Cross-study analysis of the relative efficacies of oral antiviral therapies for chronic hepatitis B infection in nucleoside-naive patients.

BACKGROUND AND
OBJECTIVE: Lamivudine and adefovir were approved for treatment of chronic hepatitis B virus (HBV) infection based on placebo-controlled trials, and entecavir was recently approved on the basis of its superiority over lamivudine in phase II/III trials; however, to date, these three therapies have not been compared head to head.
METHODS: To evaluate the relative efficacy of these therapies, we applied a predefined protocol of established statistical techniques to compare data from phase III entecavir trials with published clinical trial results with lamivudine, adefovir and placebo in nucleoside-naive hepatitis B e antigen (HBeAg)-positive and -negative populations.
RESULTS: A comprehensive literature search identified 612 publications/data sources, of which 28 satisfied predefined inclusion criteria. Independent reviewers extracted week 48-52 histological, virological, biochemical and serological endpoints from these sources, which were analysed with a fixed-effects model. For each of the three histological endpoints in HBeAg-positive patients (Histological Improvement, Ranked Assessment of Necroinflammation [RA-N] and Ranked Assessment of Fibrosis [RA-F]), entecavir was superior to adefovir. Entecavir was superior to lamivudine for Histological Improvement and comparable to lamivudine for RA-N and RA-F. With respect to reducing HBV DNA levels, entecavir (-6.98 log(10) copies/mL) was more effective than lamivudine (-5.46 log(10) copies/mL, p < 0.0001) and adefovir (-3.60 log(10) copies/mL, p < 0.0001), and lamivudine was more effective than adefovir (p < 0.0001). The parallel goals of HBV DNA reduction below the limit of quantitation (LOQ) [by polymerase chain reaction] and ALT normalisation were achieved more often with entecavir (69% and 67% of patients, respectively) than with lamivudine (38% and 59%, respectively; p < 0.0001 and p < 0.05, respectively) or adefovir (21% and 48%, respectively; both p < 0.0001), and more often with lamivudine than with adefovir (p < 0.0001 and p < 0.05, respectively). HBeAg seroconversion rates were higher with entecavir (21% of patients) and lamivudine (18%) than with adefovir (12%, p < 0.01 and p < 0.05, respectively). For each of the three histological endpoints in the HBeAg-negative population, entecavir was comparable to adefovir. Entecavir was superior to lamivudine for Histological Improvement, and comparable to lamivudine for RA-N and RA-F, and all three antivirals were superior to placebo. Entecavir proved superior to lamivudine and adefovir in lowering HBV DNA levels (-5.20 vs -4.66 vs -3.91 log(10) copies/mL, respectively; p < 0.0005 and p < 0.0001, respectively) and in suppressing HBV DNA below the LOQ (91% vs 73% vs 51% of patients, respectively; both p < 0.0001); in the latter respect, lamivudine was in turn superior to adefovir (p < 0.0001). Entecavir was also superior to lamivudine in normalising ALT (76% vs 69% patients, respectively; p < 0.05).
CONCLUSIONS: Over a 12-month treatment period, this analysis predicts that the antiviral efficacy of entecavir would be superior to that of lamivudine, which in turn would be superior to that of adefovir, in nucleoside-naive patients with chronic HBV infection.