<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/NCT03251144</url>
  </required_header>
  <id_info>
    <org_study_id>CO-US-311-4393</org_study_id>
    <secondary_id>CO-US-311-4393</secondary_id>
    <nct_id>NCT03251144</nct_id>
  </id_info>
  <brief_title>Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF)</brief_title>
  <acronym>UCLACAREMITO</acronym>
  <official_title>In Vitro and in Vivo Studies of the Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, Los Angeles</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Gilead Sciences</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, Los Angeles</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>
      Increased comorbidities such as cardiovascular disease (CVD), are emerging problems in HIV&#xD;
      infection but the mechanisms are unclear. Understanding how antiretrovirals can minimize&#xD;
      morbidity in treated HIV infection is a research priority. Nucleoside/nucleotide reverse&#xD;
      transcriptase inhibitors (NRTIs) are included in all HIV treatment regimens. Tenofovir (TFV)&#xD;
      disoproxil fumarate (TDF) has been associated with an increased risk of nephrotoxicity and&#xD;
      bone disease compared with other NRTIs. Tenofovir alafenamide (TAF) is an oral prodrug of&#xD;
      TFV, but is more stable in plasma as compared with TDF and lower plasma levels of TFV are&#xD;
      thought to lead to the favorable safety profile of TAF. Mitochondrial dysfunction has a key&#xD;
      role in HIV pathogenesis and may be the common denominator that drives pathogenesis of&#xD;
      several comorbidities. Despite the better safety profile of newer (such as TDF) compared to&#xD;
      older NRTIs, there are concerns for the potential for longer term toxicity of NRTIs since the&#xD;
      exact cellular effects of NRTIs remain unclear. It is unknown whether a four-fold increase in&#xD;
      intracellular drug levels seen in peripheral blood mononuclear cells (PBMCs) with TAF may&#xD;
      increase toxicity in mitochondria. Better understanding of these effects could provide&#xD;
      insights into mechanisms of HIV pathogenesis and selection of NRTIs that improve morbidity in&#xD;
      chronic HIV infection.&#xD;
&#xD;
      Hypothesis: Despite higher intracellular levels, TAF has minimal mitochondrial toxicity&#xD;
      compared to TDF in vivo. This research will explore the relative mitochondrial toxicity of&#xD;
      newer NRTIs (TAF, TDF) as a possible mechanism for differential NTRI-related toxicities.&#xD;
      These data will allow selection of NRTIs that may improve morbidity in chronic treated HIV&#xD;
      infection. Towards this aim, the investigators will use a robust experimental approach to&#xD;
      study NRTI-related mitochondrial dysfunction using novel methods, human cell lines and PBMC.&#xD;
      Our specific aims are: Aim 1: To evaluate the relative in vitro effects of TAF and TDF&#xD;
      compared to an older NRTI (ddC) on 5 independent measures of mitochondrial function in the&#xD;
      human cell line HepG2 and PBMC. Aim 2: To explore in vivo whether there is increased&#xD;
      mitochondrial dysfunction with the use of TAF vs. TDF in chronic treated HIV infection. The&#xD;
      investigators anticipate that the proposed experimental approach will set the basis for&#xD;
      future large scale studies to directly compare subtle potential mitochondrial toxicities of&#xD;
      newer NRTIs in large HIV cohorts.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Increased comorbidities such as cardiovascular disease (CVD), bone and kidney disease are&#xD;
      emerging problems in HIV infection but the mechanisms are unclear. Understanding how&#xD;
      antiretrovirals can minimize morbidity in treated HIV infection is a research priority.&#xD;
      Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are included in all HIV&#xD;
      treatment regimens. Tenofovir (TFV) disoproxil fumarate (TDF) has been associated with an&#xD;
      increased risk of nephrotoxicity and bone disease compared with other NRTIs. Tenofovir&#xD;
      alafenamide (TAF) is an oral prodrug of TFV, but is much more stable in plasma as compared&#xD;
      with TDF and markedly lower plasma levels of TFV are thought to lead to the favorable safety&#xD;
      profile of TAF. Mitochondrial dysfunction has a key role in HIV pathogenesis and may be the&#xD;
      common denominator that drives pathogenesis of several comorbidities. Despite the better&#xD;
