Using pharmacokinetic and viral kinetic modeling to estimate the antiviral effectiveness of telaprevir, boceprevir, and pegylated interferon during triple therapy in treatment-experienced hepatitis C virus-infected cirrhotic patients

Abstract

Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P=0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P=0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P=0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P=0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.

FIG 1

Observed concentrations over time. (a) Telaprevir in 9 patients (black line, μmol/ml) and boceprevir in 6 patients (gray line, μmol/ml); (b) PEG-IFN in the telaprevir group (black line, ng/ml) and in the boceprevir group (gray line, ng/ml); (c) RBV in the telaprevir group (black line, ng/ml) and in the boceprevir group (gray line, ng/ml). Patients who received boceprevir-based therapy had only two blood samples during the lead-in phase at baseline and week 2.

FIG 2

Individual fits of the viral decline (log₁₀, IU/ml). Nine patients in telaprevir group (black curve) and 6 patients in boceprevir group (gray curve). Black crosses represent the observed viral load, and gray stars represent the viral load under the limit of detection.

FIG 3

Goodness of fit of the viral kinetic-pharmacokinetic model. Residuals (weighted residuals calculated using individual predictions [IWRES] and normalized prediction distribution errors [NPDE]) versus time and versus prediction plots. Residuals seem to distribute homogeneously around 0. The observed viral loads are plotted as black crosses and viral load under the limit of detection as gray stars.

FIG 4

Relationship between predicted trough concentration at steady state (C_ss) and predicted antiviral effectivenesses (ε_ss). (a) Protease inhibitor (telaprevir in black and boceprevir in gray, μmol/liter); (b) PEG-IFN (PEG-IFN-α-2a in black and PEG-IFN-α-2b in gray, ng/ml). The solid lines denote the predictions with the mean antiviral effectiveness, and the dotted lines denote the 95% confidence intervals computed with the standard errors predicted by the Fisher information matrix.

FIG 5

Relationship between the long-term virological response (SVR) and parameters estimated by the viral kinetic-pharmacokinetic model. (a) Predicted antiviral effectiveness (ε_ss) of the PIs; (b) predicted antiviral effectiveness (ε_ss) of PEG-IFN; (c) δ parameter (loss rate of infected cells). P value from Wilcoxon tests.