Introduction

Authors

  • Edward C. Doo,

    Corresponding author
    1. Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institutes of Health, Bethesda, MD
    • Liver Disease Research Program, Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, NIDDK, National Institutes of Health, Two Democracy Plaza, Room 651, MSC 5450, 6707 Democracy Boulevard, Bethesda, MD 20892-5450
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    • fax: 301-480-8300

  • Jay H. Hoofnagle,

    1. Liver Diseases Research Branch, Division of Digestive Diseases and Nutrition, National Institutes of Health, Bethesda, MD
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  • Griffin P. Rodgers

    1. Office of the Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD
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  • Potential conflict of interest: Nothing to report.

The National Institutes of Health (NIH) Consensus Development Conference on the Management of Hepatitis B was held on October 20-22, 2008. The conference was the result of many years of discussions, research planning and workshops,1–3 and 2 years of active planning. The final Consensus Panel statement and summaries of the presentations at the Conference appear in this special supplement to HEPATOLOGY. This important topic and critical conference fully warrant the efforts made in converting this meeting to a lasting, printed form.

Abbreviations

HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases; NIH, National Institutes of Health.

Disease topics chosen for NIH Consensus Development Conferences must fulfill fixed criteria: they should be important, reasonably common, and surrounded by controversies or uncertainties that might be addressed by an independent, unbiased review of the medical evidence. In all these regards, hepatitis B is now an appropriate topic for a Consensus Development Conference. The hepatitis B virus (HBV) is one of the most common serious infections of humans. Chronic infection with HBV is estimated to affect 5% of the world population and is a major cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (HCC). In the United States, hepatitis B affects only 0.5%-1.5% of the general population, but is several-fold more common in certain population groups such as immigrants from countries (primarily in Asia and Africa) where hepatitis B is a frequent childhood infection. Hepatitis B also warrants the focus of a Consensus Conference because of the current uncertainties and controversies that surround its management and treatment. The Consensus Development Conference mechanism, by focusing on the scientific and medical evidence for our understanding of the natural history and treatment of hepatitis B, can provide an unbiased answer to areas of controversy that can be broadly accepted.

The current controversies about hepatitis B come at the end of 50 years of active and productive research on HBV, which has resulted in remarkable advances in our understanding of this infection and in development of means of its prevention and control. The first era of modern hepatitis B research began with the landmark description of the Australia antigen by Blumberg and coworkers in 1965.4 Although initially thought to be an inherited polymorphic lipoprotein, the Australia antigen was subsequently shown to be part and parcel of the hepatitis B virus and a reliable marker for this infection. With the availability of a reliable marker, research on HBV entered a rapid phase of progress. In a short time, the structure of the virus was defined, Australia antigen was shown to be the envelope or surface antigen (HBsAg) of the virion, and two other antigen systems—hepatitis B core and “e” antigen—were described. Tests for HBsAg were developed that allowed for accurate diagnosis and routine screening of blood donations, resulting in a marked decrease in posttransfusion hepatitis B. Animal models followed by in vitro systems for studying HBV were developed. The viral genome was isolated and the unique replicative cycle (through an RNA intermediate) was elucidated. The genomic sequence of HBV was characterized, which allowed for the full elucidation of the virus structure and development of molecular tools for its analysis, prevention, and treatment. The first modern era of hepatitis B research concluded with the development of an HBV vaccine that was shown to be safe and highly effective, first in animal models and then in randomized controlled trials in humans. The first HBV vaccine was approved for use in the United States in 1981. Subsequent application of the vaccine, first to high-risk groups and later to all newborns, has resulted in an 80% decrease in cases of acute hepatitis B in the United States and a material decrease in the prevalence of chronic hepatitis B and HCC in areas of the world where this virus infection is common. This first, great era of HBV research led to the awarding of the 1976 Nobel Prize in Medicine to Dr. Baruch Blumberg. The development of a vaccine for hepatitis B has been one of the landmark medical achievements of the 20th Century.

