBV. However, none of these medications are able to “cure” HBV infection, although antiviral drugs on their own can suppress the virus or aid the infected person’s immune system to push the virus down to low or undetectable levels. The rapidly changing understanding of HBV infection and the introduction of new drugs to combat it has led to the publication of updated evidenced-based guidelines and statements on screening, diagnosis, and management of hepatitis B from the American Association for the Study of Liver Diseases (AASLD), the National Institutes of Health (NIH), and the Centers for Disease Control and Prevention (CDC) in the past 2 years. These include 3 documents from the CDC on immunization of infants, children, and adults

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Figure 1 Suggested algorithm for primary care providers screening high-risk persons for hepatitis B virus (HBV) infection. ALT ⫽ alanine aminotransferase; Anti-HBe ⫽ HBe antigen antibody; Anti-HBs ⫽ HBs antigen antibody; HBeAg ⫽ hepatitis B e antigen; HBsAg ⫽ hepatitis B surface antigen; LFT ⫽ liver function test; WNL ⫽ within normal range.

and recommendations for screening high-risk groups to identify chronically infected persons,3–5 as well as recommendations from a 2006 NIH workshop on management of hepatitis B.6 In addition, the AASLD published the third revision of its evidenced-based practice guidelines for the management of chronic HBV infection (CHB) in 2007.7 Also, a group of hepatology experts published a consensus statement on the management of HBV.8 The purpose of this article is to take the recommendations from these documents and help guide clinicians, whether primary care providers, hepatologists, gastroenterologists, or public health workers, on how to incorporate them into their practices.

NEW RECOMMENDATIONS ON SCREENING TO IDENTIFY PERSONS INFECTED WITH HEPATITIS B VIRUS Most infected persons are unaware they have chronic HBV infection. In the United States, the Advisory Committee on Immunization Practices (ACIP) and the CDC periodically update recommendations on screening and vaccination for HBV infection. Newly updated recommendations for infants and children were published in 2005 and for adults in 2006.3,4 The CDC’s strategy has been as follows: (1) to screen all pregnant patients in the United States for hepatitis B surface antigen (HBsAg) and vaccinate infants of HBsAg-positive mothers with hepatitis B immune globulin

(HBIG) and hepatitis B vaccine at birth; (2) to implement universal newborn immunization of all infants beginning at birth and to provide a catch-up program for all children up to 18 years of age by introducing an adolescent vaccination schedule for those children who missed the infant schedule. The CDC recommends that all persons at high risk for HBV be screened for HBsAg and HBsAg antibody (anti-HBs) as part of their routine care (Figure 1), and that hepatitis B vaccine be administered to those who are HBsAg and antiHBs negative. These high-risk groups are listed in Table 1. The CDC’s strategy has resulted in a significant decrease in new cases of symptomatic HBV infection and holds great promise to eliminate this infection not only in the United States but elsewhere in the world in the next few generations. However, although newborn immunization and vaccination of high-risk individuals will eventually eradicate HBV infection, it will not provide any benefit for the 1.25 to 2 million persons currently estimated to have CHB in the United States or for the hundreds of millions infected in other parts of the world. In the past, the CDC recommended that persons born in countries with a high prevalence of HBsAg (⬎8%) be tested for HBsAg and anti-HBs. The CDC now recommends that all persons born in countries with both high and moderate prevalence of HBsAg (ⱖ2%) be tested.5 Those countries are listed in Table 1, but practically speaking, this means anyone who was born outside

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Table 1

Persons who should be screened for hepatitis B virus (HBV) infection

Persons Born in Countries with High Rates of HBV Infection ● ● ● ● ● ● ●

Asia Africa Mid-Pacific/South Pacific Islands Parts of Europe Amazon Basin of South America Parts of the Caribbean Indigenous populations of the Arctic, New Zealand, and Australia

S47

Persons at Risk Secondary to Lifestyle Factors

Other Persons

● Man who have sex with men ● Persons with history of multiple sexual partners ● Injection drug users ● Prisoners ● Institutionalized persons

