title: The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance.
abstract: Alisporivir (ALV), a cyclophilin inhibitor, is a host-targeting antiviral (HTA) with multigenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. Recent advances have supported the concept of interferon (IFN)-free regimens to treat chronic hepatitis C. As the most advanced oral HTA, ALV with direct-acting antivirals (DAAs) represents an attractive drug combination for IFN-free therapy. In this study, we investigated whether particular DAAs exhibit additive, synergistic, or antagonistic effects when combined with ALV. Drug combinations of ALV with NS3 protease, NS5B polymerase, and NS5A inhibitors were investigated in HCV replicons from genotypes 1a, 1b, 2a, 3, and 4a (GT1a to -4a). Combinations of ALV with DAAs exerted an additive effect on GT1 and -4. A significant and specific synergistic effect was observed with ALV-NS5A inhibitor combination on GT2 and -3. Furthermore, ALV was fully active against DAA-resistant variants, and ALV-resistant variants were fully susceptible to DAAs. ALV blocks the contact between cyclophilin A and domain II of NS5A, and NS5A inhibitors target domain I of NS5A; our data suggest a molecular basis for the use of these two classes of inhibitors acting on two distinct domains of NS5A. These results provide in vitro evidence that ALV with NS5A inhibitor combination represents an attractive strategy and a potentially effective IFN-free regimen for treatment of patients with chronic hepatitis C. Due to its high barrier and lack of cross-resistance, ALV could be a cornerstone drug partner for DAAs.
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Udayan
authors.initials: U
authors.lastname: Chatterji
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Garcia-Rivera
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: James
authors.initials: J
authors.lastname: Baugh
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Gawlik
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Wong
authors.affiliation: Novartis Institutes for BioMedical Research, Emeryville, California, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Brass
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Nikolai V
authors.initials: NV
authors.lastname: Naoumov
authors.affiliation: Department of Immunology & Microbial Science, The Scripps Research Institute, La Jolla, California, USA gallay@scripps.edu.
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Gallay
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D021984:Cyclophilin A / Q000378:metabolism; D021983:Cyclophilins / Q000037:antagonists & inhibitors; D016572:Cyclosporine / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D012093:Replicon / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D021984:Cyclophilin A; D021983:Cyclophilins; D016572:Cyclosporine; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C499715:alisporivir