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

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

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.

Citation

Vercauteren, K., Brown, R. J., Mesalam, A. A., Doerrbecker, J., Bhuju, S., Geffers, R., Van Den Eede, N., McClure, C. P., Troise, F., Verhoye, L., Baumert, T., Farhoudi, A., Cortese, R., Ball, J. K., Leroux-Roels, G., Pietschmann, T., Nicosia, A., & Meuleman, P. (2016). Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. Gut, 65(12), https://doi.org/10.1136/gutjnl-2014-309045

• Journal Article Type: Article
• Acceptance Date: Jul 23, 2015
• Online Publication Date: Aug 25, 2015
• Publication Date: Dec 31, 2016
• Deposit Date: Feb 21, 2017
• Publicly Available Date: Feb 21, 2017
• Journal: Gut
• Print ISSN: 0017-5749
• Electronic ISSN: 1468-3288
• Publisher: BMJ Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 65
• Issue: 12
• DOI: https://doi.org/10.1136/gutjnl-2014-309045
• Public URL: https://nottingham-repository.worktribe.com/output/831585
• Publisher URL: http://gut.bmj.com/content/65/12/2029
• Contract Date: Feb 21, 2017