Back to resultsSelection of Farnesoid X Receptor (FXR) Ligands on the Reactivation of Latent HIV Proviruses (FXR#2)
Primary Purpose
Human Immunodeficiency Virus I Infection
Status
Terminated
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Blood collection.
Sponsored by
About this trial
This is an interventional basic science trial for Human Immunodeficiency Virus I Infection focused on measuring HIV, LRA, FXR, Reactivation
Eligibility Criteria
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.
Sites / Locations
- Service des maladies infectieuses et tropicales Hôpital de la Croix Rousse
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Adult patients infected by HIV, controlled under treatment.
Arm Description
Blood sample collection from HIV controlled patients during their scheduled consultation, after obtaining their non-opposition by an investigator.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT05219916
First Posted
January 21, 2022
Last Updated
March 9, 2023
Sponsor
Hospices Civils de Lyon
1. Study Identification
Unique Protocol Identification Number
NCT05219916
Brief Title
Selection of Farnesoid X Receptor (FXR) Ligands on the Reactivation of Latent HIV Proviruses
Acronym
FXR#2
Official Title
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)
Study Type
Interventional
2. Study Status
Record Verification Date
March 2023
Overall Recruitment Status
Terminated
Why Stopped
It is unlikely that the scientific question will ever be answered. Thus, it would be considered unethical to continue the trial.
Study Start Date
April 12, 2022 (Actual)
Primary Completion Date
July 22, 2022 (Actual)
Study Completion Date
July 22, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Hospices Civils de Lyon
4. Oversight
Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Human Immunodeficiency Virus I Infection
Keywords
HIV, LRA, FXR, Reactivation
7. Study Design
Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Model Description
Descriptive physiopathological study
Masking
None (Open Label)
Allocation
N/A
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Adult patients infected by HIV, controlled under treatment.
Arm Type
Experimental
Arm Description
Blood sample collection from HIV controlled patients during their scheduled consultation, after obtaining their non-opposition by an investigator.
Intervention Type
Procedure
Intervention Name(s)
Blood collection.
Intervention Description
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.
Primary Outcome Measure Information:
Title
Measurement of the reactivation level and the EC50 of the optimized molecules.
Description
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.
Time Frame
At inclusion.
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Tristan FERRY, MD-PhD
Organizational Affiliation
Service des maladies infectieuses et tropicales, Hôpital de la Croix Rousse, Hospices Civils de Lyon
Official's Role
Principal Investigator
Facility Information:
Facility Name
Service des maladies infectieuses et tropicales Hôpital de la Croix Rousse
City
Lyon
ZIP/Postal Code
69004
Country
France
12. IPD Sharing Statement
Learn more about this trial
Selection of Farnesoid X Receptor (FXR) Ligands on the Reactivation of Latent HIV Proviruses
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