NS5a GT3

Download full data set for GT3

Daclatasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Replication Fitness (14)	Reference	DCV+P/R VF (#pts)	Comments
WT (1b_con1)	0.004	1x	likely susceptible			1,4,5		0.001-0.009
Q24K		<2.5x	likely susceptible			13
Q24R
L28A			resistance possible	Yes		14	1	Clinical TE RAS (14)
L28M		1.3x	resistance possible	Yes	122	3,10,13,14,15	3	Clinical TE RAV(3,10,14)
L28T			resistance possible	Yes		7		Clinical VF RAV(3)
L28I		3x	likely susceptible		126	15
L28V		2.3x	likely susceptible		78	15,13
P29S			resistance possible	Yes		3	1	Clinical VF RAV(3)
P29del		1,666,666x	resistance likely	Yes		3,14	1	Clinical VF RAV(3,14)
R30G		100x	resistance likely	Yes	65	15,3		Clinical VF RAV(3), DCV+P/R RAS(3)
R30H		6.7x	resistance possible	Yes	39	15,3,14	2	Clinical VF RAV(3,14)
R30K		1x	resistance possible	Yes	261	15,13	1	Clinical DCV+SOF VF RAV(14)
R30L		0.3x	likely susceptible	No	29	15,13	1	Clinical DCV+P/R VF RAV(14)
R30P			likely susceptible	No		3,14	1	Clinical VF RAV(3,14)
R30Q		0.7x	resistance possible	Yes	91,24	15,14,3,13	4	Clinical VF RAV(3,14), transient 1b replicon
R30S			likely susceptible	No		14	1	Clinical VF RAV(14)
R30T		<2.5x	likely susceptible			13
L31F		5x	resistance possible	Yes	146	3,2,10,14,15	2	Clinical TE RAV(3,10,14)
L31I		3x	resistance possible	Yes	54	3,2,14,15	7	Clinical VF RAV(3,14)
L31K
L31M	0.006	3x	resistance possible	Yes	99	14,4,3,12,15	12	Clinical VF RAV(3,14), transient 1b replicon (14)
L31T
L31V	0.053	28x	resistance likely	Yes	158,55	1,4, 3, 6,5,14,15	16	Clinical VF RAV(3,14)
L31W		91x	resistance possible		191	14
P32F						7		EASL 2016 guidelines
P32L		16x	likely susceptible		18	14,13
P32K
P32R
P32N
P32K
P32T				Yes		3	1	Clinical DCV+P/R VF RAV(3)
P32S						7		EASL 2016 guidelines
P32del		>1,666,667x	resistance likely	Yes	29.1	3,6,14,15	3	Clinical VF RAV(3,14)
F37L		1x	likely susceptible		151	14
Q54H	0.002	1x	resistance possible	Yes	83	4,14,15	14	Clinical DCV+SOF VF RAS(14), transient 1b replicon (14)
Q54N	0.003	1x	likely susceptible		83	4,14,15
Q54L		0.3x	likely susceptible		80	15
Q54Y		1.3x	likely susceptible	No	90	8,14,3,15	1	Clinical VF RAV(3,14)
P58A		0.7x	likely susceptible		118	15
P58D						7		EASL 2016 guidelines
P58L	0.004	1x	resistance possible	Yes	37	8,15		Clinical DCV+P/R VF RAV(3)
P58Q		<2.5x	likely susceptible			13
P58R		<2.5x	likely susceptible			13
P58S		1x	resistance possible	Yes	121	3,8,14,15	5	Clinical VF RAV(3,14), transient 1b replicon (14)
P58T		1x	likely susceptible		203	15,13
Q62D			likely susceptible	No		3	1	Clinical VF RAV(14,3)
Q62E		1x	resistance possible	Yes	99	14,8,4	2	Clincial DCV+SOF VF RAS (14)
Q62A		0.7x	likely susceptible		99	15
Q62H		1x	likely susceptible		68	15
Q62N		0.7x	likely susceptible		69	15
Q62R		1x	likely susceptible		39	15
Q62S		1x	likely susceptible		107	15
A92E		1.3x	resistance possible	Yes	17	15,13,14	2	Clinical VF RAV(14)
A92V							1
A92K		>100x	resistance likely	Yes		3,14	2	Clinical VF RAV(3,14)
A92P		<2.5x	likely susceptible			13
A92T		1x	likely susceptible	No	60	13,14,15	1	Clinical VF RAV(14)
A92V		0.3x	likely susceptible		98	15,13
Y93C		3x	likely susceptible	No	62	14,7,15	1	Clinical TE RAS (14)
Y93H	0.049	30x	resistance likely	Yes	27, 5	15,14,1,4,3, 6,5,8,10,12	23	Clinical VF RAV(3,10,14), transient 1b replicon (14)
Y93N		50x	resistance possible	No	19	3,14,15		Clinical VF RAV(3)
Y93F		0.7x	likely susceptible		436	13,15
Y93L		<2.5x	likely susceptible			13
Y93R
Y93T
Y93S		6.7x			160	15,7		EASL 2016 guidelines
V121I
D320E		0.9x	likely susceptible			9
L23F+L31F		13x	likely susceptible		65	14
Q24R+R30Q
L28I+R30Q		6.7x	likely susceptible		33	15
L28M+L31F
L28M+P32del
L28M+R30L		1x	likely susceptible		49	15
L28M+R30Q		1x	likely susceptible		2	15
L28M+R30Q
L28M+Y93H		1000x	resistance likely	Yes	70	15,14		Clincal VF RAV (14)
L28V+L31F
L28V+R30Q		0.3x	likely susceptible		2	15
R30H+Y93H		2,667x	resistance likely		24	15
R30L+L31M		3x	likely susceptible		75	15
R30Q+L31M		16.7x	likely susceptible		71	15
R30Q+L31F		88x	resistance possible		224	14
R30Q+L31V
R30Q+Q54H		0.3x	likely susceptible		231	15
R30Q+A92K		77,000x	resistance likely		49	15
R30Q+Y93H		200x	resistance likely		146	15
R30Q+Y93S		23.3	resistance possible		224	15
L31F+A92E
