title: Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis.
abstract: Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials.
  
  
  
  We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials. All patients received elbasvir/grazoprevir 50 mg/100 mg once daily, with or without ribavirin, for 12-18 weeks. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12), defined as a level of HCV RNA <15 IU/mL.
  
  
  
  Among treatment-naïve and treatment-experienced patients receiving elbasvir/grazoprevir for 12 weeks, 97.8% (135 of 138) and 88.9% (48 of 54) achieved SVR12, respectively. Among patients receiving elbasvir/grazoprevir for 12 weeks, addition of ribavirin did not increase the proportion of treatment-naïve patients (90.3%, 28 of 31) or treatment-experienced patients who achieved an SVR12 (91.4%, 74 of 81). All (49 of 49) treatment-experienced patients receiving elbasvir/grazoprevir with ribavirin for 16 or 18 weeks, and 93.9% (46 of 49) of patients receiving elbasvir/grazoprevir without ribavirin for 16 or 18 weeks achieved SVR12. Virologic failure was higher among patients with HCV genotype 1a infections compared with patients with genotype 1b or 4 infections, particularly in patients who had not responded to previous interferon therapy. Baseline tests for resistance-associated substitutions (RASs) led to an individualized approach for selecting treatment duration and established a need for ribavirin for patients with HCV genotype 1a infection and RASs, regardless of treatment history. Among patients with HCV genotype 1a infection with and without baseline RASs in HCV nonstructural protein 5A who received elbasvir/grazoprevir for 12 weeks, 73% (8 of 11) and 98% (96 of 98) achieved SVR12, respectively. Both patients with HCV genotype 1a infection with baseline RASs who received 16 or 18 weeks of elbasvir/grazoprevir and ribavirin achieved SVR12. Grade 3 or 4 increases in levels of alanine aminotransferase and aspartate aminotransferase, which did not cause symptoms, were reported in 2.3% (6 of 264) of patients receiving elbasvir/grazoprevir. Serious adverse events were reported in 3% (8 of 264) patients and no patient had a decompensation-related event.
  
  
  
  In an analysis of data from 6 clinical trials, rates of SVR12 ranged from 89% to 100% in patients with HCV genotype 1, 4, or 6 infections and compensated cirrhosis treated with elbasvir/grazoprevir, with or without ribavirin. Addition of ribavirin to a 12-week regimen of elbasvir/grazoprevir had little effect on the proportion of treatment-naïve or treatment-experienced patients who achieved an SVR12. However, virologic failure did not occur in any treatment-experienced patients when the duration of elbasvir/grazoprevir and ribavirin therapy was extended to 16 or 18 weeks. Baseline analysis of RASs (or in the absence of this test, a history of nonresponse to interferon) can be used to determine treatment duration and the need for ribavirin in patients with HCV genotype 1a infection. Clinicaltrials.gov ID: NCT02092350, NCT02105662, NCT02105467, NCT02105701, NCT01717326, and NCT02105454.
authors.affiliation: Mount Sinai Beth Israel and Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: ijacobson@chpnet.org.
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, Texas.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Paul Y
authors.initials: PY
authors.lastname: Kwo
authors.affiliation: Henri Mondor Hospital, Créteil, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Hézode
authors.affiliation: China Medical University Hospital, Taichung City, Taiwan.
authors.forename: Cheng-Yuan
authors.initials: CY
authors.lastname: Peng
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey.
authors.forename: Anita Y M
authors.initials: AYM
authors.lastname: Howe
authors.affiliation: Merck & Co., Inc, Kenilworth, New Jersey.
authors.forename: Peggy
authors.initials: P
authors.lastname: Hwang
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: Michael
authors.initials: M
authors.lastname: Robertson
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 A
authors.initials: BA
authors.lastname: Haber
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000577:Amides; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001572:Benzofurans / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003521:Cyclopropanes; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000503:physiopathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011810:Quinoxalines / Q000009:adverse effects / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D019233:Retreatment; D012189:Retrospective Studies; D012254:Ribavirin / Q000627:therapeutic use; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D017361:Viral Nonstructural Proteins / Q000235:genetics; D055815:Young Adult; D047029:Lactams, Macrocyclic; D012324:RNA-Dependent RNA Polymerase
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; D017361:Viral Nonstructural Proteins; C578009:grazoprevir; D047029:Lactams, Macrocyclic; C000589335:elbasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: ALT; Fibrosis; NS5A; Virus Mutation