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出境医 / 临床实验 / Immune Activation as a Cause of Insulin Resistance in Adults Living With HIV-1 on Effective Antiretroviral Therapy (MetACTIVIH)

Immune Activation as a Cause of Insulin Resistance in Adults Living With HIV-1 on Effective Antiretroviral Therapy (MetACTIVIH)

Study Description
Brief Summary:
The aim of this study is to characterize in non-viremic HIV-1 patients under antiretroviral therapy an immune activation profile that the investigators have previously shown to be strongly linked to hyperinsulinemia. This characterization will be carried out via 3 different approaches. First, the investigators will analyze the metabolites present in the plasma of patients presenting with the profile of interest. Second, the investigators will study the transcriptome of the peripheral blood mononuclear cells of these patients. Finally, the investigators will search whether some factors released by these cells are able to induce insulin resistance. In addition the ability of the profile of interest to predict an increase in insulinemia over time will be assessed.

Condition or disease Intervention/treatment
HIV Infections Other: Signaling, metabolomic and transcriptomic analysis

Detailed Description:

The working hypothesis of this study is that in efficiently treated HIV patients, various profiles of immune activation may be distinguished, each favouring particular comorbidities. Using a panel of 68 soluble and cell surface markers, the investigators have previously measured the level of activation in circulating Cluster of Differentiation 4+ (CD4+) and Cluster of Differentiation 8+ (CD8+), T cells, B cells, monocytes, Natural Killers (NK) cells, neutrophils, and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. Two independent hierarchical clustering analyses allowed the investigators to identify five patient groups, each with the same activation profile. One of these profiles, Profile#2, was strongly associated with hyperinsulinemia (Psomas et al., 2016).

The main objective of the present study is to better define Profile#2. To this aim, the investigators will analyze by mass spectrometry the metabolites in the plasma of patients with various profiles including the one of interest. Concurrently, the investigators will perform an RiboNucleic Acid Sequencing (RNASeq) analysis on peripheral blood mononuclear cells (PBMC) from the same patients. These metabolomic and transcriptomic data will help to better define the immune activation profiles.

The secondary objective is to test whether the link the investigators have observed between Profile#2 and insulin resistance is causative. To this aim, by following over time patients' insulinemia, the investigators will test whether Profile#2 is predictive of an increase in insulinemia. The investigators will also look for factors released by PBMC of patients with Profile#2 able to induce insulin resistance.

Study Design
Layout table for study information
Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Immune Activation as a Cause of Insulin Resistance in Adults Living With HIV-1 on Effective Antiretroviral Therapy
Actual Study Start Date : March 3, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023
Arms and Interventions
Group/Cohort Intervention/treatment
Non viremic HIV patients under treatment
Patients with various immune activation profiles
Other: Signaling, metabolomic and transcriptomic analysis
Signaling, metabolomic and transcriptomic analysis

Outcome Measures
Primary Outcome Measures :
  1. Metabolomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will analyze by mass spectrometry the metabolites present in the plasma of patients presenting with the profile of interest as compared with patients with other immune activation profiles. Metabolites will be extracted from the blood plasma using a salt assisted liquid-liquid extraction. The metabolites will then be allowed to crystallize on the metallic surface. Finally, the plate content will be analyzed by desorption electrospray ionisation mass spectrometry using positive and negative ionization.

  2. Transcriptomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will also analyze by RNASeq the messenger RNA (mRNA) produced by the PBMC of patients presenting with the profile of interest and compared them with the mRNA produced by the PBMC of patients with other immune activation profiles.


Secondary Outcome Measures :
  1. Follow-up over time of insulinemia in patients with various immune activation profiles [ Time Frame: 18 months ]
    The investigators will compare over time the increase in insulinemia in patients presenting or not the immune activation profile of interest.

  2. Test whether PBMC from patients with Profile#2 induce insulin resistance [ Time Frame: 18 months ]
    The investigators will analyze whether PBMC from patients with the immune activation profile of interest release factors able to inhibit insulin signaling in hepatocytes. Insulin signaling will be measured by quantifying Akt phosphorylation vie western blot.


