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

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.

• Authors: 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
• Journal: Gut (Gut) Vol. 65 Issue 12 Pg. 2029-2034 (12 2016) ISSN: 1468-3288 [Electronic] England
• PMID: 26306759 (Publication Type: Journal Article)
• Copyright: Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Chemical References

• Antiviral Agents
• Protease Inhibitors
• Viral Nonstructural Proteins
• NS-5 protein, hepatitis C virus

Topics

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