L31F+P32del		1,666,667x	resistance likely		12	15
L31F+P58L
L31F+Q54H
L31F+Y93H		5000x	resistance likely		29	15
L31IV+Y93H		33,677x	resistance likely	Yes		14		Clincal VF RAV (14)
L31I+A92V		1x	likely susceptible		65	15
L31I+Y93H		2492x	resistance likely	Yes	6	14,15		Clincail VF RAV (14)
L31M+A92K		1,281,333x	resistance likely		26	15
L31M+P58L	1.5	200x	resistance likely	Yes	37	15,8		Clinical VF RAV (8)
L31M+P58S		30x	resistance possible		36	15
L31M+Q54H		1.3x	likely susceptible		111	15
L31M+Y93C
L31M+Y93H	13.5	7105x	resistance likely	Yes	49.9	3,4, 6,8,12,14,15		Clinical VF RAV (8,14)
L31M+Y93N		28,666x			16
L31V+P32del		>1,666,667x	resistance likely	Yes	16	14,15		Clincal VF RAV (14)
L31V+Y93H	21.7	33,666x	resistance likely	Yes	10	1,3, 4, 6,5,8,9,14,15		Clincal VF RAS (14)
L31V+Y93N
P32del+Y93H	not viable	not viable
F37L+Y93H		19x	likely susceptible		34	14
Q54H+Q62E		0.3x			137	15
Q54H+A92E
Q54H+Y93H	0.018	9.2x	resistance possible	Yes	22	14,8,4,15		Clinical VF RAV (8)
Q54H+Y93S		2.7x	likely susceptible		279	15
Q54Y+Y93H	0.04	67x	resistance likely	Yes	25	15,8		Clincial DCV+ASV VF RAV (8)
P58A+Y93H
P58L+Y93H		233x	resistance likely		24	15
P58S+A92T		0.3x	likely susceptible		43	15
P58S+Y93H
Q62E+Y93H		33.3x	resistance possible		36	15
A92T+Y93H		33.3x	resistance possible		2	15
A92V+Y93H
V121I+Y93H
L28I+R30P+P32F		78,000x	resistance likely		12	15
L28I+R30Q+P32L		34,666x	resistance likely		3	15
L28M+R30L+Q54H		0.3x	likely susceptible		18	15
L28M+R30Q+A92K		1310666	resistance likely		49	15
L28M+R30Q+A92T		1.7x	likely susceptible		16	15
L28M+R30Q+Y93H		1,666,667x	resistance likely		5	15
L28M+R30Q+Y93S		667x	resistance likely		9	15
L28T+R30Q+Y93H		41,667x	resistance likely		2	15
L28V+R30Q+Y93H		2,766x	resistance likely		42	15
P29S+R30Q+Y93S		216,333x	resistance likely
R30H+P58S+Y93H		6,000x	resistance likely		22	15
R30Q+L31F+Y93H		51,666x	resistance likely			15
R30Q+L31M+Y93H		20,333x	resistance likely		88	15
R30Q+Q54H+A92K		8667x	resistance likely	Yes		14		Clincal VF RAV (14)
L31F+Q54H+Y93H		6,333x	resistance likely		161	15
L31F+Y93H+V121I
L31F+Q54F+A92E
L31I+A92V+Y93H		3,667x	resistance likely		15	15
L31I+P58S+Y93H		54,667x	resistance likely		16	15
L31M+A92V+Y93H		19,333x	resistance likely		22	15
L31M+P58A+Y93H	>1000	65000x	resistance likely	Yes	7	8,15		Clinical VF RAV (8)
L31M+P58G+Y93H	>5000	100000x	resistance likely	Yes	17	8,15		Clinical VF RAV (8)
L31M+P58L+Y93H		13,000x	resistance likely		12	15
L31M+P58S+Y93H		70,000x	resistance likely		10	15
L31M+Q54H+A92E		100x	resistance possible		33	15
L31M+Q54H+Y93H		4,233x	resistance likely	Yes	88	14,15		Clincal VF RAV (14)
L31M+Q54Y+Y93H		6466x	resistance likely		41	15
L31V+P58A+Y93H		204,000x	resistance likely		12	15
L31V+P58S+Y93H		140,333x	resistance likely		17	15
L31V+Q54H+Y93H		8,667x	resistance likely		31	15
L31V+Q54H+Y93H	36.1	19000x	resistance likely	Yes	189	4,8,14		Clincal VF RAV (14)
L31V+Q54Y+Y93H		25,333x	resistance likely		4	15
L31V+Q62E+Y93H		67,333x	resistance likely		87	15
Q54H+A92V+Y93H
Q54H+P58A+Q62E		0.7x	likely susceptible		176	15
Q54H+P58S+A92K		16,333x	resistance likely		15	15
Q54H+P58S+Y93H		200x	resistance likely		42	15
L28M+L31V+P58S+Y93N		1,666,667x	resistance likely		28	15
L28M+R30H+L31V+Y93H		1,666,667x	resistance likely		21	15
L28M+R30H+Q54H+Y93H		38,333x	resistance likely		20	15
L28M+R30Q+L31I+Y93H		194,333x	resistance likely		21	15
L28M+R30Q+L31V+Y93H		557,333x	resistance likely	Yes		14		Clincal VF RAV (14)
L28M+R30Q+Q54H+A92T		0.7x	likely susceptible		46	15
R30Q+L31M+P58S+Y93H		44,000x	resistance likely		2.5	15
R30Q+L31M+Q54H+Y93H		4,666x	resistance likely		154	15
R30Q+L31V+P58S+Y93H		76,333x	resistance likely		9.7	15
L31IM+Q54H+Q62E+Y93H		9,333x	resistance likely	Yes		14		Clincal VF RAV (14)
L31I+Q54H+P58S+Y93H		14,000x	resistance likely		95	15
L31M+Q54H+A92E+Y93H		113,333x	resistance likely		32	15
L31M+Q54H+A92V+Y93H		4,333x	resistance likely		12	15
L31M+Q54H+P58S+Y93H		17,667x	resistance likely		35	15
L31M+Q54H+Q62E+Y93H		9,333x	resistance likely		46	15
L31M+Q54Y+P58S+Y93H		50,000x	resistance likely		21	15
L31V+Q54H+P58S+Y93H		111333x	resistance likely		11	15
L31V+Q54H+Q62D+Y93H		31,333x	resistance likely		203	15
L31V+Q54H+Q62E+Y93H		31,667x	resistance likely		34	15