Biospecimen Retention:   Samples Without DNA
Plasma and peripheral blood mononuclear cells (PBMC)

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
HIV-1-infected adults under efficient antiretroviral therapy
Criteria

Inclusion criteria:

  • Subject consulting or hospitalized in the tropical and infectious diseases unit at the University Hospital of Montpellier that have been enrolled in a study during which the immune activation profile was analyzed
  • Subject aged at least 18 years
  • Subject speaking french fluently
  • Subject who is not opposed to participate to the study, after a clear information
  • Subject affiliated to a social security system
  • Infection by HIV-1 determined by a positive serology or by a measure of the plasma viral load (RNA HIV)
  • HIV-1 patients under stable antiretroviral therapy
  • HIV load < 50 copies/mL since at least 6 months before enrollment (2 measures)

Exclusion criteria:

  • Vulnerable individuals
  • Persons protected
  • Pregnant women or breastfeeding mothers
  • Bad understanding of the nature and goals of the study and/or communication difficulties with the investigator
  • Subject enrolled in an other study with an exclusion period still running
  • Non infectious pathology that might be the origin of an immune anomaly
  • Treatment by an immune modulator molecule or by chemotherapy in the 60 days before enrollment in the study
Contacts and Locations

Contacts
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Contact: Pierre CORBEAU, MD, PhD (0)434359932 ext +33 pierre.corbeau@igh.cnrs.fr
Contact: Jacques REYNES, MD, PhD (0)467337220 ext +33 j-reynes@chu-montpellier.fr

Locations
Layout table for location information
France
Saint Eloi Hospital, University Hospital of Montpellier Recruiting
Montpellier, Hérault, France, 34295
Contact: Pierre CORBEAU, MD, PhD         
Sponsors and Collaborators
University Hospital, Montpellier
Tracking Information
First Submitted Date June 12, 2019
First Posted Date July 23, 2019
Last Update Posted Date February 12, 2021
Actual Study Start Date March 3, 2020
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 29, 2019)
  • Metabolomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will analyze by mass spectrometry the metabolites present in the plasma of patients presenting with the profile of interest as compared with patients with other immune activation profiles. Metabolites will be extracted from the blood plasma using a salt assisted liquid-liquid extraction. The metabolites will then be allowed to crystallize on the metallic surface. Finally, the plate content will be analyzed by desorption electrospray ionisation mass spectrometry using positive and negative ionization.
  • Transcriptomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will also analyze by RNASeq the messenger RNA (mRNA) produced by the PBMC of patients presenting with the profile of interest and compared them with the mRNA produced by the PBMC of patients with other immune activation profiles.
Original Primary Outcome Measures
 (submitted: July 17, 2019)
  • Metabolomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will analyze by mass spectrometry the metabolites present in the plasma of patients presenting with the profile of interest as compared with patients with other immune activation profiles. Metabolites will be extracted from the blood plasma using a salt assisted liquid-liquid extraction. The metabolites will then be allowed to crystallize on the metallic surface. Finally, the plate content will be analyzed by desorption electrospray ionisation mass spectrometry using positive and negative ionization.
  • Transcriptomic analysis on plasma and PBMC [ Time Frame: 18 months ]
    The investigators will also analyze by RNASeq the mRNA produced by the PBMC of patients presenting with the profile of interest and compared them with the mRNA produced by the PBMC of patients with other immune activation profiles.
Change History
Current Secondary Outcome Measures
 (submitted: July 17, 2019)
  • Follow-up over time of insulinemia in patients with various immune activation profiles [ Time Frame: 18 months ]
    The investigators will compare over time the increase in insulinemia in patients presenting or not the immune activation profile of interest.
  • Test whether PBMC from patients with Profile#2 induce insulin resistance [ Time Frame: 18 months ]
    The investigators will analyze whether PBMC from patients with the immune activation profile of interest release factors able to inhibit insulin signaling in hepatocytes. Insulin signaling will be measured by quantifying Akt phosphorylation vie western blot.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Immune Activation as a Cause of Insulin Resistance in Adults Living With HIV-1 on Effective Antiretroviral Therapy
Official Title Immune Activation as a Cause of Insulin Resistance in Adults Living With HIV-1 on Effective Antiretroviral Therapy
Brief Summary The aim of this study is to characterize in non-viremic HIV-1 patients under antiretroviral therapy an immune activation profile that the investigators have previously shown to be strongly linked to hyperinsulinemia. This characterization will be carried out via 3 different approaches. First, the investigators will analyze the metabolites present in the plasma of patients presenting with the profile of interest. Second, the investigators will study the transcriptome of the peripheral blood mononuclear cells of these patients. Finally, the investigators will search whether some factors released by these cells are able to induce insulin resistance. In addition the ability of the profile of interest to predict an increase in insulinemia over time will be assessed.
Detailed Description

