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

NCT05219916 | Terminated

• 1 other identifier: 69HCL21_0846
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Human Immunodeficiency Virus I Infection

Keywords

HIV; LRA; FXR; Reactivation

Outcome Measures

Primary Outcomes (1)

• Measurement of the reactivation level and the EC50 of the optimized molecules.

  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.

Study Arms (1)

Adult patients infected by HIV, controlled under treatment.

EXPERIMENTAL

Blood sample collection from HIV controlled patients during their scheduled consultation, after obtaining their non-opposition by an investigator.

Procedure: Blood collection.

Interventions

Blood collection. PROCEDURE

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.

Adult patients infected by HIV, controlled under treatment.

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Hospices Civils de Lyon: lead

Study Sites (1)

Service des maladies infectieuses et tropicales Hôpital de la Croix Rousse

Lyon, 69004, France

Location

MeSH Terms

Interventions

Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Tristan FERRY, MD-PhD

  Service des maladies infectieuses et tropicales, Hôpital de la Croix Rousse, Hospices Civils de Lyon

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Descriptive physiopathological study

Study Record Dates

• First Submitted: January 21, 2022
• First Posted: February 2, 2022
• Study Start: April 12, 2022
• Primary Completion: July 22, 2022
• Study Completion: July 22, 2022
• Last Updated: March 13, 2023

Record last verified: 2023-03

Locations

FR (1)