1. Hernandez et al. (2013) J. Clin Virol 57;13-18

2. Wang et al. (2013) AAC 57:611-613

3. Lontok et al. (2015) Hepatology 62.5: 1623-1632.

4. EU Product Label 2015

5. Daklinza Canadian Product Monogram Sep 8, 2015

6. Daklinza US Product Label Feb 6 2016

7. EASL Guidelines 2016

8. Kwo PY et al.  EASL 2016 http://www.natap.org/2016/EASL/EASL_40.htm

9. FDA Microbiolog/Virology Review 206843Orig1s001, s003 (01/14/2016)

10.  McPhee, F et al.  (2017) Antiviral Therapy 22.3:237-246

11. Harrigton et al 2017 hepatology. https://doi.org/10.1002/hep.29693

12. FDA NDA Microbiology Virology Reviews_Daklinza_206843Orig1s000MicroR

13. FDA NDA Microbiology Virology Reviews_Daklinza_206843Orig1s001, s003

Elbasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Reference	Comments	SVR with any RAVs at position
WT (1b_con1)	0.003	1x	likely susceptible		2,3	0.009 in ref 1	99 - 100% (4)
Q24K
Q24R
L28A
L28M	0.006	2x	resistance possible	Yes	2,3,5	Clinical TE RAV (3,5)	80% (5)
L28T					4
L28I
L28V	0.004	1.3x	likely susceptible		5,4
P29S
P29del
R30G					4
R30H					4		100% (5)
R30K
R30L
R30P					4
R30Q	0.009	3x	resistance likely	Yes	9,4	Clincial VF RAV (5)
R30S
R30T
L31F	0.05	15x	resistance likely	Yes	2,1,3,4,5	Clinical TE RAV (3,5)
L31I					4
L31K
L31M	0.02	7x	resistance likely	Yes	2,1,3,4,6	Clinical TE RAV (3)	85% (5)
L31T					4
L31V	0.04	13x	resistance likely	Yes	1,4,2,5	Clinical TE RAV (5), stable replicon=3.3x (5)	100% (5)
L31W
P32F
P32L
P32K
P32R
P32N
P32K
P32T
P32S
P32del
F37L
Q54H
Q54N
Q54L
Q54Y
P58A
P58D							100% (4)
P58L
P58Q
P58R
P58S			resistance possible	Yes	5	Clinical VF RAV (5)
P58T
Q62D
Q62E	0.007	2.3x	likely susceptible		5
Q62A
Q62H
Q62N
Q62R
Q62S
A92E
A92V
A92K
A92P
A92T
A92V							100% (4)
Y93C	0.005	1.7x	likely susceptible		5
Y93H	0.2	67x	resistance likely	Yes	1,3,5,6	Clinical TE RAV (3,5)	94% (5)
Y93N
Y93F
Y93L
Y93R
Y93T
Y93S							100% (5)
V121I	0.0005	0.2x	likely susceptible		2
D320E
L23F+L31F
Q24R+R30Q
L28I+R30Q
L28M+L31F
L28M+P32del
L28M+R30L
L28M+R30Q
L28M+R30Q
L28M+Y93H
L28V+L31F
L28V+R30Q
R30H+Y93H
R30L+L31M
R30Q+L31M
R30Q+L31F
R30Q+L31V
R30Q+Q54H
R30Q+A92K
R30Q+Y93H
R30Q+Y93S
L31F+A92E
L31F+P32del
L31F+P58L
L31F+Q54H
L31F+Y93H
L31IV+Y93H
L31I+A92V
L31I+Y93H
L31M+A92K
L31M+P58L
L31M+P58S
L31M+Q54H
L31M+Y93C
L31M+Y93H
L31M+Y93N
L31V+P32del
L31V+Y93H
L31V+Y93N
P32del+Y93H
F37L+Y93H
Q54H+Q62E
Q54H+A92E
Q54H+Y93H
Q54H+Y93S
Q54Y+Y93H
P58A+Y93H
P58L+Y93H
P58S+A92T
P58S+Y93H
Q62E+Y93H	0.04	13.3x	resistance likely		5
A92T+Y93H
A92V+Y93H
V121I+Y93H	0.6	200x	resistance likely		5
L28I+R30P+P32F
L28I+R30Q+P32L
L28M+R30L+Q54H
L28M+R30Q+A92K
L28M+R30Q+A92T
L28M+R30Q+Y93H
L28M+R30Q+Y93S
L28T+R30Q+Y93H
L28V+R30Q+Y93H
P29S+R30Q+Y93S
R30H+P58S+Y93H
R30Q+L31F+Y93H
R30Q+L31M+Y93H
R30Q+Q54H+A92K
L31F+Q54H+Y93H
L31F+Y93H+V121I		27	resistance likely		5
L31F+Q54F+A92E
L31I+A92V+Y93H
L31I+P58S+Y93H
L31M+A92V+Y93H
L31M+P58A+Y93H
L31M+P58G+Y93H
L31M+P58L+Y93H
L31M+P58S+Y93H
L31M+Q54H+A92E
L31M+Q54H+Y93H
L31M+Q54Y+Y93H
L31V+P58A+Y93H
L31V+P58S+Y93H
L31V+Q54H+Y93H
L31V+Q54H+Y93H
L31V+Q54Y+Y93H
L31V+Q62E+Y93H
Q54H+A92V+Y93H
Q54H+P58A+Q62E
Q54H+P58S+A92K
Q54H+P58S+Y93H
L28M+L31V+P58S+Y93N
L28M+R30H+L31V+Y93H
L28M+R30H+Q54H+Y93H
L28M+R30Q+L31I+Y93H
L28M+R30Q+L31V+Y93H
L28M+R30Q+Q54H+A92T
R30Q+L31M+P58S+Y93H
R30Q+L31M+Q54H+Y93H
R30Q+L31V+P58S+Y93H
L31IM+Q54H+Q62E+Y93H
L31I+Q54H+P58S+Y93H
L31M+Q54H+A92E+Y93H
L31M+Q54H+A92V+Y93H
L31M+Q54H+P58S+Y93H
L31M+Q54H+Q62E+Y93H
L31M+Q54Y+P58S+Y93H
L31V+Q54H+P58S+Y93H
L31V+Q54H+Q62D+Y93H
L31V+Q54H+Q62E+Y93H

