TABLE 3

Selection of resistant variants in NS5A by ombitasvir in genotype 2 to 6 subgenomic chimeric replicon cell lines

GenotypeVariantPrevalence in replicon assaysaMean EC50 (pM) ± SDbFold resistance
2acWild type1.3 ± 0.1
T24A8/1550 ± 6.938
T24A (L31)20 ± 0.3715
F28S4/154,710d
2bcWild type0.71 ± 0.37
L28F1/2433 ± 6.147
L28F (M31)176 ± 30247
L31V8/24361 ± 70511
Y93H13/24NA
3awt4.4 ± 2.4
M28T3/242,934 ± 1,618659
L31F3/2428d
Y93H14/2429,940 ± 3686,728
4aWild type0.35 ± 0.07
L28V21/218.0 ± 2.823
5aWild type0.91 ± 0.34
L28I6/2372 ± 2579
L31V12/23220 ± 105243
L31F6/23263 ± 117289
6aWild type82 ± 58
L31V4/245,572 ± 73468
T58N4/248,354 ± 1,248101
T58A8/241,452 ± 59918
T58S6/241,504 ± 31918
  • a Number of times 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. NA, not available due to low replication efficiency of the variant.

  • c The genotype 2a replicon cell line contains Met at position 31; the genotype 2b replicon cell line contains Leu at position 31.

  • d F28S in GT 2a and L31F in GT 3a replicated poorly in a transient assay; therefore, the EC50 and fold resistance were evaluated in a stable chimeric replicon cell line.