● All pregnant females ● All persons with elevated liver function tests

the United States in Asia, the Pacific Islands, Africa, Eastern Europe, the Mediterranean region, the Caribbean, and the Amazon Delta of South America, as well as anyone with a lifestyle that puts them at risk for HBV infection (Table 1), or persons with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels. These new recommendations should prompt providers to incorporate screening for HBV infection into their practice with other accepted routine screening and prevention measures, especially for persons born in endemic areas. An algorithm for screening and identification of HBsAg-positive persons is shown in Figure 1.

Initial Evaluation of Persons Found to Be HBsAg Positive Persons who do not have acute symptomatic hepatitis who are newly found to be HBsAg positive should have a complete history taken, with particular attention paid to history of liver disease, alcohol use, history of metabolic syndrome or diabetes mellitus, and a physical examination, particularly looking for stigmata of advanced liver disease, including splenomegaly, ascites, spider angiomata, and encephalopathy. Laboratory evaluation should include a complete liver function panel, including ALT, AST, alkaline phosphatase, albumin, and total bilirubin. In addition, a complete blood cell count (CBC), and tests for hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe), as well as an HBV DNA test should be performed (Table 2). If any of the following are present—stigmata of cirrhosis on physical examination, elevated total bilirubin, low albumin, or platelet count ⬍120,000 —prothrombin time should also be measured to identify persons with advanced liver disease who need immediate referral and evaluation for treatment. HBsAg should be repeated in 6 months to confirm CHB.

Classification of Persons Infected with HBV Using the information obtained from the laboratory data the clinician can then classify the HBsAg-positive patient into 1 of the 4 major phases of HBV infection (Table 3). These phases are described in more detail elsewhere in this supplement.9

Persons in the immune-tolerant phase who are HBeAg positive, have normal ALT levels, and have an HBV DNA level ⱖ20,000 IU/mL (105 copies/mL) need careful monitoring every 3 to 6 months, but liver biopsy or immediate treatment is not usually indicated because these patients usually have minimal or no liver inflammation or fibrosis, and treatment can, over time, result in the development of resistance. A recent prospective study of persons in the immune-tolerant phase showed that those who remained in this phase with normal ALT levels had no significant liver disease and no progression at liver biopsy 5 years later when the cohort’s median age was 36 years.10 However, other large prospective studies have shown that persons aged ⬎40 years with high HBV DNA levels who are HBeAg positive have a high risk of developing hepatocellular carcinoma (HCC) or cirrhosis over the next decade.11–13 These findings suggest that clinicians only need to carefully monitor patients in the immune-tolerant phase through their mid 30s but, if they remain in the immune-tolerant phase above the age of 40, they should be evaluated for liver disease with a liver biopsy and treated if indicated. HBsAg-positive persons found to be in the inactive phase who have normal ALT, are anti-HBeAg positive/ HBeAg negative, and have HBV DNA levels ⱖ2,000 IU/mL (104 copies/mL) at the time of identification, must be followed every 6 to 12 months for life, because hepatitis can reactivate in up to one third of these persons at which point they will either revert back to being HBeAg positive or develop anti-HBe hepatitis. Persons in the so-called “recovery phase” of HBV infection can still have low levels of HBV DNA found in their sera and are at some risk for developing HCC, although the risk is lower than in persons in the other phases of HBV infection.14 Therefore these persons still require surveillance for HCC as per the recommendations discussed below. Primary care providers who are interested in participating in the care of HBV-infected patients might choose themselves to follow persons ⬍40 years of age in the immune-tolerant phase every 3 to 6 months with ALT, AST, HBeAg, and anti-HBe tests, and persons in the inactive HBV phase every 6 to 12 months with ALT and AST

S48 Table 2

The American Journal of Medicine, Vol 121, No 12A, December 2008 Evaluation of persons newly identified as positive for hepatitis B surface antigen (HBsAg)

