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Metabolism of antiretroviral drugs in HIV infected patients with toxicity – a pilot study

Julia Notter, Michael Zimmermann & Christian R. Kahlert

abstract

Antiretroviral drugs can be responsible for a wide range of toxic side effects ranging from acute events to long-term toxicity. We hypothesize that the microbiome-mediated metabolism plays a substantial role in antiretroviral drug toxicity through several mechanisms.

This pilot study will compare the plasma metabolome of antiretroviral drugs from four major drug classes between patients experiencing adverse drug effects and controls. The aim is:

(1) Identification of key metabolites involved in HIV drug toxicities for the described antiretroviral drugs and side effects;

(2) Generation of hypotheses regarding valid microbiota derived biomarkers and the underlying pathomechanism that will lead to toxicity and

(3) Development a study protocol based on the findings for a follow-up study to validate the generated findings/hypotheses.

We will evaluate prospectively collected plasma samples stored in the Swiss HIV Cohort Study (SHCS) biobank. Metabolomics analysis of plasma samples will be performed using liquid chromatography coupled mass spectrometry (LC-MS). Targeted integration of the signals for drug and known drug metabolites will be performed and will reveal patients’ plasma levels of drug and drug metabolites. Furthermore, we will conduct untargeted analysis of the metabolomics data and perform differential analysis (including correction for multi-hypothesis testing) between patient cohorts with and without drug-related side effects. This analysis will identify metabolites that are different between the different patient groups. Based on these results, we will design a prospective study aiming at identifying metabolic and microbiome biomarkers that are predictive for toxic side effects.
   
project partner EMBL, Heidelberg, Germany, https://www.embl.de/
type of project clinical studies
status ongoing - follow up
start of project 2020
end of project 2020
responsible person Christian R. Kahlert