Fred Poordad1, William Sievert2, Lindsay Mollison3, Michael Bennett4, Edmund Tse5, Norbert Bräu6, James Levin7, Thomas Sepe8, Samuel S Lee9, Peter Angus10, Brian Conway11, Stanislas Pol12, Nathalie Boyer13, Jean-Pierre Bronowicki14, Ira Jacobson15, Andrew J Muir16, K Rajender Reddy17, Edward Tam18, Grisell Ortiz-Lasanta19, Victor de Lédinghen20, Mark Sulkowski21, Navdeep Boparai22, Fiona McPhee23, Eric Hughes22, E Scott Swenson23, Philip D Yin23. 1. Texas Liver Institute, University of Texas Health Science Center, San Antonio. 2. Monash Health and Monash University, Melbourne, Australia. 3. Fremantle Hepatitis Services, School of Medicine and Pharmacology, University of Western Australia, Fremantle, Australia. 4. Medical Associates Research Group, San Diego, California. 5. Royal Adelaide Hospital, Adelaide, Australia. 6. James J. Peters Veterans Affairs Medical Center, Bronx, New York7Icahn School of Medicine at Mount Sinai, New York, New York. 7. Dean Foundation, Madison, Wisconsin. 8. University Gastroenterology, Providence, Rhode Island. 9. University of Calgary, Calgary, Alberta, Canada. 10. Austin Hospital, Victoria, Australia. 11. Vancouver Infectious Diseases Centre, Vancouver, British Columbia, Canada. 12. Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, INSERM UMS-20, Institut Pasteur, Paris, France. 13. Service d'Hépatologie, Hôpital Beaujon, Clichy, France. 14. INSERM U954, Centre Hospitalier Universitaire de Nancy, Université de Lorraine, Vandoeuvre les Nancy, France. 15. Weill Cornell Medical College, New York, New York. 16. Duke University Medical Center, Durham, North Carolina. 17. University of Pennsylvania, Philadelphia. 18. LAIR Centre, Vancouver, British Columbia, Canada. 19. Fundacion de Investigacion, San Juan, Puerto Rico. 20. Hôpital Du Haut-Leveque, Pessac, France. 21. Johns Hopkins University School of Medicine, Baltimore, Maryland. 22. Bristol-Myers Squibb, Princeton, New Jersey. 23. Bristol-Myers Squibb, Wallingford, Connecticut.
Abstract
IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE: To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS: Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS: Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979939.
IMPORTANCE: The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE: To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS: This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS:Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES: The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS: Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE: In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979939.
Authors: Elizabeth J Fay; Stephanie L Aron; Ian A Stone; Barbara M Waring; Richard K Plemper; Ryan A Langlois Journal: J Virol Date: 2018-12-10 Impact factor: 5.103
Authors: Meghan E Sise; Elke Backman; Guillermo A Ortiz; Gregory L Hundemer; Nneka N Ufere; Donald F Chute; Joseph Brancale; Dihua Xu; Jessica Wisocky; Ming V Lin; Arthur Y Kim; Ravi Thadhani; Raymond T Chung Journal: Clin J Am Soc Nephrol Date: 2017-09-07 Impact factor: 8.237