Modeling Hepatitis C Virus Dynamics in the Era of New Drugs

L.Rong

Dr. Libin Rong is an Assistant Professor of Mathematics at Oakland University in Michigan. He received his BS and MS from Fudan University in China, and his PhD in Applied Mathematics from Purdue University in West Lafayette, Indiana. Before he joined Oakland University, he was a postdoctoral research associate at Los Alamos National Laboratory in New Mexico.

His research interest is mathematical biology. Specifically, he develops mathematical models and computational and data analysis methods to quantitatively study virus infections and immune responses. These studies are motivated by problems of great interest to researchers in biology, medicine, and pharmacology. Recently, Dr. Rong published a paper titled ‘Analysis of hepatitis C virus decline during treatment with the protease inhibitor danoprevir using a multiscale model’  in the journal PLoS Computational Biology.

Background of the study

Chronic infection with hepatitis C virus (HCV) has caused an epidemic with approximately 170 million people infected worldwide. It is an important reason for liver fibrosis/cancer, and also a leading cause for liver transplants in the United States. Traditional therapy for HCV infection involves giving weekly injections of interferon and taking an oral drug ribavirin for up to a year. This therapy only cures about 50% of people, and both interferon and ribavirin have serious side-effects. A number of new orally administered drugs that act directly to interfere with specific steps of the HCV lifecycle have been developed and two of them have been approved by the US Food and Drug Administration.

Although many new drugs have induced substantial virus reductions in patients receiving therapy, the mechanisms of action of these drugs and their antiviral effectiveness are not fully understood. The current paradigm for studying HCV dynamics utilizes a basic viral dynamic model. However, the model does not account for any intracellular processes within infected cells and thus may not be optimal for analyzing data in patients treated with new drugs which directly interfere with intracellular viral replication.

Findings

We developed a new mathematical model that includes both intracellular viral replication and extracellular cell infection of HCV. We conducted a complete analysis of the model and examined the biological parameters contributing to different phases of the viral decline after treatment initiation. The model was also applied to the analysis of data from danoprevir, one of the new drugs that can inhibit the HCV protease enzyme and have induced substantial viral reductions in patients receiving therapy. Analysis suggests that danoprevir can significantly block intracellular viral production, enhance intracellular viral RNA degradation, and moderately inhibit viral secretion from infected cells.

Implications

The multiscale model provides a theoretical framework for studying virus dynamics in hepatitis C patients treated with other new drugs currently in clinical development. We will use the model to explore the mechanisms of action of those drugs and estimate their treatment effectiveness. This may help the development of optimal combination of drugs with complementary modes of action to maximize the HCV cure rate. Such combination strategies have achieved a great success in the management of HIV infection.

Advice from the field

Mathematical biology is truly an interdisciplinary field. The best advice I can give someone going into this field would be to find problems that are of real interest to biologists and can be addressed by quantitative methods.

About the department

The Department of Mathematics and Statistics at Oakland University has about 30 full-time faculty members, who have research strengths in pure and applied mathematics and statistics. The Department offers baccalaureate degrees in mathematics, statistics, and actuarial science; master’s degrees in mathematics, industrial and applied mathematics, and applied statistics; and PhDs in applied mathematical sciences with concentrations in the three different areas of continuous mathematics, discrete mathematics and statistics. Several faculty members are affiliated with the Center for Biomedical Research, which vigorously promotes and supports collaborative biomedical research and education at Oakland University and allied institutions.