title: NS5A resistance-associated substitutions in patients with genotype 1 hepatitis C virus: Prevalence and effect on treatment outcome.
abstract: The efficacy of NS5A inhibitors for the treatment of patients chronically infected with hepatitis C virus (HCV) can be affected by the presence of NS5A resistance-associated substitutions (RASs). We analyzed data from 35 phase I, II, and III studies in 22 countries to determine the pretreatment prevalence of various NS5A RASs, and their effect on outcomes of treatment with ledipasvir-sofosbuvir in patients with genotype 1 HCV.
  
  
  
  NS5A gene deep sequencing analysis was performed on samples from 5397 patients in Gilead clinical trials. The effect of baseline RASs on sustained virologic response (SVR) rates was assessed in the 1765 patients treated with regimens containing ledipasvir-sofosbuvir.
  
  
  
  Using a 15% cut-off, pretreatment NS5A and ledipasvir-specific RASs were detected in 13% and 8% of genotype 1a patients, respectively, and in 18% and 16% of patients with genotype 1b. Among genotype 1a treatment-naïve patients, SVR rates were 91% (42/46) vs. 99% (539/546) for those with and without ledipasvir-specific RASs, respectively. Among treatment-experienced genotype 1a patients, SVR rates were 76% (22/29) vs. 97% (409/420) for those with and without ledipasvir-specific RASs, respectively. Among treatment-naïve genotype 1b patients, SVR rates were 99% for both those with and without ledipasvir-specific RASs (71/72 vs. 331/334), and among treatment-experienced genotype 1b patients, SVR rates were 89% (41/46) vs. 98% (267/272) for those with and without ledipasvir-specific RASs, respectively.
  
  
  
  Pretreatment ledipasvir-specific RASs that were present in 8-16% of patients have an impact on treatment outcome in some patient groups, particularly treatment-experienced patients with genotype 1a HCV.
  
  
  
  The efficacy of treatments using NS5A inhibitors for patients with chronic hepatitis C virus (HCV) infection can be affected by the presence of NS5A resistance-associated substitutions (RASs). We reviewed results from 35 clinical trials where patients with genotype 1 HCV infection received treatments that included ledipasvir-sofosbuvir to determine how prevalent NS5A RASs are in patients at baseline, and found that ledipasvir-specific RASs were present in 8-16% of patients prior to treatment and had a negative impact on treatment outcome in subset of patient groups, particularly treatment-experienced patients with genotype 1a HCV.
authors.affiliation: Goethe-Universität, Frankfurt am Main, Germany. Electronic address: zeuzem@em.uni-frankfurt.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.affiliation: National Center for Global Health and Medicine, Chiba, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Mizokami
authors.affiliation: Monash Health and Monash University, Melbourne, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Pianko
authors.affiliation: IRCCS Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangia
authors.affiliation: Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kwang-Hyub
authors.initials: KH
authors.lastname: Han
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Ross
authors.initials: R
authors.lastname: Martin
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Evguenia
authors.initials: E
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: Doehle
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hedskog
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Chohee
authors.initials: C
authors.lastname: Yun
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Knox
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.affiliation: University of Dundee, Dundee, United Kingdom.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Inc., Foster City, CA, United States.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wan-Long
authors.initials: WL
authors.lastname: Chuang
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, United States.
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobson
authors.affiliation: The Kirby Institute, University of New South Wales, Sydney, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Dore
authors.affiliation: Johns Hopkins University School of Medicine, Baltimore, MD, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Sulkowski
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use; D024882:Drug Resistance, Viral; D005260:Female; D005449:Fluorenes / Q000627:therapeutic use; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D017361:Viral Nonstructural Proteins; C586541:ledipasvir; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Genotype; HCV genotype 1; Ledipasvir; NS5A RAS; Sofosbuvir; Sustained virologic response; Treatment outcome