<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/NCT03782142</url>
  </required_header>
  <id_info>
    <org_study_id>180510</org_study_id>
    <nct_id>NCT03782142</nct_id>
  </id_info>
  <brief_title>Effect on HIV Medications on EPC Cells</brief_title>
  <official_title>What is the Impact of Current HIV Medication Regimens on Endothelial Dysfunction?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sabyasachi Sen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>George Washington University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a 3 arm, non-Interventional pilot single time point cross sectional study for the&#xD;
      duration of 1 year. Total of 30 candidates (10 in each Group) will be enrolled into three&#xD;
      different groups taking three different Antiretroviral regimen.&#xD;
&#xD;
      Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will&#xD;
      include NRTI such as TAF (tenofovir alafenamide) or TDF(tenofovir disoproxil fumarate) plus&#xD;
      one of the following:&#xD;
&#xD;
      Group A: an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine Group B a&#xD;
      boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination] Group C: an&#xD;
      Integrase inhibitor (dolutegravir)&#xD;
&#xD;
      Once Informed Consent Process is obtained, blood will be drawn (55 ml) for stem/progenitor&#xD;
      cell harvest and 15-20mls for biochemistry analysis. The Investigators will also obtain&#xD;
      weight, waist-circumference, BP, pulse, BMI, Tanita body composition scale measures (which&#xD;
      gives us body habitus measurements) and arterial stiffness measures.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Metabolic and endocrine perturbations including insulin resistance, diabetes, and&#xD;
      dyslipidemia have been of significant concern in human immunodeficiency virus (HIV)-infected&#xD;
      individuals. HIV-infected individuals may be at risk of accelerated atherosclerotic&#xD;
      cardiovascular disease (CVD) and metabolic syndrome. HIV infection itself and&#xD;
      first-generation antiretroviral (ART) therapies, have been associated with adipose tissue/&#xD;
      lipodystrophic changes and disorders of glucose and lipid metabolism. More recent data&#xD;
      suggest that immune activation and inflammation from chronic HIV infection may play an&#xD;
      important role in HIV-associated metabolic dysfunction. Given the recent advances in ART, an&#xD;
      increasing number of HIV-infected individuals are virologically controlled and living longer;&#xD;
      as such, the trajectory of HIV-associated morbidity has shifted from one of primarily acute&#xD;
      opportunistic infections and immune deficiency/dysfunction to one that includes chronic&#xD;
      metabolic complications such as CVD. It is therefore important to discern the effect of&#xD;
      current HIV medications on endothelial dysfunction and cardio-metabolic health.&#xD;
&#xD;
      Endothelial progenitor cells (EPCs), are an established biomarker for cardiovascular risk&#xD;
      outcome measures. EPCs have been defined as CD34+ cells thereby identifying a defined&#xD;
      homogenous population from heterogeneous peripheral blood derived mononuclear cells. We and&#xD;
      others have previously shown that EPCs can act as a cellular biomarker that is more reliable&#xD;
      than plasma-based markers for CVD risk estimation. Though these studies were not specifically&#xD;
      directed towards HIV positive population one can postulate that CD34+ cells will act as an&#xD;
      efficient biomarker for endothelial function in this population of interest.&#xD;
&#xD;
      Regarding treatment regimens for HIV, in general, the initial regimen for HIV-infected&#xD;
      individuals usually includes two NRTIs plus an INSTI, an NNRTI, or a PI boosted with either&#xD;
      cobicistat or ritonavir. Previously, protease inhibitors such as indinavir, and reverse&#xD;
      transcriptase inhibitors such as AZT or d4t, have been implicated in mitochondrial&#xD;
      dysfunction and oxidative stress, altered adipogenesis and differentiation, and impaired&#xD;
      glucose and lipid homeostasis. Newer ART agents have been suggested to have lesser impact on&#xD;
      metabolic parameters. However, these newer agents may trigger poorly understood processes&#xD;
      that may have a negative impact on endothelium and numerous metabolic pathways.&#xD;
&#xD;
      Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will&#xD;
      include NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) plus&#xD;
      one of the following:&#xD;
&#xD;
      1: an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine (Group A) 2. a&#xD;
      boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination] (Group B), and 3:&#xD;
      an Integrase inhibitor (dolutegravir) (Group C) We are including an integrase inhibitor&#xD;
      because these agents have become the most popular initial regimen for newly infected HIV&#xD;
      individuals. To avoid effect of medication within the three groups we have identified&#xD;
      specific drugs within each class.&#xD;
&#xD;
      Significance: Although the etiology of metabolic/endocrine complications in HIV-infected&#xD;
      individuals despite viremic control is poorly understood, it is most likely related to the&#xD;
      interplay of host, viral, and ART factors and the complex interactions among the long-term&#xD;
      consequences of infection, chronic ART, and the underlying inflammatory process. As mentioned&#xD;
      before certain ARTs have raised concerns about metabolic dysfunction such as the PIs and it&#xD;
      is important to determine whether other combination medications promote or reduce the chances&#xD;
      of endothelial and metabolic dysregulation.&#xD;
&#xD;
      Pending a cure or vaccine to prevent HIV, a strong need exists to reduce long-term morbidity&#xD;
