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Managing variability in HIV therapy: integration of pharmacogenetics, pharmacokinetics and pharmacodynamics of antiretroviral drugs

English title Managing variability in HIV therapy: integration of pharmacogenetics, pharmacokinetics and pharmacodynamics of antiretroviral drugs
Applicant Decosterd Laurent Arthur
Number 112655
Funding scheme Project funding (special)
Research institution Division de Pharmacologie clinique Département de Médecine Université de Lausanne
Institution of higher education University of Lausanne - LA
Main discipline Pharmacology, Pharmacy
Start/End 01.04.2006 - 31.03.2009
Approved amount 361'104.00
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All Disciplines (2)

Discipline
Pharmacology, Pharmacy
Infectious Diseases

Keywords (8)

HIV; pharmacology; pharmacogenetics; pharmacogenomics; antiretrovirals; organic cations and anions transporters; large nested project; Swiss HIV Cohort Study

Lay Summary (English)

Lead
Lay summary
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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
127631 Contribution of multiple genetic variants, identified in genome-wide association studies, to coronary artery disease in HIV-infected individuals 01.12.2009 Project funding (special)
148522 Swiss HIV Cohort Study (SHCS) 01.01.2014 Cohort Studies Large
124943 Pharmacocinétique de population, pharmacogénétique, et profils métaboliques de la thérapie anti-HIV 01.04.2009 Project funding (special)
121314 Demande de soutien pour l'acquisition d'un instrument de chromatographie à ultra performance couplé à un détecteur de masse triple quadripôles en tandem (UPLC-MS/MS) pour la recherche biomédicale 01.08.2008 R'EQUIP
100935 Facteurs génétiques influençant la concentration intracellulaire des médicaments antirétroviraux 01.05.2003 Project funding (special)
134277 Swiss HIV Cohort Study (SHCS) 01.01.2011 Cohort Studies Large

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