1. Zapatier Canadian Product Monogram

2. Liu et al (2015) AAC(1):6922 – 6929

3. Foster et al. 2017  PMID: 29473975 DOI: 10.1002/hep.29852

4. Serfaty et al. EASL 2017 http://www.natap.org/2017/EASL/EASL_06.htm

5. Kwo PY et al.  EASL 2016 http://www.natap.org/2016/EASL/EASL_40.htm

6.FDA Zepatier Microbiology Virology Review_208261Orig1s000Micro

Ledipasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Reference	Comments
WT (1b_con1)	0.004	1x	likely susceptible		1,4,6
Q24K		<2.5x	likely susceptible		11
Q24R
L28A
L28M		<2.5x	resistance possible	Yes	4,9,11	Clinical VF RAV (4,9), BL RAV asso VF
L28T
L28I
L28V		<2.5x	likely susceptible		11
P29S
P29del
R30G
R30H		<2.5x	likely susceptible		11
R30K		<2.5x	likely susceptible		11
R30L		<2.5x	likely susceptible		11
R30P
R30Q		<2.5x	likely susceptible		11
R30S		<2.5x	likely susceptible		11
R30T		<2.5x	likely susceptible		11
L31F		2x	likely susceptible		6,3
L31I		10-50x	resistance possible	Yes	5,4, 6, 7,3	clinical TE RAV (4,8)
L31K
L31M		3x	resistance possible	Yes	10,5, 4, 6,3	clinical TE RAV (4,8)
L31T
L31V		10-50x	resistance possible	Yes	5, 4,6,3,9	clinical TE RAV (4,8,9)
L31W
P32F
P32L
P32K
P32R
P32N
P32K
P32T		2.5-10x	likely susceptible		5,3
P32S
P32del
F37L
Q54H		<2.5x	likely susceptible		11
Q54N
Q54L
Q54Y
P58A
P58D		100-1000x	resistance likely		5, 3,11
P58L
P58Q		<2.5x	likely susceptible		11
P58R		<2.5x	likely susceptible		11
P58S		<2.5x	likely susceptible		11
P58T		<2.5x	likely susceptible		11
Q62D
Q62E
Q62A
Q62H
Q62N
Q62R
Q62S
A92E		<2.5x	likely susceptible		11
A92V
A92K		>1000x	resistance likely		5,3,11
A92P
A92T		<2.5x	resistance possible	Yes	4,9	Clinical VF RAV (4,9), BL RAV asso VF
A92V		<2.5x	likely susceptible		11
Y93C			resistance possible	Yes	3,2	clinical TE RAV (2)
Y93H	5.3	1325x	resistance likely	Yes	1,4,5,6,3,2,10,11	clinical TE RAV (2,4,8)
Y93N		>100x	resistance likely		11,3
Y93F		<2.5x	likely susceptible		11
Y93L		<2.5x	likely susceptible		11
Y93R
Y93T
Y93S		<100x	resistance possible		11,3
V121I
D320E
L23F+L31F
Q24R+R30Q		<2.5x	likely susceptible		11
L28I+R30Q
L28M+L31F
L28M+P32del
L28M+R30L
L28M+R30Q
L28M+R30Q
L28M+Y93H		>100x	resistance likely		11
L28V+L31F
L28V+R30Q
R30H+Y93H
R30L+L31M
R30Q+L31M
R30Q+L31F
R30Q+L31V
R30Q+Q54H
R30Q+A92K
R30Q+Y93H		>100x	resistance likely		11
R30Q+Y93S
L31F+A92E
L31F+P32del
L31F+P58L
L31F+Q54H
L31F+Y93H
L31IV+Y93H
L31I+A92V
L31I+Y93H		>100x	resistance likely		11
L31M+A92K
L31M+P58L
L31M+P58S
L31M+Q54H
L31M+Y93C		>100x	resistance likely		11
L31M+Y93H		20270x	resistance likely		10
L31M+Y93N
L31V+P32del
L31V+Y93H		>100x	resistance likely		11
L31V+Y93N		>100x	resistance likely		11
P32del+Y93H
F37L+Y93H
Q54H+Q62E
Q54H+A92E
Q54H+Y93H
Q54H+Y93S
Q54Y+Y93H
P58A+Y93H
P58L+Y93H
P58S+A92T
P58S+Y93H
Q62E+Y93H
A92T+Y93H
A92V+Y93H
V121I+Y93H
L28I+R30P+P32F
L28I+R30Q+P32L
L28M+R30L+Q54H
L28M+R30Q+A92K
L28M+R30Q+A92T
L28M+R30Q+Y93H
L28M+R30Q+Y93S
L28T+R30Q+Y93H
L28V+R30Q+Y93H
P29S+R30Q+Y93S
R30H+P58S+Y93H
R30Q+L31F+Y93H
R30Q+L31M+Y93H
R30Q+Q54H+A92K
L31F+Q54H+Y93H
L31F+Y93H+V121I
L31F+Q54F+A92E
L31I+A92V+Y93H
L31I+P58S+Y93H
L31M+A92V+Y93H
L31M+P58A+Y93H
L31M+P58G+Y93H
L31M+P58L+Y93H
L31M+P58S+Y93H
L31M+Q54H+A92E
L31M+Q54H+Y93H
L31M+Q54Y+Y93H
L31V+P58A+Y93H
L31V+P58S+Y93H
L31V+Q54H+Y93H
L31V+Q54H+Y93H
L31V+Q54Y+Y93H
L31V+Q62E+Y93H
Q54H+A92V+Y93H
Q54H+P58A+Q62E
Q54H+P58S+A92K
Q54H+P58S+Y93H
L28M+L31V+P58S+Y93N
L28M+R30H+L31V+Y93H
L28M+R30H+Q54H+Y93H
L28M+R30Q+L31I+Y93H
L28M+R30Q+L31V+Y93H
L28M+R30Q+Q54H+A92T
R30Q+L31M+P58S+Y93H
R30Q+L31M+Q54H+Y93H
R30Q+L31V+P58S+Y93H
L31IM+Q54H+Q62E+Y93H
L31I+Q54H+P58S+Y93H
L31M+Q54H+A92E+Y93H
L31M+Q54H+A92V+Y93H
L31M+Q54H+P58S+Y93H
L31M+Q54H+Q62E+Y93H
L31M+Q54Y+P58S+Y93H
L31V+Q54H+P58S+Y93H
L31V+Q54H+Q62D+Y93H
L31V+Q54H+Q62E+Y93H

