See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/267627971
Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study): BROUWER ET AL. ARTICLE in HEPATOLOGY · OCTOBER 2014 Impact Factor: 11.19 · DOI: 10.1002/hep.27586
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19 AUTHORS, INCLUDING: Milan Johan Sonneveld
Jurrien Reijnders
Erasmus MC
Erasmus MC
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SEE PROFILE
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Elke Verhey
Bettina E Hansen
Erasmus MC
Erasmus MC
22 PUBLICATIONS 724 CITATIONS
263 PUBLICATIONS 6,282 CITATIONS
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Available from: Elke Verhey Retrieved on: 25 June 2015
ADDING PEGINTERFERON TO ENTECAVIR FOR HBEAG-POSITIVE CHRONIC HEPATITIS B: A MULTICENTRE RANDOMIZED TRIAL (ARES STUDY)
Willem Pieter Brouwer1, Qing Xie2, Milan Johan Sonneveld1, Ningping Zhang3, Qing Zhang4, Fehmi Tabak5, Anca Streinu6, Ji-Yao Wang3, Ramazan Idilman7, Hendrik Reesink8, Mircea Diculescu9, Krzysztof Simon10, Mihai Voiculescu11, Meral Akdogan12, Wlodzimierz Mazur13, Jurrien Reijnders1, Elke Verhey1, Bettina Hansen1,14, and Harry L.A. Janssen,1,15 for the ARES study group 1
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 2 Rotterdam, The Netherlands; Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, 3 China; Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China; 4 Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China; 5Cerrahpasa Medical Faculty, Istanbul, Turkey; 6National Institute of Infectious Disease, 7 8 Bucharest, Romania; University of Ankara, Medical School, Ankara, Turkey; Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands; 10 9 Department of Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania; Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Poland; 11Department of Internal Medicine, Fundeni Cinical Institute, Bucharest, Romania; 12Yuksek Ihsitas Hospital, Department of 13 Gastroenterology, Ankara, Turkey; Department of Infectious Diseases, Silesian Medical University, 14 Katowice, Poland; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, 15 The Netherlands; Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
E-mail: [email protected]
Running head: Adding-on PEG-IFN to ETV for HBeAg-positive CHB: the ARES study Word count: Title: 15 (116 characters with spaces) Abstract: 261 Manuscript: 4.910 Tables : 4 Figures : 5 Supplementary tables : 2
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27586
Page 3 of 35
Hepatology 2
Corresponding author Prof. H.L.A. Janssen, MD PhD Professor of Medicine, University of Toronto & Erasmus University Rotterdam Division of Gastroenterology, University Health Network 399 Bathurst Street, 6B FP, Room 164, Toronto, ON, M5T 2S8 Tel: 416-603-5800 Extn: 2776; Fax: 416-603-6281 E-mail: [email protected]
List of abbreviations ALT, alanine aminotransferase; CHB, chronic hepatitis B; ETV, entecavir; HAI, hepatic activity index; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; ITT, intention-to-treat; LAM, lamivudine; MITT, modified intention-to-treat; NA(s), nucleos(t)ide analogue(s); PEG-IFN, peginterferon; ULN, upper limit of normal.
Declaration of interests Harry L.A. Janssen received grants from and is a consultant for: Abbott, Anadys, Medtronic, Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Santaris, Tibotec and Innogenetics. Qing Xie has served as an advisor and speaker for F. Hoffmann-La Roche, Bristol Myers Squibb, Novartis Pharmaceutical and Merck. Milan J. Sonneveld received speakers fee from and is a consultant for Roche and Bristol Myers Squibb. Hendrik W. Reesink received grants from and is a consultant for: Santaris, PRA international and Janssen. Jurriën GP Reijnders received speakers fee from Bristol Myers Squibb and Novartis and is a consultant for Gilead Sciences. Wlodzimierz Mazur is a consultant, gave expert testimony for and received educational lecture fees from: Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck and Roche. The other authors have nothing to disclose.
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Hepatology
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Financial support The study was organized and sponsored by the Foundation for Liver research, Rotterdam, the Netherlands. Financial support was provided by Bristol Myers Squibb (BMS, New York, United States), Roche Diagnostics (F. Hoffmann-La Roche Ltd., Basel, Switzerland), and the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 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 nor the decision to submit for publication.
Author contributions Study coordination and design, data collection, data analysis, writing of manuscript, approval of final version: WPB, MJS Study coordination and design, data collection, critical review of the manuscript, approval of final version: HLAJ, EV, JGPR Data collection, critical review of the manuscript, approval of final version: QX, NZ, QZ, FT, AS, JYW, RI, HWR, MD, KS, MV, MA, WM Study design, statistical analysis, critical review of the manuscript, approval of final version: BEH All authors had access to the study data and have reviewed and approved the final manuscript.
29-09-2014
Hepatology
Page 5 of 35
Hepatology 4
ABSTRACT Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding-on peginterferon (PEG-IFN) to ETV therapy enhances serologic response rates. In this global investigator-initiated, open-label, multicentre randomized trial, HBeAg-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5mg/day) and were randomized in a 1:1 ratio to either PEG-IFN add-on therapy (180µg/week) from week 24 to 48 (n=85), or to continue ETV monotherapy (n=90). Response was defined as HBeAg loss with HBV DNA 50 ng/mL, uncontrolled thyroid disease; substance abuse in the past 2 years (such as alcohol (≥80 g/day), intravenous drugs or inhaled drugs); a history of decompensated cirrhosis defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or oesophageal varices or encephalopathy; any medical condition requiring or likely to require chronic systemic administration of corticosteroids during the course of the study; or any other contra-indication for PEG-IFN therapy.
Efficacy analysis. The efficacy analysis included all patients who fulfilled the inclusion criteria, were HBeAgpositive at week 0, were randomized and received at least one dose of the assigned medication (modified intention-to-treat (MITT) population). The predefined primary endpoint was the combined presence of HBeAg loss with an HBV DNA level
Adding pegylated interferon to entecavir for hepatitis B e antigen-positive chronic hepatitis B: A multicenter randomized trial (ARES study): BROUWER ET AL. ARTICLE in HEPATOLOGY · OCTOBER 2014 Impact Factor: 11.19 · DOI: 10.1002/hep.27586
DOWNLOADS
VIEWS
58
94
19 AUTHORS, INCLUDING: Milan Johan Sonneveld
Jurrien Reijnders
Erasmus MC
Erasmus MC
50 PUBLICATIONS 563 CITATIONS
32 PUBLICATIONS 461 CITATIONS
SEE PROFILE
SEE PROFILE
Elke Verhey
Bettina E Hansen
Erasmus MC
Erasmus MC
22 PUBLICATIONS 724 CITATIONS
263 PUBLICATIONS 6,282 CITATIONS
SEE PROFILE
SEE PROFILE
Available from: Elke Verhey Retrieved on: 25 June 2015
ADDING PEGINTERFERON TO ENTECAVIR FOR HBEAG-POSITIVE CHRONIC HEPATITIS B: A MULTICENTRE RANDOMIZED TRIAL (ARES STUDY)
Willem Pieter Brouwer1, Qing Xie2, Milan Johan Sonneveld1, Ningping Zhang3, Qing Zhang4, Fehmi Tabak5, Anca Streinu6, Ji-Yao Wang3, Ramazan Idilman7, Hendrik Reesink8, Mircea Diculescu9, Krzysztof Simon10, Mihai Voiculescu11, Meral Akdogan12, Wlodzimierz Mazur13, Jurrien Reijnders1, Elke Verhey1, Bettina Hansen1,14, and Harry L.A. Janssen,1,15 for the ARES study group 1
Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, 2 Rotterdam, The Netherlands; Infectious Diseases, Ruijin Hospital, Jiaotong University, Shanghai, 3 China; Gastroenterology and Hepatology, Zhong Shan Hospital, Fu Dan University, Shanghai, China; 4 Gastroenterology and Hepatology, Shanghai Public Health Center, Fu Dan University, Shanghai, China; 5Cerrahpasa Medical Faculty, Istanbul, Turkey; 6National Institute of Infectious Disease, 7 8 Bucharest, Romania; University of Ankara, Medical School, Ankara, Turkey; Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands; 10 9 Department of Gastroenterology, Fundeni Cinical Institute, Bucharest, Romania; Division of Infectious Diseases and Hepatology, Wroclaw Medical University, Poland; 11Department of Internal Medicine, Fundeni Cinical Institute, Bucharest, Romania; 12Yuksek Ihsitas Hospital, Department of 13 Gastroenterology, Ankara, Turkey; Department of Infectious Diseases, Silesian Medical University, 14 Katowice, Poland; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, 15 The Netherlands; Toronto Center for Liver Disease, Toronto Western and General Hospital, University Health Network, Toronto, Canada
E-mail: [email protected]
Running head: Adding-on PEG-IFN to ETV for HBeAg-positive CHB: the ARES study Word count: Title: 15 (116 characters with spaces) Abstract: 261 Manuscript: 4.910 Tables : 4 Figures : 5 Supplementary tables : 2
This article has been accepted for publication and undergone full peer review but has not bee through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27586
Page 3 of 35
Hepatology 2
Corresponding author Prof. H.L.A. Janssen, MD PhD Professor of Medicine, University of Toronto & Erasmus University Rotterdam Division of Gastroenterology, University Health Network 399 Bathurst Street, 6B FP, Room 164, Toronto, ON, M5T 2S8 Tel: 416-603-5800 Extn: 2776; Fax: 416-603-6281 E-mail: [email protected]
List of abbreviations ALT, alanine aminotransferase; CHB, chronic hepatitis B; ETV, entecavir; HAI, hepatic activity index; HBV, hepatitis B virus; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; ITT, intention-to-treat; LAM, lamivudine; MITT, modified intention-to-treat; NA(s), nucleos(t)ide analogue(s); PEG-IFN, peginterferon; ULN, upper limit of normal.
