<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04451980</url>
  </required_header>
  <id_info>
    <org_study_id>161254</org_study_id>
    <nct_id>NCT04451980</nct_id>
  </id_info>
  <brief_title>The HIV, Adipose Tissue Immunology, and Metabolism Study</brief_title>
  <acronym>HATIM</acronym>
  <official_title>The HIV, Adipose Tissue Immunology, and Metabolism Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
  </oversight_info>
  <brief_summary>
    <textblock>
      With the introduction of effective anti-retroviral therapy (ART), HIV-infected persons can&#xD;
      now survive for decades, but this success has been accompanied by an increased risk of&#xD;
      developing metabolic disease and diabetes in HIV-infected persons compared to the general&#xD;
      population. Recent studies from HIV-negative subjects have identified several associations&#xD;
      between circulating immune cell populations and impaired glucose tolerance, including&#xD;
      increased activated CD4+ and CD8+ T cells, and reduced regulatory T cells. Of note, these&#xD;
      same changes in peripheral T cell subsets are frequently observed in patients with chronic&#xD;
      HIV infection. The goal of this study is to assess whether the circulating T cell&#xD;
      distribution is reflective of the adipose tissue T cell distribution, and to understand&#xD;
      whether chronic adipose tissue T cell activation may impair adipocyte (i.e., fat cell)&#xD;
      function and insulin sensitivity. If the investigators' hypotheses are correct, this will&#xD;
      demonstrate that chronic peripheral immune activation (i.e., high memory T cells, low naïve&#xD;
      cells, and increased expression of activation surface markers) is associated with greater&#xD;
      adipose-resident CD4+ and CD8+ T cell expression of activation markers, adipose tissue&#xD;
      inflammation, and insulin resistance.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      With the introduction of effective antiretroviral therapy (ART), HIV-infected persons can now&#xD;
      survive for decades, but this success has been accompanied by an increased risk of developing&#xD;
      metabolic disease compared HIV-negative persons. In the Multicenter AIDS Cohort Study,&#xD;
      HIV-infected men had a greater than 4-fold increased incidence of a new diabetes diagnosis&#xD;
      compared to HIV-negative men after adjusting for age and body mass index (BMI). Prevalence&#xD;
      studies of diabetes in HIV-infected individuals on ART have reported incidence rates of 3.1&#xD;
      to 14 per 1000 patient-years. Furthermore, treated HIV infection appears to act&#xD;
      synergistically with other risk factors, and diabetes prevalence is especially high among&#xD;
      HIV-infected individuals with high BMI and advanced age.&#xD;
&#xD;
      Recent studies from HIV-negative subjects identified several associations between adaptive&#xD;
      immune cell populations and impaired glucose tolerance. Peripheral T regulatory (Treg) cells&#xD;
      are significantly lower in patients with type-2 diabetes , while the numbers activated T&#xD;
      cells, CD4+ TH1 (pro-inflammatory) cells, and memory CD4+ T cells are higher in diabetics.&#xD;
&#xD;
      Immune cells translocate from the circulation into adipose tissue in a dynamic process, and T&#xD;
      cells are present in the stromal fraction of adipose tissue and affect adipocyte function.&#xD;
      The striking increase in adipose tissue CD4+ TH1 cells and CD8+ T cells, and a decrease in&#xD;
      Treg cells, observed in obesity may have an important role in the development of insulin&#xD;
      resistance. Secretion of the proinflammatory cytokines interferon-γ and interleukin (IL)-17&#xD;
      by TH1 and TH17 cells are implicated in the induction of proinflammatory M1 macrophages,&#xD;
      which express IL-6 and tumor necrosis factor alpha, and inhibit adipocyte insulin signaling&#xD;
      by promoting phosphorylation of insulin receptor substrate 1. The investigators hypothesize&#xD;
      that the chronic, HIV-related activation of circulating CD4+ and CD8+ T cells may be&#xD;
      accompanied by the accumulation of activated T cells in adipose tissue with adverse effects&#xD;
      on metabolic activity.&#xD;
&#xD;
      In this study, the investigators will test the hypothesis that the oligoclonal expansion of&#xD;
      chronically activated peripheral T cells in adipose tissue is a primary driver of macrophage&#xD;
      inflammation and reduced adipocyte insulin sensitivity. Furthermore, the investigators&#xD;
      propose that this represents a central mechanistic linkage underlying the association between&#xD;
      circulating T cell activation and incident diabetes risk observed in HIV-infected and&#xD;
      HIV-negative individuals.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 31, 2017</start_date>
  <completion_date type="Anticipated">January 31, 2025</completion_date>
  <primary_completion_date type="Actual">March 13, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Adipose tissue T cell surface marker phenotype and antigen receptor sequence</measure>
    <time_frame>At study enrollment</time_frame>