1. Hernandez et al. (2013) J. Clin Virol 57;13-18

2. Lontok et al. (2015) Hepatology 62.5: 1623-1632.

3. FDA Microbiology/Virology Reviews Harvoni_Microbiology Reviews_205834Orig1a000MicroR

Ombitasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Reference	Comments
WT (1b_con1)	0.005	1x	likely susceptible		4,8
Q24K
Q24R
L28A
L28M	0.0013	2x	resistance possible	Yes	1,7,9,12	clinical VF RAV (7,9)
L28T	0.522	661x	resistance likely		1, 6, 4,9,12
L28I
L28V
P29S
P29del	285.3	361139x	resistance likely		9, 12
R30G		<10x	likely susceptible		8
R30H		<10x	likely susceptible		8
R30K
R30L
R30P		<10x	likely susceptible		8
R30Q	0.0003	0.4x	resistance possible	Yes	1,8, 7,9,12	clinical VF RAV(7,9)
R30S
R30T
L31F	0.0076	10x	resistance possible	Yes	1, 4, 7, 8,9,11,12	clinical TE RAV (7)
L31I		2x	likely susceptible		11,8
L31K
L31M	0.0007	0.9x	resistance possible	Yes	1, 8, 7,12,13	clinical VF RAV(1)
L31T		<10x	likely susceptible		8
L31V	0.0066	8X	resistance possible	Yes	1, 4, 7, 8,9,12	clinical TE RAV (7,9)
L31W
P32F
P32L
P32K
P32R
P32N
P32K
P32T		>2.5x			10
P32S
P32del					8
F37L
Q54H					7	impact equivocal (7)
Q54N					7	impact equivocal (7)
Q54L
Q54Y			resistance possible	Yes	4,11	clinical TE RAV (4,11)
P58A					9
P58D		>2.5x			10
P58L
P58Q
P58R
P58S		0.8x	resistance possible	Yes	7,9,12	clinical TE RAV (2,7,9)
P58T	0.3	0.4x	likely susceptible		12
Q62D					7	BL impact equivocal (7)
Q62E
Q62A
Q62H
Q62N
Q62R
Q62S
A92E		0.7x	likely susceptible		7,9
A92V
A92K
A92P
A92T					7	impact equivocal (7)
A92V
Y93C
Y93H	0.06	77x	resistance likely	Yes	1, 3, 5, 7, 8,9,11,12,13	clinical VF RAV (5,4,7,9,11)
Y93N		202x	resistance likely		9
Y93F
Y93L
Y93R
Y93T
Y93S		12x	resistance possible	Yes	7,9	Clinial VF RAV (9)
V121I
D320E
L23F+L31F
Q24R+R30Q
L28I+R30Q
L28M+L31F		569X	resistance likely		1
L28M+P32del
L28M+R30L
L28M+R30Q
L28M+R30Q		0.5x	resistance possible	Yes	7	clinical TE RAV(7)
L28M+Y93H	0.328	415x	resistance likely		1, 6, 7,12
L28V+L31F		2170X	resistance likely		1
L28V+R30Q
R30H+Y93H
R30L+L31M
R30Q+L31M
R30Q+L31F
R30Q+L31V
R30Q+Q54H
R30Q+A92K
R30Q+Y93H	0.224	284x	resistance likely		1, 7, 8,12
R30Q+Y93S
L31F+A92E		1022x	resistance likely		7
L31F+P32del
L31F+P58L		78x	resistance possible		1
L31F+Q54H
L31F+Y93H	0.328, 8.1	415,1027x	resistance likely		1,6,12
L31IV+Y93H
L31I+A92V
L31I+Y93H
L31M+A92K
L31M+P58L
L31M+P58S
L31M+Q54H
L31M+Y93C
L31M+Y93H	0.112	142x	resistance likely		12,6, 7, 8
L31M+Y93N
L31V+P32del
L31V+Y93H	9.7	12328x	resistance likely		12,1, 7
L31V+Y93N
P32del+Y93H
F37L+Y93H
Q54H+Q62E
Q54H+A92E
Q54H+Y93H
Q54H+Y93S
Q54Y+Y93H
P58A+Y93H	0.967	1226x	resistance likely		1
P58L+Y93H	0.107	135x	resistance likely		1
P58S+A92T
P58S+Y93H	1.1	1401x	resistance likely		7,12
Q62E+Y93H
A92T+Y93H
A92V+Y93H
V121I+Y93H
L28I+R30P+P32F
L28I+R30Q+P32L
L28M+R30L+Q54H
L28M+R30Q+A92K
L28M+R30Q+A92T
L28M+R30Q+Y93H		981x	resistance likely		7
L28M+R30Q+Y93S
L28T+R30Q+Y93H
L28V+R30Q+Y93H
P29S+R30Q+Y93S
R30H+P58S+Y93H
R30Q+L31F+Y93H
R30Q+L31M+Y93H
R30Q+Q54H+A92K
L31F+Q54H+Y93H
L31F+Y93H+V121I
L31F+Q54F+A92E
L31I+A92V+Y93H
L31I+P58S+Y93H
L31M+A92V+Y93H
L31M+P58A+Y93H
L31M+P58G+Y93H
L31M+P58L+Y93H
L31M+P58S+Y93H
L31M+Q54H+A92E
L31M+Q54H+Y93H
L31M+Q54Y+Y93H
L31V+P58A+Y93H
L31V+P58S+Y93H
L31V+Q54H+Y93H
L31V+Q54H+Y93H
L31V+Q54Y+Y93H
L31V+Q62E+Y93H
Q54H+A92V+Y93H
Q54H+P58A+Q62E
Q54H+P58S+A92K
Q54H+P58S+Y93H
L28M+L31V+P58S+Y93N
L28M+R30H+L31V+Y93H
L28M+R30H+Q54H+Y93H
L28M+R30Q+L31I+Y93H
L28M+R30Q+L31V+Y93H
L28M+R30Q+Q54H+A92T
R30Q+L31M+P58S+Y93H
R30Q+L31M+Q54H+Y93H
R30Q+L31V+P58S+Y93H
L31IM+Q54H+Q62E+Y93H
L31I+Q54H+P58S+Y93H
L31M+Q54H+A92E+Y93H
L31M+Q54H+A92V+Y93H
L31M+Q54H+P58S+Y93H
L31M+Q54H+Q62E+Y93H
L31M+Q54Y+P58S+Y93H
L31V+Q54H+P58S+Y93H
L31V+Q54H+Q62D+Y93H
L31V+Q54H+Q62E+Y93H

