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.
- ANTIVIRAL THERAPY
- CHRONIC VIRAL HEPATITIS
- HEPATITIS C
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Contributors PM, GL-R and TP initiated and supervised the study. KV and PM designed in vivo experiments and analysed data. PM, KV, TP and RJPB designed deep sequencing analyses. RJPB, JD, SB, RG, CPM and JKB performed deep sequencing experiments and analysed data. KV, AAM and LV performed in vivo experiments. AF and NVDE performed ex vivo experiments and analyses. AN, RC, FT and TB provided key reagents. KV, RJPB and PM wrote the manuscript.
Funding This project was funded by the Ghent University (Concerted Action Grant 01G01712), The Research Foundation—Flanders (FWO-Vlaanderen; project 1.5.009.10N), the Belgian state (IUAP P7/47-HEPRO-2) and the European Union (FP7, HepaMab). TP was supported by grants from the DFG (PI 734/2-1 and CRC 900 project A6), the Helmholtz Association SO-024 and the ERC (ERC-2011-StG_281473-VIRAFRONT). AAM is a recipient of a PhD Fellowship provided by the Egyptian Government.
Competing interests RC and AN are listed as inventors on the patent of the anti-SR-BI antibody used in this work and are shareholders of JVBio srl, a company that has commercial rights to these patents.
Ethics approval Animal Ethics Committee of the Faculty of Medicine and Health Sciences of the Ghent University.
Provenance and peer review Not commissioned; externally peer reviewed.