    <description>Flow cytometry measurement of adipose tissue T cell surface marker phenotypes and sequencing of T cell receptors, compared by HIV and diabetes status</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CT measurements of visceral, hepatic, and pericardial fat content</measure>
    <time_frame>At study enrollment</time_frame>
    <description>Quantification of visceral, hepatic, and pericardial adipose tissue content, compared by HIV and diabetes status</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Circulating T cell surface marker phenotype</measure>
    <time_frame>At study enrollment</time_frame>
    <description>Flow cytometry measurement of circulating T cell surface marker phenotypes, compared by HIV and diabetes status</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">172</enrollment>
  <condition>Hiv</condition>
  <condition>Diabetes Mellitus, Type 2</condition>
  <arm_group>
    <arm_group_label>HIV+ non-diabetics</arm_group_label>
    <description>HIV-infected participants with hemoglobin A1c (HbA1c) &lt;5.7% or fasting glucose &lt;100 mg/dl.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV+ pre-diabetics</arm_group_label>
    <description>HIV-infected participants with HbA1c 5.7-6.4% or fasting glucose 100-125 mg/dl.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV+ diabetics</arm_group_label>
    <description>HIV-infected participants with HbA1c &gt;=6.5% or fasting glucose &gt;=126 mg/dl or on anti-diabetic medications.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-negative diabetics</arm_group_label>
    <description>HIV-negative participants with HbA1c &gt;=6.5% or fasting glucose &gt;=126 mg/dl or on anti-diabetic medications.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Subcutaneous adipose tissue biopsy</intervention_name>
    <description>Percutaneous adipose tissue biopsy</description>
    <arm_group_label>HIV+ diabetics</arm_group_label>
    <arm_group_label>HIV+ non-diabetics</arm_group_label>
    <arm_group_label>HIV+ pre-diabetics</arm_group_label>
    <arm_group_label>HIV-negative diabetics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>CT scan</intervention_name>
    <description>CT scan of chest and abdomen without contrast</description>
    <arm_group_label>HIV+ diabetics</arm_group_label>
    <arm_group_label>HIV+ non-diabetics</arm_group_label>
    <arm_group_label>HIV+ pre-diabetics</arm_group_label>
    <arm_group_label>HIV-negative diabetics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Oral glucose tolerance test</intervention_name>
    <description>Ingestion of 75g of oral glucose syrup and measurement of blood glucose and insulin at time 0, 15 min, 30 min, 60 min, 90 min, and 120 min.</description>
    <arm_group_label>HIV+ non-diabetics</arm_group_label>
    <arm_group_label>HIV+ pre-diabetics</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Blood collection</intervention_name>
    <description>Fasting blood collection for plasma cytokines and T cell phenotypes.</description>
    <arm_group_label>HIV+ diabetics</arm_group_label>
    <arm_group_label>HIV+ non-diabetics</arm_group_label>
    <arm_group_label>HIV+ pre-diabetics</arm_group_label>
    <arm_group_label>HIV-negative diabetics</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Collection and retention of whole adipose tissue samples, adipose tissue stromal vascular&#xD;
      fraction, peripheral blood mononuclear cells, and plasma.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV-positive participants are recruited from the Vanderbilt Comprehensive Care Clinic, and&#xD;
        HIV-negative participants are recruited from Vanderbilt University Medical Center clinics&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        HIV+ Participants:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  On antiretroviral therapy for at least 18 months&#xD;
&#xD;
          -  HIV-1 RNA &lt;400 copies/ml for the prior 12 months&#xD;
&#xD;
          -  CD4+ count &gt;350 cells/µl in the prior 12 months&#xD;
&#xD;
          -  HbA1c in prior 6 months within specified limits (See Figure)&#xD;
&#xD;
          -  Pre-menopausal by self-report or post-menopausal but not on hormone replacement&#xD;
             therapy (HRT)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known inflammatory or rheumatologic conditions&#xD;
&#xD;
          -  Heavy alcohol (&gt;11 drinks per week) or cocaine, amphetamine, or illicit&#xD;
             (non-prescribed) opiate abuse by self-report&#xD;
&#xD;
          -  Current use of DPP-4 inhibitors.&#xD;
&#xD;
        HIV-negative Participants:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  A HbA1c &gt;6.5% or a fasting glucose &gt;126mg/dl, or on anti-diabetic medications for at&#xD;
             least 6 months&#xD;
&#xD;
          -  Pre-menopausal by self-report or post-menopausal but not on hormone replacement&#xD;
             therapy (HRT)&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          -  Known inflammatory or rheumatologic conditions&#xD;
&#xD;
          -  Heavy alcohol (&gt;11 drinks per week) or cocaine, amphetamine, or illicit&#xD;
             (non-prescribed) opiate abuse by self-report&#xD;
&#xD;
