TABLE 5.

Antiviral activity of glecaprevir and other HCV PIs against HCV replicons containing NS3 resistance-associated substitutions

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

^aValues were determined in ≥3 independent transient-transfection assays.

^bFold change relative to the glecaprevir EC₅₀ for the respective wild-type replicon.

^cND, not determined.

^dNV, not available, as the EC₅₀ could not be determined due to the low replication efficiency of the replicon containing the amino acid substitution.