Abstract
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.
Highlights
The hepatitis C virus (HCV) NS3N4A protease is essential for viral replication, and compounds that inhibit this enzyme represent a new class of direct acting antivirals that have been recently approved for the treatment of HCV infection [1,2,3,4,5]
Further analyses were performed in patients after treatment to evaluate the evolution of resistant variants in the absence of drug selective pressure. These analyses provided an understanding of factors involved in the selection of resistant variants in patients treated with telaprevir, and have been important in optimizing telaprevir treatment regimens by increasing sustained virologic response (SVR) rates and minimizing clinical resistance
Sequencing data were available for 521 patients with genotype 1a and 219 patients with genotype 1b at the treatment-failure time point. This large sample size allowed detection of significant variants even if they occurred only rarely in the population of patients who did not achieve an SVR with telaprevir-based treatment
Summary
The hepatitis C virus (HCV) NS3N4A protease is essential for viral replication, and compounds that inhibit this enzyme represent a new class of direct acting antivirals that have been recently approved for the treatment of HCV infection [1,2,3,4,5]. HCV has higher sequence diversity, even within an individual genotype, compared with other common chronic viral infections, such as hepatitis B virus (HBV) or human immunodeficiency virus (HIV) [12] This vast genetic diversity results from the high rate of HCV replication (with up to a trillion virions produced each day) [13] and the error-prone nature of the HCV RNA-dependent RNA polymerase (with one mutation introduced, on average, into every new genome) [14]. It has been estimated that in an HCV-infected patient, variants with every possible single and double point mutation and even some triple mutations are created at least once each day [15], some of which exhibit varying degrees of resistance to protease inhibitors These mutations may have decreased replicative fitness compared with wild-type virus, and would only be present at low levels. Genotypic changes could be observed in TVR-treated patients who did not achieve an SVR
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