      safety profile of newer (such as TDF) compared to older NRTIs, there remain concerns for the&#xD;
      potential for longer term toxicity of the current NRTIs especially since the exact cellular&#xD;
      effects of NRTIs remain unclear. It is unknown whether a four-fold increase in intracellular&#xD;
      drug levels seen in peripheral blood mononuclear cells (PBMCs) with TAF may increase toxicity&#xD;
      in mitochondria. Better understanding of these effects could provide insights into mechanisms&#xD;
      of HIV pathogenesis and selection of NRTIs that improve morbidity in chronic HIV infection.&#xD;
&#xD;
      Hypothesis: Despite higher intracellular levels, TAF has minimal/no overall mitochondrial&#xD;
      toxicity compared to TDF in vivo. The investigators anticipate that the preliminary data and&#xD;
      the proposed experimental approach will set the basis for future large scale studies to&#xD;
      directly compare subtle potential mitochondrial toxicities of newer NRTIs in large HIV&#xD;
      cohorts.&#xD;
&#xD;
      Primary Objective: This research application will explore the relative mitochondrial toxicity&#xD;
      of newer NRTIs (TAF, TDF) as a possible mechanism for differential NTRI-related toxicities.&#xD;
      These data will allow selection of NRTIs that may improve morbidity in chronic treated HIV&#xD;
      infection, given the known possible role of mitochondrial dysfunction in pathogenesis of&#xD;
      HIV-related comorbidities. Towards this aim, the investigators will use a robust experimental&#xD;
      approach to study NRTI-related mitochondrial dysfunction using novel methods, human cell&#xD;
      lines and PBMC. The specific aims of this project are: Aim 1: To evaluate the relative in&#xD;
      vitro effects of TAF and TDF compared to an older NRTI (ddC) on 5 independent measures of&#xD;
      mitochondrial function in the human cell line HepG2 and PBMC. Hypothesis: Despite higher&#xD;
      intracellular levels, TAF has minimal/no overall mitochondrial toxicity compared to TDF in&#xD;
      both the HepG2 line and PBMC. ddC will be used as a positive control for NRTI-induced&#xD;
      mitochondrial dysfunction. Aim 2: To explore in vivo whether there is increased mitochondrial&#xD;
      dysfunction with the use of TAF vs. TDF in chronic treated HIV infection. The overall goal of&#xD;
      this proposal is to determine the in vitro and in vivo effects of TAF on mitochondria.&#xD;
&#xD;
      Treatment regimen: Healthy HIV-uninfected &gt; 18 years old with no known comorbidities&#xD;
      including metabolic disease will be recruited for PBMC isolation for the in vitro studies&#xD;
      described in Aim 1 (n=30). For Aim 1, cells will be exposed to 10 μM (and other dose that&#xD;
      will be determined after discussions with Gilead) NRTIs (TDF, TAF, ddC) for up to 14 days of&#xD;
      treatment. To evaluate the relative mitochondrial toxicity of TDF vs. TAF in vivo (Aim 2), an&#xD;
      open-label switch study will be conducted in virologically-suppressed, HIV-1 positive&#xD;
      participants. The switch regimen will be Stribild® (elvitegravir 150 mg/cobicistat 150&#xD;
      mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; E/C/F/TDF) to Genvoya®&#xD;
      (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg;&#xD;
      E/C/F/TAF). For inclusion and exclusion criteria see respective sections.&#xD;
&#xD;
      Primary Endpoint: Overall, the above in vitro and in vivo measurements of mitochondrial&#xD;
      function before and after TAF and TDF will test the hypotheses that newer NRTIs have minimal&#xD;
      overall mitochondrial toxicity in humans. From all the measures of mitochondrial function,&#xD;
      cellular oxygen consumption (COC; as determined by Seahorse technology) will be considered&#xD;
      the &quot;gold standard&quot; given it is a measure of the most important mitochondrial function&#xD;
      (oxidative phosphorylation) that relates to clinical outcome. Given the uncertainty of what&#xD;
      measure of mitochondrial function can best predict NRTI-induced mitochondrial toxicity,&#xD;
      comparison of relative fold induction of mitochondrial dysfunction in PBMC vs. HepG2 cells in&#xD;
      response to a specific concentration of a known NRTI inducer of mitochondrial dysfunction&#xD;
      (ddC) will be used to guide analysis. The baseline measurement will be used to control for&#xD;
