New and experimental therapies for HCV

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Abstract

Despite improvements to treatments for HCV infection, almost half of patients cannot be cured with standard combination therapy (pegylated interferon α and ribavirin). The HCV life cycle offers a number of potential targets for molecular therapy, and several specifically targeted antiviral therapies for HCV (STAT-Cs) are in preclinical and clinical stages of development. Evidence to date suggests that monotherapy with any antiviral drug is unlikely to eradicate HCV infection. Combination therapy with interferon and ribavirin is necessary for the augmentation of antiviral drug activity and/or prevention of drug resistance. Results from clinical trials carried out in the past few years on STAT-C agents in combination with standard therapy with peginterferon and ribavirin provide great promise of higher rates of sustained virological response and, potentially, shorter duration of therapy than standard therapy alone achieves. Although pegylated interferon and ribavirin are likely to remain a cornerstone of therapeutic regimens in the short term, combinations of antiviral drugs of different classes, possibly along with novel agents that target host factors and modulate viral replication or augment antiviral defenses, offer the eventual possibility of interferon-free regimens.

Key Points

  • HCV infection is an epidemic of global proportions and up to 200 million people are estimated to be infected worldwide: standard anti-HCV therapy consists of a combination of peginterferon and ribavirin

  • The HCV life cycle offers several possible targets for specific inhibition, and many specifically targeted antiviral therapies for HCV (STAT-Cs) and other novel drugs are currently in preclinical and clinical stages of development

  • Several STAT-C drugs, including HCV protease and polymerase inhibitors, have the capacity to induce suppression of HCV replication; the frequency and characteristics of this resistance vary between drug classes

  • Evidence suggests that combining STAT-C drugs with standard therapy induces higher response rates and could afford a shorter duration of therapy than standard treatment alone does in patients infected with HCV gentotype 1

  • Non-STAT-C strategies, including augmentation of host immune response and inhibition of endogenous cellular enzymes that facilitate viral replication, also offer promise, as do modifications of standard therapy

  • Combinations of novel agents, with or without standard therapy, should be evaluated as early in their development programs as regulatory and safety considerations allow

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Figure 1: Schematic diagram of the HCV life cycle.

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Competing interests

I. M. Jacobson declares associations with the following companies: Schering-Plough, Gilead Sciences, Idenix Pharmaceuticals and Novartis AG, as recipient of grant/research support, consultant/advisor and member of the speakers' bureau; Vertex Pharmaceuticals, GlobeImmune, Human Genome Sciences, Boehringer Ingelheim, Roche and Pharmasset, as recipient of grant/research support and consultant/advisor; Bristol-Myers Squibb, as consultant/advisor and member of the speakers' bureau; Valeant Pharmaceuticals International, Intarcia Therapeutics, as recipient of0020grant/research support; and Abbott, Pfizer, Merck & Co., Sanofi-aventis, Progenics Pharmaceuticals, and ZymoGenetics as consultant/advisor. A. A. Pereira declares no competing interests.

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