History and physical exam with special emphasis on: Family history of HCC History of comorbid conditions

Physical exam

Laboratory testing Liver panel

HBeAg and anti-HBe HBV DNA CBC with platelet count Prothombin time Antibody testing for HCV, HIV, and HDV Anti-HAV

● Diabetes or risk factors for metabolic syndrome (obesity, hyperlipidemia) ● Risk factors for other coviral infections (HIV, HCV, HDV): —History of IDU ever —History of transfusion before 1992 —History of male homosexual sex or ⬎5–10 sexual partners in lifetime —Born in a country endemic for HDV ● Current and past alcohol usage ● Stigmata of liver disease (ascites, hepatomegaly, splenomegaly, encephalopathy, spider angiomater) ● ● ● ● ●

AST ALT Alkaline phosphatase Total bilirubin Albumin

● If albumin is decreased, bilirubin elevated, platelet count ⬍120,000, or stigmata of liver disease present ● Perform if appropriate (see above) ● If negative, vaccinate against HAV

ALT ⫽ alanine aminotransferase; Anti-HAV ⫽ HAV antibody; Anti-HBe ⫽ HBE antigen antibody; AST ⫽ aspartate aminotransferase; CBC ⫽ complete blood cell count; HAV ⫽ hepatitis A virus; HBeAg ⫽ hepatitis B e antigen; HCC ⫽ hepatocelular carcinoma; HCV ⫽ hepatitis C virus; HDV ⫽ hepatitis D virus; HIV ⫽ human immunodeficiency virus; IDU ⫽ intravenous drug use.

evaluations, as long as aminotransferase levels remain within normal limits. The algorithm in Figure 2 is designed as a guide to help clinicians follow persons in the immunetolerant phase or with inactive hepatitis.

Referral of Patients with Chronic HBV infection Who Are Potential Treatment Candidates All persons with elevated levels of ALT and/or AST, and an elevated HBV DNA level ⱖ2,000 IU/mL, both those who are HBeAg positive and those who are HBeAg negative/ anti-HBe positive, should be carefully evaluated for treatment. An algorithm for primary care providers providing guidance on initial evaluation, management, and referral of persons with CHB infection is shown in Figure 1. Persons in the immune-active phase, as well as those in the inactive HBV and immune-tolerant phases who develop elevated ALT or AST levels should be referred to specialists with experience in treating CHB. It is important to remember that abnormal liver function tests (LFT) are a common finding in asymptomatic patients. It has been estimated that between 15% and 20% of Americans will have ⱖ1 elevated LFT. Because of the epidemic of obesity in the United States, most persons with elevated LFTs are found to have the metabolic syndrome accompanied by fatty infiltration of the liver or nonalcoholic fatty

Table 3 The phases of chronic hepatitis B virus (HBV) infection Phase

Identifying Features

Immune tolerant

HBeAg positive; HBV DNA ⬎20,000 IU/mL (105 copies/mL); ALT/AST normal HBeAg positive or HBeAg negative/anti-HBe positive; HBV DNA ⬎2,000 IU/mL (104 copies/ mL); ALT elevated HBeAg negative/anti-HBe positive; HBV DNA ⬍2,000 IU/mL (104 copies/mL); ALT/AST normal HBsAg negative; HBV DNA absent or ⬍2,000 IU/mL; ALT normal

Immune active (HBeAg positive or HBeAg negative) Inactive HBV

Recovery*

ALT ⫽ alanine aminotransferase; Anti-HBe ⫽ HBeAg antibody; AST ⫽ aspartate aminotransferase; HBeAg ⫽ hepatitis B e antigen; HBsAg ⫽ hepatitis B surface antigen. *Risk for hepatocellular carcinoma is decreased but still can occur; liver inflammation and fibrosis usually resolves.

liver disease (NAFLD). Thus clinicians caring for persons with CHB infection often encounter persons with elevated ALT or AST and levels of HBV DNA ⱖ2,000 IU/mL. In addition to NAFLD, the most frequent other causes of elevated ALT/AST in these patients are alcohol use, con-

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S49

Figure 2 Management of persons positive for hepatitis B surface antigen/hepatitis B e antigen (HBsAg/HBeAg) with compensated liver disease. (Persons with decompensated liver disease should be treated immediately.) ALT ⫽ alanine aminotransferase; ULN ⫽ upper limit of normal; WNL ⫽ within normal range.