      confounders of NRTI-related mitochondrial dysfunction (each person will serve as his/her own&#xD;
      control) and results will be expressed as relative-fold change compared to baseline. In&#xD;
      addition, using similar approach, Aim 2 will explore whether switch from TDF to a TAF-based&#xD;
      regimen will induce any changes in measures of mitochondrial function. This approach ensures&#xD;
      that any changes in the mitochondrial function at 6 and/or 12 months will be secondary only&#xD;
      to the NRTI switch.&#xD;
&#xD;
      Secondary Endpoints: It is accepted that two independent measures of mitochondrial function&#xD;
      can more reliably predict mitochondrial dysfunction compared to each one of the measures&#xD;
      separately. The investigators will define NRTI-induced mitochondrial toxicity as significant&#xD;
      change in any of other major measures of mitochondrial toxicity [reduction in membrane&#xD;
      potential (Δψm), increase in mitochondrial reactive oxygen species (mito-ROS), decrease in&#xD;
      the amount of mitochondrial DNA (mtDNA), abnormal mitochondrial dynamics (increase&#xD;
      fragmentation of mitochondria)). Finally, other exploratory secondary endpoints (based on&#xD;
      available left-over resources) will be measurement of intracellular levels of TAF&#xD;
      metabolites. Flow cytometry and live cell imaging will be determined as needed.&#xD;
&#xD;
      The investigators will define NRTI-induced mitochondrial toxicity as significant change in&#xD;
      any of the measures of mitochondrial toxicity (COC, Δψm, mito-ROS, mtDNA, mitochondrial&#xD;
      dynamics). The baseline measurement will be used to control for confounders of NRTI-related&#xD;
      mitochondrial dysfunction (each person will serve as his/her own control) and results will be&#xD;
      expressed as relative-fold change compared to baseline. In addition, using similar approach,&#xD;
      Aim 2 will explore whether switch from TDF to a TAF-based regimen will induce any changes in&#xD;
      measures of mitochondrial function. This approach ensures that any changes in the&#xD;
      mitochondrial function at 6 and/or 12 months will be secondary only to the NRTI switch.&#xD;
&#xD;
      Since each donor will contribute samples to all experimental groups (baseline, follow up&#xD;
      measurement), paired t-test, linear mixed effects model and nonparametric test (as needed)&#xD;
      will be used to compare expression measures between groups adjusting for donor effects (age,&#xD;
      sex, race.&#xD;
&#xD;
      The results from this research will yield useful information on NRTI-related overall&#xD;
      mitochondrial dysfunction that can further be validated in large studies with data on&#xD;
      clinical outcomes.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 1, 2019</start_date>
  <completion_date type="Actual">July 1, 2021</completion_date>
  <primary_completion_date type="Actual">July 1, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals.</measure>
    <time_frame>12 month visit after switch</time_frame>
    <description>Change in mitochondrial function [abnormal mitochondrial dynamics [(cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals.</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>HIV/AIDS</condition>
  <condition>Antiviral Toxicity</condition>
  <condition>Antiviral Drug Adverse Reaction</condition>
  <condition>Mitochondrial Alteration</condition>
  <arm_group>
    <arm_group_label>Switch to E/C/FTC/TAF daily</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention: Participants will be asked to switch antiretrovirals (ART) for a period up to 12 months and mitochondrial physiology will be assessed using a variety of assays. The new ART will be&#xD;
If the participant is on an ART other than Elvitegravir (ELV)/cobicistat CO)/emtricitabine (FTC)/tenofovir (TDF)] (E/C/FTC/TDF) then the participant will be asked to switch to E/C/FTC/TDF for up to 6 months. This will allow for future switch (after these 6 months) from E/C/FTC/TDF 1 tablet once daily to E/C/FTC/ tenofovir alafenamide (TAF) 1 tablet once daily for a period of 12 months.&#xD;
If the participant is on E/C/FTC/TDF 1 tablet once daily then the participant will be asked to switch from /C/FTC/TDF 1 tablet once daily to /C/FTC/TAF 1 tablet once daily for a period of 12 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Switch to E/C/FTC/TAF daily</intervention_name>
    <description>If the participant is on an antiretroviral regimen other than Elvitegravir (ELV)/cobicistat CO)/emtricitabine (FTC)/tenofovir (TDF)] (E/C/FTC/TDF) then the participant will be asked to switch to E/C/FTC/TDF for up to 6 months. This will allow for future switch (after these 6 months) from E/C/FTC/TDF 1 tablet once daily to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/FTC/TAF) 1 tablet once daily for a period of 12 months.&#xD;
b) If the participant is on E/C/FTC/TDF 1 tablet once daily then the participant will be asked to switch from /C/FTC/TDF 1 tablet once daily to /C/FTC/TAF 1 tablet once daily for a period of 12 months.</description>
    <arm_group_label>Switch to E/C/FTC/TAF daily</arm_group_label>
    <other_name>E/C/FTC/TDF 1 tablet once daily</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Inclusion criteria for HIV negative participants&#xD;
&#xD;
        All HIV negative participants must meet the following criteria:&#xD;
&#xD;
          1. 18 years of age or older&#xD;
&#xD;
          2. Understands and agrees to local STI reporting requirements&#xD;
&#xD;
          3. HIV negative at screening by self-report, with no significant medical diagnoses&#xD;
&#xD;
          4. HIV negative by both HIV antibody and HIV PCR in blood (samples obtained during Visit&#xD;
             1)&#xD;
&#xD;
          5. Able and willing to communicate in English&#xD;
&#xD;
          6. Able and willing to provide written informed consent to take part in the study&#xD;
&#xD;
          7. Able and willing to provide adequate information for locator purposes&#xD;
&#xD;
          8. Able and willing to provide medical/surgical history&#xD;
&#xD;
          9. Availability to return for all study visits, barring unforeseen circumstances&#xD;
&#xD;
         10. Willing to abstain from insertion of anything (drug, enema, penis or sex toy) in&#xD;
             rectum for 12 hours before and 72 hours after each flexible sigmoidoscopy&#xD;
&#xD;
             In addition to the criteria listed above, female participants must meet the following&#xD;
             criteria&#xD;
&#xD;
         11. Negative pregnancy test&#xD;
&#xD;
         12. Post-menopausal or using and acceptable form of contraception (e.g. barrier method,&#xD;
             IUD, hormonal contraception, or surgical sterilization).&#xD;
&#xD;
        HIV participant inclusion criteria&#xD;
&#xD;
        Specific enrollment inclusion criteria include:&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  Cases: Chronically infected and on anti-retroviral therapy with suppressed viremia&#xD;
             (viral RNA &lt;50 copies per ml)&#xD;
&#xD;
          -  On stable antiretroviral therapy for 6 months with either a) Stribild®; elvitegravir&#xD;
             150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg;&#xD;
             E/C/F/TDF)&#xD;
&#xD;
          -  Adequate renal function determined by the Cockcroft-Gault formula for creatinine&#xD;
             clearance (&gt;60 mL/min/1.73 m2&#xD;
&#xD;
          -  Controls: HIV negative as documented in prior tests and willing to undergo repeat HIV&#xD;
             testing&#xD;
&#xD;
          -  Able and willing to communicate in English&#xD;
&#xD;
          -  Able and willing to provide written informed consent to take part in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion criteria for all study participants:&#xD;
&#xD;
        Participants who meet any of the following criteria at screening will be excluded from the&#xD;
        study:&#xD;
&#xD;
          1. History of chronic inflammatory bowel disease, radiation proctitis or other chronic&#xD;
             gastrointestinal disease, exclusive of functional bowel disease (irritable bowel&#xD;
             syndrome)&#xD;
&#xD;
          2. History of significant gastrointestinal bleeding&#xD;
&#xD;
          3. History of a bleeding disorder&#xD;
&#xD;
          4. History of colostomy&#xD;
&#xD;
          5. History of auto-immune diseases&#xD;
&#xD;
          6. Chronic viral hepatitis&#xD;
&#xD;
          7. History of diabetes&#xD;
&#xD;
          8. History of chemotherapy (for cancer or organ transplantation)&#xD;
&#xD;
          9. The chronic or recent (~2 weeks) use of antimitotic drugs, sulfonamides or antibiotics&#xD;
&#xD;
         10. History of or current coagulopathy and/or on anticoagulant therapy&#xD;
&#xD;
         11. Anticipated use or unwillingness to abstain from use of aspirin, NSAIDS or any other&#xD;
             drugs (including over the counter products) that are associated with the increased&#xD;
