Antiviral therapy for adults with chronic hepatitis B: A systematic review for a National Institutes of Health Consensus Development Conference

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 (α2b and pegylated α2a), 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-α2b, pegylated interferon-α2a, 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-α2b (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-α2b, moderate-quality evidence suggested HBeAg loss (3 RCTs; 351 patients), seroconversion (2 RCTs; 304 patients), and ALT normalization (2 RCTs; 131 patients). Pegylated interferon-α2a versus lamivudine improved HBeAg seroconversion (1 RCT; 814 patients) and ALT normalization (2 RCTs; 905 patients) off treatment. Pegylated interferon-α2a 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.