Comparing efficacies of treatments for chronic hepatitis B: A Bayesian mixed treatment comparison meta-analysis

Presenter: Gloria Woo, University of Toronto

Abstract

Rationale: Chronic hepatitis B (CHB) accounts for 50% of case of cirrhosis, liver failure and hepatocellular carcinoma worldwide. Many treatments are available; but, comparative efficacy evidence from direct, head-to-head, trials is not. We set out to estimate the relative effects of treatments for CHB in HBeAg positive patients, and to rank the treatments based on their efficacy.
Methods: The mixed treatment comparisons (MTC) method for meta-analysis of randomized controlled trial data was used to infer direct and indirect comparisons of CHB treatments. Data from 12 RCTs reporting dichotomous outcomes of undetectable HBV DNA, ALT normalization, HBeAg seroconversion, HBeAg loss and histologic improvement of the liver was collected. Nine CHB treatment strategies were included. The Bayesian random-effects MTC logistic regression model was implemented in the Bayesian software WinBUGS. The model was structured so that (A) Lamivudine (LAM) was considered the reference treatment; (B) pooled response rates of LAM were estimates across treatment arms, (C) direct effects derived, (D) indirect effects were estimated using data from (A-C) and the predicted probability of response of all treatments were estimated from (A, B and D). Assuming the relative efficacy was unknown; uninformative prior distributions for all efficacy parameters were used. Probability estimates of the clinical outcomes were then derived from the fitted MTC model. These were used in the final ranking.
Results: Tenofovir (TDF) monotherapy was estimated with the highest probability of undetectable HBV DNA, at 86% (95%CrI:59%-98%) among the nine competing treatments. Entecavir (ETV) monotherapy was estimated with the second highest probability at 58% (95%CrI:28%-85%) for undetectable HBV DNA. TDF monotherapy therapy was estimated with the highest probability for normalization of ALT, at 71% (95%CrI:27%-97%) followed by combination therapy with lamivudine and telbivudine (LAM+LdT) at 66% (95%CrI:23%-94%). Monotherapy with pegylated interferon (PEG) was estimated with the highest probability of HBeAg seroconversion, at 25% (95%CrI:14%-36%) followed closely by LAM+PEG combination therapy with an estimated probability of 24% (95%CrI:14%-39%). Monotherapy with TDF provided the highest probability of HBeAg loss, at 53% (95%CrI:7%-96%) followed by LAM+PEG at 33% (95%CrI:15%-56%). ETV monotherapy was estimated with the highest probability to improve liver histology at 56% (95%CrI:8%-93%) followed by PEG monotherapy at 50% (95%CrI:4%-93%).
Conclusion: Given the lack of direct evidence comparing these CHB treatments, the approach we used provides an evidence-based solution to discern the relative efficacy of the multitude of treatment options. No treatment strategy was superior for all five outcomes however TDF monotherapy was ranked first for three of the five outcomes and third for one. Monotherapy with ETV was ranked in the the top three for all five outcomes. The analysis suggests that TDF and ETV are the most efficacious treatment options for these five clinical outcomes.