Declaration of interests Harry L.A. Janssen received grants from and is a consultant for: Abbott, Anadys, Medtronic, Bristol Myers Squibb, Gilead Sciences, Novartis, Roche, Merck, Santaris, Tibotec and Innogenetics. Qing Xie has served as an advisor and speaker for F. Hoffmann-La Roche, Bristol Myers Squibb, Novartis Pharmaceutical and Merck. Milan J. Sonneveld received speakers fee from and is a consultant for Roche and Bristol Myers Squibb. Hendrik W. Reesink received grants from and is a consultant for: Santaris, PRA international and Janssen. Jurriën GP Reijnders received speakers fee from Bristol Myers Squibb and Novartis and is a consultant for Gilead Sciences. Wlodzimierz Mazur is a consultant, gave expert testimony for and received educational lecture fees from: Abbvie, Bristol Myers Squibb, Gilead, Janssen, Merck and Roche. The other authors have nothing to disclose.
29-09-2014
Hepatology
Hepatology
Page 4 of 35 3
Financial support The study was organized and sponsored by the Foundation for Liver research, Rotterdam, the Netherlands. Financial support was provided by Bristol Myers Squibb (BMS, New York, United States), Roche Diagnostics (F. Hoffmann-La Roche Ltd., Basel, Switzerland), and the Virgo consortium, funded by the Dutch government project number FES0908, and by the Netherlands Genomics Initiative (NGI) project number 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 nor the decision to submit for publication.
Author contributions Study coordination and design, data collection, data analysis, writing of manuscript, approval of final version: WPB, MJS Study coordination and design, data collection, critical review of the manuscript, approval of final version: HLAJ, EV, JGPR Data collection, critical review of the manuscript, approval of final version: QX, NZ, QZ, FT, AS, JYW, RI, HWR, MD, KS, MV, MA, WM Study design, statistical analysis, critical review of the manuscript, approval of final version: BEH All authors had access to the study data and have reviewed and approved the final manuscript.
29-09-2014
Hepatology
Page 5 of 35
Hepatology 4
ABSTRACT Entecavir (ETV) is a potent inhibitor of hepatitis B viral replication, but long-term therapy may be required. We investigated whether adding-on peginterferon (PEG-IFN) to ETV therapy enhances serologic response rates. In this global investigator-initiated, open-label, multicentre randomized trial, HBeAg-positive chronic hepatitis B (CHB) patients with compensated liver disease started on ETV monotherapy (0.5mg/day) and were randomized in a 1:1 ratio to either PEG-IFN add-on therapy (180µg/week) from week 24 to 48 (n=85), or to continue ETV monotherapy (n=90). Response was defined as HBeAg loss with HBV DNA 50 ng/mL, uncontrolled thyroid disease; substance abuse in the past 2 years (such as alcohol (≥80 g/day), intravenous drugs or inhaled drugs); a history of decompensated cirrhosis defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or oesophageal varices or encephalopathy; any medical condition requiring or likely to require chronic systemic administration of corticosteroids during the course of the study; or any other contra-indication for PEG-IFN therapy.
Efficacy analysis. The efficacy analysis included all patients who fulfilled the inclusion criteria, were HBeAgpositive at week 0, were randomized and received at least one dose of the assigned medication (modified intention-to-treat (MITT) population). The predefined primary endpoint was the combined presence of HBeAg loss with an HBV DNA level