      in HIV-infected individuals both by achieving viral suppression and limiting HIV- and/or&#xD;
      ART-related complications, particularly since the current World Health Organization's&#xD;
      guidelines recommend treating all HIV-infected individuals with ART. ) To discern endothelial&#xD;
      function whole blood mononuclear cell derived EPC study is very appropriate. The Investigator&#xD;
      have demonstrated that gene expression in EPCs change within two weeks of an intervention&#xD;
      such as aerobic exercise. On the other-hand serum biomarkers usually take much longer time to&#xD;
      change secondary to an intervention. The paracrine effect of damaged endothelium is secondary&#xD;
      to gene expression changes that have been altered in the progenitor cells several months&#xD;
      ahead of discernable changes in serum based biomarkers such as endothelium based inflammatory&#xD;
      markers. When serum inflammatory markers are elevated that suggests that the endothelium is&#xD;
      already damaged/ inflamed, possibly irreversibly.&#xD;
&#xD;
      EPCs are the future endothelium, therefore studying EPCs helps the Investigators to predict&#xD;
      the effect of an intervention (such as a medication or exercise) on the future of endothelium&#xD;
      and endothelial function. Their prime function is to migrate in response to a chemotactic&#xD;
      factor such as SDF1 alpha, in order to repair the damaged or dysfunctional endothelium. In&#xD;
      the normal course of events, EPCs transition to mature endothelium and replace endothelial&#xD;
      cells after normal cell death cycle or programmed apoptosis. Unfortunately, obesity and HIV,&#xD;
      both being pro-inflammatory, high reactive oxygen species (ROS) disease processes,&#xD;
      chronically depletes the EPC population by up-regulating apoptotic pathways mediated by p53.&#xD;
&#xD;
      In order to understand the cellular mechanism(s) of chronic metabolic dysfunction and&#xD;
      associated endothelial dysfunction leading to cardiovascular disease risk, in patients with&#xD;
      HIV, it will be useful to study the peripheral blood derived endothelial progenitor cells&#xD;
      (EPC, CD34+ cells) along with biochemistry, on three different treatment regimens and&#xD;
      establish their effects on endothelium.&#xD;
&#xD;
      The Investigators believe this study design allows to discern whether the medication regimens&#xD;
      have an effect on endothelium and biochemical parameters such as insulin, glucose, HbA1c,&#xD;
      fasting lipid profile and also appetite controlling hormones. The latter has been&#xD;
      particularly in focus lately with several diabetes medications, such as the incretins which&#xD;
      modify appetite management pathway to treat obesity, metabolic syndrome, diabetes and reduce&#xD;
      cardiovascular disease risk.&#xD;
&#xD;
      The arterial stiffness measure is a non-invasive procedure which provides the Investigators&#xD;
      with important data on endothelial function and vascular health. Increased arterial stiffness&#xD;
      indicates presence of increased peripheral resistance and predicts development of overt&#xD;
      systolic and diastolic hypertension.&#xD;
&#xD;
      It is expected that EPC function studies would bear a negative correlation with biochemistry&#xD;
      and arterial stiffness as demonstrated in other clinical trials. The biochemistry and&#xD;
      arterial stiffness data as secondary outcome measure would help validate results and&#xD;
      conclusions obtained from the primary outcome measures.&#xD;
&#xD;
      All together the Investigators have designed a study on HIV medication looking at their&#xD;
      effect on endothelial function that is largely non-invasive yet giving valuable information&#xD;
      on endothelial health, metabolic parameters and arterial stiffness. The study population is&#xD;
      HIV positive patients, 40-70 years, male subjects only (to avoid gender differences during&#xD;
      EPC based analysis), with a HbA1C less than 6.5% (subjects with no known history of&#xD;
      diabetes). The study team will enroll 10 subjects from each group (A,B,C) who have been on a&#xD;
      stable HIV regimen for at least one year. Total enrollment: 30 patients.&#xD;
&#xD;
      Innovation: This is an innovative study looking at different components of cardio-metabolic&#xD;
      disease in HIV subjects and the role that HIV medication regimens play. The NIH is interested&#xD;
      in this topic and has a current RFA out on this topic indicating lack of information. Our&#xD;
      study design is unique as it combines cellular, biochemical and bio-physical components as&#xD;
      outcome measures.&#xD;
&#xD;
      RESEARCH HYPOTHESIS The Investigators hypothesize that among these HIV regimens (A, B or C)&#xD;
      there will be differences in the degree of metabolic derangement and endothelial dysfunction.&#xD;
      The team plans to undertake a cross sectional study on HIV subjects on A, B or C regimens for&#xD;
      at least one year, without diabetes, with known cardio-metabolic disease predisposition such&#xD;
      as overweight and mild to moderate obesity (BMI 25.0- 39.9), but with no established coronary&#xD;
      or cerebrovascular event&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 1, 2018</start_date>
  <completion_date type="Actual">December 14, 2021</completion_date>
