National Institute of Diabetes and Digestive and Kidney Diseases, NIH
Office of Medical Applications of Research, NIH
The Johns Hopkins
University School of Medicine, Educational Provider
National Cancer Institute, NIH
National Institute of Allergy and
Infectious Diseases, NIH
Centers for Disease Control and Prevention
Food and Drug
Administration
The Agency for Healthcare Research and Quality provided
additional
support to the conference development.
The National Institutes of Health (NIH) Consensus Development Program has been organizing major conferences since 1977. The Program generates evidence-based consensus statements addressing controversial issues important to healthcare providers, policymakers, patients, researchers, and the general public. The NIH Consensus Development Program holds an average of three conferences a year. The Program is administered by the Office of Medical Applications of Research within the NIH Office of the Director. Typically, the conferences have one major NIH Institute or Center sponsor, with multiple cosponsoring agencies.
NIH Consensus Development and State-of-the-Science Conference topics must satisfy the following criteria:
Two types of conferences fall under the purview of the NIH Consensus Development Program: State-of-the-Science Conferences and Consensus Development Conferences. Both conference types utilize the same structure and methodology; they differ only in the strength of the evidence surrounding the topic under consideration. When it appears that there is very strong evidence about a particular medical topic, but that the information is not in widespread clinical practice, a Consensus Development Conference is typically chosen to consolidate, solidify, and broadly disseminate strong evidence-based recommendations for general practice. Conversely, when the available evidence is weak or contradictory, or when a common practice is not supported by high-quality evidence, the State-of-the-Science label is chosen. This highlights what evidence about a topic is available, the directions future research should take, and alerts physicians that certain practices are not supported by good data.
Before the conference, a systematic evidence review on the chosen topic is performed by one of the Agency for Healthcare Research and Quality’s Evidence-Based Practice Centers. This report is provided to the panel members approximately 6 weeks prior to the conference, and posted to the Consensus Development Program Web site once the conference begins, to serve as a foundation of high-quality evidence upon which the conference will build.
The conferences are held over 2 1/2 days. The first day and a half of the conference consist of plenary sessions in which invited expert speakers present information, followed by “town hall forums,” in which open discussion occurs among the speakers, panelists, and the general public in attendance. The panel then develops its draft statement on the afternoon and evening of the second day, and presents it on the morning of the third day for audience commentary. The panel considers these comments in executive session and may revise their draft accordingly. The conference ends with a press briefing, during which reporters are invited to question the panelists about their findings.
Each conference panel comprises 12–16 members who can give balanced, objective, and informed attention to the topic. Panel members:
In addition, the panel as a whole should appropriately reflect racial and ethnic diversity. Panel members are not paid a fee or honorarium for their efforts. They are, however, reimbursed for travel expenses related to their participation in the conference.
The conferences typically feature approximately 21 speakers; 3 present the information found in the Evidence-Based Practice Center’s systematic review of the literature. The other 18 are experts in the topic at hand, have likely published on the topic, and may have strong opinions or beliefs. Where multiple viewpoints on a topic exist, every effort is made to include speakers who address all sides of the issue.
The panel’s draft report is released online late in the conference’s third and final day. The final report is released approximately 6 weeks later. During the intervening period, the panel may edit their statement for clarity and correct any factual errors that might be discovered. No substantive changes to the panel’s findings are made during this period.
Each Consensus Development or State-of-the-Science Conference Statement reflects an independent panel’s assessment of the medical knowledge available at the time the statement was written; as such, it provides a “snapshot in time” of the state of knowledge on the conference topic. It is not a policy statement of the NIH or the Federal Government.
Consensus Development and State-of-the-Science Conference Statements have robust dissemination:
The conference statement is published in a major peer-reviewed journal.
For conference schedules, past statements and evidence reports, please
contact us:
NIH Consensus Development Program
Information Center
P.O. Box 2577
Kensington, MD 20891
1-888-NIH-CONSENSUS
(888-644-2667)
http://consensus.nih.gov
| NIH State-of-the-Science Conference: | Family History and Improving
Health August 24–26, 2009 |
| NIH State-of-the-Science Conference: | Diagnosis and Management of Ductal
Carcinoma In Situ September 22–24, 2009 |
| NIH State-of-the-Science Conference: | Enhancing Use and Quality of
Colorectal Cancer Screening February 2–4, 2010 |
| NIH Consensus Development Conference: | Vaginal Birth After Cesarean: New
Insights March 8–10, 2010 |
| NIH State-of-the-Science Conference: | Preventing Alzheimer’s Disease
and Cognitive Decline April 26–28, 2010 |
To receive registration notifications and updates about conferences and other program activities, please join the NIH Consensus Development Program Information Network at http://consensus.nih.gov/alerts.htm.
| NIH Consensus Development Conference: | Hydroxyurea Treatment for Sickle Cell
Disease February 25–27, 2008 |
| NIH State-of-the-Science Conference: | Prevention of Fecal and Urinary
Incontinence in Adults December 10–12, 2007 |
| NIH State-of-the-Science Conference: | Tobacco Use: Prevention, Cessation
and Control June 12–14, 2006 |
| NIH State-of-the-Science Conference: | Multivitamin/Mineral Supplements and
Chronic Disease Prevention May 15–17, 2006 |
| NIH State-of-the-Science Conference: | Cesarean Delivery on Maternal
Request March 27–29, 2006 |
| NIH State-of-the-Science Conference: | Manifestations and Management of
Chronic Insomnia in Adults June 13–15, 2005 |
| NIH State-of-the-Science Conference: | Management of Menopause-Related
Symptoms March 21–23, 2005 |
| NIH State-of-the-Science Conference: | Improving End-of-Life Care December 6–8, 2004 |
| NIH State-of-the-Science Conference: | Preventing Violence and Related
Health-Risking Social Behaviors in Adolescents October 13–15, 2004 |
| NIH Consensus Development Conference: | Celiac Disease June 28–30, 2004 |
| NIH Consensus Development Conference: | Total Knee Replacement December 8–10, 2003 |
To access previous conference statements, videocasts, evidence reports, and other conference materials, please visit http://consensus.nih.gov.
The NIH Consensus Development Program is convening a consensus development conference to assess the available evidence on the management of hepatitis B. The conference statement will be prepared by an independent panel on the basis of a systematic literature review, expert presentations, and audience commentary. Widely distributed to the biomedical community and covered by the news media, the statement will help inform both healthcare providers and the general public, and shape the research agenda for this complex disease.
It is important that all key stakeholders be represented, as attendees will have the opportunity to participate in engaging discussions that will influence the panel’s statement. This conference is intended for physicians and other health practitioners, healthcare system professionals, health policy specialists, public health experts, researchers, and interested members of the public.
At the end of this activity, participants will be able to:
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Johns Hopkins University School of Medicine and the National Institutes of Health. The Johns Hopkins University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.
The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 13.25 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
It is the policy of The Johns Hopkins University School of Medicine that the speaker and provider disclose real or apparent conflicts of interest relating to the topics of this educational activity, and also disclose discussions of unlabeled/unapproved uses of drugs or devices during their presentation(s). The Johns Hopkins University School of Medicine Office of Continuing Medical Education has established policies in place that will identify and resolve all conflicts of interest prior to this educational activity. Detailed disclosure will be made in the activity handout materials.
The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity.
Panel members signed a confirmation that they have no financial or other conflicts of interest pertaining to the topic under consideration.
Live and archived videocasts may be accessed at http://videocast.nih.gov. Archived videocast will be available approximately 1 week after the conference.
