Gregory J. Dore, MD; Frederick Altice, MD; Alain H. Litwin, MD; Olav Dalgard, MD; Edward J. Gane, MD; Oren Shibolet, MD; Anne Luetkemeyer, MD; Ronald Nahass, MD; Cheng-Yuan Peng, MD; Brian Conway, MD; Jason Grebely, PhD; Anita Y.M. Howe, PhD; Isaias N. Gendrano, MPH; Erluo Chen, MPH; Hsueh-Cheng Huang, PhD; Frank J. Dutko, PhD; David C. Nickle, PhD; Bach-Yen Nguyen, MD; Janice Wahl, MD; Eliav Barr, MD; Michael N. Robertson, MD; Heather L. Platt, MD; on behalf of the C-EDGE CO-STAR Study Group *
Note: All authors vouch for the completeness and accuracy of the data and data analyses and for the fidelity of this report to the study protocol. The first author wrote the first draft of the manuscript. All authors reviewed the manuscript and provided input. Editorial assistance was provided by employees of Merck.
Disclaimer: The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or the authors' affiliated universities.
Acknowledgment: The authors thank the patients and their families, the investigators, and the study personnel for their participation in this clinical trial. They greatly appreciate the expert assistance of Karyn Davis and Danielle Mancaruso from Merck in preparing this manuscript. They also appreciate the additional statistical support provided by Peggy Hwang from Merck.
Disclosures: Dr. Dore reports grants from AbbVie, Merck, Bristol-Myers Squibb (BMS), Janssen, and Roche; personal fees from Gilead, AbbVie, Merck, BMS, Janssen, Roche, GlaxoSmithKline, and Abbott Diagnostics; and nonfinancial support from Gilead, AbbVie, Merck, BMS, and Roche, outside the submitted work. Dr. Altice reports grants from Merck outside the submitted work; has served on speakers bureaus for BMS, Gilead, and Practice Point Communications; and has received research support from the Gilead Foundation, National Institute on Drug Abuse, National Institute of Mental Health, National Institute on Alcohol Abuse and Alcoholism, Substance Abuse and Mental Health Services Administration, and Health Resources and Services Administration. Dr. Litwin reports grants from Merck during the conduct of the study and has served on advisory boards for Gilead, Janssen, BMS, AbbVie, and Merck outside the submitted work. Dr. Dalgard reports grants from Merck, Gilead, and AbbVie during the conduct of the study. Dr. Gane reports membership in the HCV Scientific Advisory Board and speakers bureau for Merck during the conduct of the study. Dr. Shibolet reports grants and personal fees from Merck and personal fees from Gilead and AbbVie Israel, outside the submitted work. Dr. Luetkemeyer reports grants from Merck during the conduct of the study and grants from AbbVie, Gilead, Pfizer, and BMS outside the submitted work. Dr. Nahass reports grants and personal fees from Merck during the conduct of the study, and grants and personal fees from Gilead, Janssen, and AbbVie outside the submitted work. Dr. Peng reports membership in the HCV Advisory Board for Merck during the conduct of the study and membership in the HCV Advisory Board for AbbVie, BMS, and Gilead outside the submitted work. Dr. Conway reports grants, personal fees, and nonfinancial support from Merck, AbbVie, and Gilead outside the submitted work. Dr. Grebely reports grants from AbbVie, BMS, Gilead, and Merck and personal fees from Gilead and Merck/MSD, outside the submitted work. Dr. Howe was an employee of Merck during the conduct of the study. Mr. Gendrano, Ms. Chen, and Drs. Huang, Dutko, Nguyen, Wahl, Barr, Robertson, and Platt are current employees of Merck & Co., Kenilworth, New Jersey and hold stock and/or stock options. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-0816.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that she has no financial relationships or interests to disclose. Darren B. Taichman, MD, PhD, Executive Deputy Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See Supplement 2. Statistical code: Not available. Data set: Merck's data sharing policy, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the study data can be submitted through the EngageZone site or at dataaccess@merck.com.
Requests for Single Reprints: Gregory J. Dore, MD, The Kirby Institute, Wallace Wurth Building, UNSW Australia, UNSW, NSW 2052, Australia; e-mail, gdore@kirby.unsw.edu.au.
Current Author Addresses: Drs. Dore and Grebely: The Kirby Institute, Wallace Wurth Building, UNSW Australia, UNSW, NSW 2052, Australia.
Dr. Altice: Yale School of Medicine, 135 College Street, Suite 323, New Haven, CT 06510.
Dr. Litwin: Montefiore Medical Center, 1510 Waters Place, Bronx, NY 10461.
Dr. Dalgard: Sykehusveien 25, Infeksjonsmedisinsk poliklinikk, Akershus University Hospital, 1478 Lorenskog, Norway.
Dr. Gane: Auckland Clinical Studies, Medacs House, 3 Ferncroft Street, Ground Floor, Grafton, Auckland 1150, New Zealand.
Dr. Shibolet: Tel Aviv Sourasky Medical Center, Gastrointestinal and Liver Disease, 6 Waitzmann Street, Tel Aviv, 64239, Israel.
Dr. Luetkemeyer: University of California, 995 Potrero Avenue, Box 0874, Building 80, Fourth Floor, San Francisco, CA 94110.
