title: Compensatory substitutions in the HCV NS3/4A protease cleavage sites are not observed in patients treated unsuccessfully with telaprevir combination treatment.
abstract: BACKGROUND
  Development of compensatory mutations within the HIV p7/p1 and p1/p6 protease cleavage site region has been observed in HIV-infected patients treated with protease inhibitors. Mechanisms of fitness compensation may occur in HCV populations upon treatment of HCV protease inhibitors as well.
  
  
  RESULTS
  In this study, we investigated whether substitutions in protease cleavage site regions of HCV occur in response to a treatment regimen containing the NS3/4A protease inhibitor telaprevir (TVR). Evaluation of viral populations from 569 patients prior to treatment showed that the four NS3/4A cleavage sites were well conserved. Few changes in the cleavage site regions were observed in the 159 patients who failed TVR combination treatment, and no residues displayed evidence of directional selection after the acquisition of TVR-resistance.
  
  
  CONCLUSIONS
  Cleavage site mutations did not occur after treatment with the HCV protease inhibitor telaprevir.
authors.affiliation: Vertex Pharmaceuticals Incorporated, 130 Waverly Street, Cambridge, MA 02139, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.forename: Ann
authors.initials: A
authors.lastname: Tigges
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Dorrian
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 / Q000008:administration & dosage; D002352:Carrier Proteins / Q000235:genetics*; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000201:enzymology / Q000235:genetics* / Q000302:isolation & purification; D006521:Hepatitis, Chronic / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020125:Mutation, Missense; D009842:Oligopeptides / Q000008:administration & dosage*; D017211:Treatment Failure; 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