  <primary_completion_date type="Actual">November 12, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Only</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>CD34+/ total MNC percentage</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>Percent of CD34+ cells over total Mononuclear cell</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Colony Formation Capacity - Numbers of Colony formed</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Migratory function in response to SDF1α</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>How much the CD34+ cells migrate in response to SDF1a</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Targeted gene expression of EPCs</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>Gene expression</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Concentration of Serum Insulin</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>to assess insulin resistance</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lipid Profile</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>Cholesterol, LDL, HDL and TAG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concentration Serum Leptin</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>appetite controlling hormone</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial Stiffness through measuring Pulse wave Velocity</measure>
    <time_frame>Week 0, Single Time Point</time_frame>
    <description>through Pulse velocity</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">22</enrollment>
  <condition>AIDS</condition>
  <arm_group>
    <arm_group_label>Group A NRTI + NNRTI</arm_group_label>
    <description>Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will include NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group B NRTI + boosted PI</arm_group_label>
    <description>NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and a boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination]</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group C NRTI + II</arm_group_label>
    <description>NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and an Integrase inhibitor (dolutegravir)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tenofovir</intervention_name>
    <description>TAF (tenofovir alafenamide) or TDF(tenofovir disoproxil fumarate)</description>
    <arm_group_label>Group A NRTI + NNRTI</arm_group_label>
    <arm_group_label>Group B NRTI + boosted PI</arm_group_label>
    <arm_group_label>Group C NRTI + II</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rilpivirine</intervention_name>
    <description>NNRTI</description>
    <arm_group_label>Group A NRTI + NNRTI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prezcobix</intervention_name>
    <description>PI</description>
    <arm_group_label>Group B NRTI + boosted PI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolutegravir</intervention_name>
    <description>II</description>
    <arm_group_label>Group C NRTI + II</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Males from 40-70, with a Diagnosis of HIV, currently on HAART.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male only (as gender variation of progenitor cells along with effect of estrogen, may&#xD;
             lead to difficulty in data interpretation), Age above 40, but less than 70 years,&#xD;
&#xD;
          2. Body Mass Index (BMI) between 25.0-39.9 (both inclusive)&#xD;
&#xD;
          3. eGFR ≥ 50 mL/min/1.73 m2 by MDRD.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Uncontrolled hyperglycemia with random blood glucose &gt;200 mg/dL (&gt;13.3 mmol/L)&#xD;
&#xD;
          2. Liver disease with ALT, AST or ALP x3 ULN&#xD;
&#xD;
          3. Subjects with HCV and HBV and detectable HCV RNA or HBV DNA&#xD;
&#xD;
          4. GFR &lt;50 mL/min/1.73 m2 by MDRD&#xD;
&#xD;
          5. Prior surgery with chronic malabsorption (eg, bariatric) in prior 1 year&#xD;
&#xD;
          6. Clinically significant RBC disorders such as hemoglobinopathies&#xD;
&#xD;
          7. Chronic use of anti-inflammatory drugs for the last 3 months&#xD;
&#xD;
          8. On statin medications (ASCVD score less than or equal to 7.5%)&#xD;
&#xD;
          9. Use of consistent long-term steroid medication (oral, inhaled, injected) in last 1&#xD;
             month&#xD;
&#xD;
         10. Treatment with a strong cytochrome P450 3A4 (CYP34A) or P-gp inducer (ie:Rifampin)&#xD;
&#xD;
         11. Active smokers, Active wounds or recent surgery within 1 month&#xD;
&#xD;
         12. Untreated hyper/hypothyroidism&#xD;
&#xD;
         13. Implanted devices (eg. Pacemaker) that may interact with Tanita scale&#xD;
&#xD;
         14. Any other clinical condition that would jeopardize patient safety while participating&#xD;
&#xD;
         15. Women who are pregnant or breastfeeding&#xD;
&#xD;
         16. Chronic or persistent alcohol or drug abuse&#xD;
&#xD;
         17. Hypertriglyceridemia above 500mg/dl.&#xD;
&#xD;
         18. Prisoners or subjects who are involuntarily incarcerated&#xD;
&#xD;
         19. Subjects who are compulsorily detained for treatment of either a psychiatric illness&#xD;
&#xD;
         20. Participation in another trial with an investigational drug within 30 days prior to&#xD;
             consent&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The GW Medical Faculty Associates</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20037</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>October 17, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>March 21, 2022</last_update_submitted>
  <last_update_submitted_qc>March 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>George Washington University</investigator_affiliation>
    <investigator_full_name>Sabyasachi Sen</investigator_full_name>
    <investigator_title>Associate Professor, Dept. of Medicine (Division of Endocrinology)</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Dolutegravir</mesh_term>
    <mesh_term>Rilpivirine</mesh_term>
    <mesh_term>Cobicistat mixture with darunavir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03782142
org study id: 180510
nct id: NCT03782142
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
This is a 3 arm, non-Interventional pilot single time point cross sectional study for the
      duration of 1 year. Total of 30 candidates (10 in each Group) will be enrolled into three
      different groups taking three different Antiretroviral regimen.

      Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will
      include NRTI such as TAF (tenofovir alafenamide) or TDF(tenofovir disoproxil fumarate) plus
      one of the following:

      Group A: an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine Group B a
      boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination] Group C: an
      Integrase inhibitor (dolutegravir)

      Once Informed Consent Process is obtained, blood will be drawn (55 ml) for stem/progenitor
      cell harvest and 15-20mls for biochemistry analysis. The Investigators will also obtain
      weight, waist-circumference, BP, pulse, BMI, Tanita body composition scale measures (which
      gives us body habitus measurements) and arterial stiffness measures.
Metabolic and endocrine perturbations including insulin resistance, diabetes, and
      dyslipidemia have been of significant concern in human immunodeficiency virus (HIV)-infected
      individuals. HIV-infected individuals may be at risk of accelerated atherosclerotic
      cardiovascular disease (CVD) and metabolic syndrome. HIV infection itself and
      first-generation antiretroviral (ART) therapies, have been associated with adipose tissue/
      lipodystrophic changes and disorders of glucose and lipid metabolism. More recent data
      suggest that immune activation and inflammation from chronic HIV infection may play an
      important role in HIV-associated metabolic dysfunction. Given the recent advances in ART, an
      increasing number of HIV-infected individuals are virologically controlled and living longer;
      as such, the trajectory of HIV-associated morbidity has shifted from one of primarily acute
      opportunistic infections and immune deficiency/dysfunction to one that includes chronic
      metabolic complications such as CVD. It is therefore important to discern the effect of
      current HIV medications on endothelial dysfunction and cardio-metabolic health.

