s 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%
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 necess
