C. Laouénan (1), P. Marcellin (2), M. Lapalus (2), F. Khelifa-Mouri (3), N. Boyer (3), F. Zoulim (4), L. Serfaty (5), JP. Bronowicki (6), M. Martinot-Peignoux (2), O Lada (2), C Dorival (7), C Hézode (8), F Carrat (7), F Nicot (9), G Peytavin (10), F. Mentré (1), J. Guedj (1)
(1) IAME, UMR 1137, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France; (2) CRI, UMR 1149, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Clichy, France; (3) AP-HP, Hôpital Beaujon, Service d'Hépatologie, Clichy, France; (4) INSERM U1052, Université de Lyon, Lyon, France; (5) AP-HP, Hôpital Saint-Antoine, Service d'Hépatologie, Paris, France; (6) CHU Nancy, Service d'hépato-gastroentérologie, Vandoeuvre-les-Nancy, France; (7) UMR 707, INSERM, Université Pierre et Marie Curie, Paris, France; (8) AP-HP, Hôpital Henri Mondor, Service d’hépatologie, Créteil, France; (9) CHU Toulouse, IFB Purpan, Laboratoire de Virologie, Toulouse, France; (10) AP-HP, Hôpital Bichat, Département de pharmacocinétique clinique, Paris, France.
Objectives: Triple therapy combining pegylated-interferon (Peg-IFN), ribavirin (RBV) and a protease inhibitor (PI, telaprevir or boceprevir) have dramatically increased the chance to eradicate hepatitis C virus (HCV). However the efficacy of this treatment remains suboptimal in cirrhotic experienced-patients. Here we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug.
Methods: Genotype 1-patients with compensated cirrhosis, non-responders to a prior Peg-IFN/RBV therapy were enrolled in the non-randomized ANRS MODCUPIC study and received either telaprevir/Peg-IFN/RBV or boceprevir/Peg-IFN/RBV. HCV-RNA and drug concentrations of each drug were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetics/viral kinetics (PK/VK) model. Trough concentrations were fitted using a constant model (PIs) or an exponential model (Peg-IFN, RBV). We used the standard biphasic model of HCV kinetics [1] and Emax model was using for relationship between effectiveness and concentration of each drug. Parameters and their variability were estimated using the SAEM algorithm in MONOLIX V4.2 [2]. Corrected Wald test (permutation test) was performed to detect a difference in parameters between treatment groups [3].
Results: Fifteen patients were included (9 telaprevir, 6 boceprevir). Both PIs achieved a similar level of molar concentrations (P=0.5), but telaprevir had a significantly lower EC50 than boceprevir (P=0.008), leading to a larger antiviral effectiveness than boceprevir in blocking viral production (99.8% vs 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 on the total antiviral effectiveness. The second phase of viral decline, which was attributed to the loss rate of infected cells, was slow (0.19 day-1) and was higher in patients that subsequently eradicated HCV (P=0.03).
Conclusion: This PK/VK model provides important insights into the understanding of the impaired response to triple therapy in hard-to treat patients. Both PIs achieved a high level of antiviral effectiveness. However the suboptimal antiviral effectiveness of Peg-IFN/RBV and the low loss of infected cells suggest that longer treatment duration might be needed in cirrhotic treatment experienced-patients and that future IFN-free regimen may be particularly beneficial to these patients.
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] Laouénan C, Guedj J, Mentré F. Clinical trial simulation to evaluate power to compare the antiviral effectiveness of two hepatitis C protease inhibitors using nonlinear mixed effect models: a viral kinetic approach. BMC Med Res Methodol 2013:13-60.
Reference: PAGE 23 () Abstr 3115 [www.page-meeting.org/?abstract=3115]
Poster: Drug/Disease modeling - Infection