C. Laouénan (1,2), J. Guedj (1), M. Lapalus (3), F. Khelifa-Mouri (4), M. Martinot-Peignoux (3), N. Boyer (4), L. Serfaty (5), JP. Bronowicki (6), F. Zoulim (7), P. Marcellin (3,4), F. Mentré (1,2) and MODCUPIC ANRS-CO20 study group
(1) INSERM UMR 738, University Paris Diderot, Sorbonne Paris Cité, Paris, France; (2) AP-HP, Hosp Bichat, Service de Biostatistique, Paris, France; (3) INSERM U773-CRB3, University Paris Diderot, Sorbonne Paris Cité, Clichy, France; (4) AP-HP, Hosp Beaujon, Service d'Hépatologie, Clichy, France; (5) AP-HP, Hosp Saint-Antoine, Service d'Hépatologie, Paris, France; (6) CHU Nancy, Service d'hépato-gastroentérologie, Vandoeuvre-les-Nancy, France; (7) Hospices Civils de Lyon, Lyon, France and INSERM U1052, Université de Lyon, Lyon, France
Objectives: ANRS MODCUPIC is a clinical study designed to provide a precise description of the early hepatitis C viral kinetics during triple therapy involving a protease inhibitors (PI) in compensated cirrhotic treatment-experienced patients in real-life setting.
Methods: Patients were prospectively included to receive tripe therapy containing either telaprevir (TVR)/PEG-IFN/RBV or boceprevir (BOC)/PEG-IFN/RBV). Viral load (VL) was frequently assessed during the first week following treatment initiation at days 0, 0.33, 1, 2, 3, 7 and then at weeks 2, 3, 4, 6, 8, 12. The viral kinetic model was the standard biphasic model and data up to VL rebounds (if any) were fitted [1]. In this model, the rates of the first and second phase of viral decline are roughly equal to the clearance rate of virus (c) and the loss rate of infected cells (δ), respectively. The magnitude of the first phase of viral decline, ε, reflects therapy’s effectiveness in blocking viral production. Parameters and their variability were estimated using the SAEM algorithm in MONOLIX V4.2 [2]. The Wald test was performed to detect a difference in parameters between treatment groups.
Results: Fifteen patients were included (9 TVR, 6 BOC), 9 patients (60%) had undetectable VL at week 4 and VL rebounded in two patients (at week 3 and 8). The biphasic model described adequately VL decline in all patients. The clearance rate of virus and the loss rate of infected cells were not significantly different between treatment groups (mean values: c = 4.5 day-1 and δ = 0.20 day-1). However the antiviral effectiveness was significantly larger with TVR than with BOC (εTVR vs εBOC: 0.998 vs 0.989, P = 0.004). Permutation test should be performed to confirm the difference between TVR and BOC [3], also it should be noted that this is not a randomized trial.
Conclusion: For both PIs, the two phases of viral decline were about four times smaller than what had been observed in non-cirrhotic naive patients during TVR monotherapy [4,5] and close to typical values observed during PEG-IFN/RBV therapy. This discrepancy could be due to impaired pharmacokinetics and lower penetration capacity of PIs in hepatocytes of cirrhotic patients. Consequently cirrhotic treatment-experienced patients may need longer time to achieve viral eradication than other patients [4]. Pharmacokinetic data of PI, PEG-IFN and RBV will be available and should allow to better understand the origin of this impaired virologic response.
References:
[1] Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282(5386);103–107.
[2] Samson A, Lavielle M, Mentré F. Extension of the SAEM algorithm to left censored data in nonlinear mixed-effects model: Application to HIV dynamics model. Comput Statist Data Anal 2006, 51:1562–1574.
[3] Bertrand J, Comets E, Chenel M, Mentré F: Some alternatives to asymptotic tests for the analysis of pharmacogenetic data using nonlinear mixed effects models. Biometrics 2012, 68:146–155.
[4] Guedj J, Perelson AS. Second-phase hepatitis C virus RNA decline during telaprevir-based therapy increases with drug effectiveness: implications for treatment duration. Hepatology. 2011;53(6);1801–1808.
[5] Adiwijaya BS, Kieffer TL, Henshaw J, Eisenhauer K, Kimko H, Alam JJ, et al. A viral dynamic model for treatment regimens with direct-acting antivirals for chronic hepatitis C infection. PLoS Comput Biol. 2012;8(1):e1002339.
Reference: PAGE 22 (2013) Abstr 2847 [www.page-meeting.org/?abstract=2847]
Poster: Other Drug/Disease Modelling