David Wyles1, Heiner Wedemeyer2, Ziv Ben-Ari3, Edward J Gane4, Jesper Bach Hansen5, Ira M Jacobson6, Alex L Laursen7, Annie Luetkemeyer8, Ronald Nahass9, Stephen Pianko10, Stefan Zeuzem11, Patricia Jumes12, Hsueh-Cheng Huang12, Joan Butterton12, Michael Robertson12, Janice Wahl12, Eliav Barr12, Hee-Koung Joeng12, Elizabeth Martin12, Lawrence Serfaty13. 1. University of Colorado School of Medicine, Denver, CO. 2. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. 3. Sheba Medical Center, Tel Hashomer, Israel. 4. Auckland Hospital, Auckland, New Zealand. 5. Aalborg University Hospital, Department of Gastroenterology, Aalborg, Denmark. 6. Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, NY. 7. Department of Infectious Diseases, Aarhus University Hospital, Skejby, Aarhus, Denmark. 8. Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA. 9. ID Care, Hillsborough, NJ. 10. Monash Medical Centre, Clayton, Victoria, Australia. 11. Goethe University Hospital, Frankfurt, Germany. 12. Merck & Co., Inc., Kenilworth, NJ. 13. Service d'Hépatologie, Hôpital Saint-Antoine, Université Pierre & Marie Curie, Paris, France.
Abstract
People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. CONCLUSION:Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).
RCT Entities:
People with hepatitis C virus (HCV) infection who have failed treatment with an all-oral regimen represent a challenging treatment population. The present studies evaluated the safety and efficacy of grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, in participants who had failed an NS5A inhibitor-containing regimen. C-SURGE (PN-3682-021) and C-CREST Part C (PN-3682-011 and -012) were open-label, multicenter studies. Participants who had previously relapsed following an NS5A inhibitor-containing all-oral regimen were retreated with grazoprevir 100 mg, ruzasvir 60 mg, and uprifosbuvir 450 mg alone for 24 weeks or with ribavirin for 16 weeks. The primary efficacy endpoint was sustained virologic response (HCV RNA below the limit of quantitation [<15 IU/mL]) 12 weeks after treatment completion (SVR12). In C-SURGE, SVR12 was achieved by 49/49 (100%) and 43/44 (98%) genotype (GT)1 participants in the 24-week no ribavirin arm and the 16-week plus ribavirin arm (lost to follow-up, n = 1), respectively. In C-CREST Part C, SVR12 was achieved by 23/24 (96%) participants treated for 16 weeks with ribavirin (GT1, 2/2 [100%]; GT2, 13/14 [93%]; GT3, 8/8 [100%]). One participant with GT2 infection discontinued study medication after a single dose of grazoprevir, ruzasvir, and uprifosbuvir plus ribavirin due to serious adverse events of vomiting and tachycardia. The presence of baseline resistance-associated substitutions had no impact on SVR12. No participant who completed treatment in either study experienced virologic failure. CONCLUSION:Grazoprevir, ruzasvir, and uprifosbuvir, with or without ribavirin, for 16 or 24 weeks was safe and highly effective in participants with HCV infection who had previously failed NS5A inhibitor-containing therapy. (Hepatology 2017;66:1794-1804).
Authors: Thomas N Kakuda; Matthew W McClure; Christopher Westland; Jennifer Vuong; Marie-Claude Homery; Gwendoline Poizat; Laure Viguerie; Caroline Denot; Alain Patat; Qingling Zhang; James Hui; David Apelian; David B Smith; Sushmita M Chanda; John Fry Journal: Pharmacol Res Perspect Date: 2018-04-30
Authors: Dao Feng Xiang; Andrew N Bigley; Emily Desormeaux; Tamari Narindoshvili; Frank M Raushel Journal: Biochemistry Date: 2019-07-10 Impact factor: 3.162