Hepatitis C virus NS5A inhibitors and drug resistance mutations

Table 1 In vitro resistance profiles according to hepatitis C virus genotypes[36,40,50-54,64]

EC50	< 10 pmol/L	< 100 pmol/L	< 1 nmol/L	< 10 nmol/L	< 100 nmol/L	< 1 μmol/L	> 1 μmol/L
DCV
HCV GT
1b	Wild (2.6 pmol/L)	R30E, H	23F/93H		31F, M, V/93H		Δ30/32L
	L28M	L31F, V	30Q/31F		30Q/31M/93H
	L31M	P32L	31V/58S
	R30Q	Y93H, N	30H/31M
		37L or 54H/93H
		23F/31F
1a	Wild (6 pmol/L)			M28T	L31V	Q30E, K	31V/93H
				Q30H, R	Y93C, H	Y93N (> 500 nmol/L)
				L31M		28T/30H
				P32L		30H/93H
				H58D		30R/93C
						30R/62D
2-6		GT2a (JFH1)	GT3a	GT2a (L31M)	GT2a (Y93H)	GT2a (F28S)
		GT4a, 5a, 6a		GT2a (C92R)	GT2b (31M)	GT3a (Y93H)
					GT3a (A30K)	GT4a (L30I/Y93R)
					GT3a (L31F)
					GT4a (R30G)
					GT4a (L30H)
ACH-3102
HCV GT
1b	Wild (7 pmol/L)	Y93H	P58S/Y93H
	L31V	31V/93H	P58S/T64A/Y93H
1a		wild (20 pmol/L)	Q30R, E, K	Y93C	Y93H, N1
		Q30H	M28T		28T/30H/93C1
		L31M, V	P32L
			H58D
2-6			GT2a (JFH1)
			GT2a (L31M)
			GT2b (31M)
			GT3a, 4a, 5a, 6a

¹Analysis of hepatitis C virus (HCV) NS5A from patient samples[75]. EC₅₀: Half maximal (50%) effective concentration; DCV: Daclatasvir; GT: Genotype.

Table 2 Resistance profiles of hepatitis C virus NS5A inhibitors in hepatitis C virus genotype 1- and 2-infected patients[61,66,73-75]

HCV NS5A inhibitor	Mean maximal viral decline (log IU/mL)	Maximal viral decline in patients with RAVs at baseline (log IU/mL)
HCV genotype 1a-infected
DCV	3.8 (60 mg, 14 d)	Q30R (10%)	2.9
LDV	3.1-3.3 (10-90 mg, 3 d)	Q30E/Q	0.88
		L31M	0.16
		Y93C (12%)	1.6
PPI-668	3.3 (80-160 mg, 3 d)	M28V (50%)	3.7
		M28T (7%)	2.8
		M28T (10%)/L31M (11%)	3.6
		H58D (69%)/N (31%)	2.2
IDX719	3.2-3.6 (25-100 mg, 3 d)	M28M/V	3.6
ACH-3102	3.5-3.9 (50-300 mg, single dose)	M28V, T (2%-24%)	3.4 to 4
		L31M (28%)	3.4
		Y93C, D, H (2%-3%)	4 to 4.6
HCV genotype 1b-infected
DCV	4.3 (10 mg, 14 d)	Q54H, N	> 4
		Q54H/Y93H	> 4
LDV	3.3 (10 mg, 3 d)	L31M	2.09
PPI-668	2.9 (40 mg, 3 d; only 1 patient)	R30Q	2.9
	3.8-4 (80-240 mg, 3 d)	L31M	4
		P58S	3.8
		L28M (7%), R30Q (76%), L31M (20%)	3.5
		R30Q/L31I/Y93H	0.33
IDX-719	3-4.3 (25-50 mg, 3 d)	R30Q/Y93H	2.8
HCV genotype 2a-infected
PPI-668	0.33 (160 mg, 3 d; only 1 patient)	F28L/A30K/L31M	0.33
IDX-719	2.0 (50-100 mg, 3 d)	L31M	0.45
		L31L/M	0.85
HCV genotype 2b-infected
PPI-668	3.0 (160 mg, 3 d)	A30K	0.48
		Y93H (7%)	0.45
		Y93H	0.25

DCV: Daclatasvir; LDV: Ledipasvir; RAVs: Resistance-associated variants; HCV: Hepatitis C virus.