title: Pretreatment resistance to hepatitis C virus protease inhibitors boceprevir/telaprevir in hepatitis C virus subgenotype 1a-infected patients from Manitoba.
abstract: BACKGROUND
  Traditional therapy with pegylated interferon and ribavirin combined with the new protease inhibitors boceprevir or telaprevir has demonstrated improved outcomes in hepatitis C virus (HCV)-infected patients. Prevalence data regarding pre-existing drug-resistant variants to these two new virus inhibitors in the Canadian population are not available.
  
  
  OBJECTIVE
  To detect pre-existing mutations conferring resistance to boceprevir and⁄or telaprevir in Canadian patients infected with HCV genotype 1a.
  
  
  METHODS
  Resistance-associated mutations (RAMs) were evaluated in 85 patients infected with HCV genotype 1a who had not yet received antiviral therapy. The NS3 protease gene was sequenced and common RAMs were identified based on a recently published list.
  
  
  RESULTS
  The overall prevalence of pre-existing RAMs to boceprevir and telaprevir was higher compared with other similar studies. All of the observed RAMs were associated with a low level of resistance. A surprisingly high proportion of patients had the V55A RAM (10.6%). None of the mutations associated with a high level of resistance were observed. The simultaneous presence of two low-level resistance mutations (V36L and V55A) was observed in only one patient. Three other patients had both T54S RAM and V55I mutations, which may require a higher concentration of the protease drugs. The prevalence of various mutations in Aboriginal Canadian patients was higher (37.5%) compared with Caucasians (16.39%) (P=0.038).
  
  
  CONCLUSIONS
  The present study was the first to investigate pre-existing drug resistance to boceprevir⁄telaprevir in Canadian HCV-infected patients. A relatively high proportion of untreated HCV genotype 1a patients in Manitoba harbour low-level RAMs, especially patients of Aboriginal descent, which may contribute to an increased risk of treatment failure.
authors.affiliation: Public Health Agency of Canada, National Microbiology Laboratory, Winnipeg, Manitoba, Canada. anton.andonov@phac-aspc.gc.ca
authors.forename: Anton
authors.initials: A
authors.lastname: Andonov
authors.forename: Kamran
authors.initials: K
authors.lastname: Kadkhoda
authors.forename: Carla
authors.initials: C
authors.lastname: Osiowy
authors.forename: Kelly
authors.initials: K
authors.lastname: Kaita
mesh_terms: D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007198:Indians, North American; D008297:Male; D008350:Manitoba; D008875:Middle Aged; D009154:Mutation; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D017361:Viral Nonstructural Proteins / Q000235:genetics; D055815:Young Adult; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; 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; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide