A proof-of-concept study in HCV-infected Huh7.5 cells for shortening the duration of DAA-based triple treatment regimens.

Abstract

With the development of more effective direct-acting antivirals (DAAs), dual- or triple-therapy regimens represent the major strategy used to cure chronic hepatitis C virus (HCV) infection. Thus, shorter treatment duration regimens with low burden, few adverse effects and good patient adherence are urgently needed. This study theoretically demonstrates a proof-of-concept approach for shortening therapy duration by examining HCV-infected Huh7.5 cells after treatment with a high or low fixed dose of three DAAs (simeprevir + daclatasvir + sofosbuvir) for 6-15 days. The results demonstrated that HCV-infected Huh7.5 cells achieved an ultrarapid virologic response with undetectable HCV RNA and protein and were cured after treatment with the triple-therapy regimen for 15 days. When the treatment duration was shortened, virologic relapse might occur after treatment with a low fixed dose of the three DAAs for 9 days and did occur after treatment with a low fixed dose for 6 days, although HCV was below detectable levels at the end of treatment. However, virologic relapse could be avoided with treatment of a high fixed dose of the three DAAs for 9 or 6 days. Although a virologic breakthrough occurred after an intermittent treatment regimen at the low fixed dose, the high fixed dose cured HCV-positive Huh7.5 cells with intermittent treatment. In conclusion, HCV is persistently present below detectable levels in HCV-infected Huh7.5 cells for a long time after treatment, and a shortened therapy duration is associated with an increased risk of virologic relapse, but virologic relapse or breakthrough might be avoided by treatment with a combination of more highly effective DAAs.

• Authors: Hu Li, Jia-Li Tan, Jian-Rui Li, Nan-Nan Liu, Jin-Hua Chen, Xiao-Qin Lv, Li-Li Zou, Biao Dong, Zong-Gen Peng, Jian-Dong Jiang
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 116 Pg. 108976 (Aug 2019) ISSN: 1950-6007 [Electronic] France
• PMID: 31103827 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Antiviral Agents
• Carbamates
• Imidazoles
• Pyrrolidines
• Simeprevir
• Valine
• daclatasvir
• Sofosbuvir

Topics

• Antiviral Agents (pharmacology, therapeutic use)
• Carbamates
• Cell Death (drug effects)
• Cell Line, Tumor
• Drug Synergism
• Drug Therapy, Combination
• Hepacivirus (drug effects, physiology)
• Hepatitis C, Chronic (drug therapy, virology)
• Humans
• Imidazoles (pharmacology, therapeutic use)
• Intracellular Space (virology)
• Pyrrolidines
• Recurrence
• Simeprevir (pharmacology, therapeutic use)
• Sofosbuvir (pharmacology, therapeutic use)
• Valine (analogs & derivatives)
• Virus Replication (drug effects)