      Endothelial progenitor cells (EPCs), are an established biomarker for cardiovascular risk
      outcome measures. EPCs have been defined as CD34+ cells thereby identifying a defined
      homogenous population from heterogeneous peripheral blood derived mononuclear cells. We and
      others have previously shown that EPCs can act as a cellular biomarker that is more reliable
      than plasma-based markers for CVD risk estimation. Though these studies were not specifically
      directed towards HIV positive population one can postulate that CD34+ cells will act as an
      efficient biomarker for endothelial function in this population of interest.

      Regarding treatment regimens for HIV, in general, the initial regimen for HIV-infected
      individuals usually includes two NRTIs plus an INSTI, an NNRTI, or a PI boosted with either
      cobicistat or ritonavir. Previously, protease inhibitors such as indinavir, and reverse
      transcriptase inhibitors such as AZT or d4t, have been implicated in mitochondrial
      dysfunction and oxidative stress, altered adipogenesis and differentiation, and impaired
      glucose and lipid homeostasis. Newer ART agents have been suggested to have lesser impact on
      metabolic parameters. However, these newer agents may trigger poorly understood processes
      that may have a negative impact on endothelium and numerous metabolic pathways.

      Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will
      include NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) plus
      one of the following:

      1: an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine (Group A) 2. a
      boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination] (Group B), and 3:
      an Integrase inhibitor (dolutegravir) (Group C) We are including an integrase inhibitor
      because these agents have become the most popular initial regimen for newly infected HIV
      individuals. To avoid effect of medication within the three groups we have identified
      specific drugs within each class.

      Significance: Although the etiology of metabolic/endocrine complications in HIV-infected
      individuals despite viremic control is poorly understood, it is most likely related to the
      interplay of host, viral, and ART factors and the complex interactions among the long-term
      consequences of infection, chronic ART, and the underlying inflammatory process. As mentioned
      before certain ARTs have raised concerns about metabolic dysfunction such as the PIs and it
      is important to determine whether other combination medications promote or reduce the chances
      of endothelial and metabolic dysregulation.

      Pending a cure or vaccine to prevent HIV, a strong need exists to reduce long-term morbidity
      in HIV-infected individuals both by achieving viral suppression and limiting HIV- and/or
      ART-related complications, particularly since the current World Health Organization's
      guidelines recommend treating all HIV-infected individuals with ART. ) To discern endothelial
      function whole blood mononuclear cell derived EPC study is very appropriate. The Investigator
      have demonstrated that gene expression in EPCs change within two weeks of an intervention
      such as aerobic exercise. On the other-hand serum biomarkers usually take much longer time to
      change secondary to an intervention. The paracrine effect of damaged endothelium is secondary
      to gene expression changes that have been altered in the progenitor cells several months
      ahead of discernable changes in serum based biomarkers such as endothelium based inflammatory
      markers. When serum inflammatory markers are elevated that suggests that the endothelium is
      already damaged/ inflamed, possibly irreversibly.

      EPCs are the future endothelium, therefore studying EPCs helps the Investigators to predict
      the effect of an intervention (such as a medication or exercise) on the future of endothelium
      and endothelial function. Their prime function is to migrate in response to a chemotactic
      factor such as SDF1 alpha, in order to repair the damaged or dysfunctional endothelium. In
      the normal course of events, EPCs transition to mature endothelium and replace endothelial
      cells after normal cell death cycle or programmed apoptosis. Unfortunately, obesity and HIV,
      both being pro-inflammatory, high reactive oxygen species (ROS) disease processes,
      chronically depletes the EPC population by up-regulating apoptotic pathways mediated by p53.

      In order to understand the cellular mechanism(s) of chronic metabolic dysfunction and
      associated endothelial dysfunction leading to cardiovascular disease risk, in patients with
      HIV, it will be useful to study the peripheral blood derived endothelial progenitor cells
      (EPC, CD34+ cells) along with biochemistry, on three different treatment regimens and
      establish their effects on endothelium.

      The Investigators believe this study design allows to discern whether the medication regimens
      have an effect on endothelium and biochemical parameters such as insulin, glucose, HbA1c,
      fasting lipid profile and also appetite controlling hormones. The latter has been
      particularly in focus lately with several diabetes medications, such as the incretins which
      modify appetite management pathway to treat obesity, metabolic syndrome, diabetes and reduce
      cardiovascular disease risk.

      The arterial stiffness measure is a non-invasive procedure which provides the Investigators
      with important data on endothelial function and vascular health. Increased arterial stiffness
      indicates presence of increased peripheral resistance and predicts development of overt
      systolic and diastolic hypertension.

