TABLE 2.

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

Genotype	Variant	Prevalence in replicon assaysa			Mean EC50 (pM) ± SDb	Fold resistance	Replication efficiency (%)
		10×	100×	1,000×
1a	Wild type				2.7 ± 0.8		100
	M28T	1/23	4/21	4/24	24,475 ± 5,710	8,965	100
	M28V	10/23			159 ± 10	58	87
	Q30R	4/23	4/21	8/24	2,184 ± 687	800	60
	H58D		1/21		664 ± 222	243	66
	Y93C	4/23	5/21	3/24	4,573 ± 2,362	1,675	24
	Y93H	4/23	5/21	9/24	112,975 ± 47,977	41,383	18
	Y93N		1/21		182,200 ± 7,212	66,740	25
	Y93S		1/21			1,013c
	Q30H				7.7 ± 3.9	3	64
	L31M				4.8 ± 2.1	2	141
	Q30L + Y93H				1,137 ± 100	416	30
	Q30L + Y93S				596 ± 81	218	1
1b	Wild type				0.79 ± 0.25		100
	L28T			2/8d	522 ± 279	661	17
	L31F	4/23			7.6 ± 3.8	10	127
	L31V	2/23	2/23		6.6 ± 1.2	8	86
	Y93H	12/23	9/23	1/8	60 ± 22	77	73
	L28M + L31F		1/23	1/8		569c
	L28V + L31F			1/8		2,170c
	L31F + P58L	1/23				78c
	L31F + P58S	1/23			NDe	ND	ND
	L28M + Y93N		1/23		ND	ND	ND
	L28M + Y93H	2/23			328 ± 231	415	104
	R30Q + Y93H	1/23	7/23		224 ± 51	284	60
	L31F + Y93H			2/8	8,115 ± 2,070	10,272	35
	L31V + Y93H			1/8	9,739 ± 1,122	12,328	24
	P58A + Y93H		2/23		967 ± 230	1,226	11
	P58L + Y93H		1/23		107 ± 69	135	8
	L28M				1.3 ± 0.1	2	114
	R30Q				0.31 ± 0.23	0.4	60
	L31M				0.7 ± 0.3	0.9	119

^aNumber of times that this variant was found/ total number of colonies analyzed.

^bEC₅₀ of ombitasvir in replicon containing the variant in NS5A determined using transient luciferase assay.

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

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

^eND, not determined.