To print: Select File and then Print from your browser's menu --------------------------------------------------------------------------------------- Title: New Models Describe HBV and HCV Viral Decay Under Treatment: Presented at HEP-DART URL: http://www.pslgroup.com/dg/21908A.htm Doctor's Guide December 14, 2007
By Barbara J. Rutledge, PhD LAHAINA, HAWAII -- December 14, 2007 -- New versions of a simple model of viral decay can explain the complex patterns of decay that arise in treatment-related clearance of both hepatitis C virus (HCV) and hepatitis B virus (HBV), reported Alan S. Perelson, PhD, Senior Fellow, Theoretical Biology & Biophysics Group, Los Alamos National Laboratory, Los Alamos, Texas. Dr. Perelson presented a special lecture at the HEP-DART 2007 Frontiers in Drug Development for Viral Hepatitis symposium here on December 10. "Not all viral decays are biphasic," said Dr. Perelson. Other patterns of viral decay under therapy include triphasic and stepwise viral declines, as well as viral rebound. In models of viral decay, the effectiveness of the drug in blocking viral production is assigned a value ranging from 0 (completely ineffective) to 1 (100% effective). The critical effectiveness of the drug is defined as the value at which the steady-state viral level is 0. The standard model of HBV and HCV decay assumes biphasic decay with drug treatment. In the first phase, viral load declines as the drug blocks virus production in infected cells, resulting in a steep initial drop in viral load in the first few days. In the second phase, viral load gradually declines further as the number of virus-producing cells decreases, due to cell death or complete cessation of virus production in infected cells. However, in some patients the second phase might be flat, suggesting that there is no cell death or continued proliferation of infected cells. If the effectiveness of the drug is greater than the critical effectiveness, the model predicts that the virus will eventually be eliminated. If the critical effectiveness is greater than the effectiveness of the drug, a more complex pattern can emerge. The model predicts that the viral load will decrease to steady-state levels that are lower than at pretreatment, without viral elimination. "This pattern is seen in many patients who are said to have failed therapy," explained Dr. Perelson. "When therapy is terminated in these patients, viral levels return to pretreatment levels." The HCV genome has 104 bases, and the replication error rate is conservatively estimated to be 1 in 105 per base per replication. In a patient with a baseline HCV RNA level of 106/mL, an estimated 9% of the virions would have single point mutations and 0.5% would have double mutations. "All viable single- and double-point mutations probably pre-exist [before treatment]," commented Dr. Perelson. During therapy, compensatory mutations are also likely to arise. For example, in a patient with a baseline HCV RNA of 106/mL, treatment with a drug with an effectiveness of 0.999 would lead to a 3-log decrease in viral load within the first 2 days. However, on the second day, 108 to 109 virions per day would still be produced, and compensatory mutations would likely emerge. "All single and 20% to 100% of all double mutants are still produced each day early in [the course of] drug therapy," said Dr. Perelson. "Drug resistance is sure to arise when a single [specifically targeted antiviral therapy for HCV] drug is used as monotherapy." Dr. Perelson is a consultant for Schering Plough. [Presentation title: Insights Into the Impact of HBV and HCV Viral Dynamics on Antiviral Therapy. Abstract 08] --------------------------------------------------------------------------------------------- Copyright © 1999 P\S\L Consulting Group Inc. All rights reserved. Republication or redistribution of P\S\L content is expressly prohibited without the prior written consent of P\S\L. P\S\L shall not be liable for any errors, omissions or delays in this content or any other content on its sites, newsletters or other publications, nor for any decisions or actions taken in reliance on such content. --------------------------------------------------------------------------------------------- This news story was printed from *Doctor's Guide to the Internet* located at http://www.docguide.com --------------------------------------------------------------------------------------- Return to News Story Page This site is maintained by webmaster@pslgroup.com Please contact us with any comments, problems or bugs. All contents Copyright (c) 1998 P\S\L Consulting Group Inc. All rights reserved.