Project

drugs interactions; anti HCV drugs; large nested project (SHCS); pharmacogenetics; clinical pharmacokinetics; Population pharmacokinetics; antiretrovirals; Model-based simulation; liquid chromatography tandem mass spectrometry

Lead
Les médicaments antirétroviraux ont transformé le pronostic de l’infection HIV qui est maintenant devenue une maladie chronique: les patients vivent plus longtemps et deviennent âgés. Ils sont ainsi progressivement confrontés aux pathologies liées au vieillissement et reçoivent des médicaments contre l’hypertension, les problèmes cardio-vasculaires, le diabète, les problèmes neuropsychologiques ainsi que le cancer. De plus, jusqu’à 30% des patients HIV-positifs sont co-infectés par le virus de l'hépatite C (VHC) et sont susceptibles d’être traités par les nouveaux médicaments anti-VHC. Nos connaissances sur le potentiel d'interactions complexes de toutes ces associations médicamenteuses avec les agents antirétroviraux reposent le plus souvent sur des données dérivées d’études in vitro et leurs impacts à long terme ne sont pas complètement caractérisés.
Lay summary
Notre programme de recherche vise à réaliser au niveau de l’Etude Suisse de Cohorte HIV (SHCS) une analyse systématique des interactions médicamenteuses existant entre les traitements antiviraux et les autres médicaments pris par les patients infectés par le VIH et/ou VHC. Les concentrations sanguines des médicaments antiviraux et des principales co-médications des patients SHCS vont être mesurées simultanément par spectrométrie de masse et analysées par des approches de pharmacocinétique de population. Ces analyses intégreront également la patho-physiologie des patients, leur profil pharmacogénétique, ainsi que la réponse et la tolérance aux traitements médicamenteux. La modélisation pharmacocinétique et la simulation des interactions médicamenteuses problématiques seront validées cliniquement. Ce programme s’inscrit dans le domaine émergeant de l’individualisation des traitements et de la médecine personnalisée.

Direct link to Lay Summary

Last update: 05.08.2016

Active participation

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Highly active antiretroviral treatments (ARTs) have transformed HIV infection from a deadly disease into a manageable chronic condition. As a consequence, HIV-infected individuals live longer and become older. Besides therapeutic effectiveness, drug tolerability and long term health impact become key issues for treatments to be taken indefinitely. Moroever, aging patients encounter chronic conditions such as hypertension, cardiovascular problems, diabetes, neurocognitive impairement and malignancies, which lead to increasingly complex drugs associations with a high potential of drug-drug interactions (DDIs). Moreover, renal and hepatic functions become altered in a fraction of patients, necessitating appropriate treatment adjustments. Thus, HIV infection management becomes increasingly complex, not to mention metabolic complications and other cumulative deleterious effects of ARTs over decades. In addition, a significant percentage of HIV patients (up to 30% in the Swiss HIV Cohort Study, SHCS) are co-infected with hepatitis C virus and are likely to receive the last wave of anti-HCV drugs. Still their drug interaction potential, notably with ARTs, and their long-term safety are incompletely characterized. More generally, most information from DDI databases used by healthcare providers is extrapolated from current knowledge of drug metabolic pathways identified in vitro, which poorly account for the complexity of multiple and opposing in vivo effects, not to mention induction or pharmacogenetic issues. In the growing movement of personalized medicine, research efforts must be pursued to improve the prescription of ARTs not only with regard to antiretroviral efficacy but also according to tolerability, long-term safety and potential DDIs, possibly modulated by patients’ pharmacogenetics traits. These issues will be best addressed by an integrated strategy of drug selection and dosage individualization based on relevant demographic/clinical factors, genetic markers (precision medicine) and measurement of circulating concentrations (Therapeutic Drug Monitoring, TDM). To this end, during the last funding period, we have:1.Developped mass spectrometry assays for the TDM of new anti-HIV and anti-HCV drugs, as well as metabolites profiles analysis in various body compartments. 2.Extended our modelling expertise from single-drug population pharmacokinetic analysis to drug-drug and drug-gene interactions studies and to the kinetics of biological markers in patients from the SHCS.3.Established a logistical framework for the prospective capture of TDM data for novel anti-HIV and anti-HCV agents. Building up on our population mass spectrometry facilities, modeling expertise and established frameworks, we intend to launch a systematic analysis of complex drug-drug interactions relevant to antiviral treatments and comedication in patients infected by HIV and/or HCV. Specifically, we propose in the present request for grant renewal: 1.Large-scale, cross-sectional capture, at the occasion of the bi-annual cohort visit of SHCS patients, of TDM samples along with relevant therapeutic information (date/time of last dose and blood sampling), not only for antiviral treatments but also for all other drugs part of their co-medication (i.e. statins, cardiovascular and psychotropic drugs, anticancer agents, etc.) 2. Multiplex mass spectrometry analyses of antiviral drugs and relevant comedication in TDM samples. 3.Population kinetic modeling of the exposure to antiviral drugs and to selected comedication in genotyped SHCS patients, which will culminate to:4. Nested case-control and network analyses of drugs-drug interactions observed in active SHCS individuals in real-life conditions, followed by model-based simulations and formal small-scale validation studies of problematic drug interactions. The major strength of this proposal is to address two key issues in current therapeutics of HIV- and/or HCV-infected patients: the complexity and the long-term consequences of treatments. This pharmacokinetic-pharmacoepidemiologic analysis will contribute to personalize drug treatment (via both pharmacogenetics and TDM) while addressing the problem of DDIs actually encountered in real-life conditions