          -  Current use of DPP-4 inhibitors.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>John Koethe, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37209</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Wanjalla CN, McDonnell WJ, Barnett L, Simmons JD, Furch BD, Lima MC, Woodward BO, Fan R, Fei Y, Baker PG, Ram R, Pilkinton MA, Mashayekhi M, Brown NJ, Mallal SA, Kalams SA, Koethe JR. Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance. Front Immunol. 2019 Mar 19;10:408. doi: 10.3389/fimmu.2019.00408. eCollection 2019.</citation>
    <PMID>30941121</PMID>
  </results_reference>
  <results_reference>
    <citation>Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S. Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons. J Acquir Immune Defic Syndr. 2018 Feb 1;77(2):e14-e21. doi: 10.1097/QAI.0000000000001573.</citation>
    <PMID>29040163</PMID>
  </results_reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>June 16, 2020</study_first_submitted>
  <study_first_submitted_qc>June 25, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 30, 2020</study_first_posted>
  <last_update_submitted>March 21, 2023</last_update_submitted>
  <last_update_submitted_qc>March 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>John R. Koethe</investigator_full_name>
    <investigator_title>Assistant Professor, Infectious Disease - Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>There is no plan to share IPD.</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>May 15, 2023</submitted>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04451980
org study id: 161254
nct id: NCT04451980
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
With the introduction of effective anti-retroviral therapy (ART), HIV-infected persons can
      now survive for decades, but this success has been accompanied by an increased risk of
      developing metabolic disease and diabetes in HIV-infected persons compared to the general
      population. Recent studies from HIV-negative subjects have identified several associations
      between circulating immune cell populations and impaired glucose tolerance, including
      increased activated CD4+ and CD8+ T cells, and reduced regulatory T cells. Of note, these
      same changes in peripheral T cell subsets are frequently observed in patients with chronic
      HIV infection. The goal of this study is to assess whether the circulating T cell
      distribution is reflective of the adipose tissue T cell distribution, and to understand
      whether chronic adipose tissue T cell activation may impair adipocyte (i.e., fat cell)
      function and insulin sensitivity. If the investigators' hypotheses are correct, this will
      demonstrate that chronic peripheral immune activation (i.e., high memory T cells, low naïve
      cells, and increased expression of activation surface markers) is associated with greater
      adipose-resident CD4+ and CD8+ T cell expression of activation markers, adipose tissue
      inflammation, and insulin resistance.
With the introduction of effective antiretroviral therapy (ART), HIV-infected persons can now
      survive for decades, but this success has been accompanied by an increased risk of developing
      metabolic disease compared HIV-negative persons. In the Multicenter AIDS Cohort Study,
      HIV-infected men had a greater than 4-fold increased incidence of a new diabetes diagnosis
      compared to HIV-negative men after adjusting for age and body mass index (BMI). Prevalence
      studies of diabetes in HIV-infected individuals on ART have reported incidence rates of 3.1
      to 14 per 1000 patient-years. Furthermore, treated HIV infection appears to act
      synergistically with other risk factors, and diabetes prevalence is especially high among
      HIV-infected individuals with high BMI and advanced age.

      Recent studies from HIV-negative subjects identified several associations between adaptive
      immune cell populations and impaired glucose tolerance. Peripheral T regulatory (Treg) cells
      are significantly lower in patients with type-2 diabetes , while the numbers activated T
      cells, CD4+ TH1 (pro-inflammatory) cells, and memory CD4+ T cells are higher in diabetics.

      Immune cells translocate from the circulation into adipose tissue in a dynamic process, and T
      cells are present in the stromal fraction of adipose tissue and affect adipocyte function.
      The striking increase in adipose tissue CD4+ TH1 cells and CD8+ T cells, and a decrease in
      Treg cells, observed in obesity may have an important role in the development of insulin
      resistance. Secretion of the proinflammatory cytokines interferon-γ and interleukin (IL)-17
      by TH1 and TH17 cells are implicated in the induction of proinflammatory M1 macrophages,
      which express IL-6 and tumor necrosis factor alpha, and inhibit adipocyte insulin signaling
      by promoting phosphorylation of insulin receptor substrate 1. The investigators hypothesize
      that the chronic, HIV-related activation of circulating CD4+ and CD8+ T cells may be
      accompanied by the accumulation of activated T cells in adipose tissue with adverse effects
      on metabolic activity.