The dining center in the Natcher Conference Center is located on the main level, one floor above the auditorium. It is open from 6:30 a.m. to 2:30 p.m., serving hot breakfast and lunch, sandwiches and salads, and snack items. An additional cafeteria is available from 7:00 a.m. to 3:30 p.m., in Building 38A, level B1, across the street from the main entrance to the Natcher Conference Center.
The telephone number for the message center at the Natcher Conference Center is 301–594–7302.
All materials emanating from the NIH Consensus Development Program are available at http://consensus.nih.gov.
Background
About the Artwork
Agenda
Panel Members
Speakers
Planning
Committee
Abstracts
I. What Is the Current Burden of Hepatitis B?
II. What Is the Natural History of Hepatitis B?
III. What Are the Benefits and Risks of the Current Therapeutic Options for Hepatitis B?
IV. Which Persons With Hepatitis B Should Be Treated?
V. What Measures Are Appropriate To Monitor Therapy and Assess Outcomes?
Hepatitis B is a major cause of liver disease worldwide, ranking as a substantial cause of cirrhosis and liver cancer. In the United States, about 1.25 million people are chronically infected with the virus, resulting in 3,000 to 5,000 deaths each year. However, this condition occurs more frequently in high-risk groups, including Asian Americans, emigrants from areas of the world where hepatitis B is common (China, Korea, Southeast Asia, the Indian Subcontinent, Africa, and Micronesia), men who have sex with men, injection drug users, and recipients of blood and blood products before screening procedures with enhanced sensitivity were implemented in 1986. Since routine hepatitis B vaccination of U.S. children began in 1991, new cases of acute hepatitis B among children and adolescents have dropped by more than 95%—and by 75% across all age groups. In non-protected individuals, transmission can result from exposure to infectious blood or body fluids containing blood. A major impediment to diagnosis is that many infected individuals are either asymptomatic or experience only non-specific symptoms of disease, such as fatigue or muscle ache.
For approximately 90% of adults, acute infection with the hepatitis B virus is resolved by the body’s immune system and does not cause long-term problems. The transition from acute to chronic infection appears to occur when the immune system does not effectively destroy and clear virus-infected cells. This leads to high blood levels of both hepatitis B deoxyribonucleic acid (DNA) and antigens, as well as antibodies produced by the body in an attempt to combat the infection. The natural history of the disease is not well understood, however, which makes management of this complex disease challenging.
Many factors can influence treatment decisions for an individual patient, including age, ALT (alanine aminotransferase, a liver enzyme) level, viral load, liver biopsy results, and the presence of a co-infecting virus (i.e., human immunodeficiency virus (HIV)). Treatment decisions require in-depth analysis of multiple blood tests results, which are typically repeated at regular intervals to monitor the disease course. There are currently seven approved therapeutic agents: interferon-alpha, lamivudine, adefovir dipivoxil, entecavir, pegylated interferon, telbivudine, and tenofovir disoproxil fumarate, which are often used in combination. Generally, these drugs act to decrease the risk of liver damage from hepatitis B by slowing or stopping the replication of the virus.
Questions remain as to which groups of patients benefit from therapy and at which point in the course of their disease. Specific recommendations for hepatitis B therapy are limited by a lack of reliable long-term safety and efficacy information. This is a difficult decision for physicians and patients, as treatments are expensive and may have bothersome, if not harmful, effects on patients; left untreated, however, chronic hepatitis B can lead to liver failure and other serious liver problems. To examine these important issues, the National Institute of Diabetes and Digestive and Kidney Diseases and Office of Medical Applications of Research of the National Institutes of Health will convene a Consensus Development Conference from October 20 to 22, 2008.
The conference artwork is a stylized representation of the hepatitis B virus (Dane particle) amongst surface antigen filaments and spheres found in the blood of chronically infected patients. The bottom image represents the hepatitis B virus genome, a circular, partially double-stranded DNA molecule. Emanating from the central genome are the various RNA transcripts. The artwork was designed by Bryan Ewsichek and Ethan Tyler of NIH Medical Arts and is in the public domain. No permission is needed to use the image.
|
8:30 a.m. |
Opening Remarks |
|
8:40 a.m. |
Charge to the Panel |
|
8:50 a.m. |
Conference Overview and Panel Activities |
|
I. What Is the Current Burden of Hepatitis B? |
|
|
9:00 a.m |
Hepatitis B Virus and the Diseases It Causes |
|
9:20 a.m |
Evaluation of the Patient With Hepatitis B |
|
9:40 a.m |
Epidemiology of Hepatitis B |
|
10:00 a.m |
Recommendations for Identification and Public Health Management
of Persons With Chronic Hepatitis B Virus Infection |
|
10:20 a.m |
Discussion |
|
II. What Is the Natural History of Hepatitis B? |
|
|
11:00 a.m |
Introduction to the Natural History of Chronic Hepatitis B |
|
11:20 a.m |
Hepatitis B and Liver Cancer |
|
11:40 a.m |
Liver Biopsy Findings in Chronic Hepatitis B |
|
12:00 p.m |
Lunch |
|
1:00 p.m |
HBV DNA Levels and Outcomes in Chronic Hepatitis B |
|
1:20 p.m |
Evidence-Based Practice Center Presentation I: Population
Characteristics and Clinical Features Associated With Hepatitis B and
Predictability of Hepatocellular Carcinoma, Liver Failure, Cirrhosis, Liver
Related Death, and All-Cause Mortality |
|
1:40 p.m |
Discussion |
|
III. What Are the Benefits and Risks of the Current Therapeutic Options for Hepatitis B? |
|
|
2:30 p.m |
Overview: Benefits and Risks of Treatment for Chronic Hepatitis
B |
|
2:50 p.m |
Benefits and Risks of Interferon Therapy for Hepatitis B |
|
3:10 p.m |
Benefits and Risks of Nucleos(t)ide Analogues for Hepatitis B
|
|
3:30 p.m |
3:30 p.m. Benefits and Risks of Combination Therapy for Hepatitis
B |
|
3:50 p.m |
Evidence-Based Practice Center Presentation II:
Efficacy/Effectiveness of Interferon Therapy, Oral Therapy, and Various
Combinations in |
|
4:10 p.m |
Discussion |
|
5:00 p.m |
Adjournment |
Tuesday, October 21, 2008IV. Which Persons With Hepatitis B Should Be Treated? |
|
|
8:30 a.m |
Indications for Therapy in Hepatitis B |
|
8:50 a.m |
HIV/HBV Co-infection |
|
9:10 a.m |
Special Populations and Hepatitis B |
|
9:30 a.m |
Reactivation of Hepatitis B |
|
9:50 a.m |
Evidence-Based Practice Center Presentation III: Differences in
Efficacy/Effectiveness of Treatments for Subpopulations With Hepatitis B |
|
10:10 a.m |
Discussion |
|
V. What Measures Are Appropriate To Monitor Therapy and Assess Outcomes? |
|
|
11:00 a.m |
Monitoring During and After Antiviral Therapy for Hepatitis B |
|
11:20 a.m |
Antiviral Resistance and Hepatitis B Therapy |
|
11:40 a.m |
Side Effects of Long-Term Antiviral Therapy for Hepatitis B |
|
12:00 p.m |
Discussion |
|
12:30 p.m |
Adjournment |
Wednesday, October 22, 2008 |
|
|
9:00 a.m |
Presentation of the Draft Consensus Statement |
|
9:30 a.m |
Public Discussion |
|
11:00 a.m |
Panel Meets in Executive Session |
|
2:00 p.m |
Press Conference |
|
3:00 p.m |
Adjournment |
Panel Chair: Michael F. Sorrell, M.D.
