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

StephenW

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)

StephenW

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

文章首次在网上公布：2015年2月27日

DOI：10.1002 / hep.27586
    胃肠病学和肝病，伊拉兹马斯MC大学医学中心，鹿特丹，荷兰1系
    2传染病，瑞金医院，交通大学，上海，中国
    3胃肠病学和肝病中山医院，复旦大学，上海，中国
    4胃肠病学和肝病，上海公共卫生中心，复旦大学，上海，中国
    5 Cerrahpasa医学院，土耳其伊斯坦布尔
    传染病，布加勒斯特，罗马尼亚6研究所
    安卡拉，医学院，安卡拉，土耳其7大学
    胃肠病学和肝病，学术医学中心，阿姆斯特丹，荷兰8处
    消化内科，Fundeni Cinical研究所，布加勒斯特，罗马尼亚9处
    10部传染病和肝病，弗罗茨瓦夫医科大学，弗罗茨瓦夫，波兰
    内科，Fundeni Cinical研究所，布加勒斯特，罗马尼亚11处
    消化内科，Yuksek一起Ihsitas医院，安卡拉，土耳其12处
    传染病西里西亚医科大学13处，卡托维兹，波兰
    公共卫生，伊拉兹马斯MC大学医学中心，鹿特丹，荷兰的14处
    15多伦多中心肝病，多伦多西部和综合医院，大学健康网络多伦多，安大略省，加拿大

*地址转载要求：哈利LA扬森，医学博士，多伦多大学和鹿特丹Erasmus大学，消化内科，大学健康网络，399巴瑟斯特街，6B FP，164室，多伦多，安大略省，加拿大M5T 2S8科。电子邮件：[email protected];传真：416-603-6281。

    潜在的利益冲突：Reijnders医生咨询的基列和是扬声器的为施贵宝局。西蒙博士建议Gilead公司，罗氏和MSD。马祖尔博士咨询，是扬声器的用于电信局，从Gilead公司，罗氏公司和百时美施贵宝收到的补助。他咨询，并在扬声器的为MSD和AbbVie局。 Sonneveld医生咨询，并在扬声器的罗氏局。他咨询了施贵宝。詹森博士咨询，距离Bristol-Myers Squibb公司，Gilead公司，诺华，罗氏，默克，Innogenetics公司，雅培，Santaris，Anadys，美敦力，Tibotec公司，麒麟，和DEBIO收到的补助。 Reesink医生咨询，并从AbbVie，施贵宝，Gilead公司，扬森 - Cilag公司，默克/ MSD，PRA-国际，罗氏，Santaris和轩辕获得补助。他咨询了ASTEX，葛兰素史克，R-PHARM和韩国绿十字。他从勃林格殷格翰公司收到的补助。

    该研究组织和基金会肝病研究（鹿特丹，荷兰）主办。金融支持是由百时美施贵宝（纽约），罗氏诊断产品（F.霍夫曼罗氏公司，巴塞尔，瑞士），和处女座联盟提供的，由荷兰政府资助（项目编号：FES0908）和荷兰基因组计划（项目编号：050-060-452）。资金来源并没有对研究设计，数据收集，分析和解释数据的任何影响，写报告，或提交发表的决定。

    这项工作是Clinicaltrials.gov下登记不。 NCT00877760。

恩替卡韦（ETV）是乙型肝炎病毒复制的有效抑制剂，但长期治疗可能是必需的。我们调查是否增加对聚乙二醇干扰素（PEG-IFN），以ETV治疗提高血清学应答率。在这个全球研究者发起的，开放标签，多中心，随机试验，乙肝e抗原（HBeAg）阳性的慢性乙型肝炎（CHB）患者的代偿性肝病开始ETV单药治疗（0.5毫克/天），并随机在以1：1的比例，以任一聚乙二醇干扰素从24周附加治疗（180微克/周）至48（N = 85）或继续ETV单一治疗（N = 90）。反应定义为HBeAg消失与HBV DNA <200 IU / mL的48周急救员停产ETV在72周所有患者均随访至96周的响应是在16 85（19％）的患者分配到添加 - 实现手臂与9 90（10％）的单药治疗组（P = 0.095）。调整前，随机治疗HBV DNA水平，PEG-IFN附加了显著与响应相关（比值比：4.8; 95％的置信区间：1.6-14.0; P = 0.004）。在附加治疗的患者十（13％）ETV停止对2的90（2％）的治疗单药治疗（P = 0.007），这是79％（14中11）与25％后达到缓解病情（2 8）那些谁停产ETV（P = 0.014）的。在96周，22（26％）分配附加与12（13％）分配单药治疗达到HBeAg血清学转换（P = 0.036）的患者。 PEG-IFN附加导致乙肝表面抗原，e抗原显著更加下降，HBV DNA（均P <0.001）。组合疗法的耐受性良好。结论：虽然主要终点没有达到，PEG-IFN 24周添加治疗导致的HBeAg响应的比例较高，相比于单药治疗ETV。添加治疗导致更多的病毒性下降，出现了以预防复发停药后ETV。因此，PEG-IFN添加治疗可促进核苷（酸）类似物停药。 （2015年肝病; 61：1512年至1522年）