title: Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  NCT02105454.
authors.affiliation: Hospital Universitario Valle Hebron and Ciberehd, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: Henry Ford Health System, Detroit, Michigan.
authors.forename: Stuart C
authors.initials: SC
authors.lastname: Gordon
authors.affiliation: Carmel Medical Center, Haifa, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Zuckerman
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Servicio de Gastroenterología y Hepatología, Hospital Universitario Puerta de Hierro, Universidad Autonoma de Madrid, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Calleja
authors.affiliation: Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria.
authors.forename: Harald
authors.initials: H
authors.lastname: Hofer
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gilbert
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Palcza
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Anita Y M
authors.initials: AY
authors.lastname: Howe
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: DiNubile
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Robertson
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Merck and Co, Inc, Kenilworth, New Jersey.
authors.forename: Eliav
authors.initials: E
authors.lastname: Barr
authors.affiliation: Liver 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.
authors.forename: Xavier
authors.initials: X
authors.lastname: Forns
mesh_terms: D000577:Amides; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001572:Benzofurans / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002219:Carbamates; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016879:Salvage Therapy / Q000379:methods / Q000706:statistics & numerical data*; D013449:Sulfonamides; D016896:Treatment Outcome; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D007093:Imidazoles; D011810:Quinoxalines; D012254:Ribavirin; D013449:Sulfonamides; C578009:grazoprevir; D047029:Lactams, Macrocyclic; C000589335:elbasvir
keywords: C-SALVAGE; elbasvir; genotype 1; grazoprevir; resistance-associated variants (RAVs)