      In this study, the investigators will test the hypothesis that the oligoclonal expansion of
      chronically activated peripheral T cells in adipose tissue is a primary driver of macrophage
      inflammation and reduced adipocyte insulin sensitivity. Furthermore, the investigators
      propose that this represents a central mechanistic linkage underlying the association between
      circulating T cell activation and incident diabetes risk observed in HIV-infected and
      HIV-negative individuals.
observational model: Cohort
time perspective: Cross-Sectional
measure: Adipose tissue T cell surface marker phenotype and antigen receptor sequence
time frame: At study enrollment
description: Flow cytometry measurement of adipose tissue T cell surface marker phenotypes and sequencing of T cell receptors, compared by HIV and diabetes status
measure: CT measurements of visceral, hepatic, and pericardial fat content
time frame: At study enrollment
description: Quantification of visceral, hepatic, and pericardial adipose tissue content, compared by HIV and diabetes status
measure: Circulating T cell surface marker phenotype
time frame: At study enrollment
description: Flow cytometry measurement of circulating T cell surface marker phenotypes, compared by HIV and diabetes status
arm group label: HIV+ non-diabetics
description: HIV-infected participants with hemoglobin A1c (HbA1c) <5.7% or fasting glucose <100 mg/dl.
arm group label: HIV+ pre-diabetics
description: HIV-infected participants with HbA1c 5.7-6.4% or fasting glucose 100-125 mg/dl.
arm group label: HIV+ diabetics
description: HIV-infected participants with HbA1c >=6.5% or fasting glucose >=126 mg/dl or on anti-diabetic medications.
arm group label: HIV-negative diabetics
description: HIV-negative participants with HbA1c >=6.5% or fasting glucose >=126 mg/dl or on anti-diabetic medications.
intervention type: Procedure
intervention name: Subcutaneous adipose tissue biopsy
description: Percutaneous adipose tissue biopsy
arm group label: HIV+ diabetics
arm group label: HIV+ non-diabetics
arm group label: HIV+ pre-diabetics
arm group label: HIV-negative diabetics
intervention type: Radiation
intervention name: CT scan
description: CT scan of chest and abdomen without contrast
arm group label: HIV+ diabetics
arm group label: HIV+ non-diabetics
arm group label: HIV+ pre-diabetics
arm group label: HIV-negative diabetics
intervention type: Diagnostic Test
intervention name: Oral glucose tolerance test
description: Ingestion of 75g of oral glucose syrup and measurement of blood glucose and insulin at time 0, 15 min, 30 min, 60 min, 90 min, and 120 min.
arm group label: HIV+ non-diabetics
arm group label: HIV+ pre-diabetics
intervention type: Diagnostic Test
intervention name: Blood collection
description: Fasting blood collection for plasma cytokines and T cell phenotypes.
arm group label: HIV+ diabetics
arm group label: HIV+ non-diabetics
arm group label: HIV+ pre-diabetics
arm group label: HIV-negative diabetics
Collection and retention of whole adipose tissue samples, adipose tissue stromal vascular
      fraction, peripheral blood mononuclear cells, and plasma.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: John Koethe, MD
role: Principal Investigator
affiliation: Vanderbilt University Medical Center
facility: 
country: United States
citation: Wanjalla CN, McDonnell WJ, Barnett L, Simmons JD, Furch BD, Lima MC, Woodward BO, Fan R, Fei Y, Baker PG, Ram R, Pilkinton MA, Mashayekhi M, Brown NJ, Mallal SA, Kalams SA, Koethe JR. Adipose Tissue in Persons With HIV Is Enriched for CD4+ T Effector Memory and T Effector Memory RA+ Cells, Which Show Higher CD69 Expression and CD57, CX3CR1, GPR56 Co-expression With Increasing Glucose Intolerance. Front Immunol. 2019 Mar 19;10:408. doi: 10.3389/fimmu.2019.00408. eCollection 2019.
PMID: 30941121
citation: Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S. Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons. J Acquir Immune Defic Syndr. 2018 Feb 1;77(2):e14-e21. doi: 10.1097/QAI.0000000000001573.
PMID: 29040163
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: John R. Koethe
investigator title: Assistant Professor, Infectious Disease - Medicine
mesh term: Diabetes Mellitus, Type 2
sharing ipd: No
ipd description: There is no plan to share IPD.
submitted: May 15, 2023