1. Krishnan et al., (2015) AAC 59:979-987

2. Viekira Pak US Product Label

Pibrentasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Replicative Fitness (3)	Reference	Comments
WT (1b_con1)	0.0043	1x	likely susceptible		100	1,11,3	0.0014 - 0.0043, n=8 clincial isolates
Q24K
Q24R
L28A
L28M	0.0018	1x	resistance possible	Yes	114	3	Clinical VF RAV (3)
L28T	0.0017	0.9x	likely susceptible		17	1,3
L28I
L28V
P29S
P29del	0.0193	10x	resistance possible		5.6	3
R30G
R30H
R30K
R30L
R30P
R30Q	0.00088	0.5x	resistance possible	Yes		3	Clincal VF RAS, 2% (3)
R30S
R30T
L31F	0.0023	1.2x	likely susceptible		127	3
L31I
L31K			resistance possible	Yes			Clincal VF RAS, 2% (3)
L31M	0.0031	1.4-1.5x	likely susceptible		119	2,3,4
L31T
L31V	0.0015	0.8x	likely susceptible		86	3
L31W
P32F
P32L
P32K			resistance possible	Yes		3	Clincial TE RAS (3)
P32R			resistance possible	Yes		3	Clincal VF RAS, 4% (3)
P32N			resistance possible	Yes		3	Clinical VF RAS, 18% (3)
P32K			resistance possible	Yes		3	Clincial VF RAS, 70% (3)
P32T			resistance possible	Yes		3	Clincal VF RAS, 8% (3)
P32S
P32del	1.968	1036x	resistance likely	Yes		3	Clinical VF RAV (3) indicated as P32-
F37L
Q54H	0.0021	1.1x	likely susceptible		120	3
Q54N
Q54L
Q54Y	0.0023	1.2x	likely susceptible		112	3
P58A
P58D
P58L
P58Q
P58R
P58S	0.0028	1.3x	likely susceptible		80	2,3
P58T
Q62D
Q62E
Q62A
Q62H
Q62N
Q62R
Q62S
A92E	0.00092	0.5x	likely susceptible		29	3
A92V
A92K
A92P
A92T
A92V	0.00086	0.5x	likely susceptible		54	3
Y93C
Y93H	0.0011	0.6x	likely susceptible		73	1,2,3,4
Y93N	0.0012	0.6x	likely susceptible		52	1,3
Y93F
Y93L
Y93R
Y93T
Y93S	0.00074	0.4x	likely susceptible		23	3
V121I
D320E
L23F+L31F
Q24R+R30Q
L28I+R30Q
L28M+L31F
L28M+P32del	12.02	6326x	resistance likely			3
L28M+R30L
L28M+R30Q	0.00079	0.4x	likely susceptible		28	3
L28M+R30Q	0.00079	0.4x				3
L28M+Y93H	0.0022	1.2x	likely susceptible		104	3
L28V+L31F
L28V+R30Q
R30H+Y93H
R30L+L31M
R30Q+L31M
R30Q+L31F
R30Q+L31V
R30Q+Q54H
R30Q+A92K
R30Q+Y93H	0.0023	1.2x	likely susceptible		60	3
R30Q+Y93S
L31F+A92E	0.0012	0.6x	likely susceptible		36	3
L31F+P32del
L31F+P58L
L31F+Q54H	0.0045	2.4x	likely susceptible		99	3
L31F+Y93H	0.0028	1.5x	likely susceptible		35	3
L31IV+Y93H
L31I+A92V
L31I+Y93H
L31M+A92K
L31M+P58L
L31M+P58S
L31M+Q54H
L31M+Y93C
L31M+Y93H	0.0013	0.7x	likely susceptible		11	1,3,4
L31M+Y93N
L31V+P32del
L31V+Y93H	0.0017	0.9x	likely susceptible		24	1,3
L31V+Y93N
P32del+Y93H
F37L+Y93H
Q54H+Q62E
Q54H+A92E	0.0017	0.9x	likely susceptible		62	3
Q54H+Y93H	0.0017	0.9x	likely susceptible		35	3
Q54H+Y93S
Q54Y+Y93H	0.002	1x	likely susceptible		34	3
P58A+Y93H
P58L+Y93H
P58S+A92T
P58S+Y93H	0.0015	0.8x	likely susceptible		34	1,3
Q62E+Y93H
A92T+Y93H
A92V+Y93H	0.00068	0.4x	likely susceptible		2.5	3
V121I+Y93H
L28I+R30P+P32F
L28I+R30Q+P32L
L28M+R30L+Q54H
L28M+R30Q+A92K
L28M+R30Q+A92T
L28M+R30Q+Y93H	0.001	0.5x	likely susceptible		28	3
L28M+R30Q+Y93S
L28T+R30Q+Y93H
L28V+R30Q+Y93H
P29S+R30Q+Y93S
R30H+P58S+Y93H
R30Q+L31F+Y93H
R30Q+L31M+Y93H
R30Q+Q54H+A92K
L31F+Q54H+Y93H
L31F+Y93H+V121I
L31F+Q54F+A92E	0.0032	1.7x	likely susceptible		70	3
L31I+A92V+Y93H
L31I+P58S+Y93H
L31M+A92V+Y93H
L31M+P58A+Y93H
L31M+P58G+Y93H
L31M+P58L+Y93H
L31M+P58S+Y93H
L31M+Q54H+A92E
L31M+Q54H+Y93H
L31M+Q54Y+Y93H
L31V+P58A+Y93H
L31V+P58S+Y93H
L31V+Q54H+Y93H
L31V+Q54H+Y93H
L31V+Q54Y+Y93H
L31V+Q62E+Y93H
Q54H+A92V+Y93H	0.0018	1x	likely susceptible		1.4	3
Q54H+P58A+Q62E
Q54H+P58S+A92K
Q54H+P58S+Y93H
L28M+L31V+P58S+Y93N
L28M+R30H+L31V+Y93H
L28M+R30H+Q54H+Y93H
L28M+R30Q+L31I+Y93H
L28M+R30Q+L31V+Y93H
L28M+R30Q+Q54H+A92T
R30Q+L31M+P58S+Y93H
R30Q+L31M+Q54H+Y93H
R30Q+L31V+P58S+Y93H
L31IM+Q54H+Q62E+Y93H
L31I+Q54H+P58S+Y93H
L31M+Q54H+A92E+Y93H
L31M+Q54H+A92V+Y93H
L31M+Q54H+P58S+Y93H
L31M+Q54H+Q62E+Y93H
L31M+Q54Y+P58S+Y93H
L31V+Q54H+P58S+Y93H
L31V+Q54H+Q62D+Y93H
L31V+Q54H+Q62E+Y93H

