State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization

Table 4

Natural prevalence of NS5A inhibitor resistance-associated variants (RAVs) detected by population sequencing and mean fold change in resistance associated with RAVs.

Position

Variant

Resistant to

⁢Natural prevalence in HCV genotype

Mean fold change in resistance compared to wild-type replicon

References

1a

1b

2

3

4

5

6

Daclatasvir

Ledipasvir

Ombitasvir

K24

G/N

LDV

n.o.

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

[156]

K24

R

LDV

<1–1.5%

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

[156, 157]

M28

A

DCV/LDV

0.5%

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

[156]

M28

G

LDV

n.o.

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

[86, 156]

M28

T

DCV/LDV/OMV

0.4–1.8%

n.a.

n.d.

n.o.

82.0% (M28L)

n.d.

n.d.

205

61

8,965

[87, 100, 156, 158–160]

M28

V

OMV

3.5%

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

58 (GT 1a)

[86, 87, 100, 160–163]

F28

S

DCV

n.a.

n.a.

n.o.

n.d.

n.d.

n.d.

n.d.

[164]

L28

F/T

DCV/OMV

n.a.

n.o.

8.0%

n.d.

n.d.

n.d.

n.d.

[86, 87, 164]

Q30

H/R/E/L/T

DCV/LDV/OMV

0.3–1.3%

n.a.

n.d.

90.4–100%

50.0–100%

n.d.

n.d.

[86, 87, 156, 158, 165]

R30

H

DCV

n.a.

0.4%

n.d.

n.d.

n.o.

n.d.

n.d.

[87, 166]

R30

S

DCV

n.a.

n.a.

n.d.

n.d.

10%

n.d.

n.d.

[166]

R30

G/H

DCV

n.a.

n.a.

n.d.

n.d.

n.o.

n.d.

n.d.

[166]

A30

K

DCV

n.a.

n.a.

n.d.

2.3–6.3%

n.d.

n.d.

n.d.

[167]

L31

M

DCV/LDV

0.9–1.8%

2.1–6.3%

74.0–85.0%

1%

92.5–100%

n.d.

n.d.

105 (GT 1a); 3 (GT 1b)

554 (GT 1a)

[86, 87, 100, 145, 146, 151, 158, 160, 163, 164, 166–169]

L31

I/F/V

DCV/LDV/OMV

n.o.

0.7–1%

n.d.

n.o.

n.d.

n.d.

n.d.

15 (L31V)

[86, 87, 100, 156, 158, 159, 164, 166–168, 170]

P32

L

DCV/LDV

n.o.

<0.5%

n.d.

n.o.

n.o.

n.d.

n.d.

[86, 87, 100, 158]

S38

F

LDV

n.o.

n.o.

n.d.

n.d.

n.d.

n.d.

n.d.

[86, 100]

H58

D

DCV/LDV/OMV

<1%

n.a.

n.d.

n.d.

n.d.

n.d.

n.d.

1,127

243

[86, 87, 100, 144, 157]

P58

D

LDV

n.a.

n.o.

n.d.

n.d.

n.d.

n.d.

n.d.

[86, 100]

A92

K

LDV

n.o.

n.o.

n.d.

n.d.

n.d.

n.d.

n.d.

[86, 100]

A92

T

LDV

n.o.

2.8%

n.d.

n.d.

n.d.

n.d.

n.d.

[86, 100]

C92

R

DCV

n.a.

n.a.

n.o.

n.d.

n.d.

n.d.

n.d.

[164]

Y93

C/F/N

DCV/LDV/OMV

n.o.–0.6%

n.o.–0.7%

n.d.

n.o.

n.d.

n.d.

n.d.

[86, 87, 100, 158]

Y93

H

DCV/LDV/OMV

<1.5%

3.8%–14.1%

n.o.

1.3–8.3%

5–13%

n.d.

n.d.

12

77

[86, 87, 100, 156, 158, 159, 164–167, 169–175]

Y93

S

LDV

<0.5%

<0.5%

n.d.

n.d.

n.d.

n.d.

n.d.

[156]

DCV: daclatasvir; LDV: ledipasvir; OBV: ombitasvir.
n.a.: not applicable because of different natural amino acid sequence in the respective HCV geno-/subtype (K24, M28, Q30, and H58 are the dominant amino acids in GT1a; F28 is the dominant amino acid in subtype 2a and L28 in subtype 2b; A30 is the dominant amino acid in GT3).
n.o.: not observed.
n.d.: no data available.
GT: genotype.