1Hospital Universitario Valle Hebron and Ciberehd, Barcelona, Spain.
2Henry Ford Health System, Detroit, Michigan.
3Carmel Medical Center, Haifa, Israel.
4Texas Liver Institute, University of Texas Health Science Center, San Antonio.
5Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Spain.
6Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.
7Merck and Co, Inc, Kenilworth, New Jersey.
8Liver Unit, Hospital Clinic, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain.
The phase 2 C-SALVAGE study (Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy) demonstrated a 96.2% sustained virologic response at 12 weeks (SVR12) rate using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treatment-experienced patients with chronic hepatitis C virus (HCV) genotype 1 infection.
C-SALVAGE was a prospective open-label trial of grazoprevir 100 mg once daily and elbasvir 50 mg once daily coadministered with weight-based ribavirin twice daily for 12 weeks in genotype 1-infected cirrhotic and noncirrhotic patients who had failed treatment with ≥4 weeks of pegylated interferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Although the primary efficacy outcome was SVR12, patients were also evaluated 24 weeks after cessation of study therapy. Population sequencing was performed at baseline and periodically in virologic failures throughout the 24-week posttherapy follow-up period.
SVR24 rates were 76 of 79 (96.2%) overall, with all 3 relapses occurring by posttherapy week 8. Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period. NS3_A156T emerged in virus from each patient at relapse, but rapidly disappeared over the ensuing 2 weeks in 2 patients. NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period.
Grazoprevir and elbasvir with ribavirin for 12 weeks maintained HCV suppression for at least 24 weeks posttherapy without late relapses. Baseline resistance-associated variants (RAVs) stably reappeared at relapse in all 3 patients with virologic failure. NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period. If confirmed, this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor.
CLINICAL TRIALS REGISTRATION: