4-week PegIntron/REBETOL lead-in period), had detectable treatment-emergent substitutions, compared to 68% of subjects with less than 1-log10 decline in viral load at Treatment Week 4. Clear patterns of boceprevir treatment-emergent substitutions in the NS3 helicase domain or NS4A coding regions of the HCV genome were not observed.
Table 8 Pooled Analysis of Treatment-Emergent NS3 Protease Domain Amino Acid Substitutions Detected Among VICTRELIS-Treated Subjects in SPRINT-2 and RESPOND-2 Who Did Not Achieve a Sustained Virologic Response (SVR)
|
|
Subjects Infected with HCV Genotype 1a |
Subjects Infected with HCV Genotype 1b |
|
>10% of VICTRELIS treated subjects who did not achieve SVR |
V36M, T54S, R155K |
T54A, T54S, V55A, A156S, I/V170A |
|
<1% to 10% of VICTRELIS treated subjects who did not achieve SVR |
V36A, T54A, V55A, V55I, V107I, R155T, A156S, A156T, V158I, D168N, I/V170T, I/V170F |
V36A, V36M, T54C, T54G, V107I, R155K, A156T, A156V, V158I, I/V170T, M175L |
Persistence of Resistance-Associated Substitutions
Data from an ongoing, long-term follow-up study of subjects who did not achieve SVR in Phase 2 trials with VICTRELIS, with a median duration of follow-up of approximately 2 years, indicate that HCV populations harboring certain post-baseline, VICTRELIS-treatment-emergent substitutions may decline in relative abundance over time. However, among those subjects with available data, one or more VICTRELIS-treatment-emergent substitutions remained detectable with a population-based sequencing assay in 25% of subjects after 2.5 years of follow-up. The most common NS3 substitutions detected after 2.5 years of follow-up were T54S and R155K. The lack of detection of a substitution based on a population-based assay does not necessarily indicate that viral populations carrying that substitution have declined to a background level that may have existed prior to treatment. The long-term clinical impact of the emergence or persistence of boceprevir-resistance-associated substitutions is unknown. No data are available regarding the efficacy of VICTRELIS among subjects who were previously exposed to VICTRELIS, or who previously failed treatment with a VICTRELIS-containing regimen.
Effect of Baseline HCV Polymorphisms on Treatment Response
A pooled analysis was conducted to explore the association between the detection of baseline NS3/4A amino acid polymorphisms and treatment outcome in the two Phase 3 studies, SPRINT-2 and RESPOND-2.
Baseline resistance associated polymorphisms were detected in 7% of subjects by a population-based sequencing method. Overall, the presence of these polymorphisms alone did not impact SVR rates in subjects treated with VICTRELIS. However, among subjects with a relatively poor response to PegIntron/REBETOL during the 4-week lead-in period, the efficacy of VICTRELIS appeared to be reduced for those who had V36M, T54A, T54S, V55A or R155K detected at baseline. Subjects with these baseline polymorphisms and reduced response to PegIntron/REBETOL represented approximately 1% of the total number of subjects treated with VICTRELIS.
Cross-Resistance
Many of the treatment-emergent NS3 amino acid substitutions detected in VICTRELIS-treated subjects who did not achieve SVR in the Phase 3 clinical t