Panel and Conference
Chairperson
Robert L. Grissom Professor of Medicine
Section of
Gastroenterology and Hepatology
University of Nebraska Medical Center
Omaha, Nebraska
Edward A. Belongia, M.D.
Director, Epidemiology Research
Center
Marshfield Clinic Research Foundation
Marshfield, Wisconsin
Jose Costa, M.D.
Professor of Pathology and Medicine
(Oncology)
Vice Chair of Pathology
Director, Translational
Diagnostics
Department of Pathology
Yale University School of
Medicine
New Haven, Connecticut
Ilana F. Gareen, Ph.D.
Assistant Professor
Department of
Community Health
Center for Statistical Sciences
Brown University
Providence, Rhode Island
Jean L. Grem, M.D.
Professor of Medicine
Department of
Internal Medicine
Section of Oncology and Hematology
University of
Nebraska Medical Center
Omaha, Nebraska
John M. Inadomi, M.D.
Dean M. Craig Endowed Chair in
Gastrointestinal Medicine
Director, GI Health Outcomes, Policy and
Economics (HOPE) Research Program
University of California, San
Francisco
Chief, Clinical Gastroenterologyv San Francisco General
Hospital
San Francisco, California
Earl R. Kern, Ph.D.
Professor Emeritus
Department of
Pediatrics
The University of Alabama School of Medicine
Birmingham,
Alabama
James A. McHugh, M.D.
Assistant Clinical Professor
Department of Family Medicine
University of Washington School of
Medicine
Family Medicine
Swedish Medical Center
Swedish
Physicians—Central Seattle Clinic
Seattle, Washington
Gloria M. Petersen, Ph.D.
Professor of Epidemiology
College of Medicine
Mayo Clinic
Rochester, Minnesota
Michael F. Rein, M.D., F.A.C.P.
Professor Emeritus of
Medicine
Division of Infectious Diseases and
International Health
University of Virginia
Charlottesville, Virginia
Doris B. Strader, M.D.
Associate Professor
Division of
Gastroenterology/Hepatology
Fletcher Allen Health Care
University of
Vermont College of Medicine
Burlington, Vermont
H. Thomas Trotter, M.S.
U.S. Navy (Ret.)
Volunteer
Counselor
American Melanoma Foundation
San Diego, California
Chien-Jen Chen, Sc.D., M.P.H.
Academician and Distinguished
Research Fellow
Genomics Research Center, Academia Sinica
Professor
National Taiwan University
Nankang, Taipei City
Taiwan
Raymond T. Chung, M.D.
Associate Professor of Medicine
Harvard Medical School
Director of Hepatology
Medical Director, Liver
Transplant Program
Massachusetts General Hospital
Boston, Massachusetts
Adrian M. Di Bisceglie, M.D., F.A.C.P.
Professor of Internal
Medicine
Division of Gastroenterology and Hepatology
Chief of
Hepatology
Saint Louis University School of Medicine
Saint Louis,
Missouri
Jules L. Dienstag, M.D.
Dean for Medical Education
Carl
W. Walter Professor of Medicine
Harvard Medical School
Boston,
Massachusetts
Robert J. Fontana, M.D.
Associate Professor of Internal
Medicine
Medical Director of Liver Transplantation
Division of
Gastroenterology
Department of Internal Medicine
University of Michigan
Medical School
Ann Arbor, Michigan
Marc G. Ghany, M.D.
Investigator
Liver Diseases
Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
Bethesda, Maryland
Jenny Heathcote, M.D., FRCPC
Head, Division of Patient Based
Clinical Research
Gastroenterology
Toronto Western Hospital
University of Toronto
Toronto, Ontario
Canada
Jay H. Hoofnagle, M.D.
Director
Liver Disease Research
Branch
Division of Digestive Diseases and Nutrition
National Institute
of Diabetes and Digestive and Kidney Diseases
National Institutes of
Health
Bethesda, Maryland
W. Ray Kim, M.D., M.Sc., M.B.A.
Associate Professor of
Medicine
Division of Gastroenterology and Hepatology
Department of
Internal Medicine
Mayo Clinic
Rochester, Minnesota
David E. Kleiner, M.D., Ph.D.
Director, Clinical
Operations
Chief, Post-mortem Section
Laboratory of Pathology
National Cancer Institute
National Institutes of Health
Bethesda,
Maryland
T. Jake Liang, M.D.
Chief
Liver Diseases Branch
National Institute of Diabetes and Digestive and Kidney Diseases
National
Institutes of Health
Bethesda, Maryland
Anna S.F. Lok, M.D.
Professor of Internal Medicine
Director of Clinical Hepatology
Division of Gastroenterology
University
of Michigan Health System
Ann Arbor, Michigan
Brian J. McMahon, M.D.
Scientific Program and Clinical
Director
Liver Disease and Hepatitis Program, Alaska Native Medical
Center
Guest Researcher
Arctic Investigations Program
Centers for
Disease Control and Prevention
Anchorage, Alaska
Robert P. Perrillo, M.D.
Associate Director, Hepatology
Division
Program Director, Liver Fellowship
Baylor University Medical
Center
Dallas, Texas
Marion G. Peters, M.D., M.B.B.S.
John V. Carbone, M.D.
Endowed Chair in Medicine
Director, Hepatology Research
University of
California, San Francisco
San Francisco, California
Eugene R. Schiff, M.D., M.A.C.P., F.R.C.P., M.A.C.G.,
A.G.A.F.
Director, Schiff Liver Institute and Center for Liver
Diseases
University of Miami School of Medicine
Miami, Florida
Aasma Shaukat, M.D., M.P.H.
Investigator
University of
Minnesota
Minneapolis, Minnesota
Brent C. Taylor, Ph.D., M.P.H.
Associate Investigator
Center for Chronic Disease Outcomes Research, Minneapolis VA Medical Center
Assistant Professor
University of Minnesota
Minneapolis, Minnesota
Norah A. Terrault, M.D., M.P.H.
Associate Professor
Division of Gastroenterology
Department of Medicine
University of
California, San Francisco
San Francisco, California
Chloe L. Thio, M.D.
Associate Professor of Medicine
Division of Infectious Diseases
Johns Hopkins School of Medicine
Baltimore, Maryland
Cindy M. Weinbaum, M.D., M.P.H.
Team Leader
Prevention
Branch Research and Evaluation Team
Division of Viral Hepatitis
Centers
for Disease Control and Prevention
Atlanta, Georgia
Timothy J. Wilt, M.D., M.P.H.
Professor of Medicine
Center for Chronic Disease Outcomes Research, Minneapolis VA Medical Center
Co-Director, Minnesota AHRQ Evidence-Based Practice Center
University of
Minnesota
Minneapolis, Minnesota
Planning Chair: Jay H. Hoofnagle, M.D.
Director
Liver
Disease Research Branch
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National
Institutes of Health
Bethesda, Maryland
Lisa Ahramjian, M.S.
Communications Specialist
Office of
Medical Applications of Research
Office of the Director
National
Institutes of Health
Bethesda, Maryland
Shilpa Amin, M.D., M.Bsc., FAAFP
Medical Officer
Evidence-Based Practice Centers Program
Center for Outcomes and
Evidence
Agency for Healthcare Research and Quality
Rockville, Maryland
David Atkins, M.D., M.P.H.
Chief Medical Officer
Center
for Outcomes and Evidence
Agency for Healthcare Research and Quality
Rockville, Maryland
Diana Berard
Program Officer
Enteric and Hepatic
Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
National Institutes
of Health
Bethesda, Maryland
Robin Biswas, M.D.
Supervisory Medical Officer
Division
of Emerging and Transfusion Transmitted Diseases
U.S. Food and Drug
Administration
Rockville, Maryland
Timothy Block, Ph.D.
