TY - JOUR
T1 - Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY)
T2 - A randomised, open-label phase 2 trial
AU - Sulkowski, Mark
AU - Hezode, Christophe
AU - Gerstoft, Jan
AU - Vierling, John M.
AU - Mallolas, Josep
AU - Pol, Stanislas
AU - Kugelmas, Marcelo
AU - Murillo, Abel
AU - Weis, Nina
AU - Nahass, Ronald
AU - Shibolet, Oren
AU - Serfaty, Lawrence
AU - Bourliere, Marc
AU - Dejesus, Edwin
AU - Zuckerman, Eli
AU - Dutko, Frank
AU - Shaughnessy, Melissa
AU - Hwang, Peggy
AU - Howe, Anita Y.M.
AU - Wahl, Janice
AU - Robertson, Michael
AU - Barr, Eliav
AU - Haber, Barbara
N1 - Funding Information:
MS reports funds for research grants paid directly to Johns Hopkins University and personal fees from Merck during the conduct of the study; funds for research grants paid directly to Johns Hopkins University from AbbVie, Boehringer Ingelheim, Bristol-Meyers Squibb, and Gilead; and personal fees from AbbVie, Bristol-Meyers Squibb, Gilead, Janssen, and Tobira outside the submitted work. CH reports personal fees for advising and speaking from Merck Sharp & Dohme during the conduct of the study and personal fees for advising and speaking from AbbVie, Bristol-Meyers Squibb, Gilead, Janssen, and Roche outside the submitted work. JG reports financial compensation for the clinical trial from Merck during the conduct of the study; grant and personal fees from Gilead; and personal fees from Bristol-Meyers Squibb, Medivir, AbbVie, Glaxo, Merck, and Janssen outside the submitted work. JMV has received research grants, and personal fees for Speaker's Bureau and Scientific Advisory Board from Merck for the current study; expert testimony for the Food and Drug Administration and the Centers for Disease Control and Prevention; has grants or grants pending from Abbott (AbbVie), Bristol-Meyers Squibb, Conatus, Excalenz, Genentech, Genfit, Gilead, Globeimmune, Hyperion, Idenix-Novartis, Ikaria, Intercept, Merck (formerly Schering), Mochida, Novartis, Ocera, Pfizer, Pharmasset (now Gilead), Roche, Sundise, Tranzyme, Vertex, and Zymogenetics (now Bristol-Meyers Squibb); has received payment for continuing medical education lectures including service on speakers bureaus from the American Liver Foundation, Chronic Liver Diseases Foundation, and GI and Liver Association of the Americas (GALA); has received travel, accommodations, or meeting expenses from the National Institutes of Health and the National Institute for Diabetes and Digestive and Kidney Diseases; is a past Secretary-Treasurer for Digestive Diseases Week; and is a principal for the Clinical Research Centers of America and the Liver Drug Safety Alliance. JM reports personal fees from Merck Sharp & Dohme during the conduct of this study and personal fees for lectures or advisory boards from Merck Sharp & Dohme, Janssen, Boehringer Ingelheim, ViiV, Bristol-Meyers Squibb, Gilead, and Roche outside the submitted work. SP reports personal fees from Merck Sharp & Dohme during the conduct of the study; grants and personal fees from Merck Sharp & Dohme, and Roche; and personal fees from Bristol-Meyers Squibb, Gilead, Novartis, GlaxoSmithKline, Boehringer Ingelheim, Janssen, Sanofi, Vertex, and AbbVie outside the submitted work. MK reports grants and personal fees (consulting) from Merck during the conduct of the study and grants and personal fees (consulting) from Merck outside the submitted work. AM reports personal fees during the conduct of the clinical study. NW reports personal fees from Merck Sharp & Dohme during the conduct of the study and to be investigator, consultant, or speaker for Merck Sharp & Dohme, Abbvie, Bristol-Myers Squibb, Roche, Janssen, and Gilead outside the submitted work. RN reports grants and personal fees from Merck during the conduct of the study; grants and personal fees from Bristol-Myers Squibb; and grants from Abbvie, and Gilead outside the submitted work. OS reports financial support from Merck during the conduct of the study and personal fees from Abbvie, Gilead, and Bristol-Myers Squibb outside the submitted work. LS reports financial support for the clinical trial from Merck during the conduct of the study and personal fees from Janssen, Bristol-Myers Squibb, Gilead, Abbvie, Merck, and Roche outside the submitted work. MB reports grants and personal fees from Merck during the conduct of the study; personal fees from Bristol-Myers Squibb, AbbVie, Gilead, Roche, and GlaxoSmithKline; and grants and personal fees from Janssen outside the submitted work. ED reports financial support for the clinical trial from Merck during the conduct of the study and personal fees from Gilead Sciences, Janssen, and Vertex outside the submitted work. EZ reports financial support for the clinical trial from Merck during the conduct of the study. FD, MS, PH, AYMH, JW, MR, EB, and BH are current employees of Merck & Co, Inc (Whitehouse Station, NJ, USA) and hold stock or stock options.
