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The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance,

Chatterji, Udayan and Garcia-Rivera, Jose A. and Baugh, James and Gawlik, Katarzyna and Wong, Kelly and Zhong, Weidong and Brass, Cliff and Naoumov, Nikolai and Gallay, Philippe A. (2015) The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance,. Antimicrobial Agents and Chemotherapy.

Abstract

Background & Aims: Alisporivir (ALV), a cyclophilin inhibitor, is a host-targeting antiviral (HTA) with pan-genotypic anti-HCV activity and high barrier to resistance. Recent advances have supported the concept of IFN-free regimens to treat chronic HCV. As the most advanced oral HTA, the combination of ALV with direct-acting antivirals (DAAs) would be an attractive drug combination. In this study, we investigated whether particular DAAs exhibit additive, synergistic or antagonistic effects when combined with ALV.

Methods: Drug combinations of ALV with NS3 protease, NS5B polymerase and NS5A inhibitors were investigated on HCV replicons from genotypes 1a, 1b, 2a, 3 and 4a (GT1a to 4a).

Results: Combinations of ALV with DAAs exerted an additive effect on GT1 and 4. Remarkably, a significant and specific synergistic effect was observed with the combination of ALV with NS5A inhibitors on GT2 and 3. Furthermore, ALV was found to be 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 the domain I of NS5A, our data suggest there is a molecular basis for the use of these two classes of inhibitors acting on two distinct domains of NS5A.

Conclusions: These results provide in vitro evidence that ALV with NS5A inhibitor combination represents an attractive strategy, and is potentially an effective IFN-free combination regimen for treatment of HCV patients. Due to its high barrier to resistance, ALV is a potential cornerstone drug partner for DAAs, which possess a low barrier to resistance such as NS5A inhibitors.

Item Type: Article
Keywords: ALV; HCV; NS5A inhibitors
Date Deposited: 03 May 2016 23:45
Last Modified: 03 May 2016 23:45
URI: https://oak.novartis.com/id/eprint/20034

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