TABLE 5.
HCV subtype | NS3 amino acid substitution | Glecaprevir |
Paritaprevir |
Grazoprevir |
|||
---|---|---|---|---|---|---|---|
Mean EC50 ± SD (nM)a | Fold changeb | Mean EC50 ± SD (nM) | Fold change | Mean EC50 ± SD (nM) | Fold change | ||
1a | Wild type | 0.21 ± 0.08 | 1.4 ± 0.4 | 0.14 ± 0.06 | |||
V36M | 0.28 ± 0.10 | 1.4 | 3.0 ± 0.3 | 2.1 | 0.27 ± 0.06 | 1.9 | |
F43L | 0.05 ± 0.01 | 0.3 | 27 ± 12 | 20 | 0.19 ± 0.05 | 1.4 | |
T54S | 0.20 ± 0.06 | 1.0 | 0.54 ± 0.01 | 0.4 | NDc | ||
V55I | 0.05 ± 0.01 | 0.2 | 1.4 ± 0.14 | 1.0 | 0.10 ± 0.02 | 0.7 | |
Y56H | 0.21 ± 0.06 | 1.0 | 4.1 ± 1.1 | 2.9 | 2.2 ± 0.73 | 16 | |
Q80K | 0.19 ± 0.05 | 0.9 | 3.9 ± 0.3 | 2.8 | 0.25 ± 0.09 | 1.8 | |
R155K | 0.11 ± 0.03 | 0.5 | 51 ± 8.0 | 37 | 0.59 ± 0.19 | 4.2 | |
A156T | 286 ± 93 | 1,361 | 24 ± 3.0 | 17 | 92 ± 6.0 | 655 | |
A156V | NVd | NV | NV | ||||
D168A | 0.84 ± 0.45 | 4.0 | 70 ± 9.0 | 50 | 21 ± 9.8 | 154 | |
D168E | 0.27 ± 0.09 | 1.3 | 20 ± 0.7 | 14 | 4.6 ± 0.66 | 33 | |
D168V | 0.93 ± 0.28 | 4.4 | 135 ± 21 | 96 | 30 ± 13 | 211 | |
I170T | 0.10 ± 0.02 | 0.5 | ND | ND | |||
1b | Wild type | 0.47 ± 0.13 | 0.11 ± 0.05 | 0.19 ± 0.05 | |||
T54A | 0.45 ± 0.10 | 1.0 | 0.09 ± 0.01 | 0.8 | ND | ||
V55A | 0.21 ± 0.03 | 0.4 | 0.07 ± 0.001 | 0.6 | ND | ||
R155K | 0.27 ± 0.11 | 0.6 | 4.4 ± 0.1 | 40 | 0.21 ± 0.03 | 1.1 | |
A156T | 301 ± 62 | 640 | 0.81 ± 0.13 | 7.4 | 39 ± 4.3 | 203 | |
A156V | 839 ± 181 | 1,786 | 2.3 ± 0.53 | 21 | 68 ± 8.2 | 357 | |
D168A | 0.69 ± 0.11 | 1.5 | 3.0 ± 0.2 | 27 | 8.5 ± 0.37 | 45 | |
D168E | 0.40 ± 0.08 | 0.9 | 0.48 ± 0.05 | 4.4 | 0.78 ± 0.05 | 4.1 | |
D168V | 1.5 ± 0.43 | 3.2 | 17 ± 2.0 | 159 | 4.1 ± 0.11 | 22 | |
V170A | 0.49 ± 0.11 | 1.1 | 0.09 ± 0.03 | 0.8 | ND | ||
2a | Wild type | 2.5 ± 0.69 | 17 ± 2.0 | 10.5 ± 1.4 | |||
A156T | 541 ± 77 | 216 | 29 ± 2.8 | 1.7 | 1,151 ± 144 | 110 | |
A156V | 2,857 ± 235 | 1,143 | 37 ± 1.2 | 2.2 | 1,961 ± 244 | 187 | |
D168A | 4.8 ± 1.3 | 1.9 | 306 ± 34 | 18 | 139 ± 9.4 | 13 | |
D168E | 8.1 ± 1.9 | 3.3 | 89 ± 15 | 5.3 | 62 ± 10 | 5.9 | |
