Direct Antiviral Agents for Hepatitis C – New Developments

Lange Christian Markus, Sarrazin Christoph, Zeuzem Stefan

European Gastroenterology & Hepatology Review, 2010;6(1):70–7

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Abstract
Numerous directly acting antiviral agents (DAAs) for the treatment of chronic hepatitis C virus (HCV) infection are currently under development. The final results of phase II clinical trials that evaluated the most advanced compounds – telaprevir and boceprevir – indicate that the addition of these NS3/4A protease inhibitors to pegylated interferon-alpha (pegIFN-α) and ribavirin strongly improves the chances of achieving a sustained virological response (SVR) in treatment-naïve HCV genotype 1 patients and in prior non-responders and relapsers. However, monotherapy with DAAs frequently results in the selection of resistant quasi-species and viral breakthrough and is therefore not suitable. Generally, NS5B polymerase inhibitors have a lower antiviral efficacy than protease inhibitors, and their ability to improve SVR rates remains to be established. Future research should elaborate on whether an SVR can be achieved with combination therapies of DAA agents without IFN-α; in addition, DAAs targeting genotypes other than HCV genotype 1 should be evaluated.

Keywords
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance

Disclosure: Christian Markus Lange has no conflicts of interest to declare. Christoph Sarrazin is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, BMS, Boehringer Ingelheim, Falk, Gilead, Merck, Novartis, Roche, Siemens, Tibotec and Vertex. Stefan Zeuzum is a clinical investigator, consultant and/or a member of the speaker’s bureau of Abbott, Anadys, BMS, Boehringer Ingelheim, Gilead, HGS, Merck, Novartis, Roche, Tibotec and Vertex.

Received: 7 May 2010 Accepted: 29 June 2010 Citation: European Gastroenterology & Hepatology Review, 2010;6(1):70–6

Correspondence: Stefan Zeuzem, Klinikum der JW Goethe-Universität Frankfurt am Main Medizinische Klinik I, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. E: zeuzem@em.uni-frankfurt.de

The odds of achieving a sustained virological response (SVR) in patients with chronic hepatitis C with a therapy of pegylated interferon-alpha (pegIFN-α) and ribavirin are still too low, particularly in patients infected with hepatitis C virus (HCV) genotypes 1 or 4.1–4 Therefore, intensive efforts have been made to develop directly acting antiviral agents (DAAs) against HCV.5–12 Many of these DAAs are currently in phase I–III development and will significantly change treatment options for HCV infection in the near future. The most advanced compounds are telaprevir and boceprevir, which are both inhibitors of the HCV NS3 protease and have been shown to significantly enhance SVR rates in HCV genotype 1 patients when applied in addition to pegIFN-α and ribavirin.13–15

NS3/4A Protease Inhibitors

NS3/4A protease inhibitors can be divided into two chemical classes: macrocyclic inhibitors and linear tetra-peptide α-ketoamid derivatives. Ciluprevir has a macrocyclic structure and was the first protease inhibitor evaluated in patients with chronic hepatitis C. Ciluprevir, as well as subsequently developed NS3/4A protease inhibitors of both molecular classes, strongly inhibited HCV replication during monotherapy, but also frequently caused the selection of resistant mutants, which may be followed by viral breakthrough.12,16–18 Although the development of ciluprevir was stopped because of serious cardiotoxicity observed in an animal model, the proof of principle was provided for successful suppression of HCV replication by NS3/4A inhibitors in patients with chronic hepatitis C. Subsequent studies have shown that the frequency of resistance development against protease inhibitors can be vastly reduced by the additional administration of pegIFN and ribavirin. Telaprevir and boceprevir are the most advanced NS3/4A protease inhibitors, and are currently in phase III evaluation.

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Keywords:
Directly acting antiviral agents (DAAs), specifically targeted antiviral therapy for hepatitis c (STAT-C), protease inhibitor, polymerase inhibitor, hepatitis C, antiviral therapy, viral resistance, drug resistance

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