             likelihood of bleeding&#xD;
&#xD;
         12. Active rectal infection (gonorrhea, chlamydia trachomatis, or HSV)&#xD;
&#xD;
         13. Positive STI at screening (urine NAAT)&#xD;
&#xD;
             o Participants will be allowed one re-screening visit after appropriate STI treatment&#xD;
&#xD;
         14. History of underlying cardiac arrhythmia or renal disease&#xD;
&#xD;
         15. History of severe recent cardiac or pulmonary event&#xD;
&#xD;
         16. &gt; Grade 2 laboratory abnormality at baseline that can not be documented as stable&#xD;
             /chronic for that individual&#xD;
&#xD;
         17. Any other condition or prior therapy that, in the opinion of the investigator, would&#xD;
             make the patient unsuitable for the study or unable to comply with study requirements.&#xD;
             Such conditions may include, but are not limited to, current or recent history of&#xD;
             severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal,&#xD;
             endocrine, pulmonary, neurological or cerebral disease.&#xD;
&#xD;
         18. Pregnancy&#xD;
&#xD;
         19. Breastfeeding&#xD;
&#xD;
         20. Female of child-bearing potential unwilling to use acceptable form of contraception&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Theodoros Kelesidis, MD, PhD, Msc</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, Los Angeles</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UCLA CARE Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90035</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2022</verification_date>
  <study_first_submitted>August 6, 2017</study_first_submitted>
  <study_first_submitted_qc>August 11, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 16, 2017</study_first_posted>
  <results_first_submitted>March 22, 2022</results_first_submitted>
  <results_first_submitted_qc>April 19, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">May 10, 2022</results_first_posted>
  <last_update_submitted>April 19, 2022</last_update_submitted>
  <last_update_submitted_qc>April 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of California, Los Angeles</investigator_affiliation>
    <investigator_full_name>Theodoros Kelesidis, MD, PhD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>HIV/AIDS</keyword>
  <keyword>Tenofovir disoproxil fumarate (TDF)</keyword>
  <keyword>Tenofovir alafenamide (TAF)</keyword>
  <keyword>mitochondria</keyword>
  <keyword>toxicity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Drug-Related Side Effects and Adverse Reactions</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 22, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/44/NCT03251144/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>Assignment based on inclusion criteria TAF based vs TDF based antivirals</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>TAF Based ART</title>
          <description>HIV infected persons who receive TAF based ART</description>
        </group>
        <group group_id="P2">
          <title>TDF Based ART</title>
          <description>HIV infected persons who receive TDF based ART</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="15"/>
                <participants group_id="P2" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Patients on TAF based vs TDF based ART</population>
      <group_list>
        <group group_id="B1">
          <title>TAF Based ART</title>
          <description>HIV infected persons who receive TAF based ART</description>
        </group>
        <group group_id="B2">
          <title>TDF Based ART</title>
          <description>HIV infected persons who receive TDF based ART</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="15"/>
            <count group_id="B2" value="11"/>
            <count group_id="B3" value="26"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals.</title>
        <description>Change in mitochondrial function [abnormal mitochondrial dynamics [(cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals.</description>
        <time_frame>12 month visit after switch</time_frame>
        <group_list>
          <group group_id="O1">
            <title>TAF Based ART</title>
            <description>HIV infected persons who receive TAF based ART</description>
          </group>
          <group group_id="O2">
            <title>TDF Based ART</title>
