HCV genotype 1 subtype-associated patterns of INCIVEK treatment-emergent amino acid substitutions were observed. Subjects with HCV genotype 1a predominately had V36M and R155K or the combination of these variants, while subjects with HCV genotype 1b predominately had V36A, T54A/S, and A156S/T variants (Table 8). Among subjects treated with telaprevir, on-treatment virologic failure was more frequent in subjects with genotype 1a than with genotype 1b and more frequent in prior null responders [see Clinical Studies (14)].

Table 8: Treatment Emergent Substitutions in Pooled Phase 3 Studies: Subjects who did not achieve SVR24 in INCIVEK Combination Treatment Arms Emerging Substitutions* in NS3 Percent of No SVR Subjects (n)
N=525 Percent Subtype 1a
No SVR Subjects (n)
N=356 Percent Subtype 1b
No SVR Subjects (n)
N=169
*
Alone or in combination with other substitutions (includes mixtures)
†
Subjects with this combination are also encompassed in two V36M and R155K rows above.
Any substitution at V36, T54, R155, A156 or D168 62% (323) 69% (247) 45% (76)
R155K/T 38% (201) 56% (200) 0.6% (1)
V36M 33% (178) 49% (173) 3% (5)
V36M + R155K† 27% (142) 40% (142) 0% (0)
T54A/S 13% (68) 9% (31) 22% (37)
V36A/L 12% (65) 10% (37) 17% (28)
A156S/T 9% (48) 8% (28) 12% (20)
V36G/I, I132V, R155G/M, A156V/F/N or D168N Less than 2% Less than 2% Less than 2%

Persistence of Resistance-Associated Substitutions

Persistence of telaprevir-resistant NS3 amino acid substitutions has been observed following treatment failure. Of a combined 255 treatment-naïve and previously treated subjects from Studies 108, 111, and C216 in whom telaprevir-resistant variants had emerged during treatment, 103 (40%) had detectable resistant variants by population sequencing at end of study (follow-up range 2-70 weeks, median 45 weeks) and results for 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 unkn