Director
Drexel Institute for
Biotechnology and Virology Research
Professor
Microbiology and
Immunology
Drexel University College of Medicine
Doylestown,
Pennsylvania
John S. Cole III, Ph.D.
Chief, Cancer Etiology Branch
Division of Cancer Biology
National Cancer Institute
National
Institutes of Health
Bethesda, Maryland
Jennifer Miller Croswell, M.D.
Senior Advisor for the
Consensus Development Program
Office of Medical Applications of
Research
Office of the Director
National Institutes of Health
Bethesda, Maryland
Jules L. Dienstag, M.D.
Dean for Medical Education
Carl
W. Walter Professor of Medicine
Harvard Medical School
Boston,
Massachusetts
Edward Doo, M.D.
Director
Liver Disease Research
Programs
National Institute of Diabetes and Digestive and Kidney
Diseases
National Institutes of Health
Bethesda, Maryland
James Everhart, M.D., M.P.H.
Chief
Epidemiology and
Clinical Trials Branch
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
National
Institutes of Health
Bethesda, Maryland
Russell Fleischer, PA-C, M.P.H.
Senior Clinical Analyst
PreIND Team Leader
Division of Antiviral Products
U.S. Food and Drug
Administration
Silver Spring, Maryland
Barnett S. Kramer, M.D., M.P.H.
Director
Office of
Medical Applications of Research
Office of the Director
National
Institutes of Health
Bethesda, Maryland
Anna S. F. Lok, M.D.
Professor of Internal Medicine
Director of Clinical Hepatology
Division of Gastroenterology
University
of Michigan Health System
Ann Arbor, Michigan
Willis C. Maddrey, M.D.
Executive Vice President for
Clinical Affairs
Adelyn and Edmund M. Hoffman Distinguished Chair in
Medical Science
Arnold N. and Carol S. Ablon Professorship in Biomedical
Science
University of Texas Southwestern Medical Center at Dallas
Dallas, Texas
Brian J. McMahon, M.D.
Scientific Program and Clinical
Director
Liver Disease and Hepatitis Program,
Alaska Native Medical
Center
Guest Researcher
Arctic Investigations Program
Centers for
Disease Control and Prevention
Anchorage, Alaska
Robert P. Perrillo, M.D.
Associate Director, Hepatology
Division
Program Director, Liver Fellowship
Baylor University Medical
Center
Dallas, Texas
Michael F. Sorrell, M.D.
Panel and Conference
Chairperson
Robert L. Grissom Professor of Medicine
Section of
Gastroenterology and Hepatology
University of Nebraska Medical Center
Omaha, Nebraska
David L. Thomas, M.D.
Professor of Medicine
Infectious
Diseases Viral Hepatitis Center
The Johns Hopkins University School of
Medicine
Baltimore, Maryland
Cindy Weinbaum, M.D., M.P.H.
Team Leader
Prevention
Branch Research and Evaluation Team
Division of Viral Hepatitis
Centers
for Disease Control and Prevention
Atlanta, Georgia
Ian T. Williams, Ph.D., M.S.
Chief
Epidemiologic
Research and Field Investigations Team
Division of Viral Hepatitis
Centers for Disease Control and Prevention
Atlanta, Georgia
The abstracts are designed to inform the panel and conference participants, as well as to serve as a reference document for any other interested parties. We would like to thank the speakers for preparing and presenting their findings on this important topic.
The organizers would also like to thank the planning committee, the panel, the Minnesota Evidence-Based Practice Center, and the Agency for Healthcare Research and Quality, as well as the Centers for Disease Control and Prevention, the Food and Drug Administration, and NIH cosponsoring Institutes and Centers. We appreciate your continued interest in both the NIH Consensus Development Program and the management of hepatitis B.
Please note that where multiple authors are listed on an abstract, the underline denotes the presenting author.
Hepatitis B virus (HBV) infects more than 300 million people worldwide; it is one of the most common causes of acute and chronic liver disease and liver cancer. HBV infection is particularly endemic in sub-Saharan Africa and Southeast Asia, with a seroprevalence rate of 10%–20% of the population.
HBV is a small deoxyribonucleic acid (DNA) virus with unusual features similar to retroviruses. It is a prototype virus for the Hepadnaviridae family. Related viruses are found in woodchucks, ground squirrels, tree squirrels, Peking ducks, and herons. The virus preferentially infects the liver, although infection of other tissues has been reported. The virus can be classified into eight genotypes, each with a distinct geographic distribution in the world. HBV replicates through a ribonucleic acid (RNA) intermediate and can integrate into host genomic DNA. The unique features of the HBV replication cycle confer a distinct ability of the virus to persist in the infected cells.
Diagnosis of HBV infection requires appropriate serologic tests. Virologic and serologic assays have been developed for accurate diagnosis of various forms of HBV-associated disease. Assay to quantitatively detect HBV DNA has improved substantially over the years, and it has become a routine standard to apply this test for diagnosis and management of HBV infection. HBV infection leads to a wide spectrum of liver diseases, ranging from acute hepatitis (including fulminant hepatic failure) to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Acute HBV infection can be asymptomatic or may present with symptomatic acute hepatitis. The majority of people infected with the virus recover, but 5%–10% are unable to clear the virus and become chronically infected with the virus. However, perinatal infection, the major route of transmission in the endemic regions of the world, often leads to chronic asymptomatic infection, resulting in a large pool of HBV carriers in the world. Of those who become persistently infected, especially those infected perinatally, many have mild liver disease with little or no long-term morbidity or mortality. However, many HBV-infected individuals do develop active disease, and it can progress to chronic hepatitis, cirrhosis, and liver cancer. These patients require careful monitoring and probably therapeutic intervention if they do not have contraindications to the therapies currently available. Extrahepatic manifestions of HBV infection, including polyarteritis nodosa, glomerulonephritis, and mixed cryoglobulinemia, are rare but can be difficult to diagnose and manage.
The challenges in the area of HBV-associated disease are (1) a relative lack of knowledge in predicting outcome and progression of HBV infection and (2) an unmet need to understand the molecular, cellular, immunologic, and genetic basis of various disease manifestations associated with HBV infection.
A thorough initial assessment of patients diagnosed with hepatitis B virus (HBV) infection is imperative for appropriate patient care. The timing and mode of HBV transmission, as well as the likelihood of co-infection with hepatitis C virus (HCV), hepatitis D virus (HDV), or HIV, can often be determined via careful patient history. Differentiating between acute and chronic HBV infection, reactivation in particular, is made from clinical history, serologic markers, and sometimes follow-up blood work and liver biopsy. Risk factors for the presence of advanced fibrosis and/or hepatocellular carcinoma (HCC) must be assessed. Patients should be reassured that the disease course of chronic HBV infection can be modified with adherence to treatment, when indicated, and its spread to others can be prevented. Patient education should focus on lifestyle modifications, the necessity of communication with physicians involved in the patient’s care, the importance of lifelong follow-up with a physician experienced in the management of chronic HBV infection, and available HBV educational resources. At the same time, a level of sensitivity and empathy must be maintained.
Future research is needed in several fields. What is the optimal frequency of repeat laboratory evaluation and HCC screening in immune-tolerant and inactive carriers? Is ultrasound sufficient for HCC screening? Genetic profiling to stratify an individual’s risks for developing HCC remains unavailable. What is the role of noninvasive measures of fibrosis? Should viral resistance profiling be performed? What is the importance of patients presenting with detectable HBV deoxyribonucleic acid (DNA) levels and antibodies to the hepatitis B core antigen (anti-HBc) but who are negative for hepatitis B surface antigen (HBsAg)?
