Despite the success of antiretroviral therapy (ART), there is still a significant percentage of patients not reaching an adequate suppression of HIV, or experiencing drug toxicity. Treatment failure is clearly multifactorial and, besides viral strain characteristics, it involves host factors such as pharmacokinetic variability, genetic heterogeneity, drug interactions, and poor adherence to therapy. The development of HIV therapy has been conducted over a rather short period of time, and there is still room for improvement in the use of antiretroviral drugs already on the market : typically, dosage individualization based on demographic factors, genetic markers or the measurement of circulating concentrations may enhance both the efficacy and the tolerability of antiretrovirals.Moreover, the progression of viral resistance stimulates a sustained production of new drugs and a definite trend towards increase in treatment complexity, thus requiring thorough “therapeutic navigation” using efficient tools.
As a continuation to our previous projects “"Comprehensive program for the evaluation of treatment failure and toxicity" and “Genetic determinants of intracellular drug concentration of antiretroviral agents”, we have initiated a research effort aiming at integrating pharmacogenetic, pharmacokinetic and pharmacodynamic aspects of HIV therapy through coordinated basic and applied clinical research projects, associated to population-wide analysis, culminating in field applications in conjunction with the Swiss HIV Cohort Study (SHCS). The overall investigation strategy comprises three principal lines of research:
i)In vitro experiments for the discovery and functional consequenceassessment of pharmacogenetic determinants
ii)Drug-gene interactions studies for determining their influence on thepharmacokinetics of antiretroviral drugs, and
iii)Population analysis assessing the overall impact of geneticbackground in terms of treatment efficacy and tolerability at a Swiss-wide population level.
To that endeavour, this project necessitates a continuous development of basic and applied research tools in clinical pharmacology and pharmacogenetics, which includes:
i)the implementation of cellular models for the in vitro functionalassessment of relevant transporter-mediated drug influx/efflux and drug metabolism.
ii)the refinement of analytical tools for multigene allelicdetermination.
iii)the continuous development and validation of analytical methods withhigh-flux capacity for the Therapeutic Drug Monitoring of current and novel classes of antiretroviral drugs.
The research project should lead to a pharmacogenetically-driven proof of concept clinical study, with both pharmacokinetics and pharmacodynamics outcomes, to determine whether an integrated approach implying the careful drug choice and dosage in genotyped patients may improve the long term tolerability and response to antiretroviral treatment.