D168V | 4.9 ± 0.79 | 2.0 | 228 ± 32 | 13 | 24 ± 0.94 | 2.3 | |
2b | Wild type | 3.1 ± 0.46 | 114 ± 24 | 6.1 ± 1.3 | |||
A156T | 460 ± 172 | 148 | 338 ± 86 | 3.0 | 1,559 ± 925 | 256 | |
A156V | 4,510 ± 1,726 | 1,455 | 573 ± 204 | 5.0 | 2,886 ± 482 | 473 | |
D168A | 3.9 ± 1.0 | 1.3 | 1,309 ± 276 | 11 | 347 ± 113 | 57 | |
D168E | 6.6 ± 1.8 | 2.1 | 256 ± 58 | 2.2 | 35 ± 6.0 | 5.7 | |
D168V | 9.1 ± 1.2 | 2.9 | 1,073 ± 174 | 9.4 | 88 ± 19 | 14 | |
3a | Wild type | 0.55 ± 0.17 | 31 ± 7.0 | 47 ± 14 | |||
R155K | 0.28 ± 0.03 | 0.5 | 161 ± 20 | 5.2 | 5.8 ± 0.64 | 0.1 | |
A156G | 909 ± 349 | 1,654 | 1,768 ± 290 | 57 | 614 ± 148 | 13 | |
Q168R | 30 ± 10 | 54 | 912 ± 221 | 29 | 165 ± 46 | 3.5 | |
4a | Wild type | 0.67 ± 0.23 | 0.048 ± 0.01 | 0.28 ± 0.04 | |||
R155C | 1.7 ± 0.47 | 2.6 | 2.8 ± 0.25 | 59 | 2.0 ± 0.27 | 7.1 | |
A156T | 962 ± 374 | 1,436 | 1.9 ± 0.25 | 40 | 296 ± 22 | 1,057 | |
A156V | 2,081 ± 817 | 3,106 | 7.4 ± 1.6 | 155 | 169 ± 27 | 602 | |
D168H | 15 ± 6.1 | 22 | 12 ± 3.0 | 252 | 25 ± 6.3 | 90 | |
D168V | 6.5 ± 3.0 | 9.7 | 16 ± 1.9 | 323 | 13 ± 1.1 | 46 | |
4d | Wild type | 0.15 ± 0.04 | 0.015 ± 0.001 | 0.18 ± 0.01 | |||
D168V | 0.28 ± 0.12 | 1.9 | 4.7 ± 0.91 | 312 | 2.5 ± 0.08 | 14 | |
5a | Wild type | 0.096 ± 0.03 | 0.33 ± 0.08 | 0.06 ± 0.02 | |||
D168E | 0.41 ± 0.13 | 4.2 | 7.7 ± 1.7 | 23 | 0.58 ± 0.25 | 9.6 | |
D168H | 3.6 ± 1.1 | 38 | 184 ± 65 | 558 | 15 ± 2.0 | 244 | |
6a | Wild type | 0.15 ± 0.03 | 0.12 ± 0.04 | 0.10 ± 0.02 | |||
D168A | 12 ± 5.8 | 81 | 162 ± 80 | 1,347 | 103 ± 34 | 1,048 | |
D168H | 22 ± 5.7 | 146 | 299 ± 87 | 2,490 | 45 ± 4.1 | 459 | |
D168V | 5.8 ± 2.2 | 38 | 400 ± 139 | 3,336 | 24 ± 1.2 | 247 |
Values were determined in ≥3 independent transient-transfection assays.
Fold change relative to the glecaprevir EC50 for the respective wild-type replicon.
ND, not determined.
NV, not available, as the EC50 could not be determined due to the low replication efficiency of the replicon containing the amino acid substitution.