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

(2016) GUT. 65(12). p.2029-2034
Author
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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.
Keywords
HEPATITIS-C VIRUS, B TYPE-I, MONOCLONAL-ANTIBODY, VITRO RESISTANCE, ANIMAL-MODELS, SCID MICE, INFECTION, RECEPTOR, REPLICATION, COMBINATION

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Citation

Please use this url to cite or link to this publication:

Chicago
Vercauteren, Koen, Richard JP Brown, Ahmed Atef Ahmed Abouzeid Mesalam, Juliane Doerrbecker, Sabin Bhuju, Robert Geffers, Naomi Van den Eede, et al. 2016. “Targeting a Host-cell Entry Factor Barricades Antiviral-resistant HCV Variants from On-therapy Breakthrough in Human-liver Mice.” GUT 65 (12): 2029–2034.
APA
Vercauteren, K., Brown, R. J., Mesalam, A. A. A. A., Doerrbecker, J., Bhuju, S., Geffers, R., Van den Eede, N., et al. (2016). Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. GUT, 65(12), 2029–2034.
Vancouver
1.
Vercauteren K, Brown RJ, Mesalam AAAA, Doerrbecker J, Bhuju S, Geffers R, et al. Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice. GUT. 2016;65(12):2029–34.
MLA
Vercauteren, Koen, Richard JP Brown, Ahmed Atef Ahmed Abouzeid Mesalam, et al. “Targeting a Host-cell Entry Factor Barricades Antiviral-resistant HCV Variants from On-therapy Breakthrough in Human-liver Mice.” GUT 65.12 (2016): 2029–2034. Print.
@article{7143878,
  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.},
  author       = {Vercauteren, Koen and Brown, Richard JP and Mesalam, Ahmed Atef Ahmed Abouzeid and Doerrbecker, Juliane and Bhuju, Sabin and Geffers, Robert and Van den Eede, Naomi and McClure, C Patrick and Troise, Fulvia and Verhoye, Lieven and Baumert, Thomas and Farhoudi Moghadam, Aliasghar and Cortese, Riccardo and Ball, Jonathan K and Leroux-Roels, Geert and Pietschmann, Thomas and Nicosia, Alfredo and Meuleman, Philip},
  issn         = {0017-5749},
  journal      = {GUT},
  language     = {eng},
  number       = {12},
  pages        = {2029--2034},
  title        = {Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice},
  url          = {http://dx.doi.org/10.1136/gutjnl-2014-309045},
  volume       = {65},
  year         = {2016},
}

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