title: Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on Efficacy of Elbasvir and Grazoprevir.
abstract: Elbasvir (an NS5A inhibitor) and grazoprevir (an NS3/4A protease inhibitor) are direct-acting antiviral agents recently approved in the United States for treatment of chronic hepatitis C virus (HCV) genotype 1 and 4 infections, as a fixed-dose combination. Trials of elbasvir and grazoprevir, with or without ribavirin, demonstrated high rates of sustained virologic response 12 weeks after treatment ended (SVR12). However, 12 weeks of treatment with elbasvir and grazoprevir failed in a small proportion of patients with HCV genotype 1 infection. We summarize findings from independent US Food and Drug Administration analyses of drug resistance data from trials of elbasvir and grazoprevir, with and without ribavirin.
  
  
  
  We independently analyzed HCV drug resistance and HCV RNA measurement results that were submitted to the US Food and Drug Administration to support the regulatory approval of elbasvir and grazoprevir. These data were reported from selected phase 2 and 3 clinical trials of elbasvir and grazoprevir, with and without ribavirin. Genotypic resistance analyses were conducted using Sanger population nucleotide sequencing data derived from blood samples from study patients.
  
  
  
  In 56 of 506 (11%) patients with HCV genotype 1a infection who received elbasvir and grazoprevir for 12 weeks, baseline HCV genetic variants encoding amino acid polymorphisms in NS5A (M28, Q30, L31, or Y93) reduced treatment efficacy; rates of SVR12 were 70% and 98% for patients with or without NS5A polymorphisms, respectively (P < .0001). Most patients with treatment failure acquired resistance-associated substitutions in NS3 and/or NS5A. Based on data from a small number of patients (n = 6), an intensified 16-week regimen of elbasvir and grazoprevir plus ribavirin could increase efficacy in patients with HCV genotype 1a infection with NS5A polymorphisms. Among patients with HCV genotype 4a or 4d infections with NS5A polymorphisms, all 26 who received the elbasvir and grazoprevir regimens recommended in prescribing information achieved an SVR12.
  
  
  
  The combination of elbasvir and grazoprevir, with or without ribavirin is safe and effective for patients with HCV genotype 1 or 4 infections. In patients with HCV genotype 1a infection, polymorphisms in NS5A at baseline (before treatment) can affect the efficacy of this direct-acting antiviral regimen, and pretreatment resistance analyses can optimize treatment selection.
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland. Electronic address: takashi.komatsu@fda.hhs.gov.
authors: Takashi E
authors: TE
authors: Komatsu
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors: Sarita
authors: S
authors: Boyd
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors: Adam
authors: A
authors: Sherwat
authors: Office of Biostatistics, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors: LaRee
authors: L
authors: Tracy
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors: Lisa K
authors: LK
authors: Naeger
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland.
authors: Julian J
authors: JJ
authors: O'Rear
authors: Division of Antiviral Products, Office of Antimicrobial Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland. Electronic address: patrick.harrington@fda.hhs.gov.
authors: Patrick R
authors: PR
authors: Harrington
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use; D001572:Benzofurans / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D024882:Drug Resistance, Viral / Q000235:genetics*; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011810:Quinoxalines / Q000627:therapeutic use*; D012367:RNA, Viral / Q000235:genetics*; D012254:Ribavirin / Q000627:therapeutic use; D017211:Treatment Failure; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001572:Benzofurans; D004338:Drug Combinations; D007093:Imidazoles; D011810:Quinoxalines; D012367:RNA, Viral; D012254:Ribavirin; D017361:Viral Nonstructural Proteins; C000611265:elbasvir-grazoprevir drug combination; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: DAA; FDA; Post-Hoc Analysis; Replication