title: Post-treatment resistance analysis of hepatitis C virus from phase II and III clinical trials of ledipasvir/sofosbuvir.
abstract: Ledipasvir/sofosbuvir combination treatment in phase III clinical trials resulted in sustained viral suppression in 94-99% of patients. This study characterized drug resistance in treatment failures, which may help to inform retreatment options.
  
  
  
  We performed NS5A and NS5B deep sequencing of hepatitis C virus (HCV) from patients infected with genotype (GT) 1 who participated in ledipasvir/sofosbuvir phase II and III clinical trials.
  
  
  
  Fifty-one of 2144 (2.4%) (42 GT1a and 9 GT1b) treated patients met the criteria for resistance analysis due to virologic failure following the end of treatment. The majority of patients with virologic failure (38 of 51; 74.5%) had detectable ledipasvir-specific resistance-associated substitutions (RASs) at the time of virologic failure (1% deep sequencing cut-off). The percent of patients with NS5A RASs at virologic failure were 37.5%, 66.7%, 94.7% and 100% in patients treated for 6, 8, 12 and 24weeks, respectively. The common substitutions detected at failure were Q30R/H, and/or Y93H/N in GT1a and Y93H in GT1b. At failure, 35.3% (18/51) of virologic failure patients' viruses had two or more NS5A RASs and the majority of patients harbored NS5A RASs conferring a 100-1000-fold (n=10) or >1000-fold (n=23) reduced susceptibility to ledipasvir. One patient in a phase II study with a known ledipasvir RAS at baseline (L31M) developed the S282T sofosbuvir (NS5B) RAS at failure.
  
  
  
  In GT1 HCV-infected patients treated with ledipasvir/sofosbuvir±ribavirin, virologic failure was rare. Ledipasvir resistance in NS5A was selected or enhanced in most patients with virologic failure, one of whom also developed resistance to sofosbuvir.
  
  
  
  Clinical studies have shown that combination treatment with ledipasvir/sofosbuvir efficiently cures most patients with genotype 1 hepatitis C infection. For the few patients failing treatment, we show that resistance to ledipasvir was observed in most patients, whereas resistance to sofosbuvir was less common. This has important implications for the selection of optimal retreatment strategies for these patients.
authors.affiliation: University of California San Diego, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Wyles
authors.affiliation: Gilead Sciences, Foster City, CA, USA. Electronic address: Hadas.dvory-sobol@gilead.com.
authors.forename: Hadas
authors.initials: H
authors.lastname: Dvory-Sobol
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Evguenia S
authors.initials: ES
authors.lastname: Svarovskaia
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Doehle
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Martin
authors.affiliation: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors.forename: Nezam H
authors.initials: NH
authors.lastname: Afdhal
authors.affiliation: Swedish Medical Center, Seattle, WA, USA.
authors.forename: Kris V
authors.initials: KV
authors.lastname: Kowdley
authors.affiliation: Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lawitz
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Brainard
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Miller
authors.affiliation: Gilead Sciences, Foster City, CA, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.affiliation: New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics; D005449:Fluorenes / Q000627:therapeutic use*; D005814:Genes, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation; D000069474:Sofosbuvir; D000072230:Sustained Virologic Response; D017211:Treatment Failure; D014542:Uridine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017361:Viral Nonstructural Proteins / Q000235:genetics; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; D000069474:Sofosbuvir; D014542:Uridine Monophosphate; D017361:Viral Nonstructural Proteins; C000595958:ledipasvir, sofosbuvir drug combination; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: DAA; Drug resistance; Hepatitis C virus; Ledipasvir; NS5A; NS5B; Ribavirin; Sofosbuvir