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.