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VIEKIRA XR(dasabuvir, ombitasvir, paritaprevir, and ritonavir)extended-release tablets(二十八)
6G,
D168(any), P334S, S342P, E357K, V406A/I, T449I,
P470S, V23A (NS4A) 88 (51) 67 (4)
V36A/M/Tb 7 (4) --
V55Ib 7 (4) --
Y56Hb 10 (6) 50 (3)
I132Vb 7 (4) --
R155K 16 (9) --
D168 (any)d 72 (42) 67 (4)
D168V 59 (34) 50 (3)
P334Sb,c 7 (4) --
E357Kb,c 5 (3) 17 (1)
V406A/Ib,c 5 (3) --
T449Ib,c 5 (3) --
P470Sb,c 5 (3) --
NS4A V23Ab -- 17 (1)
F43Lb, Q80Lb, A156G, S342Pb,c <5% --
NS5A Any of the following NS5A substitutions: K24R,
M28A/T/V, Q30E/K/R, H/Q54Y, H58D/P/R,
Y93C/H/N 78 (45) 33 (2)
K24R 5 (3) --
M28A/T/V 33 (19) --
Q30E/K/R 47 (27) --
H/Q54Y -- 17 (1)
H58D/P/R 7 (4) --
Y93C/N 5 (3) --
Y93H -- 33 (2)
NS5B Any of the following NS5B substitutions: G307R,
C316Y, M414I/T, E446K/Q, A450V, A553I/T/V,
G554S, S556G/R, G558R, D559G/I/N/V, Y561H 67 (38) 33 (2)
C316Y 4 (2) 17 (1)
M414I -- 17 (1)
M414T 5 (3) 17 (1)
A553I/T/V 7 (4) --
S556G/R 39 (22) 17 (1)
D559G/I/N/V 7 (4) --
Y561H 5 (3) --
G307R, E446K/Q, A450V, G554S, G558R <5% --
N = 57 for the NS5B target.
Substitutions were observed in combination with other emergent substitutions at NS3 position R155 or D168.
Position located in NS3 helicase domain.
D168A/F/H/I/L/N/T/V/Y.
Persistence of Resistance-Associated Substitutions
The persistence of dasabuvir, ombitasvir, and paritaprevir treatment-emergent amino acid substitutions in NS5B, NS5A, and NS3, respectively, was assessed in HCV genotype 1a-infected subjects in Phase 2 trials whose virus had at least 1 treatment-emergent resistance-associated substitution in the drug target, and with available data through at least 24 weeks post-treatment. Population and clonal nucleotide sequence analyses (assay sensitivity approximately 5-10%) were conducted to detect the persistence of viral populations with treatment-emergent substitutions.
For dasabuvir, viral populations with 1 or more treatment-emergent substitutions in NS5B persisted at detectable levels through at least Post-Treatment Week 24 in 11/16 (69%) subjects, and through Post-Treatment Week 48 in 8/15 (53%) subjects with available data. Treatment-emergent S556G persisted through Post-Treatment Week 48 in 6/9 (67%) subjects.
For ombitasvir, viral populations with 1 or more resistance-associated treatment-emergent substitutions in NS5A persisted at detectable levels through at least Post-Treatment Week 24 in 24/24 (100%) subjects, and through Post-Treatment Week 48 in 18/18 (100%) subjects with available data.
For paritaprevir, viral populations with 1 or more treatment-emergent substitutions in NS3 persisted at detectable levels through at least Post-Treatment Week 24 in 17/29 (59%) subjects, and through Post-Treatment Week 48 in 5/22 (23%) subjects with available data. Resistance-associated variant R155K remained detectable in 5/8 (63%) subjects through Post-Treatment Week 24, and in 1/5 (20%) subjects through Post-Treatment Week 48. Resistance-associated D168 substitutions remained detectable in 6/22 (27% |
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