The second modern era of hepatitis B research began with the realization that vaccination could not accomplish full control of this infection and its consequences. A high proportion of persons infected in childhood and a lower proportion of those infected as adults develop chronic HBV infection. The consequences of chronic infection included cirrhosis, end-stage liver disease, and HCC. Approaches to treatment of hepatitis B were first attempted in the late 1970s and early 1980s, and by 1991, the first therapeutic agent for hepatitis B, recombinant human alpha interferon, was licensed. In multiple controlled trials, alpha interferon was shown to result in remission of disease in approximately one-third of patients. The availability of interferon was an important first step toward effective means of treatment of hepatitis B, but it was far from satisfactory. Therapy was expensive, poorly tolerated, applicable to a limited number of patients, and effective in a minority. In addition, the long-term outcomes of the remissions induced by interferon were not well defined. Safer and better-tolerated agents were needed. In answer to these needs and partially as a consequence of the expansion of interest in antiviral agents triggered by the human immunodeficiency virus epidemic, agents for hepatitis B were also developed. In 1998, lamivudine, the first effective oral nucleoside analog for hepatitis B, was approved for use in the United States. This important first step was followed by development of other nucleoside analogs with different and/or more potent activities. At present, five nucleoside analogs and two forms of interferon are approved for use as therapy of hepatitis B, a remarkable achievement that is already showing an effect on the incident rates of end-stage liver disease related to hepatitis B.

The first era of hepatitis B research culminated in development of an HBV vaccine, the efficacy and usefulness of which was immediately and widely accepted. The second era of hepatitis B research has culminated in development of multiple agents to treat hepatitis B. Yet, in contrast to HBV vaccine, therapies for hepatitis B have not been immediately or widely accepted. Questions and controversies remain about their use: Which patients with hepatitis B should be treated? With which agent or agents? For how long? Using what markers to assess effectiveness? And, most importantly: Does therapy of hepatitis B alter its natural history and prevent its serious long-term outcomes? These controversies and questions were the focus of this Consensus Conference.

NIH Consensus Development Conferences are designed to bring together experts coupled with systematic reviews of the scientific literature in an unbiased, independent, and evidenced-based approach. The experts present data related to specific questions to a Consensus Panel consisting of independent, nongovernmental medical professionals, academicians, researchers, and at least one public representative. The Consensus Panel is charged with integrating the data from the systematic evidence review, the presentations by the experts, and the ensuing public discussions to generate a Panel Statement that attempts to answer specific questions based on the best medical evidence. The questions posed to the Consensus Panel are identified and prepared by a Conference Planning Committee and focus on the central controversies confronting clinicians and investigators. The six questions posed to this Panel were: What is the current burden of hepatitis B? What is its natural history? What are the benefits and risks of the current therapeutic options? Which persons should be treated? What measures are appropriate to monitor therapy and assess outcomes? What are the greatest needs and opportunities for future research on hepatitis B? Further information on the purpose, process, and design of Consensus Development Conferences can be found at: http://consensus.nih.gov/ABOUTCDP.htm.

In preparation of the Consensus Development Conference on Management of Hepatitis B, the Conference Planning Committee commissioned a formal systematic review of the literature on the medical evidence for effects of therapy on clinical outcomes of chronic hepatitis B. A formal request for proposals to conduct the systematic review was issued under the auspices of the Agency for Healthcare Research and Quality (AHRQ) and awarded to the Minnesota Evidence-based Practice Center. The principal investigator for this systematic evidence review was Dr. Timothy Wilt of the Division of Health Policy and Management of the University of Minnesota School of Public Health, Minneapolis, MN. The systematic review was conducted with supervision of an independent, expert technical panel and was used to advise the Consensus Panel in their deliberations and in preparation of the final statement. A summary of the systematic review on hepatitis B was recently published with the Consensus Panel Statement in the Annals of Internal Medicine.5, 6 In addition, the full technical report of the systematic review is available online at: www.ahrq.gov/downloads/pub/evidence/pdf/hepb/hepb.pdf.

Central to the development and success of this Consensus Conference were the efforts by the sponsors, including the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Office of Medical Applications of Research (OMAR) of the NIH Office of the Director; cosponsors, including the National Institute of Allergy and Infectious Diseases (NIAID) and the National Cancer Institute (NCI); and partners, including the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). Responsible for the organization and conduct of the Consensus Development Conference was the Office of Medical Applications of Research under the direction of Drs. Barnett Kramer, Susan Rossi, and Jennifer Croswell. The success of the Conference was the direct result of the quality of the presentations by the invited speakers and the presenters of the systematic evidence reviews. Ultimately, however, the lasting success of the Consensus Development Conference is dependent on the commitment and quality of the Consensus Panel members who spent many hours reviewing publications, presentations, reports, and reviews and integrating this information into the final Consensus Statement. Finally, very special thanks must be given to Dr. Michael Sorrell, the Consensus Panel's distinguished and efficient chairman.

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