Quantifying antiviral activity optimizes drug combinations against hepatitis C virus infection.
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.
School of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa 920-8640, Japan.
Yoshiki
Y
Koizumi
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.|Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan.
Hirofumi
H
Ohashi
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.|Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan.
Syo
S
Nakajima
Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya 467-8601, Japan.
Yasuhito
Y
Tanaka
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Takaji
T
Wakita
Theoretical Biology and Biophysics Group, Los Alamos National Laboratory, Los Alamos, NM 87545.
Alan S
AS
Perelson
Mathematical Biology Laboratory, Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan; siwami@kyushu-u.org kwatashi@nih.go.jp.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
Shingo
S
Iwami
Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; siwami@kyushu-u.org kwatashi@nih.go.jp.|Department of Applied Biological Sciences, Faculty of Science and Technology, Tokyo University of Sciences, Chiba 278-8510, Japan.|Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Saitama 332-0012, Japan.
Koichi
K
Watashi
D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral / Q000187:drug effects; D004359:Drug Therapy, Combination / Q000401:mortality; D016174:Hepacivirus / Q000187:drug effects / Q000502:physiology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
HCV; antiviral; instantaneous inhibitory potential; mathematical model; replicon