Modeling HCV cure after an ultra-short duration of therapy with direct acting agents

Abstract

Background Cases of sustained-virological response (SVR or cure) after an ultra-short duration (≤27 days) of direct-acting antiviral (DAA)-based therapy, despite HCV being detected at end of treatment (EOT), have been reported. Established HCV mathematical models that predict the treatment duration required to achieve cure do not take into account the possibility that the infectivity of virus produced during treatment might be reduced. The aim of this study was to develop a new mathematical model that considers the fundamental and critical concept that HCV RNA in serum represents both infectious virus (Vi) and non-infectious virus (Vni) in order to explain the observation of cure with ultrashort DAA therapy. Methods Established HCV models were compared to the new mathematical model to retrospectively explain cure in 2 patients who achieved cure after 24 or 27 days of paritaprevir, ombitasvir, dasabuvir, ritonavir and ribavirin or sofosbuvir plus ribavirin, respectively. Results Fitting established models with measured longitudinal HCV viral loads indicated that in both cases, cure would not have been expected without an additional 3 to 6 weeks of therapy after the actual EOT. In contrast, the new model fits the observed outcome by considering that in addition to blocking Vi and Vni production (ε~0.998), these DAA + ribavirin treatments further enhanced the ratio of Vni to Vi, thus increasing the log(Vni/Vi) from 1 at pretreatment to 6 by EOT, which led to <1 infectious-virus particle in the extracellular body fluid (i.e., cure) prior to EOT. Conclusions This new model can explain cure after short duration of DAA+ribavirin therapy by suggesting that a minimum 6-fold increase of log(Vni/Vi) results from drug-induced enhancement of the Vni/Vi.

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…”

“…The same data have been employed in a recent modeling study based on the virologic hypothesis 18. One patient received treatment with sofosbuvir and ribavirin for 27 days 10.…”

“…Fitting the reduced model to patient data from one patient10 during treatment then allowed estimation of ε, c , and the composite parameter δ = ω +  mE 0 . With the other patient,11 because of infrequent sampling, we set ε and c to the values obtained above, which were similar to the values estimated elsewhere,18 and fit the data using δ as an adjustable parameter. We performed data fitting using the function NLINFIT in MATLAB.…”

“…Evidence for this hypothesis comes from studies that show a reduction in viral infectivity following exposure to DAAs, including a preferential targeting of infectious over non‐infectious virion production by some DAAs 15, 16, 17. Furthermore, mathematical models of viral kinetics that account for this mode of DAA action have been constructed and shown to describe data of viral load changes during therapy in patients who experience EOT + /SVR, as well as SVR rates elicited by certain DAA combinations 18, 19. The hypothesis, however, remains to be established conclusively.…”

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

“…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]. In the age of DAAs, new models are being developed to meet the challenge associated with these new agents [37][38][39]. Notably, the first age-based multiscale mathematical model for HCV kinetics has been developed [25,40,41] providing a more comprehensive understanding of viral treatment response kinetics observed in patients treated with IFN, HCV protease inhibitors (telaprevir and danoprevir), or the HCV NS5A inhibitor daclatasvir as well as modes of action of these drugs.…”