title: Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection.
abstract: Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.
  
  
  
  We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%).
  
  
  
  With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferon and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).
  
  
  
  The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.
authors.affiliation: Indiana University, Indianapolis, Indiana. Electronic address: pkwo@stanford.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Kwo
authors.affiliation: Auckland Clinical Studies, Grafton, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.affiliation: School of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Center for Hepatitis C, Atlanta Medical Center, Atlanta, Georgia.
authors.forename: Brian
authors.initials: B
authors.lastname: Pearlman
authors.affiliation: Baylor College of Medicine, Baylor-St. Luke's Medical Center, Houston, Texas.
authors.forename: John M
authors.initials: JM
authors.lastname: Vierling
authors.affiliation: Service d'Hépatologie, Hôpital Saint-Antoine, APHP, UPMC Paris 6, Paris, France.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Serfaty
authors.affiliation: Hospital Universitari Vall d'Hebron, and Ciberehd del Instituto Carlos III, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Buti
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Stephen
authors.initials: S
authors.lastname: Shafran
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Paul
authors.initials: P
authors.lastname: Stryszak
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gress
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Stuart
authors.initials: S
authors.lastname: Black
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Dutko
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Robertson
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Janice
authors.initials: J
authors.lastname: Wahl
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lupinacci
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Eliav
authors.initials: E
authors.lastname: Barr
authors.affiliation: Merck & Co, Inc, Kenilworth, New Jersey.
authors.forename: Barbara
authors.initials: B
authors.lastname: Haber
mesh_terms: D000328:Adult; D000368:Aged; D000577:Amides; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001572:Benzofurans / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood*; D019233:Retreatment; D012254:Ribavirin / Q000627:therapeutic use*; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D055815:Young Adult; D047029:Lactams, Macrocyclic
chemical_list: D000577:Amides; D000998:Antiviral Agents; D001572:Benzofurans; D002219:Carbamates; D003521:Cyclopropanes; D004338:Drug Combinations; D007093:Imidazoles; D011810:Quinoxalines; D012367:RNA, Viral; D012254:Ribavirin; D013449:Sulfonamides; C578009:grazoprevir; D047029:Lactams, Macrocyclic; C000589335:elbasvir
keywords: C-EDGE Treatment-Experienced; Hepatitis C; Randomized; Therapy