|Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses
|Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DK, Pham B, Ungar WJ, Einarson TR, Heathcote EJ, Krahn M
The authors concluded that over a one year period, tenofovir and entecavir were the most potent oral antiviral agents for HBeAg-positive chronic hepatitis B patients and tenofovir for HBeAg-negative patients. Potential for language bias, uncertain study quality, a small number of studies available for comparisons and limitations inherent with network analysis mean the authors’ conclusions should be interpreted with caution.
To assess the relative treatment efficacies of drugs used to treat chronic hepatitis B as monotherapies or combination therapies at the end of one year of treatment and to rank the treatments according to the success rates for each outcome.
MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Web of Science databases were searched from inception to October 2009 for studies in English; search terms were reported. Reference lists were examined for further studies. Clinical experts were consulted to assess whether any published studies were missing.
Randomised controlled trials (RCTs) that compared new drug treatments with either placebo or already licensed drugs in treatment-naive adults with HBeAg-positive and/or HBeAg-negative chronic hepatitis B for a one-year period were eligible. Trials that used standard interferon therapy were excluded, as were those of patients who were resistant to lamivudine or where patients were co-infected with human immunodeficiency virus, hepatitis C or D or where efficacy measures were not reported.
Treatments evaluated were lamivudine, pegylated interferon, adefovir, entecavir, telbivudine, tenofovir and placebo; these were delivered as either monotherapy or combination therapy over a one-year period (defined as 48 to 52 weeks). Outcomes included rates of virologic and biochemical response (defined as normalisation of alanine aminotransferase levels to below the upper limit of normal for that study), HBeAg seroconversion (defined as undetectable HBeAg and presence of anti-HBeAg), HBeAg and HBsAg loss (defined as undetectable using the threshold of detection used in each corresponding study), histologic improvement (defined as a two-point improvement on the Knodell inflammation score without an increase in fibrosis) and serious adverse events (events that required withdrawal from treatment or reduction in treatment dosage).
Two reviewers carried out the study selection. Disagreements were resolved by a third reviewer.
Assessment of study quality
Two reviewers independently assessed study quality using the Cochrane risk of bias tool based on assessment of sequence generation, allocation concealment, blinding, reporting of data and other sources of bias. Discrepancies were resolved through consultation with a third reviewer.
Two reviewers independently extracted outcome measurements at intermediate end points (12 months). For studies that did not include a complete list of all surrogate outcomes, only outcomes that were available were included in the analysis. Discrepancies were resolved through consultation with a third reviewer.
Methods of synthesis
Bayesian mixed treatment comparisons where lamivudine was used as the common comparator were used to calculate the odds ratios (OR), including 95% credible intervals (95% CrI) and predicted probabilities (PP) of surrogate outcomes to determine the relative effects of each treatment. A Bayesian random-effects meta-analysis of pairs compared directly in trials was run with the median of the posterior probability distribution and 95% credible interval (CrI) for each odds ratio. Treatments were then ranked for each of the surrogate outcomes on the basis of their predicted probabilities; heterogeneity for each surrogate outcome was assessed through between-study standard deviation (SD) in log-odds ratios (SD (log OR) 0.1 to 0.5 was reasonable heterogeneity, SD (log OR) 0.5 to 1.0 was fairly high heterogeneity and SD (log OR) >1.0 was extreme heterogeneity). Separate analyses were conducted for HBeAg-negative and HBeAg-positive patients.
Results of the review
Twenty RCTs were included in the review: 15 in HBeAg-positive patients (5,296 participants), eight in HBeAg-negative patients (3,328 participants) and three that evaluated both HBeAg-positive and HBeAg-negative patients. Twelve trials described double-blinding fully and two trials described it partially. Four trials were open-label studies. Two trials did not report blinding. Use of adequate methods for sequence generation was unclear in 16 studies; one study used inadequate methods.
HBeAg-positive patients: Tenofovir (one trial) was most effective in inducing undetectable levels of HBV DNA (PP 88%, 95% CrI 69% to 97%), normalization of alanine aminotransferase levels (PP 66%, 95% CrI 41% to 91%), HBeAg seroconversion (PP 20%, 95% CrI 7% to 43%) and hepatitis B surface antigen loss (PP 5%, 95% CrI 0% to 54%). Entecavir (three studies) was most effective in improving liver histology (PP 56%, 95% CrI 12% to 94%). Lamivudine plus pegylated interferon was most effective in inducing HBeAg loss (PP 39%, 95% CrI 18% to 63%). Heterogeneity was reasonable (SD (log OR) <0.5) for all outcomes except for hepatitis B surface antigen loss where it was fairly high (SD (log OR)=0.58).
HBeAg-negative patients: Tenofovir (one trial) was the most effective in inducing undetectable levels of HBV DNA (PP 94%, 95% CrI 56% to 100%) and improving liver histology (PP 65%, 95% CrI 1% to 100%). Telbivudine (two trials) was most effective for normalization of alanine aminotransferase levels (PP 82%, 95% CrI 47% to 99%). Heterogeneity was reasonable (SD<0.5) for all outcomes except for normalization of alanine aminotransferase levels where it was fairly high (SD (log OR)=0.83).
In the first year of treatment for chronic hepatitis B, tenofovir and entecavir were the most potent oral antiviral agents for HBeAg-positive patients and tenofovir was most effective for HBeAg-negative patients.
The review question and supporting inclusion criteria were clearly defined. The search strategy included several databases. There was no specific attempt to locate unpublished material, so relevant studies may have been missed. The review was restricted to studies in English, so language bias could not be ruled out; the authors acknowledged that a number of chronic hepatitis B studies had been conducted and published in languages other than English. Limited study details were reported. Each stage of the review process was undertaken in duplicate, which minimised potential for reviewer error and bias. The authors assessed the quality of the trials using appropriate criteria with and reported the results in full. The methods of synthesis seemed appropriate. Sources of heterogeneity in the meta-analyses were investigated. As noted by the authors, the synthesis was limited by the small number of studies for each comparison.
This was generally a well-conducted review, but potential for language bias, some uncertainties surrounding study quality, the small number of studies available to inform many of the comparisons and limitations inherent with network analysis mean the authors’ conclusions should be interpreted with caution.
Implications of the review for practice and research
Practice: The authors stated that entecavir and tenofovir were the most effective treatments for patients with HBeAg-positive chronic hepatitis B. Tenofovir was the most effective treatment for HBeAg-negative patients. Because of potentially lengthy treatment durations, the potential benefits of antiviral therapy on liver-related morbidity and mortality must be weighed carefully against the possibility of future drug resistance, high lifetime costs and adverse effects.
Research: The authors did not state any recommendations for further research.
Woo G, Tomlinson G, Nishikawa Y, Kowgier M, Sherman M, Wong DK, Pham B, Ungar WJ, Einarson TR, Heathcote EJ, Krahn M. Tenofovir and entecavir are the most effective antiviral agents for chronic hepatitis B: a systematic review and Bayesian meta-analyses. Gastroenterology 2010; 139(4): 1218-1229.e5
Subject indexing assigned by NLM
Adenine /analogs & Antiviral Agents /administration & Drug Therapy, Combination; Guanine /analogs & Hepatitis B e Antigens /analysis; Hepatitis B, Chronic /drug therapy; Humans; Lamivudine /therapeutic use; Organophosphonates /therapeutic use; derivatives /therapeutic use; derivatives /therapeutic use; dosage /adverse effects /therapeutic use
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.