Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B


  • Hui Zhang, Robert Hindes, Uchenna Iloeje, Suzanne Beebe, and Bruce Kreter are employees of Bristol-Myers Squibb Co. Shun-Sheng Wu, Rifaat Safadi, and Waldemar Halota have no major conflicts of interest. Ting-Tsung Chang reports research funding from Gilead Sciences, Bristol-Myers Squibb, GlaxoSmithKline, Schering-Plough Corp., and Pfizer, Inc., and speech honoraria from Bristol-Myers Squibb and Schering-Plough. Yun-Fan Liaw is a consultant to Bristol-Myers Squibb, Novartis, and Roche and also has grant/research support from Bristol-Myers Squibb, Novartis, Roche, and Gilead Sciences. Eugene Schiff is a member of the scientific advisory boards for Anadys Pharmaceuticals, Bayer, Bristol-Myers Squibb, Conatus, Evivar, Gilead, GlobeImmune, Inc., Johnson and Johnson, Merck, Novartis/Idenix, Roche Molecular, Schering-Plough, and Vertex Pharmaceuticals and is a member of the data and safety monitoring boards for Daiichi-Sankyo, Johnson and Johnson, Pfizer, Salix Pharmaceuticals, Inc., Sanofi Aventis, and Wyeth. Eugene Schiff has also received grant/research support (including clinical trials) from Abbott, Boehring Ingelheim, Bristol-Myers Squibb, Conatus, Debio Pharm, Gilead, GlobeImmune, Idenix, Labcore, Merck, Novartis/Idenix, Roche Diagnostics, Roche Molecular, Roche Pharmaceutical, Salix Pharmaceuticals, Sanofi Aventis, Schering-Plough, Vertex Pharmaceuticals, and Wyeth and is a member of the speaker bureaus of Gilead Sciences and Schering-Plough. Kwang-Hyub Han has received a clinical research grant from Bristol-Myers Squibb. Ching-Lung Lai has received fees for consulting and speaking from Bristol-Myers Squibb and is a member of the Bristol-Myers Squibb global advisory board. Samuel S. Lee reports consulting fees, research grants, and speaker honoraria from Bristol-Myers Squibb. Zachary Goodman has received grant support from Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, Schering-Plough, Novartis, and New England Research Institutes.

  • Potential conflict of interest: This study was sponsored by the Bristol-Myers Squibb Pharmaceutical Research Institute. The sponsor collated the data, monitored the study conduct, performed the statistical analysis, and coordinated the writing of the article with the authors. Dr. Lee is a consultant for, advises, is on the speakers' bureau of, and received grants from Bristol-Myers Squibb and Roche. He is also a consultant for, is on the speakers' bureau of, and received grants from Gilead. Drs. Iloege and Kreter own stock in Bristol-Myers Squibb. Dr. Chang received grants from Gilead, Pfizer, Bristol-Myers Squibb, and GlaxoSmithKline. Dr. Goodman received grants from Bristol-Myers Squibb, Gilead, and Novartis.


One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis. (HEPATOLOGY 2010)