title: Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects.
abstract: BACKGROUND
  The prevalence and clinical implications of naturally occurring variants that are resistant to hepatitis C virus (HCV) protease inhibitors in treatment-naive patients has not been reported. We report here the prevalence of such variants and their effect on clinical response.
  
  
  METHODS
  Population sequence analysis of the NS3.4A protease was conducted in 570 treatment-naive subjects.
  
  
  RESULTS
  Most subjects (98%) had wild-type virus. The remaining subjects had the following variants present in significant proportions (100%): V36M, 0.9%; R155K, 0.7%; V170A, 0.2%; and R109K, 0.2%. The V36M, R109K, and V170A substitutions confer low-level resistance (<7-fold) to protease inhibitors in replicon cells. The R155K substitution confers low-level resistance to telaprevir (TVR) and boceprevir and confers high-level resistance (>70-fold) to BILN 2061 and ITMN-191. Five subjects with the V36M or R109K variant were treated with 8-24 weeks of TVR and peginterferon-alpha2a (P) with or without ribavirin (R). Four achieved a sustained viral response, and 1 was lost to follow-up. In subjects with the R155K variant, TVR/PR provided greater antiviral activity than PR alone; however, the antiviral response was lower than that observed in subjects with wild-type virus.
  
  
  CONCLUSIONS
  High levels of naturally occurring protease inhibitor-resistant variants were uncommon (<1% each) in HCV treatment-naive patients. TVR/PR efficiently inhibited V36M and R109K variants and contributed partial antiviral activity against the R155K variant. As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity.
authors.affiliation: Department of Infectious Diseases, Vertex Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhou
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Michelle
authors.initials: M
authors.lastname: Marcial
authors.forename: Randal A
authors.initials: RA
authors.lastname: Byrn
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeiffer
authors.forename: Ann M
authors.initials: AM
authors.lastname: Tigges
authors.forename: Bambang S
authors.initials: BS
authors.lastname: Adiwijaya
authors.forename: Chao
authors.initials: C
authors.lastname: Lin
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
mesh_terms: D019943:Amino Acid Substitution; D000998:Antiviral Agents / Q000627:therapeutic use*; D005784:Gene Amplification; D014644:Genetic Variation; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D011480:Protease Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome; 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; 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