Copyright
©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Phase 3 trial of first generation protease inhibitor therapy for hepatitis C virus/human immunodeficiency virus coinfection
Kenneth E Sherman, Minhee Kang, Richard Sterling, Triin Umbleja, Kristen Marks, Jennifer J Kiser, Beverly Alston-Smith, Wayne Greaves, Adeel A Butt, the ACTG 5294 BIRTH Study Team
Kenneth E Sherman, Division of Digestive Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 45267, United States
Minhee Kang, Triin Umbleja, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
Richard Sterling, Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA 23284, United States
Kristen Marks, Division of Infectious Disease, Weill Cornell Medical School, New York, NY 10065, United States
Jennifer J Kiser, University of Colorado School of Pharmacy, Aurora, CO 80045, United States
Beverly Alston-Smith, NIAID-Division of AIDS, Rockville, MD 20852, United States
Wayne Greaves, Merck and Co, Inc., Kenilworth, NJ 07033, United States
Author contributions: Sherman KE, Sterling R and Butt AA conceived of the study, managed study implementation, provided critical review of the analysis, and wrote the first draft of the manuscript; Kang M and Umbleja T managed study implementation, data collection and data analysis; Sterling R, Marks K, Kiser JJ, Alston-Smith B, Greaves W and Butt AA provided study oversight, critical review of the analysis and manuscript; and all authors read and approved the final manuscript.
Institutional review board statement: The study was performed in the NIH AIDS Clinical Trials Group network (ACTG, National Institutes of Health Registration number NCT01482767) with enrollment of participants at 42 sites across the United States. The study was conducted with approval of Institutional Review Boards (IRB) at each individual site.
Clinical trial registration statement: This study is registered at ClinicalTrials.gov. The registration identifier is NCT01482767.
Informed consent statement: All participants provided written informed consent prior to study enrollment.
Conflict-of-interest statement: Sherman KE serves on a Merck Advisory Board (paid to institution); the other authors declare no conflict of interests.
Data sharing statement: No additional data are available.
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: Kenneth E Sherman, MD, PhD, Gould Professor of Medicine, Division of Digestive Diseases, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267, United States.
kenneth.sherman@uc.edu
Telephone: +1-513-5583918 Fax: +1-513-5581744
Received: July 6, 2016
Peer-review started: July 9, 2016
First decision: September 7, 2016
Revised: October 12, 2016
Accepted: December 13, 2016
Article in press: December 14, 2016
Published online: February 8, 2017
Processing time: 215 Days and 8.8 Hours
AIM
To evaluate efficacy/safety of hepatitis C virus (HCV) protease inhibitor boceprevir with pegylated interferon (PEG-IFN) alfa and weight-based ribavirin (RBV) in a phase 3 trial.
METHODS
A prospective, multicenter, phase 3, open-label, single-arm study of PEG-IFN alfa, weight-based RBV, and boceprevir, with a PEG-IFN/RBV lead-in phase was performed. The HCV/human immunodeficiency virus coinfected study population included treatment naïve (TN) and treatment experienced (TE) patients. Treatment duration ranged from 28 to 48 wk dependent upon response-guided criteria. All patients had HCV Genotype 1 with a viral load > 10000 IU/mL. Compensated cirrhosis was allowed. Sample size was determined to establish superiority to historical (PEG-IFN plus RBV) rates in sustained viral response (SVR).
RESULTS
A total of 257 enrolled participants were analyzed (135 TN and 122 TE). In the TN group, 81.5% were male and 54.1% were black. In the TE group, 76.2% were male and 47.5% were white. Overall SVR12 rates (HCV RNA < lower limit of quantification, target not detected, target not detected) were 35.6% in TN and 30.3% in TE. Response rates at SVR24 were 28% in TN and 10% in TE, and exceeded those in historical controls. The highest rate was observed in TN non-cirrhotic participants (36.8% and the lowest in TE cirrhotics (26.3%). Cirrhotic TN participants had a 27.8% SVR12 rate and 32.1% of TE non-cirrhotics achieved SVR12. Significantly lower response rates were observed among black participants; in the TE, SVR12 was 39.7% in white participants but only 13.2% of black subjects (P = 0.002). Among the TN, SVR12 was 42.1% among whites and 27.4% among blacks (P = 0.09).
CONCLUSION
The trial met its hypothesis of improved SVR compared to historical controls but overall SVR rates were low. All-oral HCV treatments will mitigate these difficulties.
Core tip: Approval of first generation hepatitis C virus (HCV) protease inhibitors has initiated a change in care of HCV infected patients. Phase 2 trials in HCV/human immunodeficiency virus coinfected patients have suggested improved efficacy and tolerability for regimens that combined pegylated interferon (PEG-IFN) + ribavirin (RBV) with either boceprevir or telaprevir. We evaluated an HCV treatment regimen using a first generation HCV protease inhibitor (boceprevir) with PEG-IFN, and weight-based RBV in a phase 3 treatment trial, including HCV treatment-naïve and treatment-experienced coinfected subjects. While sustained viral response rates were low overall they did exceed historical PEG-IFN/RBV rates. Use of new interferon-free direct acting antiviral agents modalities in this population is indicated.
