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HCV Drug Resistance

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Antimicrobial Drug Resistance

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Abstract

Treatment of hepatitis C virus (HCV) infection has rapidly evolved since the initial interferon-alfa (IFN-α)-based therapy was introduced in 1989 [1]. Improved formulations of IFN-α and coadministration of ribavirin (RBV) resulted in HCV-sustained viral response (SVR) rates of approximately 50 %, which is dependent on HCV genotype (Fig. 39.1) [2]. The approval of the first direct-acting antiviral (DAA) protease inhibitors (PIs) in 2010, when used in combination with IFN-α and RBV, further improved SVR rates to 70–80 % (Fig. 39.1) [2]. However, a low barrier to resistance associated with the protease inhibitors allowed for frequent emergence of treatment-associated resistance variants. Rapid emergence of resistance-associated variants (RAVs) was also observed with the superbly potent class of NS5A replication inhibitors, precluding their use as a single agent and for specific genotype variants. Although nucleoside inhibitors were one of the first classes of HCV DAAs in preclinical development, approval of a nucleotide prodrug-based HCV treatment regimen with IFN-α and RBV was secondary to the protease inhibitors. Therapies that include nucleotide prodrugs can achieve SVR rates of nearly 100 % depending on the genotypes and DAA drug combinations assessed. Clinical trials are focusing mainly on combination regimens that include a nucleotide prodrug and at least one other DAA class, with the focus residing in prevention of RAV emergence and shorter treatment duration. Knowledge of treatment-emergent RAVs will either guide clinicians in their selection of combination therapies for HCV or serve as a historical perspective of resistance once observed prior to a single-pill combination regimen that does not select resistant variants [3].

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Authors and Affiliations

  1. Genomic Assays, Abcam, Inc., 1400W 3rd Floor, One Kendall Square, Cambridge, MA, 02139, USA

    Bianca Heinrich Ph.D.

  2. Infectious Diseases Biology-Discovery, Merck, West Point, PA, USA

    John P. Bilello Ph.D.

Authors
  1. Bianca Heinrich Ph.D.
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  2. John P. Bilello Ph.D.
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Correspondence to John P. Bilello Ph.D. .

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Editors and Affiliations

  1. Treiber Therapeutics, Cambridge, Massachusetts, USA

    Douglas L. Mayers

  2. Wayne State University School of Medicine, Detroit Medical Center, Detroit, Michigan, USA

    Jack D. Sobel

  3. Centre de recherche en Infectiologie, University of Laval, Quebec City, Canada

    Marc Ouellette

  4. Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, Michigan, USA

    Keith S. Kaye

  5. Infection Control and Prevention Unit of Infectious Diseases, Assaf Harofeh Medical Center, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel

    Dror Marchaim

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Heinrich, B., Bilello, J.P. (2017). HCV Drug Resistance. In: Mayers, D., Sobel, J., Ouellette, M., Kaye, K., Marchaim, D. (eds) Antimicrobial Drug Resistance. Springer, Cham. https://doi.org/10.1007/978-3-319-46718-4_39

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