FDA-APPROVED HEPATITIS C VIRUS (HCV) DRUGSMUTATIONS IN THE HCV PROTEASE GENE ASSOCIATED WITH RESISTANCE TO NONSTRUCTURAL PROTEIN 3 (NS3) PROTEASE INHIBITORS

V T V R A V IaV MBoceprevir 36 54 55 155 156 158 170 175

A A A K S I FaA LM S I T T TaT

G VC

V T I R A DTelaprevir 36 54 132 155 156 168

A A Vb K S Nb

M S T TG G VL M

INVESTIGATIONAL HCV DRUGSc

MUTATIONS IN THE HCV PROTEASE GENE ASSOCIATED WITH RESISTANCE TO NONSTRUCTURAL 3 PROTEIN (NS3) PROTEASE INHIBITORS

V F Q S R A D ISimeprevir 36 43 80 122 155 156 168 170

M S K A K T A TR R V VL E

HT

R A DFaldaprevir 155 156 168

K T AV V

EHYNPI

V V R A DABT-450 36 55 155 156 168

M I K T AA V VG Y

EK

V V R DDanoprevir 36 55 155 168

M I K EA TG

MUTATIONS IN THE HCV NONSTRUCTURAL PROTEIN 5A (NS5A) GENE ASSOCIATED WITH RESISTANCE TO NS5A INHIBITORS

Md Qd L Qe H Q A YDaclatasvir 28 30 31 54 58 62 92 93

V R V H D R K HA E M N E T NT H F Y C

MUTATIONS IN THE HCV POLYMERASE GENE ASSOCIATED WITH RESISTANCE TO NONSTRUCTURAL PROTEIN 5B (NS5B) NUCLEOS(T)IDE INHIBITORS

SSofosbuvir 282

T

SMericitabine 282

T

MUTATIONS IN THE HCV POLYMERASE GENE ASSOCIATED WITH RESISTANCE TO NONNUCLEOSIDE POLYMERASE INHIBITORSf P P V

BI207127 NNI-1 (thumb 1)

495 496 499L S ASATQ

L R MVX222

NNI-2 (thumb 2)419 422 423S K T

VM G D

Setrobuvir NNI-3 (palm 1)

414 554 559T D GL

January 2013. Mutations in hepatitis C virus (HCV) that impact susceptibility to HCV drugs approved by the US Food and Drug Administration (FDA) and to investigational drugs. The number on the bar refers to the amino acid position; the letter above the number refers to the wild-type amino acid and the letter(s) below the bar are relevant substitutions. Amino acid abbreviations: A, alanine; C, cysteine; D, aspartate; E, glutamate; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. Bolded type under the amino acid position number represents the key mutations that are clearly associated with virologic failure and result in a resistant phenotype. ©IAS–USA 2013

User NotesUpdates since the October 2012 edition: mutations at positions 54 and 138 on the simeprevir bar have been removed because the mutations at position 54 have been observed in only a few patients and in vitro does not confer resistance to the drug; the S138T mutation has only been observed in vitro.1,2 I170T has been added to the simeprevir bar.3

a The majority of mutations seen in HCV genotype 1a are I170F/T substitutions in which I is the consensus amino acid. The majority of mutations seen in HCV genotype 1b are V170A/T, in which V is the consensus amino acid.

b Variants are rarely seen in vivo and are of unclear clinical significance. These variants are most frequently seen in combination with other resistance-associated mutations. In vitro, they do not confer substantial resistance to telaprevir (< 2-fold increase in median effective concentration [EC50]).

c Comprehensive resistance data have not been published. The mutations listed should be consid-ered provisional.

d Indicates wild-type in HCV genotype 1a only.e Indicates HCV genotype 1b only.f NNI position designations according to Pauwels et al.4

1. Lenz O, Verbinnen T, Lin TI, et al. In vitro resistance profile of the hepatitis C virus NS3/4A prote-ase inhibitor TMC435. Antimicrob Agents Chemother. 2010;54(5):1878-1887.

2. Lenz O, Fevery B, Vijgen L, et al. TMC435 in combination with peginterferon alpha-2a/ribavi-rin in treatment-naive patients infected with HCV genotype 1: virology analysis of the PILLAR study. [Abstract 1329.] 62nd Annual Meeting of the American Association for the Study of Liver Disease (AASLD). November 4-8, 2011; San Francisco, CA.

3. Lenz O, Fevery B, Vijgen L, et al. TMC435 in patients infected with HCV genotype 1 who have failed previous pegylated interferon/ribavirin treatment: virologic analyses of the ASPIRE trial. [Abstract 9.] 47th Annual Meeting of the European Association for the Study of the Liver (EASL). April 18-22, 2012; Barcelona, Spain.

4. Pauwels F, Mostmans W, Quirynen LM, et al. Binding-site identification and genotype profiling of hepatitis C virus polymerase inhibitors. J Virol. 2007;81(13):6909-6919