PLoS ONE (Jan 2012)

Hepatitis C viral evolution in genotype 1 treatment-naïve and treatment-experienced patients receiving telaprevir-based therapy in clinical trials.

  • Tara L Kieffer,
  • Sandra De Meyer,
  • Doug J Bartels,
  • James C Sullivan,
  • Eileen Z Zhang,
  • Ann Tigges,
  • Inge Dierynck,
  • Joan Spanks,
  • Jennifer Dorrian,
  • Min Jiang,
  • Bambang Adiwijaya,
  • Anne Ghys,
  • Maria Beumont,
  • Robert S Kauffman,
  • Nathalie Adda,
  • Ira M Jacobson,
  • Kenneth E Sherman,
  • Stefan Zeuzem,
  • Ann D Kwong,
  • Gaston Picchio

DOI
https://doi.org/10.1371/journal.pone.0034372
Journal volume & issue
Vol. 7, no. 4
p. e34372

Abstract

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BackgroundIn 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.MethodsPopulation sequence analysis of the NS3•4A region was performed in patients who did not achieve SVR with TVR-based treatment.ResultsResistant 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.ConclusionsA 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.