Approximately 2 billion people worldwide are estimated to have been infected with hepatitis B virus (HBV); of these persons, 350 million have ongoing infection.1 Each year, 500,000 to 1.2 million lives are lost as a result of HBV infection. It is well-recognized that the geographic distribution of HBV is not uniform. HBV infection is most commonly seen in Asia, sub-Saharan Africa, the Amazon basin, and the Mediterranean region. The United States does not belong in the endemic regions for HBV: however, a number of features of the epidemiology of hepatitis B are important for both clinicians and public health policymakers.
HBV is transmitted by percutaneous and mucous membrane exposures to infectious body fluids, such as serum, semen, and saliva. Thus, with the exception of perinatal transmission, HBV transmission may be preventable by controlling these exposures. In addition, effective HBV vaccines are available; these can contribute to reducing the incidence of acute HBV infection.
According to estimates by the Centers for Disease Control and Prevention (CDC), between 1987 and 2004, the incidence of acute hepatitis B declined 80%, from 10.7 per 100,000 population (25,916 cases reported) to 2.1 per 100,000 population (6,212 cases reported).2 The decrease in the incidence occurred in all age and racial groups.
Population-wide data for the prevalence of chronic HBV infection in the United States have been estimated by using the National Health and Nutrition Examination Surveys (NHANES). In the initial report, the prevalence of hepatitis B surface antigen (HBsAg) in 1976–1980 was 0.33%.3 Subsequent surveys have shown similar results (0.42% for 1988–1994 and 0.30% for 2005–2006). One significant limitation of the estimates from these surveys is that they did not include statistically valid samples of populations in which HBV is most common, such as Asians, Pacific Islander and Alaskan Natives, or persons who are homeless or incarcerated. Thus, these results represent an underestimate of the true prevalence of HBV in the United States; that number remains to be determined accurately.
A survey conducted in New York City provides a snapshot of the prevalence of chronic HBV infection within high prevalence populations in the United States.4 Among 925 survey participants who reported not having been tested previously for HBV infection, 137 (14.8%) were HBsAg-positive. The prevalence of chronic HBV infection was the highest in the youngest age group (less than 30 years). The majority of the respondents in the survey were immigrants; 46% had lived in the United States for less than 10 years.
Similar surveys have been conducted in Atlanta, Chicago, New York City, Philadelphia, and California; these survey results indicate that 10%–15% of Asian/Pacific Islander immigrants to the United States have HBV infection.5 Since these surveys did not utilize systematic sampling of the population, a certain degree of self-selection is undoubtedly present. However, the age distribution almost certainly reflects that HBV acquisition in this population occurred during childhood and is thus associated with highest risk of progressive liver disease, culminating in hepatocellular carcinoma (HCC) in many patients. It is not only Asian and Pacific Islander Americans among whom HBV is prevalent. Many recent immigrants from Africa and Eastern Europe have been found to have a much higher prevalence of HBsAg than is found in the general U.S. population.
“Disease burden” is a term that encompasses a number of aspects of the impact of a disease on the health of a population, such as mortality, morbidity, health-related quality of life, and healthcare expenditures. In the case of HBV infection, this burden may result from the following four conditions: (1) Acute hepatitis may range from symptomatic cases that require outpatient and inpatient care to fulminant cases leading to liver failure and death unless liver transplantation is performed. (2) Chronic hepatitis and cirrhosis are largely asymptomatic, yet require monitoring and treatment, if indicated, as well as screening for HCC. (3) Decompensated cirrhosis is usually associated with significant reduction in quality of life, substantial risk of mortality, and increased resource utilization from frequent inpatient and outpatient care. (4) HCC has extremely high risk of mortality, and patients incur significant use of healthcare for curative or palliative treatment. When all of these are taken into account, the total burden of HBV-related liver disease is likely substantial. To date, however, only limited data are available about the burden of liver disease associated with hepatitis B in the United States.
In the United States, data about mortality secondary to HBV have been reported based on death certificates. Between 1978 and 1998, the age-adjusted death rate for HBV increased fourfold from 0.1 to 0.4 per 100,000.6 The death rate was higher in men (0.5 for men, 0.2 for women) and in nonwhites (0.3 for whites, 0.4 for blacks, and 1.2 for other races). The increase in death rate over time was observed in all races and both genders. A preliminary analysis of more recent data indicates that HBV mortality has been declining since the late 1990s.
A similar trend has been seen in the waitlist registration for HBV-related liver disease. The number of patients registered to the United Network for Organ Sharing (UNOS) waitlist peaked in 2000, followed by a 30% reduction in subsequent years. The largest decrease in waitlist registration occurred among patients with endstage liver disease, whereas the number of patients with HCC remained on the rise. On the basis of the temporal relationship, these trends are believed to reflect the effect of widespread use of anti-HBV agents, primarily lamivudine.
Finally, limited data are available about healthcare resource use associated with HBV-related liver disease. According to an analysis based on nationally representative hospital utilization data, a 4.9-fold increase occurred in the number of hospitalizations for HBV related liver disease, a 3.8-fold increase occurred in the number of hospitalizations for HCC, and a 2.2-fold increase occurred in hospital charges between 1989 and 1998. The total hospital charges for HBV-related liver disease increased from $290 million in 1989–1990 to $624 million in 1997–1998. More recently, expenditure on antiviral agents has increased substantially as well. In 2007 alone, it is estimated that more than 390,000 prescriptions for anti-HBV drugs were filled, with a total expenditure of $254 million.
In the United States, the incidence of new infections with HBV has been decreasing in the past two decades, largely due to widespread vaccination programs in children as well as safer needle using practices and universal precautions in healthcare as well as exclusion of blood donors with infection. Despite these decreases in acute infections, the prevalence and burden of chronic HBV infection remain substantial in the United States. The prevalence estimates (approximately 0.4%) for chronic hepatitis B infection in the U.S. population at large have underestimated the number of Americans with chronic HBV infection, as the estimates did not include population groups in whom the burden of chronic hepatitis B infection is disproportionately high. Despite increases in the prevalent cases of chronic HBV infection, recent data indicate that the mortality and morbidity burden of chronic HBV infection may have started to decrease, a trend that may be attributable to effective antiviral agents. Continued public health efforts to control transmission of HBV by prevention programs and effective strategies to identify, monitor, and provide effective treatment for individuals with chronic infection are necessary to reduce and eliminate HBV disease in the United States.
Approximately 800,000 to 1.4 million (0.27%–0.47%) of U.S. residents are chronically infected with hepatitis B virus (HBV); of these persons, 47%–70% were born in other countries.1–5 Prompt identification of chronic infection with HBV enables infected persons to receive necessary care to prevent or delay onset of liver disease and to receive services to prevent transmission to others; for example, approximately one-third of infected Asian-born persons tested in several U.S. screening projects were unaware of their HBV infection.6–10
To prevent transmission of HBV, previous guidelines have recommended hepatitis B surface antigen (HBsAg) testing for hemodialysis patients, pregnant women, and persons known to have been or suspected of having been exposed to HBV (i.e., infants born to HBV-infected mothers, household contacts and sex partners of infected persons, and persons with known occupational or other exposures to infectious blood or body fluids).11,12 Testing for HBsAg is also required for donors of blood, organs, and tissues.13 To guide immunization efforts and identify infected persons, testing has also been previously recommended for certain high-prevalence populations, including foreign-born persons from countries of high rates of endemic HBV.4,14 Finally, testing has been recommended for human immunodeficiency virus (HIV)-positive persons on the basis of their high prevalence of HBV co-infection and their increased risk for HBV-associated morbidity and mortality.15 The Centers for Disease Control and Prevention (CDC) recommends expanding HBV testing to include all foreign-born persons from regions with HBsAg prevalence of 2% or more (high and intermediate endemicity) and recommends HBsAg testing, in addition to vaccination, for men who have sex with men and injection-drug users on the basis of their higher-than-population prevalence of and their ongoing risk for infection with HBV (see table).
