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Utilisation des modèles dynamiques pour l'évaluation des traitements de l'hépatite C

Abstract : Since 2011, the introduction of triple therapies combining a protease inhibitor (PI), telaprevir or boceprevir, with the pegylated-interferon and the ribavirin (Peg-IFN/RBV) marked a milestone for anti hepatitis C virus (HCV) therapy. However, the response to treatment in cirrhotic patients remains unclear and poses serious safety problems. Viral kinetic models, analyzed by nonlinear mixed effect models (NLMEM), are a powerful tool for understanding the response to treatment. We have demonstrated, by means of clinical trial simulation, the power of the Wald test within NLMEM to detect a HCV drug’s antiviral effectiveness difference. This approach, even for a small number of samples, provided consistently higher power to the standard approach based on a non parametric Wilcoxon test on the viral load decay. However, we have highlighted an inflation of the type I error with the Wald test when the number of patients is low and have proposed a permutation correction. We applied this approach to estimate the antiviral effectiveness of the triple therapies in cirrhotic patients and non-responders to a prior therapy (ANRS MODCUPIC). We have shown that over 99% of the viral replication was blocked by PI, with a significantly superior effectiveness of telaprevir compared to boceprevir and suboptimal effectiveness of Peg-IFN/RBV. Finally, by modeling the kinetics of blood parameters, we demonstrated that the concentrations of Peg-IFN and RBV are associated with, respectively, anemia and thrombocytopenia which are frequently observed in these patients.
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https://www.hal.inserm.fr/tel-01077435
Contributor : Cédric Laouénan <>
Submitted on : Friday, October 24, 2014 - 4:37:24 PM
Last modification on : Friday, October 23, 2020 - 4:45:08 PM
Long-term archiving on: : Sunday, January 25, 2015 - 10:50:23 AM

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  • HAL Id : tel-01077435, version 1

Citation

Cédric Laouénan. Utilisation des modèles dynamiques pour l'évaluation des traitements de l'hépatite C. Santé publique et épidémiologie. UNIVERSITÉ PARIS DIDEROT (Paris 7) SORBONNE PARIS CITÉ, 2014. Français. ⟨tel-01077435⟩

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