Ontogenesis of the P-Glycoprotein in Human Lymphocytes Influence of HIV and Antiretroviral Therapeutics (Onto-Pgp)

Ontogenesis of the P-glycoprotein in Human Lymphocytes: Influence of the Human Immunodeficiency Virus (HIV) and Antiretroviral Therapeutics

The P-glycoprotein (P-gp) is a membranous transporter that modulates the intracellular concentrations of many drugs and plays thus a major role in the efficacy of the therapeutics that act within the lymphocytes, such as antiretroviral drugs. We aim at studying the evolution of this transporter's expression and activity on lymphocytes in relation with the human development from newborns to adults. We also aim at studying the influence of HIV and antiretroviral treatments on this transporter, especially anti-protease drugs, within the children population.

Study Overview

• Status: Completed
• Conditions: HIV Infections

Detailed Description

Several groups of drugs involved in the treatment of major pathologies act within the lymphocyte, such as anticancer, immunosuppressive and antiretroviral drugs. These molecules depend on membranous transporters to get inside the lymphocyte and be effective. Among those transporters, the P-glycoprotein (P-gp) plays a major role, especially because of the variety of its substrates among therapeutic molecules. Its expression and activity are well known within the adult population, as well as its modulations mediated by certain groups of drugs, such as protease inhibitors in the treatment of HIV. Yet, there is very little data on children, even though they are exposed to the same therapeutic molecules as the adults. Therefore, we aim at studying the evolution of this transporter's expression and activity on the different lymphocyte populations, in relation to the human development from newborns to adults. We also aim at studying the influence of HIV and antiretroviral treatments on this transporter, especially anti-protease drugs, within the children population. P-gp activity is quantified by flow cytometry, through the efflux of a fluorescent substrate, in the presence or absence of a P-gp inhibitor. P-gp expression is measured on isolated motonucleus cells with the quantification of mRNA encoded for the transporter by RT-PCR (Reverse Transcription - Polymerase Chain Reaction). Patients of every age, from newborns to adults, are recruited within eight different age groups and three HIV status groups (HIV non infected, HIV infected untreated, HIV infected treated). The objective is to recruit ten patients in each age group for each HIV status. Blood samples are obtained from hospitalized children and adults with their consent. The patients will be recruited for one year. Our objective is to determine whether the P-gp expression and/or activity are influenced by age, HIV status and antiretroviral treatments, in order to prevent, depending on developmental stages, ineffectiveness or toxicity due to inadequate intracellular concentrations.

After the first evaluations, principal investigators decided to add one year more for three groups on eight.

For two groups of these three, genetic polymorphism of Mdr1 will be done.

• Study Type: Observational
• Enrollment (Actual): 310

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Hopital Necker Enfants Malades

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

HIV Patients children and adults and controls

Description

Inclusion Criteria:

• age, HIV status

Exclusion Criteria:

• None

Study Plan

How is the study designed?

Number of groups / cohorts

8

Cohorts and Interventions

Group / Cohort
1
2
3
4
5
6
7
8

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The activity and expression of P-glycoprotein at the time when the blood sample was taken.	immediately

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start: March 1, 2007
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): August 1, 2009

Study Registration Dates

• First Submitted: June 18, 2008
• First Submitted That Met QC Criteria: June 18, 2008
• First Posted (Estimate): June 19, 2008

Study Record Updates

• Last Update Posted (Estimate): November 11, 2010
• Last Update Submitted That Met QC Criteria: November 10, 2010
• Last Verified: October 1, 2010

More Information

Terms related to this study

• Keywords: HIV; children; P-glycoprotein; lymphocyte; ontogenesis; Ontogenesis P-gp in human lymphocytes; Study of the influence of HIV infection; Antiretroviral treatments on P-gp activity; Expression in human lymphocytes
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; HIV Infections
• Other Study ID Numbers: P070102