Publisher Copyright:
© 2015 Elsevier Ltd.
PY - 2015/3/21
Y1 - 2015/3/21
N2 - Background Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. Methods The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. Findings 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). Interpretation Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.
AB - Background Both hepatitis C virus (HCV) mono-infected and HIV/HCV co-infected patients are in need of safe, effective, all-oral HCV regimens. In a phase 2 study we aimed to assess the efficacy and safety of grazoprevir (MK-5172; HCV NS3/4A protease inhibitor) and two doses of elbasvir (MK-8742; HCV NS5A inhibitor) in patients with HCV mono-infection and HIV/HCV co-infection. Methods The C-WORTHY study is a phase 2, multicentre, randomised controlled trial of grazoprevir plus elbasvir with or without ribavirin in patients with HCV; here, we report findings for previously untreated (genotype 1) patients without cirrhosis who were HCV mono-infected or HIV/HCV co-infected. Eligible patients were previously untreated adults aged 18 years or older with chronic HCV genoype 1 infection and HCV RNA at least 10 000 IU/mL in peripheral blood without evidence of cirrhosis, hepatocellular carcinoma, or decompensated liver disease. In part A of the study we randomly assigned HCV-mono-infected patients to receive 12 weeks of grazoprevir (100 mg) plus elbasvir (20 mg or 50 mg) with or without ribavirin (arms A1-3); in part B we assigned HCV-mono-infected patients to 8 or 12 weeks of grazoprevir (100 mg) plus elbasvir (50 mg) with or without ribavirin (arms B1-3) and HIV/HCV co-infected patients to 12 weeks of therapy with or without ribavirin. The primary endpoint was the proportion of patients achieving HCV RNA less than 25 IU/mL 12 weeks after end of treatment (SVR12). Randomisation was by presence or absence of ribavirin, 8 or 12 weeks of treatment, and dosage of elbasvir. Patients were stratified by gentoype 1a versus 1b. The patients, investigators, and study site personnel were masked to treatment group assignements but the funder was not. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01717326. Findings 218 patients with HCV mono-infection (n=159) and HIV/HCV co-infection (n=59) were enrolled. SVR12 for patients treated for 12 weeks with or without ribavirin ranged from 93-98% in mono-infected and 87-97% in co-infected patients. SVR12 rates in mono-infected and co-infected patients treated for 12 weeks without ribavirin were 98% (95% CI 88-100; 43/44) and 87% (95% CI 69-96; 26/30), respectively, and with ribavirin were 93% (95% CI 85-97; 79/85) and 97% (95% CI 82-100; 28/29), respectively. Among mono-infected patients with genotype 1a infection treated for 8 weeks, SVR12 was 80% (95% CI 61-92; 24/30). Five of six patients who discontinued early for reasons other than virological failure had HCV RNA less than 25 IU/mL at their last study visit. Virological failure among patients treated for 12 weeks occurred in seven patients (7/188, 4%) and was associated with emergence of resistance-associated variants to one or both drugs. The safety profile of grazoprevir plus elbasvir with or without ribavirin was similar in mono-infected and co-infected patients. No patient discontinued due to an adverse event or laboratory abnormality. The most common adverse events were fatigue (51 patients, 23%), headache (44, 20%), nausea (32, 15%), and diarrhoea (21, 10%). Interpretation Once-daily grazoprevir plus elbasvir with or without ribavirin for 12 weeks in previously untreated HCV-mono-infected and HIV/HCV-co-infected patients without cirrhosis achieved SVR12 rates of 87-98%. These results support the ongoing phase 3 development of grazoprevir plus elbasvir. Funding Merck & Co, Inc.
UR - http://www.scopus.com/inward/record.url?scp=84925423399&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925423399&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(14)61793-1
DO - 10.1016/S0140-6736(14)61793-1
M3 - Article
C2 - 25467560
AN - SCOPUS:84925423399
SN - 0140-6736
VL - 385
SP - 1087
EP - 1097
JO - The Lancet
JF - The Lancet
IS - 9973
ER -