Advanced search
1 file | 730.14 KB Add to list

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
Organization
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

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 730.14 KB

Citation

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

MLA
Vercauteren, Koen, et al. “Targeting a Host-Cell Entry Factor Barricades Antiviral-Resistant HCV Variants from on-Therapy Breakthrough in Human-Liver Mice.” GUT, vol. 65, no. 12, 2016, pp. 2029–34, doi:10.1136/gutjnl-2014-309045.
APA
Vercauteren, K., Brown, R. J., Mesalam, A. A. 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), 2029–2034. https://doi.org/10.1136/gutjnl-2014-309045
Chicago author-date
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): 2029–34. https://doi.org/10.1136/gutjnl-2014-309045.
Chicago author-date (all authors)
Vercauteren, Koen, Richard JP Brown, Ahmed Atef Ahmed Abouzeid Mesalam, Juliane Doerrbecker, Sabin Bhuju, Robert Geffers, Naomi Van den Eede, C Patrick McClure, Fulvia Troise, Lieven Verhoye, Thomas Baumert, Aliasghar Farhoudi Moghadam, Riccardo Cortese, Jonathan K Ball, Geert Leroux-Roels, Thomas Pietschmann, Alfredo Nicosia, and Philip Meuleman. 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. doi:10.1136/gutjnl-2014-309045.
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.
IEEE
[1]
K. Vercauteren et al., “Targeting a host-cell entry factor barricades antiviral-resistant HCV variants from on-therapy breakthrough in human-liver mice,” GUT, vol. 65, no. 12, pp. 2029–2034, 2016.
@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}},
  keywords     = {{HEPATITIS-C VIRUS,B TYPE-I,MONOCLONAL-ANTIBODY,VITRO RESISTANCE,ANIMAL-MODELS,SCID MICE,INFECTION,RECEPTOR,REPLICATION,COMBINATION}},
  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}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: