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Entry inhibitors, DAA synergistically inhibited HCV infection
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Combinations of entry inhibitors and direct-acting antivirals or host-targeting agents resulted in a synergistic effect that was efficacious in preventing hepatitis C virus infection, according to recent research data.
To explore alternatives to the current standard of care (SOC), or interferon (IFN)-free regimens, researchers studied the antiviral efficacy of entry inhibitors (EIs) and direct-acting antiviral agents (DAA) and host-targeting agents (HTAs) in cell culture models and human liver-chimeric mice. DAA and HTA were tested individually and in combination with EIs, and data were analyzed by inhibitory concentrations (ICs) of 50, 75 and 90.
Combining DAAs and HTAs with EIs (CD81-, scavenger receptor class B type I-, or claudin-1- specific antibodies, or small-molecule inhibitors erlotinib and dasatinib) in various ICs demonstrated synergistic inhibition of HCV infection without detectable toxicity. Of the DAAs, telaprevir or boceprevir combined with all EIs tested (at sub-IC50) demonstrated synergy with combination indexes (CIs) of 0.48-0.71 at IC90 (95% CI), as well as at IC50 and IC75. Combinations of simeprevir or danoprevir with EIs at all ICs also demonstrated synergy (CIs, 0.06-0.65 at IC90), as did daclatasvir (CIs, 0.27-0.89 at IC90), sofosbuvir at all ICs (CIs, 0.41-0.61 at IC90) and mericitabine (CIs, 0.18-0.68 at IC90). Of the HTAs, combinations of alisporivir with EIs demonstrated synergy at IC75 (CIs, 0.19-0.69) and IC50 (CIs, 0.06-0.5). Combinations of two EIs resulted in synergy at all ICs as well (CIs, 0.13-0.68 at IC90), and combinations of IFN with EIs at sub-IC50 were synergistic at all ICs (CIs, 0.16-0.53 at IC90).
“Collectively, novel combinations based on synergy uncovered in this study may widen the therapeutic arsenal against HCV infection for prevention of liver graft infection, treatment of difficult-to-treat patients and provide alternatives for patients with contraindications to particular compounds of SOC or future IFN-free regimens,” the researchers concluded.
Disclosure: See the study for a full list of relevant financial disclosures.
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