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
Richard J.P. Brown
Ahmed Atef Mesalam
Naomi Van Den Eede
C. Patrick McClure
Jonathan K. Ball
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.
|Journal Article Type||Article|
|Publication Date||Dec 31, 2016|
|Publisher||BMJ Publishing Group|
|Peer Reviewed||Peer Reviewed|
|APA6 Citation||Vercauteren, K., Brown, R. J., Mesalam, A. A., Doerrbecker, J., Bhuju, S., Geffers, R., …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), doi:10.1136/gutjnl-2014-309045|
|Copyright Statement||Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf|
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf
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