title: Evaluation of persistence of resistant variants with ultra-deep pyrosequencing in chronic hepatitis C patients treated with telaprevir.
abstract: OBJECTIVE
  Telaprevir, a hepatitis C virus NS3/4A protease inhibitor has significantly improved sustained viral response rates when given in combination with pegylated interferon alfa-2a and ribavirin, compared with current standard of care in hepatitis C virus genotype 1 infected patients. In patients with a failed sustained response, the emergence of drug-resistant variants during treatment has been reported. It is unclear to what extent these variants persist in untreated patients. The aim of this study was to assess using ultra-deep pyrosequencing, whether after 4 years follow-up, the frequency of resistant variants is increased compared to pre-treatment frequencies following 14 days of telaprevir treatment.
  
  
  METHODS
  Fifteen patients from 2 previous telaprevir phase 1 clinical studies (VX04-950-101 and VX05-950-103) were included. These patients all received telaprevir monotherapy for 14 days, and 2 patients subsequently received standard of care. Variants at previously well-characterized NS3 protease positions V36, T54, R155 and A156 were assessed at baseline and after a follow-up of 4±1.2 years by ultra-deep pyrosequencing. The prevalence of resistant variants at follow-up was compared to baseline.
  
  
  RESULTS
  Resistance associated mutations were detectable at low frequency at baseline. In general, prevalence of resistance mutations at follow-up was not increased compared to baseline. Only one patient had a small, but statistically significant, increase in the number of V36M and T54S variants 4 years after telaprevir-dosing.
  
  
  CONCLUSIONS
  In patients treated for 14 days with telaprevir monotherapy, ultra-deep pyrosequencing indicates that long-term persistence of resistant variants is rare.
authors: Academic Medical Center, Department of Medical Microbiology, Section of Clinical Virology, Amsterdam, The Netherlands. x.v.thomas@amc.uva.nl
authors: Xiomara V
authors: XV
authors: Thomas
authors: Joep
authors: J
authors: de Bruijne
authors: James C
authors: JC
authors: Sullivan
authors: Tara L
authors: TL
authors: Kieffer
authors: Cynthia K Y
authors: CK
authors: Ho
authors: Sjoerd P
authors: SP
authors: Rebers
authors: Michel
authors: M
authors: de Vries
authors: Hendrik W
authors: HW
authors: Reesink
authors: Christine J
authors: CJ
authors: Weegink
authors: Richard
authors: R
authors: Molenkamp
authors: Janke
authors: J
authors: Schinkel
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis / Q000379:methods; D024882:Drug Resistance, Viral / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009842:Oligopeptides / Q000008:administration & dosage*; D013997:Time Factors; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: 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; C486464:telaprevir