Dr. Nahass: ID Care, 105 Raider Boulevard, Suite 101, Hillsborough, NJ 08844.
Dr. Peng: School of Medicine, China Medical University, 2 Yuh-Der Road, Taichung 40447, Taiwan.
Dr. Conway: Vancouver Infectious Diseases Centre, 201–1200 Burrard Street, Vancouver, British Columbia V6Z 2C7, Canada.
Dr. Howe: British Columbia Centre for Excellence in HIV/AIDS, St. Paul's Hospital, 608–1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada.
Mr. Gendrano: Merck & Co., Inc., 126 East Lincoln Avenue, PO Box 2000, RY34-A474, Rahway, NJ 07065.
Mr. Chen: Merck & Co., Inc., 126 East Lincoln Avenue, PO Box 2000, RY34-A316, Rahway, NJ 07065.
Dr. Huang: Merck & Co., Inc., 2000 Galloping Hill Road, PO Box 539, K-15-4-D402, Kenilworth, NJ 07033.
Dr. Dutko: Merck & Co., Inc., 351 North Sumneytown Pike, UG3C-06, North Wales, PA 19454.
Dr. Nickle: Merck Sharp & Dohme Corp., 33 Avenue Louis Pasteur, Boston, MA 02115.
Dr. Nguyen: Merck & Co., Inc., 351 North Sumneytown Pike, UG4C-06, North Wales, PA 19454.
Dr. Wahl: Merck & Co. Merck & Co., Inc., 126 East Lincoln Avenue, PO Box 2000, RY34-A484, Rahway, NJ 07065.
Dr. Barr: Merck & Co., Inc., 351 North Sumneytown Pike, UG3C-96, North Wales, PA 19454.
Dr. Robertson: Merck & Co., Inc., 351 North Sumneytown Pike, UG3D-056, North Wales, PA 19454.
Dr. Platt: Merck & Co., Inc., 351 North Sumneytown Pike, North Wales, PA 19454.
Author Contributions: Conception and design: G.J. Dore, A.H. Litwin, O. Dalgard, J. Grebely, A.Y.M. Howe, I.N. Gendrano, B.Y. Nguyen, J. Wahl, E. Barr, M.N. Robertson, H.L. Platt.
Analysis and interpretation of the data: G.J. Dore, F. Altice, A.H. Litwin, O. Dalgard, O. Shibolet, A. Luetkemeyer, R. Nahass, C.Y. Peng, B. Conway, J. Grebely, A.Y.M. Howe, I.N. Gendrano, E. Chen, H.C. Huang, F.J. Dutko, D.C. Nickle, B.Y. Nguyen, J. Wahl, E. Barr, M.N. Robertson, H.L. Platt.
Drafting of the article: G.J. Dore, F. Altice, A.H. Litwin, A. Luetkemeyer, R. Nahass, B. Conway, I.N. Gendrano, H.C. Huang, F.J. Dutko, B.Y. Nguyen, E. Barr, M.N. Robertson, H.L. Platt.
Critical revision for important intellectual content: G.J. Dore, F. Altice, A.H. Litwin, O. Dalgard, O. Shibolet, C.Y. Peng, B. Conway, J. Grebely, B.Y. Nguyen, J. Wahl, E. Barr, M.N. Robertson, H.L. Platt.
Final approval of the article: G.J. Dore, F. Altice, A.H. Litwin, O. Dalgard, E.J. Gane, O. Shibolet, A. Luetkemeyer, R. Nahass, C.Y. Peng, B. Conway, J. Grebely, A.Y.M. Howe, I.N. Gendrano, E. Chen, H.C. Huang, F.J. Dutko, D.C. Nickle, B.Y. Nguyen, J. Wahl, E. Barr, M.N. Robertson, H.L. Platt.
Provision of study materials or patients: G.J. Dore, A.H. Litwin, O. Shibolet, R. Nahass, C.Y. Peng, B. Conway, B.Y. Nguyen.
Statistical expertise: E. Chen, D.C. Nickle.
Obtaining of funding: B.Y. Nguyen.
Administrative, technical, or logistic support: I.N. Gendrano, B.Y. Nguyen.
Collection and assembly of data: G.J. Dore, A.H. Litwin, O. Dalgard, O. Shibolet, A. Luetkemeyer, R. Nahass, C.Y. Peng, A.Y.M. Howe, I.N. Gendrano, H.C. Huang, E. Barr, H.L. Platt.
Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID).
To evaluate elbasvir–grazoprevir in treating HCV infection in PWID.
Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688)
Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States.
301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT).
The immediate-treatment group (ITG) received elbasvir–grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir–grazoprevir for 12 weeks.
The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events.
The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event.
These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID.
Patients with HCV infection who were receiving OAT and treated with elbasvir–grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT.
Merck & Co.
Dore GJ, Altice F, Litwin AH, Dalgard O, Gane EJ, Shibolet O, et al. Elbasvir–Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med. 2016;165:625–634. doi: 10.7326/M16-0816
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© 2019
Published: Ann Intern Med. 2016;165(9):625-634.
DOI: 10.7326/M16-0816
Published at www.annals.org on 9 August 2016
Gastroenterology/Hepatology, Infectious Disease, Liver Disease, Viral Hepatitis.
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