Table 4 Evaluation of persons in the immune-active phase* of chronic hepatitis B virus (HBV) infection Status HBeAg positive ● ALT ⬎2 ⫻ ULN —Decompensated liver disease —Compensated liver disease

● ALT 1–2 ⫻ ULN

Anti-HBe positive

Action

Refer for immediate treatment Monitor every 3 mo for 6–12 mo to observe for spontaneous HBeAg/ anti-HBe seroconversion before treatment Refer for treatment if age ⱖ40 yr Monitor every 3–6 mo if age ⬍40 yr; refer for liver biopsy if ALT elevation persists Refer for liver biopsy and evaluation for treatment

ALT ⫽ alanine aminotransferase; Anti-HBe ⫽ HBeAg antibody; HBeAg ⫽ hepatitis B e antigen; ULN ⫽ upper limit of normal. *Immune-active phase is defined as elevated ALT/AST; HBeAg positive or anti-HBe positive; and HBV DNA ⬎2,000 IU/mL (⬎104 copies/mL).

current medications, or coinfection with hepatitis C or ␦-hepatitis (hepatitis D). However, it is important to remember that it is not uncommon to encounter patients with fluctuating levels of HBV DNA and ALT that are not synchronized. Thus serial HBV DNA levels should be or-

dered in patients with elevated ALT or AST who initially have levels of HBV DNA ⬍2,000 IU/mL.

Evaluation of Persons in the Immune-Active Phase of HBV Infection Persons who are HBeAg positive. Criteria for the evaluation of persons in the immune-active phase are shown in Table 4 and Figure 2. For patients who are HBeAg positive, candidates for treatment are those with ALT levels greater than twice the upper limit of normal (ULN). If compensated liver disease is present, it is recommended to wait ⱖ6 months before initiating antiviral therapy, because up to 25% of persons in this category will undergo spontaneous seroconversion from HBeAg to anti-HBe without medication.14 Persons who are HBeAg positive and whose ALT levels are in the normal range (immune-tolerant phase) or between 1 and 2 times the ULN have a very low chance of anti-HBe seroconversion on antiviral therapy in the subsequent 1 or 2 years (⬍5% and ⬍10%, respectively), because they have very high levels of HBV DNA. HBeAgpositive persons with normal or slightly elevated ALT levels often do not get complete suppression of HBV DNA and thus carry the risk of acquiring antiviral resistance before HBeAg seroconversion. It is controversial at what age to initiate antiviral therapy in HBeAg-positive persons, because most patients who are not infected with HBV genotype C will undergo spontaneous anti-HBe seroconversion before their mid-20s.15 However, persons who have not undergone anti-HBe seroconversion and fit the above ALT

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The American Journal of Medicine, Vol 121, No 12A, December 2008 Table 5 First- and second-line antiviral drugs for the treatment of hepatitis B virus (HBV) in patients naive for previous antiviral therapy First-line

Second-line

Licensed but not Approved for HBV (at Time of Writing)

● ● ● ●

● Lamivudine ● Telbivudine

● Emtricitibine ● Tenofovir plus emtricitibine

Interferon/peginterferon Entecavir Adefovir Tenofovir

FDA ⫽ US Food and Drug Administration.