            <description>HIV infected persons who receive TDF based ART</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals.</title>
          <description>Change in mitochondrial function [abnormal mitochondrial dynamics [(cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals.</description>
          <units>pmoles O2/min</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="11"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="50" lower_limit="42" upper_limit="58"/>
                    <measurement group_id="O2" value="70" lower_limit="65" upper_limit="72"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>t-test, 2 sided</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>20</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>3.0</dispersion_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up to 9 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>TAF Based ART</title>
          <description>HIV infected persons who receive TAF based ART</description>
        </group>
        <group group_id="E2">
          <title>TDF Based ART</title>
          <description>HIV infected persons who receive TDF based ART</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="15"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Theodoros Kelesidis</name_or_title>
      <organization>University of California Los Angeles</organization>
      <phone>3108257875</phone>
      <email>tkelesidis@mednet.ucla.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03251144
org study id: CO-US-311-4393
secondary id: CO-US-311-4393
nct id: NCT03251144
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Increased comorbidities such as cardiovascular disease (CVD), are emerging problems in HIV
      infection but the mechanisms are unclear. Understanding how antiretrovirals can minimize
      morbidity in treated HIV infection is a research priority. Nucleoside/nucleotide reverse
      transcriptase inhibitors (NRTIs) are included in all HIV treatment regimens. Tenofovir (TFV)
      disoproxil fumarate (TDF) has been associated with an increased risk of nephrotoxicity and
      bone disease compared with other NRTIs. Tenofovir alafenamide (TAF) is an oral prodrug of
      TFV, but is more stable in plasma as compared with TDF and lower plasma levels of TFV are
      thought to lead to the favorable safety profile of TAF. Mitochondrial dysfunction has a key
      role in HIV pathogenesis and may be the common denominator that drives pathogenesis of
      several comorbidities. Despite the better safety profile of newer (such as TDF) compared to
      older NRTIs, there are concerns for the potential for longer term toxicity of NRTIs since the
      exact cellular effects of NRTIs remain unclear. It is unknown whether a four-fold increase in
      intracellular drug levels seen in peripheral blood mononuclear cells (PBMCs) with TAF may
      increase toxicity in mitochondria. Better understanding of these effects could provide
      insights into mechanisms of HIV pathogenesis and selection of NRTIs that improve morbidity in
      chronic HIV infection.

      Hypothesis: Despite higher intracellular levels, TAF has minimal mitochondrial toxicity
      compared to TDF in vivo. This research will explore the relative mitochondrial toxicity of
      newer NRTIs (TAF, TDF) as a possible mechanism for differential NTRI-related toxicities.
      These data will allow selection of NRTIs that may improve morbidity in chronic treated HIV
      infection. Towards this aim, the investigators will use a robust experimental approach to
      study NRTI-related mitochondrial dysfunction using novel methods, human cell lines and PBMC.
      Our specific aims are: Aim 1: To evaluate the relative in vitro effects of TAF and TDF
      compared to an older NRTI (ddC) on 5 independent measures of mitochondrial function in the
      human cell line HepG2 and PBMC. Aim 2: To explore in vivo whether there is increased
      mitochondrial dysfunction with the use of TAF vs. TDF in chronic treated HIV infection. The
      investigators anticipate that the proposed experimental approach will set the basis for
      future large scale studies to directly compare subtle potential mitochondrial toxicities of
      newer NRTIs in large HIV cohorts.
Increased comorbidities such as cardiovascular disease (CVD), bone and kidney disease are
      emerging problems in HIV infection but the mechanisms are unclear. Understanding how
      antiretrovirals can minimize morbidity in treated HIV infection is a research priority.
      Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are included in all HIV
      treatment regimens. Tenofovir (TFV) disoproxil fumarate (TDF) has been associated with an
      increased risk of nephrotoxicity and bone disease compared with other NRTIs. Tenofovir
      alafenamide (TAF) is an oral prodrug of TFV, but is much more stable in plasma as compared
      with TDF and markedly lower plasma levels of TFV are thought to lead to the favorable safety
      profile of TAF. Mitochondrial dysfunction has a key role in HIV pathogenesis and may be the
      common denominator that drives pathogenesis of several comorbidities. Despite the better
      safety profile of newer (such as TDF) compared to older NRTIs, there remain concerns for the
      potential for longer term toxicity of the current NRTIs especially since the exact cellular
      effects of NRTIs remain unclear. It is unknown whether a four-fold increase in intracellular
      drug levels seen in peripheral blood mononuclear cells (PBMCs) with TAF may increase toxicity
      in mitochondria. Better understanding of these effects could provide insights into mechanisms
      of HIV pathogenesis and selection of NRTIs that improve morbidity in chronic HIV infection.

      Hypothesis: Despite higher intracellular levels, TAF has minimal/no overall mitochondrial
      toxicity compared to TDF in vivo. The investigators anticipate that the preliminary data and
      the proposed experimental approach will set the basis for future large scale studies to
      directly compare subtle potential mitochondrial toxicities of newer NRTIs in large HIV
      cohorts.

      Primary Objective: This research application will explore the relative mitochondrial toxicity
      of newer NRTIs (TAF, TDF) as a possible mechanism for differential NTRI-related toxicities.
      These data will allow selection of NRTIs that may improve morbidity in chronic treated HIV
      infection, given the known possible role of mitochondrial dysfunction in pathogenesis of
      HIV-related comorbidities. Towards this aim, the investigators will use a robust experimental
      approach to study NRTI-related mitochondrial dysfunction using novel methods, human cell
      lines and PBMC. The specific aims of this project are: Aim 1: To evaluate the relative in
      vitro effects of TAF and TDF compared to an older NRTI (ddC) on 5 independent measures of
      mitochondrial function in the human cell line HepG2 and PBMC. Hypothesis: Despite higher
      intracellular levels, TAF has minimal/no overall mitochondrial toxicity compared to TDF in
      both the HepG2 line and PBMC. ddC will be used as a positive control for NRTI-induced
      mitochondrial dysfunction. Aim 2: To explore in vivo whether there is increased mitochondrial
      dysfunction with the use of TAF vs. TDF in chronic treated HIV infection. The overall goal of
      this proposal is to determine the in vitro and in vivo effects of TAF on mitochondria.

      Treatment regimen: Healthy HIV-uninfected > 18 years old with no known comorbidities
      including metabolic disease will be recruited for PBMC isolation for the in vitro studies
      described in Aim 1 (n=30). For Aim 1, cells will be exposed to 10 μM (and other dose that
      will be determined after discussions with Gilead) NRTIs (TDF, TAF, ddC) for up to 14 days of
      treatment. To evaluate the relative mitochondrial toxicity of TDF vs. TAF in vivo (Aim 2), an
      open-label switch study will be conducted in virologically-suppressed, HIV-1 positive
      participants. The switch regimen will be Stribild® (elvitegravir 150 mg/cobicistat 150
      mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; E/C/F/TDF) to Genvoya®
      (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg;
      E/C/F/TAF). For inclusion and exclusion criteria see respective sections.

      Primary Endpoint: Overall, the above in vitro and in vivo measurements of mitochondrial
      function before and after TAF and TDF will test the hypotheses that newer NRTIs have minimal
      overall mitochondrial toxicity in humans. From all the measures of mitochondrial function,
      cellular oxygen consumption (COC; as determined by Seahorse technology) will be considered
      the "gold standard" given it is a measure of the most important mitochondrial function
      (oxidative phosphorylation) that relates to clinical outcome. Given the uncertainty of what
      measure of mitochondrial function can best predict NRTI-induced mitochondrial toxicity,
      comparison of relative fold induction of mitochondrial dysfunction in PBMC vs. HepG2 cells in
      response to a specific concentration of a known NRTI inducer of mitochondrial dysfunction
      (ddC) will be used to guide analysis. The baseline measurement will be used to control for
      confounders of NRTI-related mitochondrial dysfunction (each person will serve as his/her own
      control) and results will be expressed as relative-fold change compared to baseline. In
      addition, using similar approach, Aim 2 will explore whether switch from TDF to a TAF-based
      regimen will induce any changes in measures of mitochondrial function. This approach ensures
      that any changes in the mitochondrial function at 6 and/or 12 months will be secondary only
      to the NRTI switch.

