Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. Issue 12 (25th August 2015)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Gut. Volume 65:Issue 12(2016)
• Page Start: 2029
• Page End: 2034
• Publication Date: 2015-08-25
• Subjects: ANTIVIRAL THERAPY -- HCV -- CHRONIC VIRAL HEPATITIS -- HEPATITIS C -- LIVER; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2014-309045
• Languages: English
• ISSNs: 0017-5749

Abstract

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.