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Hepatitis C Viral Evolution in Genotype 1 Treatment-Naive and Treatment-Experienced Patients Receiving Telaprevir-Based Therapy in Clinical Trials
Journal article   Open access   Peer reviewed

Hepatitis C Viral Evolution in Genotype 1 Treatment-Naive 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, …
PloS one, Vol.7(4), pp.e34372-e34372
04/12/2012
DOI: 10.1371/journal.pone.0034372
PMCID: PMC3325239
PMID: 22511937
url
https://doi.org/10.1371/journal.pone.0034372View
Published (Version of record) Open Access

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 NS3N4A 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-naive 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.
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