title: Deep-sequencing analysis of the gene encoding the hepatitis C virus nonstructural 3-4A protease confirms a low prevalence of telaprevir-resistant variants at baseline and the end of the REALIZE study.
abstract: BACKGROUND
  Population sequencing (PS) has shown that telaprevir-resistant variants are not typically detectable at baseline (prevalence, ≤5% of patients), and most variants present at the time of treatment failure are no longer detectable at the end of the study.
  
  
  METHODS
  To gain insight into the evolution of telaprevir-resistant variants, their baseline prevalence and persistence after treatment was investigated using a more sensitive, deep-sequencing (DS) technique in a large number of treatment-experienced patients from the REALIZE study who were infected with hepatitis C virus genotype 1.
  
  
  RESULTS
  Before treatment initiation, telaprevir-resistant variants (T54A, T54S, or R155K in 1%-2% of the viral population) were detected by DS in a fraction (2%) of patients for whom PS failed to detect resistance; these variants were not necessarily detected at the time of treatment failure. Of 49 patients in whom telaprevir-resistant variants were detected by PS at the time of treatment failure but not at the end of the study, DS revealed the presence of variants (V36A/L/M, T54S, or R155K in 1%-36% of the viral population) in 16 patients (33%) at the end of the study.
  
  
  CONCLUSIONS
  Similar to PS findings, DS analysis revealed that the frequency of telaprevir-resistant variants before treatment was also low, and variants detected at the time of treatment failure were no longer detectable in the majority of patients during follow-up.
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Kim
authors.initials: K
authors.lastname: Thys
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Ghys
authors.affiliation: Vertex Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.affiliation: Vertex Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Aerssens
authors.affiliation: Janssen Research and Development, Titusville, New Jersey.
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
authors.affiliation: Janssen Infectious Diseases, Beerse, Belgium.
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000201:enzymology* / Q000235:genetics* / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D059645:Mutation Rate; D009842:Oligopeptides / Q000627:therapeutic use*; D015995:Prevalence; D017361:Viral Nonstructural Proteins / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009842:Oligopeptides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C486464:telaprevir
keywords: Genotype 1; HCV; deep sequencing technique; mutation; population sequencing; resistance; telaprevir