title: Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort.
abstract: BACKGROUND
  Protease inhibitors (PI) including boceprevir, telaprevir and simeprevir have revolutionised HCV genotype 1 treatment since their introduction. A number of pre-treatment resistance associated amino acid variants (RAVs) and polymorphisms have been associated with reduced response to treatment.
  
  
  OBJECTIVE
  We measured the prevalence of RAVs/polymorphisms in a PI treatment-naïve HCV genotype 1 Scottish cohort using Sanger sequencing.
  
  
  METHODS
  Chronically infected, treatment-naïve, HCV genotype 1 patients (n = 146) attending NHS Greater Glasgow and Clyde clinics were investigated for RAVs/polymorphisms to the PIs boceprevir, telaprevir and simeprevir. The NS3/4A region was amplified by nested polymerase chain reaction. The 1.4 kb amplified product was sequenced using an ABI 3710XL DNA sequencer. Sequence analysis was performed using web-based ReCall (beta 2.10). Amino acid positions 36, 41, 43, 54, 55, 80, 109, 122, 155, 156, 168 and 170 were analysed for RAVs/polymorphisms.
  
  
  RESULTS
  Overall, 23.29% (34/146) of patients had an RAV or polymorphism detected. Overall, 13.69% (20/146) of patients had HCV virus that contained the Q8 K polymorphism. Other RAVs detected were: V36 M 0.70% (1/146), V36L 0.70% (1/146), T54S 6.85% (10/146), V55A 3.42% (5/146) and V/I170A 0.68% (1/146). Four patients had dual combinations of mutations (T54S+V36L; T54S+V55A and 2 patients with T54S+Q80K).
  
  
  CONCLUSIONS
  Q80K was the most prevalent baseline polymorphism detected in the Scottish cohort. Simeprevir treatment is not recommended in patients infected with the Q80K genotype 1a variant. This highlights the need for baseline sequencing prior to administration of this drug in this population.
authors.affiliation: West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom. Electronic address: Samantha.Shepherd@ggc.scot.nhs.uk.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Shepherd
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Stoker Building, 464 Bearsden Road, Glasgow G61 1QH, United Kingdom.
authors.forename: Tamer
authors.initials: T
authors.lastname: Abdelrahman
authors.affiliation: West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom.
authors.forename: Alasdair R
authors.initials: AR
authors.lastname: MacLean
authors.affiliation: MRC-University of Glasgow Centre for Virus Research, Stoker Building, 464 Bearsden Road, Glasgow G61 1QH, United Kingdom.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Thomson
authors.affiliation: West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom.
authors.forename: Celia
authors.initials: C
authors.lastname: Aitken
authors.affiliation: West of Scotland Specialist Virology Centre, Level 5, New Lister Building, 10-16 Alexandra Parade, Glasgow G31 2ER, United Kingdom.
authors.forename: Rory N
authors.initials: RN
authors.lastname: Gunson
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000494:pharmacology; D024882:Drug Resistance, Viral; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D008297:Male; D009154:Mutation / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015995:Prevalence; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D012606:Scotland; D017422:Sequence Analysis, DNA; D000069616:Simeprevir / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011392:Proline; D000069616:Simeprevir; 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
keywords: HCV; Prevalence; Protease inhibitor; RAV; Simeprevir