criteria should be treated. Persons with ALT levels between 1 and 2 times the ULN who are HBeAg positive should be followed closely, and if this situation continues longer than 6 to 12 months they should undergo liver biopsy. These patients should be treated if more than mild fibrosis or inflammation is found on biopsy. In addition, persons ⱖ40 years of age who are still in the immune-tolerant phase (HBeAg positive with normal ALT) should undergo liver biopsy and likewise be treated if they have more than mild fibrosis or mild inflammation. Persons in the immune-active phase who are HBeAg negative/anti-HBe positive. In general, persons appropriate for treatment are those with HBV DNA ⱖ2,000 IU/mL and ALT elevated above the ULN. In those with elevated HBV DNA and elevated ALT between 1 and 2 times the ULN, liver biopsy is recommended, and if there is more than mild inflammation and/or fibrosis, treatment should be initiated. As in HBeAg-positive CHB, patients aged ⱖ40 years with HBV DNA levels ⱖ2,000 IU/mL should be considered for liver biopsy regardless of ALT level.

SELECTING MEDICATIONS TO TREAT PATIENTS IN THE IMMUNE-TOLERANT PHASE OF CHRONIC HEPATITIS B VIRUS INFECTION Seven medications are currently licensed in the United States for treatment of HBV infection: regular interferon␣2b, peginterferon-␣2a, lamivudine, adefovir, entecavir, telbivudine and tenofovir. First-line drugs for treatment of HBV infection are peginterferon, entecavir, and adefovir, and tenofovir. The benefits and limitations of each of these drugs are listed in Table 5 and discussed in detail in a preceding article in this supplement.16 Algorithms for the management of persons in the immune-active phase who are HBeAg positive and HBeAg negative/anti-HBe positive are displayed in Figure 2 and Figure 3.

Monitoring Patients on Antiviral Agents for Effectiveness and Resistance Patients treated with interferon-␣ do not need to be monitored for antiviral resistance, but HBV DNA levels should be tested before starting treatment, at least once during

treatment (e.g., at 6 months), and at the end of treatment. Patients on nucleoside/nucleotide analogues should be monitored for response to therapy and antiviral resistance every 3 to 6 months with assessment of HBV DNA levels and ALT/AST. Those patients treated with nucleoside analogues who fail to have at least a 2 log10 decrease in HBV DNA in the first 6 months of treatment should be considered treatment failures and switched to another agent. Those who experienced a decrease in HBV DNA level and later have a 1 log10 increase in HBV DNA should be tested for resistance to these drugs. Tests for resistance to lamivudine, adefovir, and entecavir are available in commercial laboratories, usually using a DNA-line probe assay. For patients who develop resistance to a nucleoside/nucleotide analogue, secondary choices of medications are listed in Table 6.

Duration of Therapy Patients who are HBeAg positive should be treated with nucleoside/nucleotide analogues for ⱖ6 months after HBeAg is lost and anti-HBe appears. Persons who are anti-HBe positive should be treated indefinitely. If peginterferon is used, treatment duration is 48 weeks, regardless of HBe status.

SURVEILLANCE FOR HEPATOCELLULAR CARCINOMA IN PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION Because persons with CHB are at such high risk for developing HCC during their lifetime, these patients should be monitored on a regular basis to detect HCC at a potentially treatable stage. Those at the highest risk for developing HCC include men ⬎40 years of age and women aged ⬎50 years. Other high-risk persons in whom screening for HCC should be initiated at a younger age are listed in Table 7. The AASLD has developed a separate evidenced-based practice guideline for HCC, and this guideline specifically addresses management of persons infected with HBV who are at the highest risk for HCC.17 The guideline specifically recommends routine surveillance with hepatic ultrasound examination every 6 months. The guideline did not recommend AFP monitoring be added because the authors felt that AFP was less sensitive and specific than ultrasound and could lead to unnecessary additional tests that could in-

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S51

Figure 3 Management of persons with hepatitis B e antigen (HBeAg)–negative/HBe antigen antibody (anti-HBe)–positive hepatitis B virus (HBV) disease. ALT ⫽ alanine aminotransferase; AST ⫽ aspartate aminotransferase; HCV ⫽ hepatitis C virus; NAFLD ⫽ nonalcoholic fatty liver disease; WNL ⫽ within normal range.

Table 6 Alternative medications for patients who develop resistance to ⱖ 1 nucleoside/nucleotide analogue drug for the treatment of hepatitis B virus infection Drug with Resistance

Treatment Response

Lamivudine or telbivudine

● Continue lamivudine/telbivudine and add adefovir or tenofovir ● Switch to entecavir* ● Continue adefovir and add lamivudine or telbivudine ● Switch to entecavir ● Switch to adefovir plus lamivudine or telbivudine† ● Switch to tenofovir or Truvada†‡ ● Switch to entecavir ● Switch to tenofovir or Truvada†‡

Adefovir

Entecavir

Lamivudine and adefovir Lamivudine, adefovir, and entecavir

*Increased risk of developing resistance to entecavir compared with entecavir use in nucleoside-naive patients. †Minimal data to support recommendation. ‡Truvada is tenofovir plus emtricitabine (Gilead Sciences, Inc., Foster City, CA.

crease the cost of screening. However, studies have shown that AFP can be elevated before tumors are detected by ultrasound and elevated AFP is itself an independent risk factor for subsequent development of HCC. Thus, many clinicians still include AFP with ultrasound every 6 months in those at highest risk for HCC.

Table 7 Persons with chronic hepatitis B virus (HBV) infection who should undergo regular surveillance for hepatocellular carcinoma (HCC) every 6 months ● All men aged ⬎40 yr and women aged ⬎50 yr ● Men aged ⱕ40 yr/women ⱕ50 yr with the following characteristics: — Family history of HCC — Severe liver fibrosis (cirrhosis or bridging fibrosis) — AFP ⬎10 ng/mL — Women ⱖ40 yr with HBV DNA ⬎2,000 IU/mL or HBeAg positive status AFP ⫽ ␣-fetoprotein; HBeAg ⫽ hepatitis B e antigen.

SUMMARY In conclusion, mounting a successful campaign against CHB requires the participation of both primary care practitioners and specialists skilled in treating persons who need antiviral therapy. The key steps involve (1) identification of persons with a high probability of having CHB, especially persons born in endemic countries including Asia, Africa, and the South Pacific; (2) initial evaluation of the person with newly identified HBV infection to determine which phase of hepatitis B infection he or she is in; (3) commitment by providers to follow all persons chronically infected with HBV for their lifetimes, every 3 to 12 months depending on the phase of their infection; (4) referral of patients who fit the criteria as potential candidates for antiviral therapy; (5) for persons needing antiviral therapy, selecting the best medication that fulfills their individual circum-

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The American Journal of Medicine, Vol 121, No 12A, December 2008

stances; (6) for those patients who are started on a nucleoside analogue, monitoring their laboratory tests every 3 to 6 months for signs of emerging resistance to the agent chosen, and following guidelines to select alternative therapeutic regimens if resistance does arise; and (7) screening those at highest risk for HCC every 6 months to attempt to detect tumors early when treatment outcome can be favorable. Implementing these key steps into managed care and individual medical practices will have a positive effect on the outcomes of CHB by decreasing the incidence of HBVassociated HCC and cirrhosis.

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AUTHOR DISCLOSURES

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The author of this article has disclosed the following industry relationships: Brian J. McMahon, MD, reports no relationships to a manufacturer of a product or device discussed in this supplement.

