In vitro and in vivo antiviral activity and resistance profile of the hepatitis C virus NS3/4A protease inhibitor ABT-450

Abstract

The development of direct-acting antiviral agents is a promising therapeutic advance in the treatment of hepatitis C virus (HCV) infection. However, rapid emergence of drug resistance can limit efficacy and lead to cross-resistance among members of the same drug class. ABT-450 is an efficacious inhibitor of HCV NS3/4A protease, with 50% effective concentration values of 1.0, 0.21, 5.3, 19, 0.09, and 0.69 nM against stable HCV replicons with NS3 protease from genotypes 1a, 1b, 2a, 3a, 4a, and 6a, respectively. In vitro, the most common amino acid variants selected by ABT-450 in genotype 1 were located in NS3 at positions 155, 156, and 168, with the D168Y variant conferring the highest level of resistance to ABT-450 in both genotype 1a and 1b replicons (219- and 337-fold, respectively). In a 3-day monotherapy study with HCV genotype 1-infected patients, ABT-450 was coadministered with ritonavir, a cytochrome P450 3A4 inhibitor shown previously to markedly increase peak, trough, and overall drug exposures of ABT-450. A mean maximum HCV RNA decline of 4.02 log10 was observed at the end of the 3-day dosing period across all doses. The most common variants selected in these patients were R155K and D168V in genotype 1a and D168V in genotype 1b. However, selection of resistant variants was significantly reduced at the highest ABT-450 dose compared to lower doses. These findings were informative for the subsequent evaluation of ABT-450 in combination with additional drug classes in clinical trials in HCV-infected patients. (Study M11-602 is registered at ClinicalTrials.gov under registration no. NCT01074008.).

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Figures

FIG 1

Chemical structure of ABT-450.

FIG 2

Schematic diagrams of HCV replicons used in this study. (A) Replicons for stable cell lines. (B) Replicons for transient assays. C, cysteine; E, glutamic acid; delta ribozyme, ribozyme from hepatitis delta virus; E, glutamic acid; EMCV, encephalomyocarditis virus; F-luc, firefly luciferase; G, glycine; I, isoleucine; IRES, internal ribosome entry site; K, lysine; L, leucine; Neo, neomycin phosphotransferase gene; NTR, nontranslated region; P, proline; polio, poliovirus; R, arginine; S, serine; T, threonine, Y, tyrosine.

FIG 3

Mean (± standard deviation [SD]) ABT-450 plasma trough concentration levels after 3-day monotherapy in HCV genotype 1-infected patients following various ABT-450/r doses.

FIG 4

Mean (± standard error [SE]) HCV RNA change from baseline during 3-day treatment with ABT-450/r in HCV genotype 1-infected patients. BL, baseline; PBO, placebo; P/R, pegylated interferon plus ribavirin.

FIG 5

Distribution of wild-type virus and resistant variants in patient samples with viral loads of ≥500 IU/ml after 3 days of treatment with ABT-450/r. A, alanine; D, aspartic acid; E, glutamic acid; G, glycine; K, lysine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine.