Antiviral Therapy for Adults with Chronic Hepatitis B: A Systematic Review for a National Institutes of Health Consensus Development Conference

20 January 2009 | Volume 150 Issue 2

Background: Chronic hepatitis B infection can lead to liver failure, hepatocellular carcinoma, and death.

Purpose: To evaluate the effectiveness of antiviral therapy for adults with chronic hepatitis B infection.

Data Sources: Randomized, controlled trials (RCTs) of interferon (2b and pegylated 2a), lamivudine, adefovir, entecavir, and telbivudine published from 1990 to 2008.

Study Selection: Randomized, controlled clinical trials of adults with chronic hepatitis B published in English after 1989 that reported death; incidence of hepatocellular carcinoma or liver failure; prevalence and incidence of cirrhosis; presence or seroconversion of hepatitis B e antigen (HBeAg) or surface antigen (HBsAg), viral load of hepatitis B virus DNA; aspartate aminotransferase and alanine aminotransferase (ALT) levels; or fibrosis scores after therapy with interferon-2b, pegylated interferon-2a, lamivudine, adefovir, entecavir, and telbivudine.

Data Extraction: Data extracted with standard protocols to calculate risk difference for clinical outcomes, viral load, HBeAg and HBsAg, ALT, histologic scores, and adverse events.

Data Synthesis: In 16 RCTs (4431 patients), drug treatment did not improve clinical outcomes of chronic hepatitis B infection, but the trials were underpowered. In 60 RCTs that examined intermediate outcomes, no single treatment improved all intermediate outcomes. Low-quality evidence suggested HBsAg clearance after interferon-2b (2 RCTs; 211 patients). Moderate-quality evidence suggested ALT normalization at follow-up after treatment with adefovir (2 RCTs; 600 patients) and HBeAg loss with lamivudine (2 RCTs; 318 patients). With interferon-2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-2a combined with lamivudine versus lamivudine improved HBeAg loss (1 RCT; 543 patients) and ALT normalization (2 RCTs; 905 patients). Adverse events during antiretroviral therapy occurred in more than 50% of patients but were not associated with increased treatment discontinuation. However, most studies excluded patients with hepatic or renal insufficiency or other serious comorbid conditions.

Limitation: Marked heterogeneity in study samples, interventions, and measured outcomes preclude definitive conclusions.

Conclusion: Evidence was insufficient to assess treatment effect on clinical outcomes or determine whether inconsistent improvements in selected intermediate measures are reliable surrogates. Future research is needed to provide evidence-based recommendations about optimal antiviral therapy in adults with chronic hepatitis B infection.

Author and Article Information

From the Minnesota Evidence-based Practice Center, University of Minnesota School of Public Health, Minneapolis Veterans Affairs Center for Chronic Disease Outcomes Research, and the University of Minnesota Medical School, Minneapolis, Minnesota.

Disclaimer: The authors of this report are responsible for its content. Statements in the paper should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank the technical expert panel members Dr. Miriam Alter, Dr. Gary Davis, Dr. Daryl Lau, Dr. Michael Sorrell, and Dr. Myron Tong for their scientific and clinical input throughout this project; Shilpa Amin, MD, MBSC, AHRQ Task Order Officer, for her guidance throughout the project; and Dr. John Ward for reviewing and commenting on the draft. They also thank the librarians, Judith Stanke and Dr. Del Reed, for their contributions to the literature search; Maureen Carlyle and Marilyn Eells for their excellent technical assistance in preparation of the full evidence report and this manuscript; and Rebecca Schultz and Nancy Russell for her assistance with formatting the tables.

Grant Support: By the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services contract number 290-02-0009.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Tatyana A. Shamliyan, MD, MS, Division of Health Policy and Management, University of Minnesota School of Public Health, D351 Mayo (MMC 197), 420 Delaware Street SE, Minneapolis, MN 55455; e-mail, shaml005{at}umn.edu.

Current Author Addresses: Drs. Shamliyan and Kane: Division of Health Policy and Management, University of Minnesota School of Public Health, D351 Mayo (MMC 197), 420 Delaware Street SE, Minneapolis, MN.

Mr. MacDonald, Drs. Taylor and Wilt and Mr. Rutks: Center for Chronic Disease Outcomes Research, Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.

Dr. Shaukat: Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota Medical School, 420 Delaware Street SE (MMC 36), Minneapolis, MN 55455.

Dr. Yuan: Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Room 300, West Bank Office Building, 1300 South Second Street, Minneapolis, MN 55454.

Dr. Johnson: Department of Infectious Diseases, Minneapolis Veterans Affairs Medical Center (111-F), 1 Veterans Drive, Minneapolis, MN 55417.

Mr. Tacklind: Agency for Healthcare Research and Quality Center for Chronic Disease Outcomes Research and the Cochrane Prostatic Diseases and Urologic Cancers Group, Minneapolis Veterans Affairs Medical Center, 1 Veterans Drive, Minneapolis, MN 55417.

Author Contributions: Conception and design: T.A. Shamliyan, R.L. Kane, T.J. Wilt.

Analysis and interpretation of the data: T.A. Shamliyan, R. MacDonald, A. Shaukat, B.C. Taylor, J.R. Johnson, T.J. Wilt.

Drafting of the article: T.A. Shamliyan, R. MacDonald, A. Shaukat.

Critical revision of the article for important intellectual content: T.A. Shamliyan, A. Shaukat, B.C. Taylor, J.-M. Yuan, J.R. Johnson, R.L. Kane, T.J. Wilt.

Final approval of the article: T.A. Shamliyan, A. Shaukat, B.C. Taylor, J.-M. Yuan, J.R. Johnson, R.L. Kane, T.J. Wilt.

Provision of study materials or patients: I. Rutks.

Statistical expertise: R. MacDonald.

Obtaining of funding: R.L. Kane, T.J. Wilt.

Administrative, technical, or logistic support: R. MacDonald, J. Tacklind, I. Rutks, R.L. Kane, T.J. Wilt.

Collection and assembly of data: T.A. Shamliyan, R. MacDonald, A. Shaukat, J. Tacklind, I. Rutks.

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