Because persons with chronic HBV infection serve as the reservoir for new HBV infections in the United States, identification of these persons, with prevention of secondary cases, is an essential complement to a successful vaccination program. With the availability of effective treatments for chronic hepatitis B, the infected person, once identified, can benefit from testing as well.
Persons who are most likely to be actively infected with HBV in the United States should be tested for chronic HBV infection using a serologic assay for HBsAg, and testing should be accompanied by appropriate counseling and referral for appropriate clinical evaluation and care. Recommendations for management of persons tested for chronic HBV infection are included in updated CDC recommendations (including laboratory reporting of HBsAg-positive persons to local health authorities, see http://www.cdc.gov/epo/dphsi/casedef/hepatitisbcurrent.htm), contact management, patient education, medical management, development of surveillance registries, and program implementation.
Table. Populations Recommended or Required To Have Routine Testing for Chronic Hepatitis B Virus Infection
| Population | Population-specific considerations | Source |
|---|---|---|
| Persons born in regions of high- and intermediate-level hepatitis B virus (HBV) endemicity (hepatitis B surface antigen [HBsAg] prevalence >2%) |
|
|
| Persons born in the United States, not vaccinated as infants, whose parents were born in regions with high HBV endemicity |
|
New recommendation |
| Injection-drug users (IDUs) |
|
New recommendation |
| Men who have sex with men (MSM) |
|
New recommendation |
| Persons needing immunosuppressive therapy, including chemotherapy, immunosuppression related to organ transplantation, and immunosuppression for rheumatologic or gastroenterologic disorders |
|
New recommendation |
| Persons with elevated alanine aminotransferase (ALT)/aspartate aminotransferase (AST) of unknown etiology |
|
New recommendation |
| Donors of blood, plasma, organs, tissues, or semen |
|
Code of Federal Regulations. Title 21. Food and Drugs. Part 610.40 |
| Hemodialysis patients |
|
MMWR 2001;50(RR-5) |
| All pregnant women |
|
MMWR 2005;54(RR-16) |
| Infants born to HBsAg-positive mothers |
|
MMWR 2005;54(RR-16); MMWR 2007;56(41): Q1–Q4 |
| Household, needle-sharing, or sexual contacts with persons known to be HBsAg positive |
|
MMWR 2005;54(RR-16) |
| Persons who are the sources of blood or body fluids for exposures that might require postexposure prophylaxis (e.g., needlestick, sexual assault) |
|
MMWR 2001;50(RR-11): 17–20 |
| HIV-positive persons |
|
MMWR 2004;53(RR-15) |
The natural history of chronic hepatitis B virus (HBV) infection in individuals is complex, and infected persons can go through several clinical phases of the disease. Although many studies pertaining to the natural history of HBV have been published, the quality of these studies differs greatly. Therefore, a scoring system was developed to rank the evidence presented in individual studies (see table 1). The highest scores are given to population-based prospective cohort studies with or without HBV-free controls, the next highest score to case-control studies, and the lowest score to case series reports.
The two major adverse outcomes in chronic HBV infection include liver inflammation and fibrosis that can lead to cirrhosis and hepatic decompensation and hepatocellular carcinoma (HCC).1,2 Risk factors for HCC include older age (1A), male gender (1B), family history of HCC (2C), presence of cirrhosis (1A, 2A) and hepatitis C (HCV) co-infection (2C).3 One population-based study found the incidence to be 0.5% per 1,000 person years (1B).2 In clinic-based longitudinal studies, the overall incidence of cirrhosis is 2%–3% per year (2A).4,5 Risk factors for developing cirrhosis include older age, presence of hepatitis B e antigen (HBeAg), and elevated alanine aminotransferase (ALT) levels (2A). The survival rate for untreated persons with compensated cirrhosis is 84% and 68% at 5 and 10 years, respectively, but the survival rate is only 14% at 5 years among persons who present with decompensated cirrhosis (2A).
Three phases of chronic HBV infection have been observed.6 In the immune tolerant phase, persons infected with HBV are HBeAg-positive, have high levels of HBV deoxyribonucleic acid (DNA) (>20,000 international units per milliliter [IU/mL]), normal ALT levels, and no or minimal liver inflammation and fibrosis is seen with biopsy. Those in the immune active phase can be either HBeAg-positive or -negative, have elevated ALT levels, have active liver inflammation with or without fibrosis, and have HBV DNA levels above 20,000 IU/mL in persons with HBeAg and above 2,000 IU/mL in those who are HBeAg-negative. Those in the inactive hepatitis B phase are anti-HBeAg-positive, have normal ALT, and have no or minimal disease seen in liver biopsy. HBV-infected patients initially are HBeAg-positive, both in the immune tolerant phase, if infected at birth, or in the immune active phase if infected later in life. Seroconversion from HBeAg to positivity for antibodies to the hepatitis B e antigen (anti-HBe) occurs in about 8%–12% of patients per year (1B, 2A). Unfortunately, the natural history of HBV is not linear. After HBeAg seroconversion, persons can go into and remain in the inactive disease phase, revert back to HBeAg-positive status, or develop anti-HBe-positive chronic hepatitis (1B, 2A). About 0.5% of infected persons per year clear hepatitis B surface antigen (HBsAg), primarily those who are older and in the inactive HBV phase (1B, 2B).2 This has been referred to as the “recovered HBV phase”; however, some patients still develop HCC after HBsAg clearance occurs (1B, 2B).2
Studies have found several factors associated with risk of developing liver fibrosis, cirrhosis, or HCC (see table 2). These include older age (1A), male sex (1A), alcohol use (2C), and exposure to aflatoxin. One of the important viral factors associated with disease progression in this chronic infection is HBV genotype and subgenotype. Of the eight genotypes identified, the strongest evidence of risk of HCC occurs with infection from genotypes A1, C, and F1 and risk of cirrhosis with genotype C.7,8 Genotypes Ba, A2, and D are associated with cirrhosis and HCC in older persons who are infected, and HBV genotype B6 may have the least association with adverse outcome. Certain viral mutations, especially in basal core promoter and pre-core regions have been associated with higher risk of HCC and cirrhosis.9 Co-infection with human immunodeficiency virus (HIV) results in higher levels of HBV DNA and may be associated with greater disease progression. HCV/HBV co-infection is associated with a greater risk of HCC and hepatitis D virus (HDV) co-infection with cirrhosis.10
Well-designed population-based prospective cohort studies have shown that HBV DNA above 2,000 IU/mL in persons above the average age of 40 years is a risk factor for subsequent development of both HCC and cirrhosis (1B).11,12 However, one smaller 5-year prospective study of persons, average age 30, in the immune-tolerant stage did not show evidence of any disease progression. and prospective studies of persons in the inactive phase have not shown liver disease progression or risk of HCC over time (1B).13
To fill in the missing gaps in the natural history of HBV, well-designed population-based and nested case-control studies are needed. Specific areas for investigation include (1) prospective cohort studies examining the prevalence and incidence of immune active hepatitis in persons who are anti-HBe-positive; (2) prospective cohort studies to identify risk factors for the development of liver inflammation/fibrosis and HCC in persons who are anti-HBe positive, examining such factors as HBV genotype/subgenotype, specific HBV mutations such as in the basal core promoter region, HBV DNA levels, and the rate of quasi-species evolution; (3) prospective studies of persons in the immune-tolerant phase, starting in childhood to determine factors associated with HBeAg seroconversion, such as genotype, rate of fall in HBV DNA levels, and HBsAg titers and disease outcome; (4) nested case-control studies of population-based cohorts to examine full genome sequences to identify unique patterns of viral mutation associated with active liver disease or HCC in comparison with inactive HBV infection; (5) immunology cross-sectional studies employing case-control cohorts from population-based studies to determine the characteristics of cellular immunity in persons in the three phases of HBV infection; (6) prospective studies of cellular immunity as chronically infected patients go through the three stages of HBV; (7) prospective evaluation of risk factors for non-alcoholic fatty liver disease on progression of liver inflammation and fibrosis in chronic HBV infection; and (8) prospective studies evaluating markers for inflammation and fibrosis versus liver biopsy in HBV infection.
