TABLE 2

Selection of resistant variants in NS5A by ombitasvir in genotype 1 replicon cell lines and resistance in transient assays

GenotypeVariantPrevalence in replicon assaysaMean EC50 (pM) ± SDbFold resistanceReplication efficiency (%)
10×100×1,000×
1aWild type2.7 ± 0.8100
M28T1/234/214/2424,475 ± 5,7108,965100
M28V10/23159 ± 105887
Q30R4/234/218/242,184 ± 68780060
H58D1/21664 ± 22224366
Y93C4/235/213/244,573 ± 2,3621,67524
Y93H4/235/219/24112,975 ± 47,97741,38318
Y93N1/21182,200 ± 7,21266,74025
Y93S1/211,013c
Q30H7.7 ± 3.9364
L31M4.8 ± 2.12141
Q30L + Y93H1,137 ± 10041630
Q30L + Y93S596 ± 812181
1bWild type0.79 ± 0.25100
L28T2/8d522 ± 27966117
L31F4/237.6 ± 3.810127
L31V2/232/236.6 ± 1.2886
Y93H12/239/231/860 ± 227773
L28M + L31F1/231/8569c
L28V + L31F1/82,170c
L31F + P58L1/2378c
L31F + P58S1/23NDeNDND
L28M + Y93N1/23NDNDND
L28M + Y93H2/23328 ± 231415104
R30Q + Y93H1/237/23224 ± 5128460
L31F + Y93H2/88,115 ± 2,07010,27235
L31V + Y93H1/89,739 ± 1,12212,32824
P58A + Y93H2/23967 ± 2301,22611
P58L + Y93H1/23107 ± 691358
L28M1.3 ± 0.12114
R30Q0.31 ± 0.230.460
L31M0.7 ± 0.30.9119
  • a Number of times that this variant was found/ total number of colonies analyzed.

  • b EC50 of ombitasvir in replicon containing the variant in NS5A determined using transient luciferase assay.

  • c Fold resistance was evaluated in a stable chimeric replicon cell line harboring the amino acid substitution; therefore, the EC50 in transient assay is not shown.

  • d Only 8 colonies (out of 1 × 106 cells) survived exposure to 1,000-fold the EC50 of ombitasvir.

  • e ND, not determined.