Antiviral activity, dose–response relationship, and safety of entecavir following 24-week oral dosing in nucleoside-naive Japanese adult patients with chronic hepatitis B: a randomized, double-blind, phase II clinical trial

摘要

PurposeA randomized, double-blind, multicenter study (ETV-047) was conducted to evaluate the dose–response relationship of entecavir and compare its antiviral activity and safety with lamivudine in Japanese patients with chronic hepatitis B (CHB).MethodsOne hundred thirty-seven nucleoside-naive adult patients with CHB were randomized to once-daily oral doses of entecavir 0.01, 0.1, or 0.5?mg or lamivudine 100?mg for 24?weeks. The primary efficacy end point used to evaluate the dose–response relationship was mean change from baseline in serum hepatitis B virus (HBV) DNA level at week 22, as determined by polymerase chain reaction assay.ResultsEntecavir demonstrated a clear dose–response relationship, with mean change from baseline in serum HBV DNA level of ?3.11, ?4.77, and ?5.16?log10?copies/ml with entecavir 0.01, 0.1, and 0.5?mg, respectively. Entecavir 0.5?mg was superior to lamivudine 100?mg for the mean change in HBV DNA level (?5.16 vs. ?4.29?log10?copies/ml; P?=?0.007). The overall incidence of adverse events was comparable between treatment groups. Two patients discontinued treatment because of adverse events (one with liver cirrhosis [entecavir 0.5?mg] and one with grade 4 serum alanine aminotransferase (ALT) elevation, nausea, and malaise [lamivudine 100?mg]). Serum ALT flares were observed in four patients; flares were associated with 2?log10 reductions or more in HBV DNA level and resolved without dose interruption.ConclusionEntecavir 0.01–0.5?mg is well tolerated and produces a dose-dependent reduction in viral load in nucleoside-naive Japanese patients with CHB. Compared with lamivudine 100?mg, entecavir 0.1?mg demonstrated noninferiority and entecavir 0.5?mg was superior in this population.