NS5b GT3 | SHARED - A Hepatitis C Resource

Sofosbuvir

	1. Harvoni US Product Lable
	2. Lam et al (2012) AAC 56:3359-3368
	3. Daklinza US Product Label Feb 2016
	4. Donaldson (2015) Hepatology 61:56-65
	5. Lontok et al. (2015) Hepatology 62.5: 1623-1632.
	6. Hezode et al. EASL 2015, Barcelona, Spain. P216
	7. Epclusa US Product Label. July 2016
	8. EASL Guidelines 2106
	9. Epclusa Canadian Product Label July 8, 2016
	10. Xu et al. (2017) Antiviral therapy 22:587-97.
	11. McPhee, F et al. (2017) Antiviral Therapy 22.3:237-246
	12.FDA Microbiology/Virology Reviews Epclusa_ 208341Orig1s000 (2015)
	13 Svarovskaia ES, et al. 2014. Clinical Infectious Diseases 59: 1666-74
	Sofosbuvir in GT3
	EC50 (uM)	Fold-shift	Phenotype	Replicative Fitness	Reference	Clinical RAS	Comments
WT (3a_S52)	0.05	1x	likely susceptible	100	2
K100R			resistance possible		12	Yes	Clincial TE RAS (12)
R120C			resistance possible		12	Yes	Clincial TE RAS (12)
T130N		1x	likely susceptible	138	13
N142S			resistance possible		12	Yes	Clincal VF RAS (12)
N142T			resistance possible		6, 7, 9,12	Yes	clinical TE RAV (6,7,9)
A150T		1.1x	likely susceptible	90	13
A150v		1.0x	likely susceptible	133	13
L159F	0.061	1.3x	resistance possible	10	4,5,6,8,9,12,13	Yes	clinical TE RAV (4,5,9,12)
K206E		0.9x	likely susceptible	115	13
K212R				<0.1	13
E237G		1.1x	resistance possible		6,7,9	Yes	clinical TE RAV (6,7,9)
S282T	0.175	3.5x	resistance likely	11.3 (10)	2, 1, 3,4,8,9,10,11	Yes	clinical TE RAV (3, 4,9)
S282R			resistance likely				catalytic triad
S282G			resistance likely		12	Yes	Clinical TE RAS (12)
L314I			resistance possible		7	Yes	clinical TE RAV (7)
L314F			resistance possible		7,12	Yes	clinical TE RAV (7,12)
L314P			resistance possible		7	Yes	clinical TE RAV (7)
L320I			resistance possible		12	Yes	Clinical TE RAS (12)
L320F			resistance possible		12	Yes	Clincial TE RAS (12)
V321A	0.021	1.3x	resistance possible	15	2,4,5,12, 13	Yes	clinical TE RAV (4,5,12)
A335T		1.0x	likely susceptible	90	13
Q355H			resistance possible		3,4	Yes	clinical TE RAV (3, 4)
Q355R			resistance possible		12	Yes	Clincial TE RAS (12)
G543S		0.05x	likely susceptible	73	13
V553I		1x	likely susceptible	88	13




		The current dataset does not contain resistance possible classification
		>2.5x FS, resistance likely
		All S282 substitutions are considered resistance likely

		Multiple RASs:
		Data for variants with multiple mutations take precedence over estimation from individual RASs
		If RAV data are not available, follow rules for individual RASs in the variant
		2 likely susceptible = likely susceptible
		2 resistance possible = resistance likely
		likely susceptible + resistance possible = resistance possible
		>/= 1 resistance likely RASs = resistance likely


		Clinical RAV:
		without data but observed in Clinical VF = resistance possible
		likely susceptible RASs + clinical RAV = resistance possible


		Positions monitored for "Mutations Detected, effects unknown"
		159, 282, 316, 320, 321

		For NGS data: only RASs with >/=2% frequency will be included

		strikthrough= mutations obsreved in VFs with NGS but deemed unimportant by FDA.

1. Harvoni US Product Lable

2. Lam et al (2012) AAC 56:3359-3368

3. Daklinza US Product Label Feb 2016

4. Donaldson (2015) Hepatology 61:56-65

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

6. Hezode et al. EASL 2015, Barcelona, Spain. P216

7. Epclusa US Product Label. July 2016

8. EASL Guidelines 2106

9. Epclusa Canadian Product Label July 8, 2016

10. Xu et al. (2017) Antiviral therapy 22:587-97.

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

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

13 Svarovskaia ES, et al. 2014. Clinical Infectious Diseases 59: 1666-74