Clinical Trials Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2016; 22(12): 3418-3431
Published online Mar 28, 2016. doi: 10.3748/wjg.v22.i12.3418
Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1
Ira Jacobson, Stefan Zeuzem, Robert Flisiak, Brygida Knysz, Stefan Lueth, Dorota Zarebska-Michaluk, Ewa Janczewska, Peter Ferenci, Moises Diago, Anna Linda Zignego, Rifaat Safadi, Yaacov Baruch, Dzhamal Abdurakhmanov, Stephen Shafran, Dominique Thabut, Rafael Bruck, Adrian Gadano, Alexander James Thompson, Justin Kopit, Fiona McPhee, Tracy Michener, Eric A Hughes, Philip D Yin, Stephanie Noviello
Ira Jacobson, Weill Cornell Medical College, New York, NY 10029, United States
Ira Jacobson, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Stefan Zeuzem, JW Goethe University Hospital, 60323 Frankfurt, Germany
Robert Flisiak, Uniwersytet Medyczny w Białymstoku, 15-089 Białystok, Poland
Brygida Knysz, EMC and Medical University, 50-220 Wrocław, Poland
Stefan Lueth, Universitatsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany
Dorota Zarebska-Michaluk, Wojewodzki Szpital Zespolony w Kielcach, 25-736 Kielce, Poland
Ewa Janczewska, ID Clinic, 41-400 Mysłowice, Poland
Peter Ferenci, Medizinische Universität Wien, 1090 Vienna, Austria
Moises Diago, Clinica Quiron, 46010 Valencia, Spain
Anna Linda Zignego, Università degli Studi di Firenze, 50121 Florence, Italy
Rifaat Safadi, Holy Family Hospital, Nazareth 6004, Israel
Yaacov Baruch, Rambam Medical Center, Haifa 31096, Israel
Dzhamal Abdurakhmanov, 1st Moscow State Medical University N.A.I.M. Sechenov, 119991 Moscow, Russia
Stephen Shafran, University of Alberta Hospital, Edmonton, Alberta T6G 2B7, Canada
Dominique Thabut, Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France
Rafael Bruck, Tel Aviv Sourasky Medical Center and Tel Aviv University, Tel Aviv 64239, Israel
Adrian Gadano, Hospital Italiano de Buenos Aires, Buenos Aires C1181ACH, Argentina
Alexander James Thompson, St. Vincents Hospital and the University of Melbourne, Melbourne 3065, Australia
Justin Kopit, Fiona McPhee, Philip D Yin, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, United States
Tracy Michener, Eric A Hughes, Stephanie Noviello, Bristol-Myers Squibb Research and Development, Princeton, NJ 08450, United States
Author contributions: Hughes EA, Yin PD, Noviello S, McPhee F, Kopit J, and Jacobson I designed the research; Jacobson I, Zeuzem S, Flisiak R, Knysz B, Lueth S, Zarebska-Michaluk D, Janczewska E, Ferenci P, Diago M, Zignego AL, Safadi R, Baruch Y, Abdurakhmanov D, Shafran S, Thabut D, Bruck R, Gadano A, Thompson AJ, and McPhee F performed the research; Kopit J analyzed the data; Michener T, Hughes EA, Yin PD, and Noviello S monitored the study conduct; all authors wrote the paper; all authors had access to the study data and have reviewed and approved the final manuscript.
Supported by Bristol-Myers Squibb.
Institutional review board statement: The protocol was approved by the Institutional Review Board/human research committee at each participating institution, and conformed to the ethical guidelines of the 2008 Declaration of Helsinki.
Clinical trial registration statement: This study is registered at clinicaltrials.gov, registration number NCT01492426.
Informed consent statement: All patients provided informed written consent prior to study enrollment.
Conflict-of-interest statement: Abdurakhmanov D has acted as a speaker and advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Flisiak R has acted as a speaker and advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, MSD, Novartis, and Roche. Jacobson I has acted as a consultant for AbbVie, Achillion, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; has acted as a speaker for Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; and has received research funding from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Tobira. Janczewska E has acted as speaker and/or consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, MSD, and Roche. Knysz B has acted as a speaker and advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and MSD. Thompson AJ is supported by a Fellowship from the National Health and Medical Research Council of Australia (NHMRC); he has acted as a consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Roche, Merck and Spring Bank Pharmaceuticals; as a speaker for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck; and has received research funding from AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. Shafran S has received funding for HCV clinical trials from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Merck, Roche, and Vertex. Zeuzem S has acted as a consultant for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and Merck. Kopit J, McPhee F, Michener T, Hughes EA, Yin PD, and Noviello S are employees of Bristol-Myers Squibb.
Data sharing statement: Technical appendix, statistical code, and dataset are available from Ira Jacobson at ijacobson@chpnet.org. Patients gave informed consent regarding the relevant use and sharing of key-coded data.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Dr. Ira Jacobson, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, United States. ijacobson@chpnet.org
Telephone: +1-917-7978812
Received: August 22, 2015
Peer-review started: August 25, 2015
First decision: September 9, 2015
Revised: October 17, 2015
Accepted: November 30, 2015
Article in press: December 1, 2015
Published online: March 28, 2016
Processing time: 214 Days and 15.4 Hours
Abstract

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.

METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.

RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.

CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.

Keywords: Direct-acting antiviral; Chronic hepatitis C; Daclatasvir; Genotype 1b; NS5A inhibitor; Liver disease

Core tip: This phase 3 study describes the first prospective comparison of an NS5A inhibitor and an NS3/4A protease inhibitor in peginterferon-based regimens. Combinations of peginterferon alfa-2a/ribavirin (pegIFN/RBV) with boceprevir or telaprevir were the standard-of-care for genotype (GT) 1-infected patients at the time of study design. In treatment-naive GT1b-infected patients, daclatasvir (NS5A inhibitor) plus pegIFN/RBV achieved a sustained virologic response at posttreatment week 12 (SVR12) of 85% and demonstrated noninferiority to telaprevir plus pegIFN/RBV showing 81% SVR12. Daclatasvir plus pegIFN/RBV was well-tolerated, with a superior safety profile for anemia compared with telaprevir plus pegIFN/RBV. These results support the ongoing investigation of daclatasvir in all-oral combinations in multiple patient populations.