Modeling Early Viral Kinetics with Alisporivir: Interferon-free Treatment and SVR Predictions in HCV G2/3 patients
Jeremie Guedj, Jing Yu, Micha Levi, Bin Li, Steven Kern, Nikolai V. Naoumov, Alan S. Perelson
1INSERM UMR 738, University Paris Diderot, F-75018 Paris
Objectives: Alisporivir (ALV) is a cyclophilin inhibitor with pan-genotypic activity against hepatitis C virus (HCV). We characterized viral kinetics (VK) in 249 patients infected with HCV genotypes 2 or 3 during treatment with ALV interferon-free regimens for six weeks ±800 mg ribavirin (RBV) daily.
Methods:We used a VK model that integrated pharmacokinetic (PK) and pharmacodynamic effects to analyze patient data as well as to predict the effect of different doses of ALV twice a day with RBV on the sustained virologic response (SVR) rate.
Results: The VK model was able to fit the individual viral load profiles of 214 (86%) patients by assuming that ALV blocked viral production. A mean antiviral effectiveness of 0.93, 0.86 and 0.75 in patients treated with 1000, 800 and 600 mg ALV QD, respectively was estimated. Patients receiving RBV had a significantly faster rate of viral decline, which was attributed in our model to an effect of RBV in increasing the loss rate of infected cells, δ (mean δ=0.35 d-1 vs 0.21 d-1 in patients +/- RBV, respectively, P=0.0001). The remaining 35 patients (14%) had a suboptimal response (i.e. flat or increasing levels of HCV RNA after week 1), and their viral kinetic profile was not described using the model. The occurrence of this suboptimal response was higher in patients that received ALV monotherapy than those receiving ALV+RBV (21.5 vs 10.5%, P=0.02). Moreover, high body weight and low RBV levels were associated with suboptimal response (in patients receiving RBV). There was a trend for low exposure to ALV to be associated with suboptimal response as well, suggesting that high RBV and ALV exposures are important in reducing the suboptimal response rate. The model predicts 71.5% SVR following 400 mg ALV BID + 400 mg RBV BID for 24 weeks. The predicted SVR rate following response-guided therapy was 79%.
Conclusions: Alisporivir 400 mg BID plus RBV may represent an effective IFN-free treatment that is predicted to achieve high SVR rates in genotypes 2 or 3 patients. Response-guided therapy would further increase SVR. In addition, weight-based RBV dosing should be considered to prevent suboptimal exposure.