Two classes of
hepatitis C antiviral agents currently exist, i.e., direct-acting
antivirals and host-targeting
antivirals. Direct-acting
antivirals target
viral proteins including NS3/NS4A
protease, NS5B polymerase and NS5A
protein, while host-targeting
antivirals target various host
proteins critical for replication of the hepatitis C virus (HCV).
Alisporivir is the most advanced host-targeting
antiviral in clinical development.
Alisporivir blocks HCV replication by neutralizing the peptidyl-
prolyl isomerase activity of the abundant host cytosolic
protein,
cyclophilin A. Due to its unique mechanism of
antiviral action,
alisporivir is pangenotypic, provides a high barrier for development of viral resistance, and does not permit cross-resistance to direct-acting
antivirals.
Alisporivir has an excellent pharmacokinetic and safety profile. Phase I and II clinical studies have demonstrated that
alisporivir causes a dramatic reduction in viral loads in HCV-infected patients.
Alisporivir was shown to be highly potent in treatment-naïve and treatment-experienced patients with genotype 1 as well as in those with genotypes 2 or 3. Low viral breakthrough rates were observed and the most frequent clinical and laboratory adverse events associated with
alisporivir in combination with pegylated
interferon-alpha and
ribavirin were similar to those associated with pegylated
interferon-alpha and
ribavirin used alone. A laboratory abnormality observed in some patients receiving
alisporivir is
hyperbilirubinemia, which is related to transporter inhibition and not to liver toxicity. The most recent clinical results suggest that
alisporivir plus other direct-acting
antivirals should provide a successful treatment option for difficult-to-treat populations, such as nonresponders to prior
interferon-alpha therapy and patients with
cirrhosis. In conclusion,
alisporivir represents an attractive candidate component of future
interferon-free regimens.