Hepatitis C Viral Kinetics in the Era of Direct Acting Antiviral Agents and Interleukin-28B

Abstract

In the last decade hepatitis C virus (HCV) kinetics has become an important clinical tool for the optimization of therapy with (pegylated)-interferon-α (IFN) and ribavirin (RBV). Mathematical models have generated important insights into HCV pathogenesis, HCV- host dynamics, and IFN and RBV’s modes of action. Clinical trials with direct acting agents (DAAs) against various steps of the HCV life cycle have revealed new viral kinetic patterns that have not been observed with IFN±RBV. Very recently, studies have showed that single nucleotide polymorphisms (SNPs) in the IL28B gene region were associated with race/ethnicity and with response to IFN±RBV. Here we review our current knowledge of HCV kinetics and related mathematical models during IFN±RBV and/or DAA based therapies, HCV pathogenesis, and the role of IL28B polymorphism on early HCV kinetics. Better understanding of the mode of actions of drug(s) and viral kinetics may help to develop, in the near future, new individualized therapeutic regimens that include DAAs in combination with IFN+RBV.

Resurrection of response-guided therapy for sofosbuvir combination therapies

“…For example, patients with HCV genotype-1 who had viral suppression (i.e., below HCV RNA assay quantification and/or detection) 4 weeks after initiation of therapy were termed rapid viral responders and were likely to achieve cure (>90%), while those with less than a 1-2 log viral decline from pretreatment level by week 12 were advised to discontinue therapy. Viral kinetics and mathematical modeling were used to refine the RGT approach by identifying responses at earlier time points that could predict treatment outcomes [3]. …”

Direct-Acting Antiviral Agents and the Path to Interferon Independence

“…Viral kinetic modeling studies performed on patient blood samples established two viral disappearance rates during IFN treatment that are necessary to achieve a SVR. 11 (i) a rapid phase I decline in circulating HCV RNA indicating inhibition of viral production, and (ii) a significant second phase decline in circulating HCV RNA that is steep enough to ensure complete eradication of virus from liver cells during the treatment time. Otherwise infected cells remain and rapidly restore infection after treatment is completed.…”

A Robust and Efficient Numerical Method for RNA-Mediated Viral Dynamics

“…Mathematical modeling is also improving our understanding of intracellular viral genome dynamics [25][26][27][28] and the quantitative events that underlie the immune response to pathogens [6,9]. The standard model for HCV kinetics during treatment provided many insights into the effectiveness and mechanism of action of IFN and ribavirin (reviewed in [29,30]). This model has been able to retrospectively predict the duration of treatment needed for HCV eradication (cure) [31][32][33][34][35] and more recently was used in real-time (on treatment) to predict the duration of therapy needed to achieve cure with an IFN-free regimen of silibinin +ribarivin [36].…”