Objectives: Synthesize evidence of the natural history of chronic hepatitis B (CHB) and effects and harms of antiviral drugs on clinical, virological, histological, and biochemical outcomes.
Data Sources: MEDLINE®, electronic databases, and manual searches of systematic reviews.
Review Methods: We included original observational studies to assess natural history and randomized controlled trials (RCTs) of adults with CHB published in English to assess treatment effects and harms if they reported mortality, incidence of hepato-cellular carcinoma (HCC), cirrhosis or failure, HBeAg or HBsAg, viral load (HBV DNA), alanine aminotransferase (ALT) levels, histological necroinflammatory and fibrosis scores, and adverse events after interferon alfa-2b, pegylated interferon alfa 2-a, lamivudine, adefovir, entecavir, tenovir or telbivudine. We excluded pregnant women, transplant patients, and individuals undergoing cancer chemotherapy. We calculated relative risk or absolute risk differences at end of treatment and post-treatment.
Results: Observational studies (41 publications) suggested that male gender, coinfection with hepatitis C, D, or HIV, increased HBV DNA, and cirrhosis were associated with increased risk of HCC and death. Drugs did not reduce death, liver failure, or HCC in 16 RCTs not designed to test long-term clinical outcomes. Evidence from 93 publications of 60 RCTs suggested drug effects on viral load or replication, liver enzymes, and histology at end of treatment and lasting from <3 to >6 months off treatment. No one treatment improved all outcomes and there was limited evidence on comparative effects.
Two RCTs suggested interferon alfa-2b increased CHB solution versus placebo. Interferon alfa-2b or lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization. Adefovir improved off treatment ALT normalization and HBV DNA clearance. Pegylated interferon alfa 2-a versus lamivudine improved off-treatment HBV DNA and HBeAg clearance and seroconversion, ALT normalization and liver histology. Lamivudine combined with interferon alfa-2b versus lamivudine improved off treatment HBV DNA clearance and HBeAg seroconversion and reduced HBV DNA mutations. Pegylated interferon alfa 2-a plus lamivudine improved off treatment HBV DNA and HBeAg clearance and seroconversion and ALT normalization compared to lamivudine but not pegylated interferon alfa 2-a monotherapy. Adverse events were common but generally mild and did not result in increased treatment discontinuation.
Longer hepatitis duration, male gender, baseline viral load and genotype, HBeAg, and histological status may modify treatment effect on intermediate outcomes. Adefovir and pegylated interferon alfa 2-a with lamivudine improved off treatment viral clearance in HBeAg negative patients. There was insufficient evidence to determine if biochemical, viral, or histological measures are valid surrogates of treatment effect on mortality, liver failure, or cancer.
Conclusion: Adults with CHB have an increased risk of death, hepatic decompensation, and HCC. Mono or combined drug therapy improves selected virological, biochemical, and histological markers with no consistent effects on all examined outcomes. Patient and disease characteristics may modify treatment-induced intermediate outcomes. Evidence was insufficient to assess treatment effect on clinical outcomes, predict individualized patient response, or determine if intermediate measures are reliable surrogates. Future research should assess long-term drug effects on clinical outcomes and among patient subpopulations.
Management of Chronic Hepatitis B
Evidence-based Practice Center: Minnesota Evidence-based Practice Center, Minneapolis, Minnesota
Topic Nominator: National Institutes of Health (NIH) Office of Medical Applications of Research (OMAR)