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Antiviral Targets in HCV

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Chronic Hepatitis C Virus

Abstract

For almost one decade pegylated interferon alfa in combination with ribavirin is the standard of care (SOC) in the treatment of patients with chronic hepatitis C. Despite extensive research on optimization of peginterferon alfa/ribavirin therapy, still half of the patients cannot be cured with SOC. The limitations of antiviral therapy with SOC may be overcome by direct antiviral agents (DAA) specifically targeted against hepatitis C virus (HCV) proteins.

Cell culture infection models for HCV and the structure identification of HCV proteins were the prerequisite for the identification of target structures for DAAs against HCV. Potential targets for DAA are blocking of attachment and entry as well as inhibition of translation, post-translational processing, replication and assembly. The identification of target structures and the resulting strategies for direct antiviral treatment are discussed in this chapter.

At present the most promising targets for DAA are inhibitors of the NS3/4A protease, the NS5B polymerase, and the NS5A protein. Several DAA against these targets have entered clinical evaluation. An important lesson from early clinical trials is that HCV has a high potential for selection of resistant variants. Furthermore, development of many DAA had to be stopped due to tolerability and safety concerns. In 2010, two phase three trials with the NS3/4A protease inhibitors boceprevir and telaprevir showed that the combination of these compounds with SOC increases sustained virologic response rates in treatment-naïve genotype one patients from 38–44% to 66–75%.

Future goals of antiviral therapy with DAAs are improvement of tolerability, shortening of therapy, and to overcome the issues of resistance. Recent studies on combination therapies of different DAAs with and without interferon alfa/ribavirin are summarized and approaches for combination therapies are discussed.

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  1. Department of Internal Medicine 1, Hospital of the Johann Wolfgang Goethe-University, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    B. Kronenberger MD & S. Zeuzem MD

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    Mitchell L. Shiffman

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Kronenberger, B., Zeuzem, S. (2012). Antiviral Targets in HCV. In: Shiffman, M. (eds) Chronic Hepatitis C Virus. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1192-5_17

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