Pharmacogenomics of New Antiretrovirals

Pharmacogenetics of New Antiretroviral Drugs

Some genetic polymorphisms are known to interfere with ARV metabolism and are therefore likely to explain some of the inter-individual variations (efficacy,toxicity,resistance) observed during ART. The most common form of human DNA variations consists of a change of a base in the nucleotide sequence of an individual at a given position, the single nucleotide polymorphism (SNP). Therefore,the purpose of this research will be the identification and characterization of the clinical impact of several SNPs in gene coding for transport proteins (e.g.ABCB1,ABCC1) and biotransformation enzymes (e.g.CYP3A4,CYP2B6) known to be involved in the pharmacokinetic pathway of selected ARV drugs for which the therapeutic response is difficult to predict. Aside,the influence of these SNPs on the response to treatment (CD4+cell,viral load) and on the toxicity will be evaluated. Plasma concentrations of ARV drugs correlate with therapeutic efficacy but also with the risk of toxicity and of virological failure, which is the basis of the therapeutic drug monitoring. However,given the intracellular location of HIV, analyzing intracellular drug concentrations is fundamental and the investigators will also focus of this new topic.

Study Overview

• Status: Completed
• Conditions: HIV

Detailed Description

Some genetic polymorphisms are known to interfere with ARV metabolism and are therefore likely to explain some of the inter-individual variations (efficacy,toxicity,resistance) observed during ART. The most common form of human DNA variations consists of a change of a base in the nucleotide sequence of an individual at a given position, the single nucleotide polymorphism (SNP). Therefore,the purpose of this research will be the identification and characterization of the clinical impact of several SNPs in gene coding for transport proteins (e.g.ABCB1,ABCC1) and biotransformation enzymes (e.g.CYP3A4,CYP2B6) known to be involved in the pharmacokinetic pathway of selected ARV drugs for which the therapeutic response is difficult to predict. Considering that CYP3A5 may represent up to 50% of the total hepatic CYP3A content in CYP3A5*1 allele carriers, the CYP3A5 genetic polymorphism may be therefore the most important genetic contributor not only to interindividual but also to interracial differences in CYP3A-dependent drug clearance.

Aside,the influence of these SNPs on the response to treatment (CD4+cell,viral load) and on the toxicity will be evaluated.

Plasma concentrations of ARV drugs correlate with therapeutic efficacy but also with the risk of toxicity and of virological failure, which is the basis of the therapeutic drug monitoring. However,given the intracellular location of HIV, analyzing intracellular drug concentrations is fundamental and the investigators will also focus of this new topic.

• Study Type: Observational
• Enrollment (Actual): 179

Contacts and Locations

• Study Contact: Name: Leila Belkhir, MD; Phone Number: 003227647087; Email: leila.belkhir@uclouvain.be

Study Locations

• Belgium
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

HIV1-positive patients

Description

Inclusion Criteria:

• HIV-1 positive treated with drug of interest

Exclusion Criteria:

• <18 years old

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Impact of pharmacogenomics on plasma concentration of new antiretroviral drugs	The geometric mean (GM) of cell associated concentration and plasmatic concentration of ARV drug	up to 48 months
Impact of pharmacogenomics on intracellular concentration of new antiretroviral drugs	The geometric mean (GM) of cell associated concentration and plasmatic concentration of ARV drug	up to 48 months

Collaborators and Investigators

• Sponsor: Cliniques universitaires Saint-Luc- Université Catholique de Louvain
• Collaborators: Université Catholique de Louvain
• Investigators: Principal Investigator: Leila Belkhir, MD, Université Catholique de Louvain

Publications and helpful links

General Publications

• Belkhir L, De Laveleye M, Vandercam B, Zech F, Delongie KA, Capron A, Yombi J, Vincent A, Elens L, Haufroid V. Quantification of darunavir and etravirine in human peripheral blood mononuclear cells using high performance liquid chromatography tandem mass spectrometry (LC-MS/MS), clinical application in a cohort of 110 HIV-1 infected patients and evidence of a potential drug-drug interaction. Clin Biochem. 2016 May;49(7-8):580-6. doi: 10.1016/j.clinbiochem.2015.12.011. Epub 2015 Dec 29.

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: July 30, 2015
• First Submitted That Met QC Criteria: July 31, 2015
• First Posted (Estimated): August 3, 2015

Study Record Updates

• Last Update Posted (Actual): January 16, 2024
• Last Update Submitted That Met QC Criteria: January 11, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: ARVLB01