title: Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials.
abstract: BACKGROUND
  In patients with genotype 1 chronic hepatitis C infection, telaprevir (TVR) in combination with peginterferon and ribavirin (PR) significantly increased sustained virologic response (SVR) rates compared with PR alone. However, genotypic changes could be observed in TVR-treated patients who did not achieve an SVR.
  
  
  METHODS
  Population sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.
  
  
  RESULTS
  Resistant variants were observed after treatment with a telaprevir-based regimen in 12% of treatment-naïve patients (ADVANCE; T12PR arm), 6% of prior relapsers, 24% of prior partial responders, and 51% of prior null responder patients (REALIZE, T12PR48 arms). NS3 protease variants V36M, R155K, and V36M+R155K emerged frequently in patients with genotype 1a and V36A, T54A, and A156S/T in patients with genotype 1b. Lower-level resistance to telaprevir was conferred by V36A/M, T54A/S, R155K/T, and A156S variants; and higher-level resistance to telaprevir was conferred by A156T and V36M+R155K variants. Virologic failure during telaprevir treatment was more common in patients with genotype 1a and in prior PR nonresponder patients and was associated with higher-level telaprevir-resistant variants. Relapse was usually associated with wild-type or lower-level resistant variants. After treatment, viral populations were wild-type with a median time of 10 months for genotype 1a and 3 weeks for genotype 1b patients.
  
  
  CONCLUSIONS
  A consistent, subtype-dependent resistance profile was observed in patients who did not achieve an SVR with telaprevir-based treatment. The primary role of TVR is to inhibit wild-type virus and variants with lower-levels of resistance to telaprevir. The complementary role of PR is to clear any remaining telaprevir-resistant variants, especially higher-level telaprevir-resistant variants. Resistant variants are detectable in most patients who fail to achieve SVR, but their levels decline over time after treatment.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts, United States of America. tara_kieffer@vrtx.com
authors.forename: Tara L
authors.initials: TL
authors.lastname: Kieffer
authors.forename: Sandra
authors.initials: S
authors.lastname: De Meyer
authors.forename: Doug J
authors.initials: DJ
authors.lastname: Bartels
authors.forename: James C
authors.initials: JC
authors.lastname: Sullivan
authors.forename: Eileen Z
authors.initials: EZ
authors.lastname: Zhang
authors.forename: Ann
authors.initials: A
authors.lastname: Tigges
authors.forename: Inge
authors.initials: I
authors.lastname: Dierynck
authors.forename: Joan
authors.initials: J
authors.lastname: Spanks
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dorrian
authors.forename: Min
authors.initials: M
authors.lastname: Jiang
authors.forename: Bambang
authors.initials: B
authors.lastname: Adiwijaya
authors.forename: Anne
authors.initials: A
authors.lastname: Ghys
authors.forename: Maria
authors.initials: M
authors.lastname: Beumont
authors.forename: Robert S
authors.initials: RS
authors.lastname: Kauffman
authors.forename: Nathalie
authors.initials: N
authors.lastname: Adda
authors.forename: Ira M
authors.initials: IM
authors.lastname: Jacobson
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Sherman
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
authors.forename: Ann D
authors.initials: AD
authors.lastname: Kwong
authors.forename: Gaston
authors.initials: G
authors.lastname: Picchio
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D024882:Drug Resistance, Viral / Q000235:genetics; D004359:Drug Therapy, Combination; D019143:Evolution, Molecular; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000627:therapeutic use; D009842:Oligopeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; D007372:Interferons