Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice

Koen Vercauteren, Richard J P Brown, Ahmed Atef Mesalam, Juliane Doerrbecker, Sabin Bhuju, Robert Geffers, Naomi Van Den Eede, C Patrick McClure, Fulvia Troise, Lieven Verhoye, Thomas Baumert, Ali Farhoudi, Riccardo Cortese, Jonathan K Ball, Geert Leroux-Roels, Thomas Pietschmann, Alfredo Nicosia, Philip Meuleman

Research output: Contribution to journalArticle

Abstract

OBJECTIVE: Direct-acting antivirals (DAAs) inhibit hepatitis C virus (HCV) infection by targeting viral proteins that play essential roles in the replication process. However, selection of resistance-associated variants (RAVs) during DAA therapy has been a cause of therapeutic failure. In this study, we wished to address whether such RAVs could be controlled by the co-administration of host-targeting entry inhibitors that prevent intrahepatic viral spread.

DESIGN: We investigated the effect of adding an entry inhibitor (the anti-scavenger receptor class B type I mAb1671) to a DAA monotherapy (the protease inhibitor ciluprevir) in human-liver mice chronically infected with HCV of genotype 1b. Clinically relevant non-laboratory strains were used to achieve viraemia consisting of a cloud of related viral variants (quasispecies) and the emergence of RAVs was monitored at high resolution using next-generation sequencing.

RESULTS: HCV-infected human-liver mice receiving DAA monotherapy rapidly experienced on-therapy viral breakthrough. Deep sequencing of the HCV protease domain confirmed the manifestation of drug-resistant mutants upon viral rebound. In contrast, none of the mice treated with a combination of the DAA and the entry inhibitor experienced on-therapy viral breakthrough, despite detection of RAV emergence in some animals.

CONCLUSIONS: This study provides preclinical in vivo evidence that addition of an entry inhibitor to an anti-HCV DAA regimen restricts the breakthrough of DAA-resistant viruses. Our approach is an excellent strategy to prevent therapeutic failure caused by on-therapy rebound of DAA-RAVs. Inclusion of an entry inhibitor to the newest DAA combination therapies may further increase response rates, especially in difficult-to-treat patient populations.

Original languageEnglish
JournalGut
Volume65
Issue number12
Pages (from-to)2029-2034
Number of pages6
DOIs
Publication statusPublished - Dec-2016

Keywords

  • Amino Acid Substitution
  • Animals
  • Antiviral Agents/pharmacology
  • Disease Models, Animal
  • Drug Resistance, Viral/genetics
  • Genotype
  • Hepacivirus/drug effects
  • Hepatitis C, Chronic/drug therapy
  • Liver/drug effects
  • Mice
  • Mutation, Missense
  • Protease Inhibitors/pharmacology
  • Viral Nonstructural Proteins/genetics

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