Outcomes of Long-term Treatment of Chronic HBV Infection With Entecavir or Other Agents From a Randomized Trial in 24 Countries

Abstract

Treatment of chronic hepatitis B virus (HBV) infection with entecavir suppresses virus replication and reduces disease progression, but could require life-long therapy. To investigate clinical outcome events and safety associated with long-term treatment with entecavir, we followed up patients treated with entecavir or another standard-of-care HBV nucleos(t)ide analogue for up to 10 years. We assessed long-term outcomes and relationships with virologic response. Patients with chronic HBV infection at 299 centers in Asia, Europe, and North and South America were assigned randomly to groups that received entecavir (n= 6216) or an investigator-selected nonentecavir HBV nucleos(t)ide analogue (n= 6162). Study participants were followed up for up to 10 years in hospital-based or community clinics. Key end points were time to adjudicated clinical outcome events and serious adverse events. In a substudy, we examined relationships between these events and virologic response. There were no significant differences between groups in time to event assessments for primary end points including malignant neoplasms, liver-related HBV disease progression, and death. There were no differences between groups in the secondary end points of nonhepatocellular carcinoma malignant neoplasms and hepatocellular carcinoma. In a substudy of 5305 patients in China, virologic response, regardless of treatment group, was associated with a reduced risk of liver-related HBV disease progression (hazard ratio, 0.09; 95% CI, 0.038-0.221) and hepatocellular carcinoma (hazard ratio, 0.03; 95% CI, 0.009-0.113). Twelve patients given entecavir (0.2%) and 50 patients given nonentecavir drugs (0.8%) reported treatment-related serious adverse events. In a randomized controlled trial of patients with chronic HBV infection, we associated entecavir therapy with a low rate of adverse events over 10 years of follow-up evaluation. Patients receiving entecavir vs another nucleos(t)ide analogue had comparable rates of liver- and non-liver-related clinical outcome events. Participants in a China cohort who maintained a virologic response, regardless of treatment group, had a reduced risk of HBV-related outcome events including hepatocellular carcinoma. ClinicalTrials.gov identifier no: NCT00388674.