Anti-HIV drugs

In close collaboration with the infectious disease unit of Saint Luc hospital (Brussels, Belgium), our challenge is to try to better characterize the origins of the large inter-individual variability in response to anti-HIV drugs, focusing on new promising anti-HIV drug treatments. At this moment, we have recruited more than 150 patients treated with a new protease inhibitor, Darunavir, for which literature data are very limited. For that particular project, not only plasma drug concentrations are being monitored in every patient and DNA collected but also intra-lymphocytic concentrations are being determined. To our knowledge, this study constitutes the first large study allowing studying pharmacogenetic determinants of plasma as well as intracellular accumulation of the drug. This is particularly important as lymphocytes represent the site where the drug exerts his therapeutic action. Thus, while variations in plasma drug concentrations are important to explicate the apparition of adverse drug reactions, differences intracellular concentrations would appear to better correlate with therapeutic efficacy and apparition of virus mutation and/or resistances against the drug. At this stage, the development and the validation of appropriate analytical methods have been completed. Concerning the pharmacogenetic part of the study, we have highlighted that a particular SNP in CYP3A5, an enzyme involved in the metabolism of Darunavir, might predisposed the patient to drug-drug interaction with etravirin that is commonly co-administrated with Darunavir. It appears clear that our observation could be of clinical relevance as it can be predictive of the treatment response. This information will be of crucial importance in the frame of individualized medicine and could be of direct benefit for the patients. Our next objective is to confirm this observation in healthy volunteers by performing a complete PK course to characterize more precisely the real genetic impact of CYP3A5 variations and to quantify the effect for potential dosage adjustments.
In parallel, we are collecting random plasma samples in patients at the “clinique universitaire Saint-Luc” in an aim of performing Darunavir Population pharmacokinetics. At this stage, we have collected approximately 30 samples with a final objective of more than 100 samples. This will be conducted in collaboration with Dr Pierre Marquet (Limoges).