Table 1. Proposed Scoring System for Evidenced-Based Studies on the Natural History of Chronic Hepatitis B Virus Infection
|
|
|
Table 2. Factors Associated with the Increased Risk of Progression of Liver Disease and Risk of Hepatocellular Carcinoma and Cirrhosis in Persons with Chronic Hepatitis B Virus Infection
|
|
|
Hepatocellular carcinoma (HCC) is one of the most common solid malignancies worldwide. It represents a major cause of cancer death in Asia and southern Africa and is rising in incidence in the developed western world. 1 HCC is usually related to the presence of underlying liver disease, and the most common causes are chronic hepatitis B virus (HBV) infection, chronic hepatitis C, and cirrhosis due to a variety of other causes. A large proportion of HCCs worldwide can be attributed to HBV infection.
Several lines of evidence have been described that link HBV infection and HCC (see table).2 In regions with a high incidence of HCC, as many as 70%–80% of patients are actively infected with HBV, evidenced by seropositivity for hepatitis B surface antigen (HBsAg). Second, among patients known to have chronic HBV infection and followed up over a prolonged period of time, the relative risk for developing HCC is more than 60 times higher than among non-HBV-infected controls. Finally, it has been well demonstrated now that introduction of a universal infant vaccination program against HBV in Taiwan in the early 1980s has resulted in a measurable and significantly lower incidence of childhood HCC, most of which would be related to HBV infection.
Table. Evidence Linking HBV Infection and HCC
|
HBV deoxyribonucleic acid (DNA) is integrated into cellular DNA in approximately 90% of HBV-related hepatocellular carcinomas.2 The sites of chromosomal insertion appear to be random, and whether viral integration is essential for hepatocarcinogenesis is still uncertain. The virus appears to be both directly and indirectly carcinogenic. Possible direct carcinogenic effects include cis-activation of cellular genes as a result of viral integration, changes in the DNA sequences flanking the integrated viral DNA, transcriptional activation of remote cellular genes by HBV-encoded proteins (particularly the X protein), and effects resulting from viral mutations. The transcriptional activity of the HBV X protein may be mediated by interaction with specific transcription factors, activation of the mitogen-activated protein (MAP) kinase and Janus kinase–signal transducer and activator of transcription (JAK/STAT) pathways, an effect on apoptosis, and modulation of DNA repair.
Recent studies have shown a clear link between the amount of HBV replication (measured as serum viral load) and subsequent risk of HCC, suggesting that HBV may also be directly carcinogenic. Thus, the long-term risk of HCC increases markedly in patients with serum HBV DNA levels greater than 104 copies per milliliter.3
As described above, universal infant vaccination has been shown to be effective in reducing the rate of HCC and should be adopted by all countries, particularly those where HBV and HCC are endemic. The gains noted in avoiding childhood HCC are expected to become even more readily apparent as the cohort of vaccinated children grows into adulthood.4 For those patients already chronically infected with HBV, there has been considerable interest in decreasing their risk of HCC with antiviral treatments. Interferon-based therapies have not been shown to have this effect. However, prolonged treatment with small molecule antiviral agents holds more promise. Thus, a randomized controlled trial of lamivudine in patients with chronic hepatitis B and relatively advanced liver disease showed a statistically significant decrease in the occurrence of liver disease progression, mostly in terms of hepatic decompensation, although there was a numerical decrease in HCC rates too.5
The pathology of hepatitis B is diverse and reflects the clinical course of the disease. After acute infection, most subjects clear the virus, but others develop chronic hepatitis B. The natural history of chronic hepatitis B is divided into immune tolerant, immune reactive, and inactive hepatitis B virus (HBV) carrier phases. Histologically, acute hepatitis B is characterized by lobular disarray, ballooning degeneration, numerous apoptotic bodies, Kupffer cell activation, and lymphocyte-predominant lobular and portal inflammation. Significant lobular necrosis leads to fulminant hepatic failure. Although patients with acute hepatitis B usually do not have biopsies, a similar pattern of injury may also be seen in patients with chronic hepatitis B with acute disease flares, superinfection with hepatitis D, or a second hepatic insult (such as by drugs). In addition, the virus may develop a precore mutation, leading to a hepatitis B e antigen (HBeAg)-negative chronic and often relapsing hepatitis. In chronic hepatitis B infection, the pattern of injury is characterized predominantly by lymphocytic portal inflammation with interface hepatitis, associated with spotty lobular inflammation and portal-based fibrosis, similar to the pattern of injury in other causes of chronic hepatitis. Inflammation is minimal in the immune tolerant and inactive carrier phases, but inflammation is prominent in the immune reactive phase. Unlike chronic hepatitis C, chronic hepatitis B is usually not associated with lymphoid aggregates, duct (Poulsen) lesions, or steatosis. Ground glass hepatocytes may be seen and immunostains—hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg)—aid in identifying the etiology. The inflammatory infiltrates of chronic hepatitis B and hepatitis C have similar cellular composition, with the majority of cells being T cells (with CD4-(+) T cells predominating over CD8-(+) T cells). Although expression of HBcAg is associated with greater histologic activity; inflammatory activity does not correlate with the intensity of HBsAg expression.1
Numerous grading systems are available for assessing the severity of necroinflammation. The Knodell and Ishak systems are commonly used in clinical trial situations. Histological responses in most trials have been defined as a two-point decrease in the inflammation scores of these systems without worsening of fibrosis between pretreatment and posttreatment biopsies. The clinical significance of this improvement, however, has not been shown. Scoring is probably best restricted to clinical trials and is not advisable for use in routine clinical practice. Simpler systems such as the Metavir and Batts-Ludwig systems may be more useful in daily clinical practice and have also been used in clinical trials to monitor response.
Although noninvasive methods are currently available to assess fibrosis, histology is still the best method for stratification of fibrosis stage. Patients with cirrhosis are at greater risk of flare-related hepatic decompensation. Sampling errors can underestimate fibrosis;2 therefore, a biopsy with 11 complete portal tracts is suggested as adequate for staging.3 Cirrhotic livers are at greater risk for development of hepatocellular carcinoma (HCC); however, unlike in chronic hepatitis C, chronic hepatitis B patients can develop HCC in the absence of cirrhosis.
