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  • Review Article
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Direct-acting antiviral agents for hepatitis C: structural and mechanistic insights

Nature Reviews Gastroenterology & Hepatology volume 13, pages 338–351 (2016)Cite this article

Subjects

Key Points

  • Direct-acting antiviral agents targeting the viral NS3/4A protease, NS5B polymerase and NS5A protein have been developed

  • Combinations of antiviral agents with different mechanism of action lead to high rates of sustained virologic response without the need for PEG-IFN

  • Classes of direct-acting antiviral agents have different antiviral attributes such as barrier to resistance and genotypic coverage, and different clinical attributes such as adverse effects, dosing, and drug–drug interactions

  • The importance of resistance-associated variants present at baseline or after a course of unsuccessful therapy differs by antiviral class and the genotype subtype

Abstract

The treatment of HCV infection has evolved at an extremely rapid pace over the past few years. The development of direct-acting antiviral agents, which potently inhibit different stages in the viral life cycle, has led to the replacement of interferon with well-tolerated oral therapies with cure rates of >90% in most patient populations. Understanding the mechanisms of action of the various agents as well as related issues, including the molecular basis for resistance, helps to guide drug development and clinical use. In this Review, we provide a mechanistic description of NS3/4A protease inhibitors, nucleotide and non-nucleotide inhibitors of the NS5B viral polymerase and inhibitors of the NS5A protein, followed by a summary of clinical data from studies of each drug class alone and in combination. Remaining challenges in drug development efforts are also discussed.

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Figure 1: HCV life cycle and site of action of DAAs.
Figure 2: Location of resistance-associated amino acid substitutions in relation to drug binding.
Figure 3: Mechanisms of NS5B-mediated RNA synthesis.
Figure 4: Effect of baseline RAVs on different direct-acting antiviral regimens.

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Authors and Affiliations

  1. Department of Medical Microbiology & Immunology, 6-020K Katz Group Centre, University of Alberta, Edmonton, T6G 2E1, Alberta, Canada

    Matthias Götte

  2. Toronto Centre for Liver Disease, University Health Network, University of Toronto, 200 Elizabeth Street, Toronto, M5C 2C4, Ontario, Canada

    Jordan J. Feld

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  1. Matthias Götte
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  2. Jordan J. Feld
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Both authors contributed equally to all aspects of this manuscript.

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Correspondence to Jordan J. Feld.

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Competing interests

M.G. has received scientific consulting fees and/or research support from AstraZeneca, Gilead Sciences, GlaxoSmithKline, Medivir, Merck, Microbiotix, Pfizer and Tibotec/Johnson & Johnson, as well as funding from the Canadian Institutes of Health Research. J.J.F. has received scientific consulting fees and/or research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Theravance, as well as grants from Physician Services' Incorporated Foundation, the National Institutes of Health and the Canadian Institutes of Health Research.

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Götte, M., Feld, J. Direct-acting antiviral agents for hepatitis C: structural and mechanistic insights. Nat Rev Gastroenterol Hepatol 13, 338–351 (2016). https://doi.org/10.1038/nrgastro.2016.60

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