New Kinetic Models for the Hepatitis C Virus *

Abstract

K inetic models of hepatitis C virus (HCV) RNA decay induced by interferon (IFN) therapy have been developed by us and others. [1][2][3][4][5][6] The models, inspired by previous work on HIV and hepatitis B virus kinetics, 7-9 stimulated the collection of frequent viral loads and alanine aminotransferase (ALT) measurements after the initiation of therapy that revealed previously unknown kinetic patterns of HCV RNA change. The models have successfully summarized much of these new kinetic data and have given insights into features of HCV biology in vivo, such as the rate of virion clearance and the daily rate of virion production. More importantly from a clinical perspective, the models have allowed quantification of the antiviral effects of therapy and thus have made comparison of the antiviral effectiveness of different drug regimens possible using data collected over short intervals.

Genomic response to interferon-α in chimpanzees: Implications of rapid downregulation for hepatitis C kinetics

“…As previously hypothesized, the rapid decline of virus during phase I would be due to the initial inhibition of viral secretion brought on by synchronous induction of ISGs by the first dose of IFN-␣. [7][8][9] After phase I, a brief rebound of virus is often observed, 9 which may occur during the downregulation period observed in the current study. The decreased slope in phase II may be due to the cumulative effects of reduction in the number of infected cells as previously hypothesized, 7 as well as a reduction in efficacy of IFN, with efficacy being negatively impacted by a decreased responsiveness to IFN in cells with partially or completely downregulated IFN-␣ pathways.…”

“…Phase I occurs during the first 24 to 48 hours and is presumed to be due to the decrease in secretion of new virions, whereas phase II kinetics vary between individuals, are predictive of the outcome of therapy, and are thought to be a measurement of loss of infected cells. [7][8][9] We 10,11 and others 12 have previously performed gene expression analyses on liver from chimpanzees that experienced acute-resolving or chronic HCV infections. The most notable changes in gene expression occurred in the IFN-stimulated genes (ISGs), suggesting that an ongoing type I IFN or double-stranded RNA (dsRNA) response is occurring in the liver during both acute and chronic infections.…”

Triphasic decline of hepatitis C virus RNA during antiviral therapy

“…Hermann et al 12 suggested-and Dixit et al 10 showed explicitlythat if RBV has a mutagenic effect that leads to the generation of less-infectious or noninfectious virus particles, then de novo infection would be slowed and the lastphase slope would be increased. 18 We present an extended model of HCV dynamics during IFN-␣ plus RBV therapy 10 that accounts for proliferation of uninfected and infected cells. The model explains the "shoulder phase" and provides conditions under which a three-phase HCV RNA decline is expected to occur.…”

Advances in Genomic Research on Hepatitis C Virus with a Useful Tool, Replicon System

“…Since HCV is highly mutatable, monotherapy using one of these drugs results in immediate appearance of a resistant clone. 49,50 Therefore, clinical trials on VX950 with or without IFN and in combination with RBV are ongoing in the U.S. and European countries. Similarly, clinical trials of SCH503034 with and without IFN are underway in patients refractory to a combination of Peg-IFN-α2b and RBV.…”