It should be remembered that liver fibrogenesis is an active, dynamic processes that may regress as well as progress. Reversal is a slow process and may take years. It may only occur if the patient becomes immune tolerant or if the virus is eliminated. Some authors suggest that histologic classification of the severity of cirrhosis could identify features to predict the potential for its reversal.4
The purposes of a liver biopsy are to grade and stage liver disease, identify precursor lesions of HCC (i.e., dysplasia and small cell change), and identify confounding diseases such as steatohepatitis, autoimmune hepatitis, and drug-induced liver disease. The 2006 American Association for the Study of Liver Diseases (AASLD) guidelines recommend biopsies only in specific groups of patients, based on age, HBeAg status, and HBV deoxyribonucleic acid (DNA) and alanine aminotransferase (ALT) levels.5 The guidelines state that liver biopsy usually is not necessary in young patients (below 30 years of age) who are HBeAg-positive and have persistently normal ALT. However, more recent studies have shown that HBV-infected patients with near-normal ALT may have abnormal histology, can be at increased risk of mortality, and may be candidates for therapy.6–8 Also, no consistent relationship exists between HBV DNA levels and histology, both in HBeAg-positive and -negative subjects.9,10 Although many studies suggest that certain genotypes (especially genotypes C and D) are associated with worse histology and a greater chance of progression to carcinoma, these studies are hampered by the fact that genotypes have different ethnic, geographic, and epidemiologic associations.11,12 Large, multicenter studies are needed to resolve these issues.
Biopsies also play an important role in monitoring a liver allograft, where the histopathology of recurrrent hepatitis B is similar to that seen in native livers.13 The expression pattern of HBsAg and HBcAg immunostains may be helpful in determining whether the liver injury is mainly from HBV or from other coexisting causes. Fibrosing cholestatic hepatitis is an atypical pattern of recurrent hepatitis B that occurs in a small number of patients. It is characterized by severe parenchymal damage, extensive periportal sinusoidal fibrosis, and a generally mild inflammatory reaction. Patients with this condition present with a rapidly progressive severe cholestatic syndrome, which may clinically resemble acute or chronic rejection.
Chronic hepatitis B is a liver disease caused by persistent inflammation of the liver as a result of chronic infection with the hepatitis B virus (HBV). The persistence of insult to the liver leads to transformational changes in the function of hepatic stellate cells, which in turn promote the development of liver fibrosis, eventually ending up in cirrhosis.1 The process of hepatic fibrogenesis is a dynamic one, and removal of the insult (viral and nonviral) may lead to reversal of fibrosis.1–3 In chronic hepatitis B, presence of circulating virus is a marker of active infection and signifies persistent insult to the liver. The importance of serum HBV deoxyribonucleic acid (DNA) level as a predictor of the development of cirrhosis and hepatocellular carcinoma (HCC) has been extensively reviewed recently.4 Hospital-based and community-based case-control and cohort studies consistently found significant associations between elevated HBV DNA level and risk of liver cirrhosis and HCC. However, most of the studies were limited by small number of cases and controls, inadequate matching or adjustment of confounding factors, and lack of causal temporality.
The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV study (REVEAL-HBV study) evaluated the relationship between HBV viral load across a gradient and disease progression to liver cirrhosis, HCC, and death in a Taiwanese population.5–7 It was a population-based prospective cohort study of 4,155 hepatitis B surface antigen (HBsAg)-seropositive participants, untreated with any chronic hepatitis B-specific antiviral therapy, with an average follow-up of 11.4 years. Study participants were enrolled from 1991 to 1992 and followed through June 30, 2004 for newly developed cirrhosis and HCC and through December 31, 2004 for deaths. Serum samples were collected and frozen at study entry and during follow-up for future analyses of HBV DNA. In the analyses of the relationship between HBV viral load and chronic hepatitis B outcomes, only subjects with serum samples sufficient for HBV quantification at baseline and who tested antibody negative for the hepatitis C virus (HCV) by immunoassay technique were included (n = 3,653).
Several factors were significantly associated with the baseline HBV DNA level. Elevated HBV DNA levels were found to be associated with hepatitis B e antigen (HBeAg) seropositivity, male gender, younger age, elevated alanine aminotransferase (ALT) level, liver cirrhosis status, and HBV genotype B.
The incidence of liver cirrhosis (per 100,000 person years) increased with baseline HBV DNA level (copies/mL) ranging from 339 (<300), 430 (300–9.9 x 103), 774 (1.0–9.9999 x 104), 1,879 (1.0–9.99999 x 105) to 2,498 (≥1 x 106). The biological gradient remained significant in stratified analyses across a variety of baseline characteristics such as gender (Male:Female), age (≤50:>50), alcohol consumption (No:Yes), and cigarette smoking (No:Yes). In multivariable Cox regression analyses of risk factors predicting progression to liver cirrhosis, increasing HBV DNA category was the strongest independent predictor.
The HCC incidence (per 100,000 person years) increased with baseline HBV DNA level (copies/mL) ranging from 108 (<300), 111 (300–9.9 x103), 297 (1.0–9.9999 x 104), 962 (1.0–9.99999 x 105) to 1,152 (≥1 x 106). In multivariable Cox regression analyses of risk factors predicting progression to HCC, increasing HBV DNA category was the strongest independent predictor of HCC risk after liver cirrhosis. In subset analyses, the REVEAL-HBV study tested the relationship between persistent elevation of viral load over time and risk of HCC.
The mortality (per 100,000 person years) increased with baseline HBV DNA level (copies/mL) ranging from 9 (<300), 48 (300–9.9 x 103), 75 (1.0–9.9999 x 104), 143 (1.0–9.99999 x 105) to 267 (≥1 x 106) for chronic liver disease and cirrhosis; and 73, 48, 174, 692, 816, respectively, for liver cancer. In multivariable Cox regression analyses of risk factors predicting progression to mortality, increasing HBV DNA level was the strongest independent predictor of death from chronic liver diseases and cirrhosis, was second to liver cirrhosis in predicting death from HCC, and had no relationship with non-liver-related causes of mortality.
All serial serum samples collected from entry to last follow-up were tested for HBV DNA levels to examine their predictability for HCC development, using time-dependent Cox regression analyses, as reported at a recent conference.8 The follow-up serums were tested only for 1,564 participants with baseline HBV DNA ≥1 x 104 copies/mL, resulting in 7,644 individual HBV DNA timepoints. In multivariable time-dependent Cox regression analyses of risk factors predicting progression to HCC, increasing HBV DNA level was the strongest independent predictor of HCC. Serum ALT levels at baseline and follow-up were also independent predictors of HCC. Considering baseline and follow-up HBV DNA and ALT levels as separate variables in the model, all were independent predictors of HCC risk.
In a recent publication, the independent effect of HBV viral load on HCC was assessed after adjustment for HBV genotype and mutants.9 The HBV genotype was tested only for participants with detectable baseline HBV DNA levels (n = 2,762), and HBV mutants were tested only for participants with baseline HBV DNA levels ≥1 x 104 copies/mL. Genotype C HBV infection was associated with a higher risk of HCC than was genotype B HBV infection. The G1896A mutation in the pre-core region had a lower risk of HCC compared to the wild type virus; while the double mutation (A1767T/G1764A) in the basal core promoter region was associated with a higher risk than the wild type. Elevated HBV DNA levels remained a significant HCC risk predictor after adjustment for HBV genotype and mutants.
The REVEAL-HBV study demonstrated that elevated serum level of HBV DNA is a major risk factor for disease progression and adverse outcomes in chronic hepatitis B after adjustment for other HCC risk predictors. REVEAL-HBV participants were selected from a population of people who were most likely infected with HBV of genotypes B and C in early life but were recruited into this study after age of 30 years. Therefore, the REVEAL-HBV study findings may not necessarily be reflective of other populations of chronic hepatitis B patients. However, the association between serum HBV DNA level and adverse outcomes in chronic hepatitis B has been demonstrated in other studies, corroborating the findings presented here.10-13 Additionally, serum HBV DNA level has been associated with differences in survival14 and postsurgical recurrence of disease15 in patients with chronic hepatitis B-related HCC. Because HBV DNA level is dynamic and changes over time, the risk of disease progression associated with viral load will also be dynamic. As shown by these data, the persistence of high viral load over time is associated with the highest risk of HCC.