The working hypothesis of this study is that in efficiently treated HIV patients, various profiles of immune activation may be distinguished, each favouring particular comorbidities. Using a panel of 68 soluble and cell surface markers, the investigators have previously measured the level of activation in circulating Cluster of Differentiation 4+ (CD4+) and Cluster of Differentiation 8+ (CD8+), T cells, B cells, monocytes, Natural Killers (NK) cells, neutrophils, and endothelial cells as well as of inflammation and fibrinolysis in 120 virologic responders over 45 years of age. Two independent hierarchical clustering analyses allowed the investigators to identify five patient groups, each with the same activation profile. One of these profiles, Profile#2, was strongly associated with hyperinsulinemia (Psomas et al., 2016).

The main objective of the present study is to better define Profile#2. To this aim, the investigators will analyze by mass spectrometry the metabolites in the plasma of patients with various profiles including the one of interest. Concurrently, the investigators will perform an RiboNucleic Acid Sequencing (RNASeq) analysis on peripheral blood mononuclear cells (PBMC) from the same patients. These metabolomic and transcriptomic data will help to better define the immune activation profiles.

The secondary objective is to test whether the link the investigators have observed between Profile#2 and insulin resistance is causative. To this aim, by following over time patients' insulinemia, the investigators will test whether Profile#2 is predictive of an increase in insulinemia. The investigators will also look for factors released by PBMC of patients with Profile#2 able to induce insulin resistance.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
Plasma and peripheral blood mononuclear cells (PBMC)
Sampling Method Non-Probability Sample
Study Population HIV-1-infected adults under efficient antiretroviral therapy
Condition HIV Infections
Intervention Other: Signaling, metabolomic and transcriptomic analysis
Signaling, metabolomic and transcriptomic analysis
Study Groups/Cohorts Non viremic HIV patients under treatment
Patients with various immune activation profiles
Intervention: Other: Signaling, metabolomic and transcriptomic analysis
Publications * Psomas C, Younas M, Reynes C, Cezar R, Portalès P, Tuaillon E, Guigues A, Merle C, Atoui N, Fernandez C, Le Moing V, Barbuat C, Marin G, Nagot N, Sotto A, Eliaou JF, Sabatier R, Reynes J, Corbeau P. One of the immune activation profiles observed in HIV-1-infected adults with suppressed viremia is linked to metabolic syndrome: The ACTIVIH study. EBioMedicine. 2016 Jun;8:265-276. doi: 10.1016/j.ebiom.2016.05.008. Epub 2016 May 10. Erratum in: EBioMedicine. 2016 Aug;10:318-322.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: July 17, 2019)
300
Original Estimated Enrollment Same as current
Estimated Study Completion Date March 2023
Estimated Primary Completion Date March 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion criteria:

  • Subject consulting or hospitalized in the tropical and infectious diseases unit at the University Hospital of Montpellier that have been enrolled in a study during which the immune activation profile was analyzed
  • Subject aged at least 18 years
  • Subject speaking french fluently
  • Subject who is not opposed to participate to the study, after a clear information
  • Subject affiliated to a social security system
  • Infection by HIV-1 determined by a positive serology or by a measure of the plasma viral load (RNA HIV)
  • HIV-1 patients under stable antiretroviral therapy
  • HIV load < 50 copies/mL since at least 6 months before enrollment (2 measures)

Exclusion criteria:

  • Vulnerable individuals
  • Persons protected
  • Pregnant women or breastfeeding mothers
  • Bad understanding of the nature and goals of the study and/or communication difficulties with the investigator
  • Subject enrolled in an other study with an exclusion period still running
  • Non infectious pathology that might be the origin of an immune anomaly
  • Treatment by an immune modulator molecule or by chemotherapy in the 60 days before enrollment in the study
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Pierre CORBEAU, MD, PhD (0)434359932 ext +33 pierre.corbeau@igh.cnrs.fr
Contact: Jacques REYNES, MD, PhD (0)467337220 ext +33 j-reynes@chu-montpellier.fr
Listed Location Countries France
Removed Location Countries  
 
Administrative Information
NCT Number NCT04028882
Other Study ID Numbers RECHMPL18_0373
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Responsible Party University Hospital, Montpellier
Study Sponsor University Hospital, Montpellier
Collaborators Not Provided
Investigators Not Provided
PRS Account University Hospital, Montpellier
Verification Date February 2021

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