      It is expected that EPC function studies would bear a negative correlation with biochemistry
      and arterial stiffness as demonstrated in other clinical trials. The biochemistry and
      arterial stiffness data as secondary outcome measure would help validate results and
      conclusions obtained from the primary outcome measures.

      All together the Investigators have designed a study on HIV medication looking at their
      effect on endothelial function that is largely non-invasive yet giving valuable information
      on endothelial health, metabolic parameters and arterial stiffness. The study population is
      HIV positive patients, 40-70 years, male subjects only (to avoid gender differences during
      EPC based analysis), with a HbA1C less than 6.5% (subjects with no known history of
      diabetes). The study team will enroll 10 subjects from each group (A,B,C) who have been on a
      stable HIV regimen for at least one year. Total enrollment: 30 patients.

      Innovation: This is an innovative study looking at different components of cardio-metabolic
      disease in HIV subjects and the role that HIV medication regimens play. The NIH is interested
      in this topic and has a current RFA out on this topic indicating lack of information. Our
      study design is unique as it combines cellular, biochemical and bio-physical components as
      outcome measures.

      RESEARCH HYPOTHESIS The Investigators hypothesize that among these HIV regimens (A, B or C)
      there will be differences in the degree of metabolic derangement and endothelial dysfunction.
      The team plans to undertake a cross sectional study on HIV subjects on A, B or C regimens for
      at least one year, without diabetes, with known cardio-metabolic disease predisposition such
      as overweight and mild to moderate obesity (BMI 25.0- 39.9), but with no established coronary
      or cerebrovascular event
observational model: Case-Only
time perspective: Cross-Sectional
measure: CD34+/ total MNC percentage
time frame: Week 0, Single Time Point
description: Percent of CD34+ cells over total Mononuclear cell
measure: Colony Formation Capacity - Numbers of Colony formed
time frame: Week 0, Single Time Point
measure: Migratory function in response to SDF1α
time frame: Week 0, Single Time Point
description: How much the CD34+ cells migrate in response to SDF1a
measure: Targeted gene expression of EPCs
time frame: Week 0, Single Time Point
description: Gene expression
measure: Concentration of Serum Insulin
time frame: Week 0, Single Time Point
description: to assess insulin resistance
measure: Lipid Profile
time frame: Week 0, Single Time Point
description: Cholesterol, LDL, HDL and TAG
measure: Concentration Serum Leptin
time frame: Week 0, Single Time Point
description: appetite controlling hormone
measure: Arterial Stiffness through measuring Pulse wave Velocity
time frame: Week 0, Single Time Point
description: through Pulse velocity
arm group label: Group A NRTI + NNRTI
description: Based on current regimens that are commonly used (2017-2018 ART guidelines), our groups will include NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and an NNRTI (Non-nucleoside reverse transcriptase inhibitor, Rilpivirine
arm group label: Group B NRTI + boosted PI
description: NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and a boosted Protease Inhibitor: Prezcobix- [darunavir+cobicistat combination]
arm group label: Group C NRTI + II
description: NRTI such as TAF (tenofovir alafenamide) or TDF (tenofovir disoproxil fumarate) and an Integrase inhibitor (dolutegravir)
intervention type: Drug
intervention name: Tenofovir
description: TAF (tenofovir alafenamide) or TDF(tenofovir disoproxil fumarate)
arm group label: Group A NRTI + NNRTI
arm group label: Group B NRTI + boosted PI
arm group label: Group C NRTI + II
intervention type: Drug
intervention name: Rilpivirine
description: NNRTI
arm group label: Group A NRTI + NNRTI
intervention type: Drug
intervention name: Prezcobix
description: PI
arm group label: Group B NRTI + boosted PI
intervention type: Drug
intervention name: Dolutegravir
description: II
arm group label: Group C NRTI + II
study pop: 
sampling method: Probability Sample
criteria: 
gender: Male
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: George Washington University
investigator full name: Sabyasachi Sen
investigator title: Associate Professor, Dept. of Medicine (Division of Endocrinology)
mesh term: Tenofovir
mesh term: Dolutegravir
mesh term: Rilpivirine
mesh term: Cobicistat mixture with darunavir
sharing ipd: No