PhD thesis

Use of dynamical models for treatment optimization in HIV infected patients

Informations :

Defended November 15th, 2013 - University of Bordeaux


Today, most HIV-infected patients viral loads can be made undetectable by highly active combination of antiretroviral therapy (cART), but there are side effects of these treatments taken for life. The use of dynamic mechanistic models based on ordinary di erential equations (ODE) has greatly improved the knowledge of the dynamics of HIV and of the immune system and can now be considered for personalization of treatment. The aim of these PhD works is to improve the statistical techniques for estimating parameters in dynamic mechanistic models so as to elaborate strategies for monitoring and optimizing treatments in HIV-infected patients.
In the first part, we present the problem of inference in ODE models with mixed effects on parameters. We introduce a Bayesian estimation procedure based on the maximization of the penalized likelihood. We present the related program called NIMROD. Then, we show the power of dynamic mechanistic approaches for the evaluation of treatment effects compared to methods based on the descriptive analysis of the biomarkers trajectories.
In a second part, we build the "target cells model" which is a four compartments ODE system with HIV, quiescent, activated and activated-infected CD4. We adjust it to clinical data and we demonstrate it has good predictive capabilities. We build a proof of concept for drug dose individualization. This is an adaptive strategy based on the equilibrium criteria of ODE models. It consists in tuning the dose of the patient based on his reaction to the previous doses using a Bayesian update procedure. Finally, we introduce the various factors, including genetic and pharmacological considerations, that are important to design an individualized change of cART. This work involves the quanti cation of in vivo effects of cART using antiviral activity indicators established in vitro. We discuss the validity of the results and the further steps needed for the integration of these methods in clinical practice.


 @phdthesis{prague2013utilisation,title={Utilisation des mod{\`e}les dynamiques pour l'optimisation des traitements des patients infect{\'e}s par le VIH},author={Prague, Melanie},year={2013},school={Bordeaux 2}}

Key words :

AIDS ; antiretroviral drugs ; Bayesian approach ; causal models ; dynamical models ; HIV ; in vitro ; in vivo ; mixed e ects models ; model choice ; normal approximation of the a posteriori ; mutations ; numerical optimization ; ordinary di erential equation (ODE) ; personalized medicine ; pharmacology ; predictions.