      Secondary Endpoints: It is accepted that two independent measures of mitochondrial function
      can more reliably predict mitochondrial dysfunction compared to each one of the measures
      separately. The investigators will define NRTI-induced mitochondrial toxicity as significant
      change in any of other major measures of mitochondrial toxicity [reduction in membrane
      potential (Δψm), increase in mitochondrial reactive oxygen species (mito-ROS), decrease in
      the amount of mitochondrial DNA (mtDNA), abnormal mitochondrial dynamics (increase
      fragmentation of mitochondria)). Finally, other exploratory secondary endpoints (based on
      available left-over resources) will be measurement of intracellular levels of TAF
      metabolites. Flow cytometry and live cell imaging will be determined as needed.

      The investigators will define NRTI-induced mitochondrial toxicity as significant change in
      any of the measures of mitochondrial toxicity (COC, Δψm, mito-ROS, mtDNA, mitochondrial
      dynamics). The baseline measurement will be used to control for confounders of NRTI-related
      mitochondrial dysfunction (each person will serve as his/her own control) and results will be
      expressed as relative-fold change compared to baseline. In addition, using similar approach,
      Aim 2 will explore whether switch from TDF to a TAF-based regimen will induce any changes in
      measures of mitochondrial function. This approach ensures that any changes in the
      mitochondrial function at 6 and/or 12 months will be secondary only to the NRTI switch.

      Since each donor will contribute samples to all experimental groups (baseline, follow up
      measurement), paired t-test, linear mixed effects model and nonparametric test (as needed)
      will be used to compare expression measures between groups adjusting for donor effects (age,
      sex, race.

      The results from this research will yield useful information on NRTI-related overall
      mitochondrial dysfunction that can further be validated in large studies with data on
      clinical outcomes.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals.
time frame: 12 month visit after switch
description: Change in mitochondrial function [abnormal mitochondrial dynamics [(cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals.
arm group label: Switch to E/C/FTC/TAF daily
arm group type: Experimental
description: Intervention: Participants will be asked to switch antiretrovirals (ART) for a period up to 12 months and mitochondrial physiology will be assessed using a variety of assays. The new ART will be
If the participant is on an ART other than Elvitegravir (ELV)/cobicistat CO)/emtricitabine (FTC)/tenofovir (TDF)] (E/C/FTC/TDF) then the participant will be asked to switch to E/C/FTC/TDF for up to 6 months. This will allow for future switch (after these 6 months) from E/C/FTC/TDF 1 tablet once daily to E/C/FTC/ tenofovir alafenamide (TAF) 1 tablet once daily for a period of 12 months.
If the participant is on E/C/FTC/TDF 1 tablet once daily then the participant will be asked to switch from /C/FTC/TDF 1 tablet once daily to /C/FTC/TAF 1 tablet once daily for a period of 12 months.
intervention type: Drug
intervention name: Switch to E/C/FTC/TAF daily
description: If the participant is on an antiretroviral regimen other than Elvitegravir (ELV)/cobicistat CO)/emtricitabine (FTC)/tenofovir (TDF)] (E/C/FTC/TDF) then the participant will be asked to switch to E/C/FTC/TDF for up to 6 months. This will allow for future switch (after these 6 months) from E/C/FTC/TDF 1 tablet once daily to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/FTC/TAF) 1 tablet once daily for a period of 12 months.
b) If the participant is on E/C/FTC/TDF 1 tablet once daily then the participant will be asked to switch from /C/FTC/TDF 1 tablet once daily to /C/FTC/TAF 1 tablet once daily for a period of 12 months.
arm group label: Switch to E/C/FTC/TAF daily
other name: E/C/FTC/TDF 1 tablet once daily
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Theodoros Kelesidis, MD, PhD, Msc
role: Principal Investigator
affiliation: University of California, Los Angeles
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of California, Los Angeles
investigator full name: Theodoros Kelesidis, MD, PhD
investigator title: Principal Investigator
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Drug-Related Side Effects and Adverse Reactions
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 