Modelling how ribavirin improves interferon response rates in hepatitis C virus infection

Abstract

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…The best‐fit parameter values (Table 1) are consistent with previous estimates. For instance, the viral clearance rate, c  =   6.3 day −1 , is close to the reported38 average of 6.2 ± 1.8 day −1 ; the drug efficacy, ε = 0.9991, is consistent with the mean of 0.997 estimated for sofosbuvir‐based treatments14, 18; and the death rate of infected cells, δ = 0.06 day −1 and 0.2 day −1 for the two patients, is in the range of values, 0.01–0.4 day −1 , reported earlier 20…”

Kinetics of hepatitis C virus RNA decay, quasispecies evolution and risk of virological failure during telaprevir-based triple therapy in clinical practice

“…In our population, the slope of first-phase decline was optimal and consistent with previous estimates [11,13,10], thus highlighting an independence of the first HCV-RNA decay from baseline clinical and virological characteristics. In particular, the slope of HCV-RNA decay was at its height at 24 h after treatment start.…”

“…Vice versa, the second-phase of viral kinetics is in general slower than that found in easier patients [10], and even more compromised in those that experienced virological-failure. Previous results on non-cirrhotic drug-naïve patients treated with either telaprevir-monotherapy or triple-therapy [10] have shown a much more rapid first phase and second phase HCV-RNA decline in comparison to dual IFN-based treatments [11,13].…”

“…After this time-point, the decay rate suffered a slowdown, thus assuming an early start of the second-phase kinetic. The higher potency of telaprevir in blocking viral production, respecting to IFN, can account for the shortening of first-phase decline, as supported by the higher values of treatment effectiveness (ε) and free virions clearance rate (c) [11,13].…”

“…In the past, mathematical models of HCV dynamics have contributed in understanding the mechanisms of action of IFN, pegIFN and pegIFN + RBV, and consequently in better characterising viral behaviour under drug pressure [11][12][13]. Recently, dynamic parameters have been estimated in patients treated with DAAs, particularly in monotherapy [14].…”