Hepatitis C virus (HCV) infection affects about 4 million in the United States and is the primary cause of liver cirrhosis and liver cancer. Current therapy against HCV is suboptimal. Daclatasvir, a direct acting antiviral (DAA) agent in development for the treatment of HCV, targets one of the HCV proteins (i.e., NS5A) and causes the fastest viral decline (within 12 hours of treatment) ever seen with anti-HCV drugs. An interdisciplinary effort by mathematical modelers, clinicians and molecular virologists has revealed that daclatasvir has two main modes of action against HCV and also yields a new, more accurate estimate of the HCV half-life. Results of the NS5A study are published in the Proceedings of the National Academy of Sciences (PNAS) on Feb. 18, 2013.
“Ultimately, our study will help design better DAA drug cocktails to treat HCV,” says Loyola University Health System (LUHS) and Stritch School of Medicine (SSOM) mathematical modeler Harel Dahari, PhD, who co-led the study. Dahari is one of five members of the Division of Hepatology at Loyola headed by Scott Cotler, MD who authored the study along with Thomas Layden, MD, HCV virologist Susan L. Uprichard, PhD and Dr. Uprichard’s PhD graduate student Natasha Sansone. The study was conducted with Drs. Alan Perelson (Senior Fellow at Los Alamos National Laboratory), Jeremie Guedj (Institut National de la Santé et de la Recherche Médicale), Libin Rong (Oakland University) and Richard Nettles (Bristol-Myers Squibb).
The new study documents HCV kinetic modeling during treatment both in patients and in cell culture that provides insight into the modes of action of daclatasvir. In addition, the study suggests a more accurate estimate of HCV clearance from circulation previously estimated in 1998 by Dahari, Layden, Perelson and colleagues in Science.
“Our modeling of viral kinetics in treated patients predicts that daclatasvir not only blocks the synthesis of the viral RNA within infected cells but also blocks the secretion of infectious virus from the cells,” explains Dahari. This prediction was confirmed in Uprichard’s laboratory using cultured liver cells that support the entire life cycle of HCV infection. Dahari and Uprichard are directors of a new program for experimental and translational modeling recently established at Loyola to promote the type of interdisciplinary research exemplified in this publication.
Additional research conducted by Dahari and colleagues related to the new Loyola program for experimental and translational modeling has been recently published or in press for publication in other professional journals:
- A study on the effect of ribavirin on HCV kinetics and liver gene expression, led by researchers from the National Institute of Health and published in Gut.
- A letter on understanding triphasic HCV decline during treatment in the era of IL28B polymorphisms and direct acting antiviral agents via mathematical modeling, published in the Journal of Hepatology.
- A review on silymarin for the treatment of HCV, published in Antiviral Therapy.
- A study showcasing a mathematical model of the acute and chronic phases of Theiler murine encephalomyelitis virus (TMEV) infection that can serve as an important tool in understanding TMEV infectious mechanisms and may prove useful in evaluating antivirals and/or therapeutic modalities to prevent or inhibit demyelination multiple sclerosis, published in the Journal of Virology.
Source: Loyola University Health System