loss of variants were similar across the three studies. In the combined studies, 46% of the telaprevir-resistant substitutions in subtype 1a and 16% of the substitutions in subtype 1b were still detected by the end of study: 29% of V36, 16% of T54, 38% of R155, 14% of A156, and 44% of V36M+R155K variants were detected at the end of study.
In a 3-year follow-up study of 56 treatment-naïve and prior treatment-failure subjects who did not achieve SVR with a telaprevir regimen in a Phase 2 study and had telaprevir-resistant variants after treatment failure, variants were detected by population sequencing in 11% (6/56) of subjects (median follow-up of 25 months). Telaprevir-resistant variants V36L/M, T54S, and R155K were detectable (present at greater than 25% of the viral population) in some subjects at 24 months. By 36 months, V36M, T54A/S, and A156N/S/T variants had fallen below the level of detection by population sequencing in all subjects. At 36 months, 3% of the subject isolates that had the R155K variant still had detectable R155K variants by population sequencing.
The lack of detection of a substitution based on a population-based assay does not necessarily indicate the substitution has declined to the pre-treatment level. The long-term clinical impact of the emergence or persistence of detectable INCIVEK resistance-associated substitutions is unknown. No data are available regarding INCIVEK efficacy among patients who were previously exposed to INCIVEK, or who previously failed treatment with an INCIVEK-containing regimen.
Effect of Baseline HCV Substitutions/Polymorphisms on Treatment Response
A pooled analysis was conducted to explore the association between the detection (population-based assay) of baseline NS3/4A amino acid substitutions/polymorphisms and treatment outcome in Studies 108, 111, and C216. Baseline polymorphisms at NS3 position Q80 (Q80K, Q80L, Q80R), which are frequently observed in HCV genotype 1a-infected subjects and have been reported to reduce the activity of some HCV NS3/4A protease inhibitors, were not associated with reduced INCIVEK efficacy.
Telaprevir-associated resistance substitutions (substitutions at positions V36, T54, R155 or D168) were present at baseline in 5% (117/2217) of the available subject samples in the combined clinical trials. Given the small number of subjects with baseline telaprevir resistance substitutions, conclusions about their effect on response outcomes when these substitutions are present at baseline cannot be determined.
Cross-Resistance
Treatment-emergent NS3 amino acid substitutions detected in INCIVEK-treated subjects who did not achieve SVR in the clinical trials (substitutions at positions V36, T54, R155, A156 or D168) have been demonstrated to reduce the anti-HCV activity of boceprevir and other HCV NS3/4A protease inhibitors. The impact of prior INCIVEK exposure or treatment failure on the efficacy of boceprevir or other HCV NS3/4A protease inhibitors has not been studied. INCIVEK efficacy has not been established for patients with a history of exposure to NS3/4A protease inhibitors.
resistance is not expected between INCIVEK and interferons, or INCIVEK and ribavirin. HCV replicons expressing telaprevir-associated resistance substitutions remained fully sensitive to interferon-alfa and ribavirin, as well as other direct-acting antivirals with different mechanisms of action, such as NS5B polymerase inhibitors.
12.5 Pharmacogenomics
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