Adding pegylated interferon to entecavir for hepatitis B e antigen–positive chronic hepatitis B: A multicenter randomized trial (ARES study)
Willem Pieter Brouwer1, Qing Xie2, Milan J. Sonneveld1, Ningping Zhang3, Qin Zhang4, Fehmi Tabak5, Adrian Streinu-Cercel6, Ji-Yao Wang3, Ramazan Idilman7, Hendrik W. Reesink8, Mircea Diculescu9, Krzysztof Simon10, Mihai Voiculescu11, Meral Akdogan12, Wlodzimierz Mazur13, Jurrien G.P. Reijnders1, Elke Verhey1, Bettina E. Hansen1,14, Harry L.A. Janssen1,15,* andfor the ARES Study Group
Article first published online: 27 FEB 2015
DOI: 10.1002/hep.27586
1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
2 Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, China
3 Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China
4 Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China
5 Cerrahpasa Medical Faculty, Istanbul, Turkey
6 National Institute of Infectious Disease, Bucharest, Romania
7 University of Ankara, Medical School, Ankara, Turkey
8 Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
9 Department of Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania
10 Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Wroclaw, Poland
11 Department of Internal Medicine, Fundeni Cinical Institute, Bucharest, Romania
12 Department of Gastroenterology, Yuksek Ihsitas Hospital, Ankara, Turkey
13 Department of Infectious Diseases, Silesian Medical University, Katowice, Poland
14 Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands
15 Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Ontario, Canada
*Address reprint requests to: Harry L.A. Janssen, M.D., Ph.D., University of Toronto and Erasmus University Rotterdam, Division of Gastroenterology, University Health Network, 399 Bathurst Street, 6B FP, Room 164, Toronto, Ontario, Canada M5T 2S8. E-mail: [email protected]; fax: 416-603-6281.
Potential conflict of interest: Dr. Reijnders consults for Gilead and is on the speakers' bureau for Bristol-Myers Squibb. Dr. Simon advises Gilead, Roche, and MSD. Dr. Mazur consults, is on the speakers' bureau for, and received grants from Gilead, Roche, and Bristol-Myers Squibb. He consults and is on the speakers' bureau for MSD and AbbVie. Dr. Sonneveld consults and is on the speakers' bureau for Roche. He consults for Bristol-Myers Squibb. Dr. Janssen consults and received grants from Bristol-Myers Squibb, Gilead, Novartis, Roche, Merck, Innogenetics, Abbott, Santaris, Anadys, Medtronic, Tibotec, Kirin, and Debio. Dr. Reesink consults and received grants from AbbVie, Bristol-Myers Squibb, Gilead, Janssen-Cilag, Merck/MSD, PRA-International, Roche, Santaris, and Regulus. He consults for Astex, GlaxoSmithKline, R-Pharm, and Korean Green Cross. He received grants from Boehringer Ingelheim.
The study was organized and sponsored by the Foundation for Liver Research (Rotterdam, The Netherlands). Financial support was provided by Bristol-Myers Squibb (New York, NY), Roche Diagnostics (F. Hoffmann-La Roche Ltd., Basel, Switzerland), and the Virgo Consortium, funded by the Dutch government (project no.: FES0908), and by The Netherlands Genomics Initiative (project no.: 050-060-452). The funding sources did not have any influence on study design, data collection, analysis and interpretation of the data, writing of the report, or the decision to submit for publication.
This work is registered under Clinicaltrials.gov no. NCT00877760.
Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding on pegylated interferon (Peg-IFN) to ETV therapy enhances serological response rates. In this global investigator-initiated, open-label, multicenter, randomized trial, hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5 mg/day) and were randomized in a 1:1 ratio to either Peg-IFN add-on therapy (180 µg/week) from week 24 to 48 (n = 85) or to continue ETV monotherapy (n = 90). Response was defined as HBeAg loss with HBV DNA <200 IU/mL at week 48. Responders discontinued ETV at week 72. All patients were followed until week 96. Response was achieved in 16 of 85 (19%) patients allocated to the add-on arm versus 9 of 90 (10%) in the monotherapy arm (P = 0.095). Adjusted for HBV DNA levels before randomized therapy, Peg-IFN add-on was significantly associated with response (odds ratio: 4.8; 95% confidence interval: 1.6-14.0; P = 0.004). Eleven (13%) of the add-on-treated patients achieved disease remission after ETV cessation versus 2 of 90 (2%) of those treated with monotherapy (P = 0.007), which was 79% (11 of 14) versus 25% (2 of 8) of those who discontinued ETV (P = 0.014). At week 96, 22 (26%) patients assigned add-on versus 12 (13%) assigned monotherapy achieved HBeAg seroconversion (P = 0.036). Peg-IFN add-on led to significantly more decline in hepatitis B surface antigen, HBeAg, and HBV DNA (all P < 0.001). Combination therapy was well tolerated. Conclusion: Although the primary endpoint was not reached, 24 weeks of Peg-IFN add-on therapy led to a higher proportion of HBeAg response, compared to ETV monotherapy. Add-on therapy resulted in more viral decline and appeared to prevent relapse after stopping ETV. Hence, Peg-IFN add-on therapy may facilitate the discontinuation of nucleos(t)ide analogs. (Hepatology 2015;61:1512–1522) 作者: StephenW 时间: 2015-4-21 17:52
加入聚乙二醇干扰素来恩替卡韦乙肝e抗原阳性慢性乙型肝炎的多中心随机试验（ARES研究）
威廉彼得Brouwer1，清Xie2，米兰J. Sonneveld1，Ningping Zhang3，秦Zhang4，费赫米Tabak5，阿德里安Streinu-Cercel6，纪尧Wang3，拉马赞Idilman7，亨德里克·W. Reesink8，米尔恰Diculescu9，克日什托夫·Simon10，米哈伊Voiculescu11，梅拉Akdogan12 ，沃齐米日Mazur13，Jurrien GP Reijnders1，埃尔克Verhey1，贝蒂娜E. Hansen1,14，哈利LA Janssen1,15，* andfor的ARES研究组