The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.

Disclosures

Semin Liver Dis. 2011;31(4):399-409. 

In This Article

Cyclophilin Inhibitors

Cyclophilin inhibitors are derived from cyclosporine A, but lack calcineurin-binding properties and thus do not exhibit immunosuppressive effects.[41,42] Alisporivir (Debio 025) is the first-in-class cyclophilin inhibitor that recently initiated a phase III trial. It binds to cyclophilin A, an essential cofactor for HCV replication and shows additive antiviral effect with pegIFN in patients with genotype 1 and 4 HCV.[41] Cyclophilin inhibitors are sometimes referred to as host-targeted agents, but can also be part of the DAAs because they are known to interact with the NS5A protein.

In a phase II study of patients with HCV genotype 1, 2, 3, and 4 naïve to HCV treatment, alisporivir doses of 200, 600, and 1,000 mg/day in combination with pegIFN for 4 weeks were compared with monotherapy with alisporivir 1,000 mg/day or pegIFN.[42] In patients with genotypes 1 and 4, the 600- and 1,000-mg combination treatments reduced HCV RNA by up to 4.61 ( ± 1.88) log10 IU/ml and 4.75 (±2.19) log10 IU/mL at week 4, respectively. In patients with genotypes 2 and 3, HCV RNA levels were reduced by -5.91 (±1.11) log10 IU/mL and -5.89 (±0.43) log10 IU/mL at week 4, respectively, with the same treatment regimens. Alisporivir 1000 mg/day was associated with a higher incidence of isolated hyperbilirubinemia. SVR results of the phase II ESSENTIAL study were recently presented.[43] Alisporivir (600 mg twice daily during one week followed by once-daily dosing) with pegIFN/RBV led to SVR in 76% of patients taking the triple therapy for 48 weeks compared with 55% of the control group (P = .008). Triple therapy with alisporivir for 24 weeks was as effective as pegIFN/RBV dual therapy for 48 weeks with 53% SVR compared with 55%, respectively. In the RGT arm in which patients could stop triple therapy at week 24 if they achieved RVR, the SVR rate was 69%. Alisporivir demonstrates a high barrier to resistance and interestingly, the resistance mutation identified with its use (D320E) is mainly located in the NS5A domain II. Recent findings indicate that alisporivir inhibits hepatitis C virus replication by preventing a cyclophilin A induced cis-trans isomerization in domain II of NS5A.[44] Metabolism is through cytochrome P450 3A4, which can compromise its ability to be given concomitantly with substrates, inhibitors, or inducers of this cytochrome. Cyclophilin inhibitors could be part of a potent DAA combination in patients not taking concomitant P450 3A4 medications.

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