Background & Aims: 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. Methods: 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. Results: 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. Conclusions: 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.
Bibliographical noteFunding Information:
Funding This study was sponsored by Bristol-Myers Squibb, which designed the study, conducted statistical analyses, and provided financial support for the study and manuscript preparation. Supported in part by the Ministry of Science and Technology of China (2018ZX10301202 and 2017ZX10202202 to J.-L.H. and J.S.), and by the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131 to J.-L.H.). Editorial assistance for manuscript preparation was provided by Richard Boehme of Articulate Science and funded by Bristol-Myers Squibb. Conflicts of interest These authors disclose the following: Jin-Lin Hou received grants and personal fees from Bristol-Myers Squibb during the conduct of the study, and grants and personal fees from Bristol-Myers Squibb, GlaxoSmithKline, and Novartis outside the submitted work; Hie-Won Hann received research grants from Bristol-Myers Squibb during the conduct of this study, received research grants from Gilead, Assembly Biosciences, Arbutus Biopharma, and TrioHealth, and serves on the national advisory board of Gilead; Cheng-Yuan Peng has served as an advisory committee member for AbbVie, Bristol-Myers Squibb, Gilead, and Merck; Tawesak Tanwandee received grants from Bristol-Myers Squibb and Merck during the conduct of the study; Hartwig Klinker has served as a speaker and/or an advisory board member for AbbVie, Bristol-Myers Squibb, Gilead, Hexal, Janssen, and Merck, and has received research funding from AbbVie, Arrowhead, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Novartis; Adrian Streinu-Cercel received research funding from Bristol-Myers Squibb during the conduct of the study, other support from Arbutus Biopharma, and personal fees and other support from Gilead, Janssen, and Bristol-Myers Squibb outside the submitted work; Lai Wei has received research grants from AbbVie, Bristol-Myers Squibb, and Roche, and consulting fees from AbbVie, Allergan, Bristol-Myers Squibb, Gilead, and Johnson & Johnson; Ji-Dong Jia has received consulting and speaker fees from AbbVie, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, and Merck; Hong Ren has received grants and personal fees from Gilead, and personal fees from Roche and Bristol-Myers Squibb outside the submitted work; Yongpeng Chen has received speaker fees from Bristol-Myers Squibb; Elizabeth L. Cooney was a salaried employee of Bristol-Myers Squibb and worked as medical monitor during the conduct of the study, and owns stock in Bristol-Myers Squibb; and Seng-Gee Lim has received grants, personal fees, and nonfinancial support from Gilead and Abbott Diagnostics, personal fees from AbbVie, Bristol Myers Squibb, and Janssen, grants and personal fees from Merck and Biopredictive, and other support from Roche outside the submitted work. The remaining authors disclose no conflicts.
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