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A cell-based infection assay using infectious HCV with full-length HCV genomes is more biologically relevant to in vivo infection. In addition, the replicon-containing cells are highly selected and may not reflect the native cellular environment for HCV replication in vivo. However, replicon systems cannot reproduce the entire infectious HCV life cycle. Recently, more combination studies have utilized an infectious HCV system. Most in vitro combination studies published to date use the subgenomic replicon system to evaluate combinations of certain novel agents with well-developed antivirals that have completed advanced clinical trials or obtained FDA approval. To facilitate selective development of such regimens, it is therefore important to investigate the potential synergistic or antagonistic effects of such combinations first with a robust in vitro HCV model system. In light of HCV’s high rate of developing mutations that confer drug resistance, combination therapies of DAAs have been crucial for the development of effective regimens for chronic HCV infection.
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Many regimens demonstrated improved viral clearance in patients infected with HCV genotype-1.
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Recently, the US Food and Drug Administration (FDA) has approved direct-acting antivirals (DAAs), including the protease, NS5A and polymerase inhibitors telaprevir, boceprevir, simeprevir, paritaprevir, ledipasvir, daclatasvir, ombitasvir, sofosbuvir and dasabuvir for use in combination or with PEG-IFN and RBV. For many years, combination antiviral therapies utilizing pegylated interferon-α (PEG-IFN) and ribavirin (RBV) were the first line of care. Effective vaccination for HCV is not yet available. Chronic HCV infection is a leading cause of hepatocellular carcinoma and a leading indication for liver transplantation in developed countries. HCV is a positive-stranded RNA virus infecting over 200 million people worldwide. We also demonstrate that these DAAs in combination with host-targeting agents or entry inhibitors may improve HCV treatment response. Combinations of these drugs did not show any added or unexpected cytotoxicity.Ĭonclusions: Our results show that in vitro combination studies of anti-HCV DAAs in the HCVcc system may provide useful guidance for drug combination designs in clinical studies. Combination studies between these DAA classes and cyclosporin A or ( S)-chlorcyclizine demonstrated additive to synergistic effects and highly synergistic effects, respectively. As expected, combinations of antivirals of the same class were additive. Combinations between NS5A and nucleotide NS5B inhibitors were synergistic, while combinations of protease inhibitors with the other two classes were additive to slightly antagonistic. Results: Combinations between different classes showed good consistency across the two viral assay systems and two software platforms. Two computational software packages, MacSynergyII and CalcuSyn, were used for data analysis. Methods: Using cell-based HCV Con1b replicon and an infectious full-length HCV (HCVcc-Luc) infection system, we systematically tested the synergy, additivity or antagonism of combinations of protease, NS5A and nucleotide NS5B inhibitor classes as well as the combination of these DAAs with host-targeting agent cyclosporin A or non-antibody entry inhibitor ( S)-chlorcyclizine. Infectious full-length HCV systems have been developed and are being used to test drug efficacy. Regimens are often first assessed in vitro, with most combination studies to date using subgenomic replicon systems, which do not replicate the complete HCV life cycle and preclude study of entry and assembly inhibitors.
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To improve response and prevent resistance, combination regimens have been the focus of clinical development. Abstractīackground: Direct-acting antivirals (DAAs) have greatly improved the treatment of HCV infection. Evaluation of antiviral drug synergy in an infectious HCV systemBilly Lin 1, Shanshan He 1, Hyung Joon Yim 1, T Jake Liang 1, Zongyi Hu 1, * 1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA *Corresponding author e-mail: Citation: Antiviral Therapy 2016 21:595-603 doi: 10.3851/IMP3044Ĭopyright (c) 2016 International Medical Press, all rights reserved.