TABLE 4.
HCV PI and NS5A inhibitor class amino acid positions of interest and resistance profile of glecaprevir and pibrentasvir as determined by a transient-replicon assay
| Inhibitor and inhibitor class-specific amino acid positions | HCV GT | Amino acid substitution(s) leading to a change in inhibitor EC50 ofb: |
||
|---|---|---|---|---|
| <10-fold | 10- to 100-fold | >100 fold | ||
| Glecaprevir, NS3 positions 36, 43, 54, 55, 56, 80, 155, 156, 168a | 1a | V36A/L/M, F43L, T54S, V55I, Y56H, Q80K/L/R, R155K/M/S/T/V, A156G, D168A/E/H/N/V | D168F/Y | A156T |
| 1b | T54A, V55A, Q80K/L, R155K, A156S, D168A/E/F/H/T/V/Y | D168K | A156T/V | |
| 2a | V55A/I, Y56F/H, D168A/E/H/V/Y | None | A156T/V | |
| 2b | Y56F, D168A/E/F/H/S/T/V/Y | None | A156M/T/V | |
| 3a | R155K, S166T, Q168H | Q80R, Q168L/R | A156G | |
| 4a | R155C, D168V | D168H | A156T/V | |
| 4d | Y56H, D168V | None | None | |
| 5a | None | None | None | |
| 6a | None | D168A/V | D168G/H/Y | |
| Pibrentasvir, NS5A positions 24, 28, 30, 31, 32, 58, 92, 93 | 1a | K24R, M28A/T/V, Q30E/G/H/K/L/R/Y, L31M/V, P32L, H58C/D/P/R, A92T, Y93C/F/H/L/N/S | Q30D | M28G |
| 1b | L28M/T, R30Q, L31F/M/V, P58S, A92E/V, Y93H/N/S | None | P32deletion | |
| 2a | T24A/S, F28C/S, K30G/M, M31I, C92S | None | None | |
| 2b | L28F, L31I/M/V, C92S/Y | None | None | |
| 3a | M28T, A30K, Y93H | None | None | |
| 4a | L28I/M/V, L30H, P58L | None | None | |
| 4d | L28V, M31I/L, T58A/P/S | None | None | |
| 5a | L28I, L31F/V | None | None | |
| 6a | L31V, T58A/N | None | None | |
a
Amino acid position 166 in GT3 in NS3 is also considered a position of interest.
b
Available data for single amino acid substitutions are included. The fold change was calculated as the ratio of the EC50 in a replicon with the amino acid substitution relative to the EC50 in the wild-type replicon. Variants that are underlined were detected at baseline in DAA-naive patients.