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 February 18th, 2013.
"Ultimately, our study will help design better DAA drug cocktails to treat HCV," said Loyola University Health System (LUHS) and Stritch School of Medicine (SSOM) mathematical modeler Harel Dahari, Ph.D, 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, Ph.D and Dr. Uprichard's Ph.D graduate student Natasha Sansone. The study was co-led with Jeremie Guedj (Institut National de la Santé et de la Recherche Médicale) and conducted with Drs. Alan Perelson (Senior Fellow at Los Alamos National Laboratory), 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 Drs. 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," explained Dahari. This prediction was confirmed in Dr. Uprichard's laboratory using cultured liver cells that support the entire life cycle of HCV infection. Drs. 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.
- J. Guedj, H. Dahari, L. Rong, N. D. Sansone, R. E. Nettles, S. J. Cotler, T. J. Layden, S. L. Uprichard, A. S. Perelson. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proceedings of the National Academy of Sciences, 2013; DOI: 10.1073/pnas.1203110110
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