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References 1. Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004;11:97-107. 2. McMahon BJ. Epidemiology and natural history of hepatitis B. Semin Liver Dis. 2005;25(suppl 1):3-8. 3. Mast EE, Margolis HS, Fiore AE, et al, for the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP). Part I: immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54(RR-16):1-31. 4. Mast EE WC, Fiore AE, Alter MJ, et al, for the Advisory Committee on Immunization Practices (ACIP) and the Centers for Disease Control and Prevention (CDC). A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization

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Practices (ACIP). Part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1-33. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B infection. MMWR 2008;57:1-20. Hoofnagle JH DE, Liang TJ, Fleischer R, Lok ASK. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056-1075. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507539. 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. 2008 doi 10.1016/jcgh 2008.08.021. Heathcote EJ. Demography and presentation of chronic hepatitis B infection. Am J Med. 2008;121[suppl]:S3-S11. Hui DK LN, Yuen ST, Zhang HY, et al, for the Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007;46:395-401. Chen CJ, Yang HI, Su J, et al, for the REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65-73. Harris RA, Chen G, Lin WY, Shen FM, London WT, Evans AA. Spontaneous clearance of high-titer serum HBV DNA and risk of hepatocellular carcinoma in a Chinese population. Cancer Causes Control. 2003;14:995-1000. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, for the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/ Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678-686. McMahon BJ, Holck P, Bulkow L, Snowball MM. Serologic and clinical outcomes of 1536 Alaska Natives chronically infected with hepatitis B virus. Ann Intern Med. 2001;135:759-768. Livingston SE, Bulkow LR, Homan CE, et al. Clearance of hepatitis B e antigen in patients with chronic hepatitis B and genotypes A, B, C, D and F. Gastroenterology. 2007;133:1452-1457. Khokhar A, Afdhal N. Therapeutic strategies for chronic hepatitis B virus infection in 2008. Am J Med. 2008;121[suppl]:S33-S44. Bruix J, Sherman M, for the Practice Guidelines Committee of the American Association for the Study of Liver Diseases. Management of hepatocellular carcinoma. Hepatology. 2005;42:1208-1236.

Supplement to

The American Journal of Medicine

Optimizing Management Strategies in Patients with Chronic Hepatitis B Infection

CME SECTION ASSESSMENT TEST

Sponsored by:

Release Date: December 2008

Expiration Date: December 31, 2009

CME ASSESSMENT TEST Optimizing Management Strategies in Patients with Chronic Hepatitis B Infection 1. What proportion of patients with chronic hepatitis B infection will develop HCC or cirrhosis? a. 10% b. 25% c. 50% d. 75%

2. Which of the following is characteristic of the immune tolerant phase of CHB? a. High serum HBV DNA, HBeAg positivity, normal ALT and little histological activity b. Low serum HBV DNA, HBeAg positivity, normal ALT and little histological activity c. High serum HBV DNA, HBeAg positivity, raised ALT, and significant histological changes d. High serum HBV DNA, HBeAg-negative, raised ALT, and significant histological activity

3. Which of the following is part of the WHO HBV vaccination strategy? a. Universal infant vaccination b. Vaccination of all under-18’s who have not previously been vaccinated c. Vaccination of all adults at high-risk of infection d. All of the above

4. Which of the following is not associated with resolved HBV infection in individuals with a history of CHB? a. Elevated ALT b. HBsAg negativity c. HBV DNA negativity (though it may be evident using sensitive PCR) d. Normal ALT

5. Which of the following does not appear to be related to HBV genotype? a. Response to therapy b. Prognosis without therapy c. Likelihood of developing resistance to therapy d. Duration of immune tolerant phase

6. HBV DNA quantification has replaced histology as a test of disease activity. Which of the following changes in HBV DNA on therapy would be considered to reflect primary treatment failure? a. HBV DNA ⬍1 log10 IU/mL from baseline at week 6 b. HBV DNA ⬍1 log10 IU/mL from baseline at week 12 c. HBV DNA ⬍2 log10 IU/mL from baseline at week 6 d. HBV DNA ⬍2 log10 IU/mL from baseline at week 12

7. Which of the following subpopulations should be targeted for hepatitis B screening? a. All individuals of western origin b. All individuals under the age of 18 c. Persons with multiple sex partners or sexually transmitted diseases d. Female homosexuals

8. Biopsy is recommended in patients with chronic hepatitis B infection to assess the degree of liver injury. However, in patients with normal ALT, biopsy results rarely detect significant liver injury – True or false? a. True b. False

