Selection of Farnesoid X Receptor (FXR) Ligands on the Reactivation of Latent HIV Proviruses (FXR#2)

March 9, 2023 updated by: Hospices Civils de Lyon

Selection of Farnesoid X Receptor (FXR) Ligands as Latency Reversal Agents (LRA) of Latent HIV Proviruses in Circulating CD4+ T Lymphocytes Isolated From Patients With Undetectable HIV Viremia Under cART (Combined Antiretroviral Treatments)

The FXReservoir#1 study (NCT03618862) showed that certain FXR ligands reactivate latent viruses in the reservoir circulating in all HIV+ patients tested. These molecules appear as latency reversal agents (LRA) of silent viruses of the HIV reservoir. They can be part of the strategy to eradicate this reservoir, responsible for recurrences of the infection when combined anti-retroviral treatments are stopped.

Two effective leads have been identified on in vitro tests and on ex vivo reactivation using FXReservoir#1. These molecules come from a chemical library of FXR ligands developed by the Inserm team behind the discovery of a role for FXR in viral infections.

A first series of optimized molecules derived from these leads has been synthesized; these molecules, after screening on viral and ADMET (Absorption, Distribution, Metabolisme, Excretion and Toxicity) in vitro tests, must be tested ex vivo on CD4+ lymphocytes from the circulating peripheral reservoir of HIV+ patients in order to select the best molecules with LRA activity. This step is essential before considering the clinical development of an LRA.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

17

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Lyon, France, 69004
        • Service des maladies infectieuses et tropicales Hôpital de la Croix Rousse

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Criteria relating to the population studied: patients aged 18 to 65 years old, men or women, regardless of ethnic origin.
  • Nosological criteria: HIV-1 infection, documented by a complete western blot and/or a detectable viral load at the time of diagnosis, regardless of the viral subtype.
  • Pathology severity and progression criteria: patients with a CD4+ count greater than 500 elements/mm3 at the last follow-up visit prior to inclusion in the study. Undetectable viral load for at least six months on stable treatment.
  • Criteria relating to treatments/strategies/procedures: Current cART treatment mandatory, regardless of the combination of anti-retrovirals, effective with undetectable viral load. The number of processing lines is not limited.
  • Criteria relating to regulation: Absence of opposition

Exclusion Criteria:

  • Criteria relating to the population studied: pregnant or breastfeeding women
  • Criteria relating to contraindications to the protocol explorations:

Acute or chronic anaemias Acute infections, fever Coagulation disorders, patients taking anticoagulants

- Criteria relating to regulation: Subjects placed under judicial safeguard, guardianship or curatorship Subjects participating in another research with an ongoing exclusion period.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Adult patients infected by HIV, controlled under treatment.
Blood sample collection from HIV controlled patients during their scheduled consultation, after obtaining their non-opposition by an investigator.
Procedure: Blood collection.

One additional 80 mL blood collection will be collected from HIV patients during a scheduled blood collection as part of their regular follow-up.

Samples will be transported within 3-5 hours by a carrier approved for the transportation of infectious biological samples from the Croix Rousse hospital to the P3 laboratory of the Ecole Normale Supérieure, Lyon for analysis.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of the reactivation level and the EC50 of the optimized molecules.
Time Frame: At inclusion.

Measurement of reactivation level compared to that obtained with the reference LRA Ingenol, and EC50 of molecules derived from active leads and preselected on viral and ADMET criteria in vitro to allow the choice of the best molecule for future clinical development.

PBMCs (peripheral blood mononuclear cells) and rCD4+Tcells will be isolated and treated with the test molecules for 3 days. The treated cells will be incubated to determine the number of cells producing HIV/ million of rCD4+ T cells. FXR ligands will be used at 10 µM. Dose-response assay will be carried out to determine the EC50 (half maximal effective concentration) of the active molecules and the best molecules in the final selection will be tested in combination with inhibitors of the metabolic pathway to confirm their specificity of action.

Molecules derived from the 2 leads will be screened in successive series.
At inclusion.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospices Civils de Lyon

Investigators

  • Principal Investigator: Tristan FERRY, MD-PhD, Service des maladies infectieuses et tropicales, Hôpital de la Croix Rousse, Hospices Civils de Lyon

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 12, 2022

Primary Completion (Actual)

July 22, 2022

Study Completion (Actual)

July 22, 2022

Study Registration Dates

First Submitted

January 21, 2022

First Submitted That Met QC Criteria

January 21, 2022

First Posted (Actual)

February 2, 2022

Study Record Updates

Last Update Posted (Actual)

March 13, 2023

Last Update Submitted That Met QC Criteria

March 9, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 69HCL21_0846

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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