title: Dynamic and rapid changes in viral quasispecies by UDPS in chronic hepatitis C patients receiving telaprevir-based therapy.
abstract: BACKGROUND
  Telaprevir (TVR) is a protease inhibitor (PI) used in chronic hepatitis C treatment with pegylated interferon plus ribavirin. We analysed the prevalence and kinetic development of TVR resistance upon treatment.
  
  
  METHODS
  A total of 24 cirrhotic patients (genotype 1a, n=8; genotype 1b, n=16) previously non-responders to standard therapy were treated with TVR-based therapy. The distribution of TVR-resistant variants was assessed at every HCV-RNA-positive time point by 454 ultra-deep pyrosequencing (UDPS) during a mean follow-up period of 9.4 months.
  
  
  RESULTS
  A median of 6,837 reads/specimen was studied. Based on control UDPS, we considered mutations as real when present >0.4%. TVR-resistant variants were found at baseline in 8/24 patients (33.3%). Four of the 24 patients (16.7%), all genotype 1a, did not achieve HCV RNA<100 IU/ml between week (W)2 and W12 and stopped treatment. No statistical significant difference was observed in the prevalence of resistant mutants between responders and non-responders (25% [5/20] and 75% [3/4], respectively). The proportion of genotype 1a patients with R155K/T/Q at baseline was higher in non-responders than in responders (50% versus 0%). During treatment failure, significant enrichment in V36A/M and R155K/T/Q was observed but their frequency reverted back to baseline after TVR discontinuation.
  
  
  CONCLUSIONS
  TVR-resistant variants are widely present at baseline. The presence of TVR-resistant mutants at baseline, even in high abundance (>20%), did not always preclude TVR treatment success. The detection of R155K/T/Q at baseline may predict failure in genotype 1a patients. At failure, which occurred in genotype 1a patients, a significant enrichment in V36A/M and R155K/T/Q was observed.
authors.affiliation: Laboratoire de Virologie, CHU de Bordeaux, Bordeaux, France. pascale.trimoulet@chu-bordeaux.fr.
authors.forename: Pascale
authors.initials: P
authors.lastname: Trimoulet
authors.forename: Patricia
authors.initials: P
authors.lastname: Pinson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Papuchon
authors.forename: Juliette
authors.initials: J
authors.lastname: Foucher
authors.forename: Julien
authors.initials: J
authors.lastname: Vergniol
authors.forename: Faiza
authors.initials: F
authors.lastname: Chermak
authors.forename: Linda
authors.initials: L
authors.lastname: Wittkop
authors.forename: Nadège
authors.initials: N
authors.lastname: Castaing
authors.forename: Wassil
authors.initials: W
authors.lastname: Merrouche
authors.forename: Sandrine
authors.initials: S
authors.lastname: Reigadas
authors.forename: Mathieu
authors.initials: M
authors.lastname: Molimard
authors.forename: Michael
authors.initials: M
authors.lastname: Kann
authors.forename: Hervé
authors.initials: H
authors.lastname: Fleury
authors.forename: Victor
authors.initials: V
authors.lastname: de Lédinghen
mesh_terms: D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009842:Oligopeptides / Q000627:therapeutic use*; D012367:RNA, Viral; D016896:Treatment Outcome; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D012367:RNA, Viral; C486464:telaprevir