9. Is prophylactic oral antiviral therapy recommended in inactive HBsAg carriers who are about to receive immunosuppressive therapy? a. Yes b. No

10. It is recommended that newly diagnosed HBeAg-positive patients with elevated ALT levels are monitored for 6-12 months prior to initiation with therapy because a. HBeAg clearance occurs at a rate of 35-50% per year b. ALT levels normalize in 50% of patients at one year c. Spontaneous HBeAg clearance occurs at a rate of 8-12% per year d. ALT levels normalize in 20% of patients at one year

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which subgroup of hepatitis patients is interferon therapy most effective? Chronic HBV infection, HBeAg-positive with evidence of active viral replication and active liver disease Chronic HBV infection, HBeAg-negative with evidence of active viral replication and active liver disease Chronic HBV infection, HBeAg-positive with normal ALT Chronic HBV infection, HBeAg-negative with normal ALT

12. Which of the nucleoside agents is the most potent in terms of its effect on serum HBV DNA? a. Lamivudine b. Adefovir c. Telbivudine d. Entecavir

13. Lamivudine and adefovir have been studied in combination, which of the following best describes the reported advantages of this combination? a. Lamivudine and adefovir are synergistic b. Lamivudine and adefovir have an additive effect c. Addition of adefovir to lamivudine in lamivudine resistant patients reduces the incidence of adefovir resistance d. In nucleoside resistant patients, use of both lamivudine and adefovir completely prevents lamivudine resistance

14. What is the approximate rate of entecavir resistance reported in nucleoside naive patients receiving up to 5 years therapy (patients who have not received prior lamivudine)? a. 1% b. 5% c. 10% d. 15%

15. How often during nucleoside therapy should HBV DNA and ALT/AST be tested? a. Monthly b. Annually c. Every 6-12 months d. Every 3-6 months

16. What is the clinical utility of measuring alfa-fetoprotein (AFP) in addition to ultrasound to detect HCC in HBV infected individuals? a. AFP is more sensitive than ultrasound for HCC b. AFP is more specific than ultrasound for HCC c. AFP levels can be elevated before tumors can be detected by ultrasound d. AFP levels can be diminished before tumors can be identified by ultrasound

CME ASSESSMENT TEST ANSWER SHEET Optimizing Management Strategies in Patients with Chronic Hepatitis B Infection If you wish to receive acknowledgment for completing for this activity, please complete the posttest by selecting the best answer to each question, complete this evaluation verification of participation, and fax to: (303) 790-4876. Posttest Answer Key 1

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CME Evaluation Form Optimizing Management Strategies in Patients with Chronic Hepatitis B Infection Project ID: 6105-ES-37 To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this evaluation form. You must complete this evaluation form to receive acknowledgment for completing this activity. Please answer the following questions by circling the appropriate rating: 1 ⫽ Strongly 5 ⫽ Strongly Disagree 2 ⫽ Disagree 3 ⫽ Neutral 4 ⫽ Agree Agree Extent to Which Program Activities Met the Identified Objectives After completing this activity, I am now better able to: ● Identify patients at high risk 1 2 of hepatitis B infection. 1 2 ● Identify the serological markers that can be used to distinguish different sub-types of chronic hepatitis B infection. ● Outline appropriate follow-up 1 2 strategies in patients with chronic hepatitis B infection. ● Describe the eligibility criteria 1 2 for treatment for HBeAg-positive and HBeAg-negative disease. 1 2 ● Describe the effect of various options for the long-term virological control of chronic hepatitis B and the potential impact on clinical outcomes. ● Outline the clinical application 1 2 of the latest guidelines for treatment of chronic hepatitis B. Overall Effectiveness of the Activity The content presented: Was timely and will influence how I practice 1 2 Enhanced my current knowledge base 1 2 Addressed my most pressing questions 1 2 Provided new ideas or information I expect to use 1 2 Addressed competencies identified by my specialty 1 2 Avoided commercial bias or influence 1 2

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