New HCV Therapies on the Horizon

Clinical Microbiology and Infection
DOI: 10.1111/j.1469-0691.2010.03430.x
Copyright © 2010 European Society of Clinical Microbiology and Infectious
Accepted Article (Accepted, unedited articles published online for future issues)

Author Information
Medizinische Klinik 1, Klinikum der J. W. Goethe-Universität, Frankfurt am Main, Germany

*Correspondence: Christoph Sarrazin,
*Correspondence: Corresponding author: Christoph Sarrazin, MD Medizinische Klinik 1 Klinikum der J.W. Goethe-Universität Theodor-Stern-Kai 7 60590 Frankfurt am Main, Germany Phone: +496963015122; Fax: +4969630183112 Email: sarrazin@em.uni-frankfurt.de

Abstract

Improved understanding of the hepatitis C virus (HCV) life-cycle has led to the discovery of numerous potential targets for antiviral therapy. HCV polyprotein processing and replication have been identified as the most promising viral targets. However, viral entry and fusion, RNA translation, virus assembly and release and several host cell factors may provide alternative attractive targets for future anti-HCV therapies.

Inhibitors of the HCV NS3/4A protease are currently the most advanced in clinical development. Monotherapy with protease inhibitors revealed high antiviral activity but was associated with a frequent selection of resistant HCV variants, often resulting in viral breakthrough. However, there is encouraging evidence from phase 2/3 trials, indicating that the addition of a protease inhibitor (e.g. telaprevir and boceprevir) to pegylated interferon-alfa/ribavirin substantially improves sustained virologic response rates in both treatment-naïve and -experienced patients with HCV genotype 1.

Nucleos(t)ide inhibitors of the HCV NS5B polymerase have shown variable antiviral activity against different HCV genotypes but seem to have a higher genetic barrier to resistance compared to protease inhibitors. In addition, several allosteric binding sites have been identified for non-nucleoside inhibitors of the NS5B polymerase. However, development of a substance with high antiviral activity and a high genetic barrier to resistance seems to be difficult. Among the different host-cell targeting compounds in early clinical development, cyclophilin-inhibitors have shown the most promising results.

Although advances have also been made towards the improvement of interferons, combinations of antiviral agents with different mechanisms of action may lead to the eventual possibility of interferon-free regimens.

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