1. Kwo PY et al.  EASL 2016 http://www.natap.org/2016/EASL/EASL_40.htm

2. Ng TI, et al. 2017. Antimicrobial agents and chemotherapy 61: e02558-16  https://doi.org/10.1128/ AAC.02558-16.

3. Krishnan et al.  EASL 2017.. http://natap.org/2017/EASL/EASL_18.htm

4. Kwo PY, et al. 2017. Journal of Hepatology 67: 263-71

5. FDA Microbiology Review https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209394Orig1s000MicroR.pdf

6. Ng 2016 EASL  http://www.natap.org/2016/EASL/EASL_123.htm

7. FDA MNDA Microbiology/Virology Reviews_Mayvret_209394Orig1s000micror

8. Harrigton et al 2017 hepatology. https://doi.org/10.1002/hep.29693

Velpatasvir

Mutation	EC50 (nM)	Fold-shift	Phenotype	Clinical RAS	Reference	Comments
WT (1b_con1)	0.015	1	likely susceptible		1,2,5
Q24K		2.5 - 100x	resistance possible		4,5,6	VEL RAS (6)
Q24R
L28A
L28M		0.7x	likely susceptible		8
L28T
L28I
L28V		<2.5x	likely susceptible		8
P29S
P29del
R30G
R30H		<2.5x	likely susceptible		8
R30K		<2.5x	likely susceptible		8
R30L		<2.5x	likely susceptible		8
R30P
R30Q		<2.5x	likely susceptible		8
R30S		<2.5x	likely susceptible		8
R30T		<2.5x	likely susceptible		8
L31F		0.7x	likely susceptible		4,5,6	VEL RAS (6)
L31I		3.8x	resistance possible		4,5
L31K
L31M	0.008	1.7x	resistance possible	Yes	1,3,4,7,8	Clincal TE RAV (3)
L31T
L31V	0.008	2x	resistance possible	Yes	3,1,8	Clincal TE RAV (3,8)
L31W
P32F
P32L		<2.5x	likely susceptible		8
P32K
P32R
P32N
P32K
P32T
P32S
P32del
F37L
Q54H		1x	likely susceptible		8
Q54N
Q54L
Q54Y
P58A
P58D		<2.5x	likely susceptible		8
P58L
P58Q		<2.5x	likely susceptible		8
P58R		<2.5x	likely susceptible		8,4
P58S		<2.5x	likely susceptible		8
P58T		2.5 - 100x	resistance possible		4,5,6	VEL RAS (6)
Q62D
Q62E
Q62A
Q62H
Q62N
Q62R
Q62S
A92E		<2.5x	likely susceptible		8
A92V
A92K		>100x	resistance likely		4,5,6	VEL RAS (6)
A92P		<2.5x	likely susceptible		8
A92T		<2.5x	likely susceptible		8
A92V		<2.5x	likely susceptible		8
Y93C		0.2x	resistance possible	Yes	3,8	Clincal TE RAV (3)
Y93H	0.011	3x	resistance likely	Yes	3,1,5,4,6,7	Clincal TE RAV (3)
Y93N		3x	resistance likely	Yes	3,5,6	Clincal TE RAV (3)
Y93F		<2.5x	likely susceptible		8
Y93L		<2.5x	likely susceptible		8
Y93R		>2.5 - 100x	resistance possible		6	VEL RAS (6)
Y93T		2.5 - 100x	resistance possible		4,5,6
Y93S		0.6x	resistance possible	Yes	3,8	Clincal TE RAV (3)
V121I
D320E
L23F+L31F
Q24R+R30Q		<2.5x	likely susceptible		8
L28I+R30Q
L28M+L31F
L28M+P32del
L28M+R30L
L28M+R30Q
L28M+R30Q
L28M+Y93H		5x	resistance possible		8
L28V+L31F
L28V+R30Q
R30H+Y93H
