New Study on Hepatitis C Drug Treatment In Vivo and In Vitro

News Archive February 18, 2013

New Study on Hepatitis C Drug Treatment In Vivo and In Vitro

Researchers from Loyola Show HCV NS5A Inhibitor Daclatasvir has 2 Modes of Action
MAYWOOD, Ill. – Hepatitis C virus (HCV) infection affects about 4 million people 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 prestigious Proceedings of the National Academy of Sciences (PNAS) on Feb. 18.

“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, 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, 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 cultures, which provides insight into daclatasvir’s modes of action. In addition, the study suggests a more accurate estimate of HCV clearance from circulation than 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,” Dahari said. 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.

Additional Dahari Research Papers

Additional research conducted by Dr. Dahari and colleagues related to the new Loyola program for experimental and translational modeling in other professional journals includes:

  • A study on the effect of ribavirin on HCV kinetics and liver gene expression led by researchers from the National Institutes of Health accepted 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 study showcasing a mathematical model of the acute and chronic phases of Theiler murine encephalomyelitis virus (TMEV) infection - a highly relevant experimental animal model for multiple sclerosis - 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 published in the Journal of Virology.

Dr. Dahari is a recognized international leader in the field of viral kinetics.

“Loyola Stritch School of Medicine is honored to have Dr. Dahari as a member of the Hepatology faculty and his ground-breaking study will help reinforce Loyola’s leadership in medical research,” said Richard H. Kennedy, Ph.D, Vice Provost for Research and Graduate Programs, Health Sciences Division, Senior Associate Dean, Research, SSOM.

“Loyola and SSOM Hepatology partners experts in research with physicians to make a real difference in the fight against disease,” said David W. Hecht, MD, MS, MBA, Chair, Internal Medicine in the SSOM and interim senior vice president, Clinical Affairs at LUHS.

Hepatology at Loyola

Loyola University Health System (LUHS) has expanded hepatology services with physicians now available in Moline, Peoria, Rockford, Burr Ridge, Park Ridge, Homer Glen and Maywood as well as in the Dearborn Station building in the South Loop and in Chicago’s Chinatown neighborhood.

To make an appointment with a Loyola hepatologist, call 85-LIVERDOC (855-483-7362). To make an appointment online, please visit loyolamedicine.org.

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The Loyola University Chicago Health Sciences Division (HSD) advances interprofessional, multidisciplinary, and transformative education and research while promoting service to others through stewardship of scientific knowledge and preparation of tomorrow's leaders. The HSD is located on the Health Sciences Campus in Maywood, Illinois. It includes the Marcella Niehoff School of Nursing, the Stritch School of Medicine, the biomedical research programs of the Graduate School, and several other institutes and centers encouraging new research and interprofessional education opportunities across all of Loyola University Chicago. The faculty and staff of the HSD bring a wealth of knowledge, experience, and a strong commitment to seeing that Loyola's health sciences continue to excel and exceed the standard for academic and research excellence. For more on the HSD, visit LUC.edu/hsd.
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