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  3. Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection

  • Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1922-1927. doi: 10.1073/pnas.1610197114.
Yoshiki Koizumi 1,  Hirofumi Ohashi 2 3,  Syo Nakajima 2 3,  Yasuhito Tanaka 4,  Takaji Wakita 2,  Alan S Perelson 5,  Shingo Iwami 6 7 8,  Koichi Watashi 9 3 8
Affiliations

Affiliations

  • 1 School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa 920-8640, Japan.
  • 2 Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • 3 Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan.
  • 4 Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya 467-8601, Japan.
  • 5 Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
  • 6 Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan; siwami@kyushu-u.org kwatashi@nih.go.jp.
  • 7 Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.
  • 8 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
  • 9 Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; siwami@kyushu-u.org kwatashi@nih.go.jp.
PMID: 28174263 DOI: 10.1073/pnas.1610197114
Abstract

With the introduction of direct-acting antivirals (DAAs), treatment against hepatitis C virus (HCV) has significantly improved. To manage and control this worldwide infectious disease better, the "best" multidrug treatment is demanded based on scientific evidence. However, there is no method available that systematically quantifies and compares the Antiviral efficacy and drug-resistance profiles of drug combinations. Based on experimental anti-HCV profiles in a Cell Culture system, we quantified the instantaneous inhibitory potential (IIP), which is the logarithm of the reduction in viral replication events, for both single drugs and multiple-drug combinations. From the calculated IIP of 15 anti-HCV drugs from different classes [telaprevir, danoprevir, asunaprevir, simeprevir, sofosbuvir (SOF), VX-222, dasabuvir, nesbuvir, tegobuvir, daclatasvir, ledipasvir, IFN-α, IFN-λ1, cyclosporin A, and SCY-635], we found that the nucleoside polymerase inhibitor SOF had one of the largest potentials to inhibit viral replication events. We also compared intrinsic Antiviral activities of a panel of drug combinations. Our quantification analysis clearly indicated an advantage of triple-DAA treatments over double-DAA treatments, with triple-DAA treatments showing enhanced Antiviral activity and a significantly lower probability for drug resistance to emerge at clinically relevant drug concentrations. Our framework provides quantitative information to consider in designing multidrug strategies before costly clinical trials.

Keywords

HCV; antiviral; instantaneous inhibitory potential; mathematical model; replicon.

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