R30L+L31M
R30Q+L31M		<2.5x	likely susceptible		8
R30Q+L31F
R30Q+L31V		<2.5x	likely susceptible		8
R30Q+Q54H
R30Q+A92K
R30Q+Y93H		<2.5x	likely susceptible		8
R30Q+Y93S
L31F+A92E
L31F+P32del
L31F+P58L
L31F+Q54H
L31F+Y93H		27	resistance likely		8
L31IV+Y93H
L31I+A92V
L31I+Y93H
L31M+A92K
L31M+P58L
L31M+P58S
L31M+Q54H
L31M+Y93C
L31M+Y93H		44x	resistance likely		4,7,8
L31M+Y93N		>100x	resistance likely		8
L31V+P32del
L31V+Y93H		986x	resistance likely		2,8
L31V+Y93N		>100x	resistance likely		8
P32del+Y93H
F37L+Y93H
Q54H+Q62E
Q54H+A92E
Q54H+Y93H
Q54H+Y93S
Q54Y+Y93H
P58A+Y93H
P58L+Y93H
P58S+A92T
P58S+Y93H
Q62E+Y93H
A92T+Y93H
A92V+Y93H
V121I+Y93H
L28I+R30P+P32F
L28I+R30Q+P32L
L28M+R30L+Q54H
L28M+R30Q+A92K
L28M+R30Q+A92T
L28M+R30Q+Y93H
L28M+R30Q+Y93S
L28T+R30Q+Y93H
L28V+R30Q+Y93H
P29S+R30Q+Y93S
R30H+P58S+Y93H
R30Q+L31F+Y93H
R30Q+L31M+Y93H
R30Q+Q54H+A92K
L31F+Q54H+Y93H
L31F+Y93H+V121I
L31F+Q54F+A92E
L31I+A92V+Y93H
L31I+P58S+Y93H
L31M+A92V+Y93H
L31M+P58A+Y93H
L31M+P58G+Y93H
L31M+P58L+Y93H
L31M+P58S+Y93H
L31M+Q54H+A92E
L31M+Q54H+Y93H
L31M+Q54Y+Y93H
L31V+P58A+Y93H
L31V+P58S+Y93H
L31V+Q54H+Y93H
L31V+Q54H+Y93H		263x	resistance likely		8
L31V+Q54Y+Y93H
L31V+Q62E+Y93H
Q54H+A92V+Y93H
Q54H+P58A+Q62E
Q54H+P58S+A92K
Q54H+P58S+Y93H
L28M+L31V+P58S+Y93N
L28M+R30H+L31V+Y93H
L28M+R30H+Q54H+Y93H
L28M+R30Q+L31I+Y93H
L28M+R30Q+L31V+Y93H
L28M+R30Q+Q54H+A92T
R30Q+L31M+P58S+Y93H
R30Q+L31M+Q54H+Y93H
R30Q+L31V+P58S+Y93H
L31IM+Q54H+Q62E+Y93H
L31I+Q54H+P58S+Y93H
L31M+Q54H+A92E+Y93H
L31M+Q54H+A92V+Y93H
L31M+Q54H+P58S+Y93H
L31M+Q54H+Q62E+Y93H
L31M+Q54Y+P58S+Y93H
L31V+Q54H+P58S+Y93H
L31V+Q54H+Q62D+Y93H
L31V+Q54H+Q62E+Y93H

1 Cheng G et al. (2013) Journal of Hepatology 58:S484-S5.

2. Hezode et al. EASL 2015, Barcelona, Spain.  P216.    http://www.natap.org/2016/EASL/EASL_15.htm

3. Epclusa US Product Label.  July 2016

4. Lawitz (2016) AAC 60(9):5368-5378.  doi:10.1128/AAC.00763-16.

5. Foster et al (2015) N Engl J Med 2015;373:2608-17. DOI: 10.1056/NEJMoa1512612

6.  Epclusa Canadian Product Label July 8, 2016

7. Sarrazin C, et al. 2017. Gastroenterology 152: S1062

8. Vosevi US Product Label 2017

9. Verrmhren et al.  Www.natap.org/2017/AASLD_156.htm

10. Sarrazin C. (2016)  Journal of hepatology 64:486-504.

11. FDA Microbiology/Virology Reviews VoseviMicrobiology Reviews_2091950Orig1a000MicroR

12. Harrigton et al 2017 hepatology. https://doi.org/10.1002/hep.29693

13. .FDA Microbiology/Virology Reviews Epclusa_ 208341Orig1s000 (2015)

14. J. Llaneras et al. AASLD 2018. http://www.natap.org/2018/AASLD/AASLD_09.htm