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Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF) (UCLACAREMITO)

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ClinicalTrials.gov Identifier: NCT03251144
Recruitment Status : Recruiting
First Posted : August 16, 2017
Last Update Posted : April 16, 2019
Sponsor:
Collaborator:
Gilead Sciences
Information provided by (Responsible Party):
Theodoros Kelesidis, MD, PhD, University of California, Los Angeles

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
HIV/AIDS Antiviral Toxicity Antiviral Drug Adverse Reaction Mitochondrial Alteration Drug: Switch to E/C/FTC/TAF daily Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: In Vitro and in Vivo Studies of the Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF)
Actual Study Start Date : April 1, 2019
Estimated Primary Completion Date : January 8, 2020
Estimated Study Completion Date : July 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Switch to E/C/FTC/TAF daily

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

  1. 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.
  2. 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.
Drug: Switch to E/C/FTC/TAF daily

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.

Other Name: E/C/FTC/TDF 1 tablet once daily




Primary Outcome Measures :
  1. Change in mitochondrial function [cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals. [ Time Frame: 12 month visit after switch ]
    Change in mitochondrial function [abnormal mitochondrial dynamics [(cellular oxygen consumption (COC)] over 12 months after switch of antiretrovirals.


Secondary Outcome Measures :
  1. Change in mitochondrial function [membrane potential (Δψm)] over 12 months after switch of antiretrovirals. [ Time Frame: 12 month visit after switch ]
    Change in mitochondrial function [membrane potential (Δψm)] over 12 months after switch of antiretrovirals.

  2. Change in mitochondrial function [mitochondrial reactive oxygen species (mito-ROS)] over 12 months after switch of antiretrovirals. [ Time Frame: 12 month visit after switch ]
    Change in mitochondrial function [mitochondrial reactive oxygen species (mito-ROS)] over 12 months after switch of antiretrovirals.

  3. Change in amount of mitochondrial DNA (mtDNA) over 12 months after switch of antiretrovirals. [ Time Frame: 12 month visit after switch ]
    Change in amount of mitochondrial DNA (mtDNA) over 12 months after switch of antiretrovirals.

  4. Change in mitochondrial function [abnormal mitochondrial dynamics (increase fragmentation of mitochondria)] over 12 months after switch of antiretrovirals. [ Time Frame: 12 month visit after switch ]
    Change in mitochondrial function [abnormal mitochondrial dynamics (increase fragmentation of mitochondria)] over 12 months after switch of antiretrovirals.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Inclusion criteria for HIV negative participants

All HIV negative participants must meet the following criteria:

  1. 18 years of age or older
  2. Understands and agrees to local STI reporting requirements
  3. HIV negative at screening by self-report, with no significant medical diagnoses
  4. HIV negative by both HIV antibody and HIV PCR in blood (samples obtained during Visit 1)
  5. Able and willing to communicate in English
  6. Able and willing to provide written informed consent to take part in the study
  7. Able and willing to provide adequate information for locator purposes
  8. Able and willing to provide medical/surgical history
  9. Availability to return for all study visits, barring unforeseen circumstances
  10. Willing to abstain from insertion of anything (drug, enema, penis or sex toy) in rectum for 12 hours before and 72 hours after each flexible sigmoidoscopy

    In addition to the criteria listed above, female participants must meet the following criteria

  11. Negative pregnancy test
  12. Post-menopausal or using and acceptable form of contraception (e.g. barrier method, IUD, hormonal contraception, or surgical sterilization).

HIV participant inclusion criteria

Specific enrollment inclusion criteria include:

  • 18 years of age or older
  • Cases: Chronically infected and on anti-retroviral therapy with suppressed viremia (viral RNA <50 copies per ml)
  • On stable antiretroviral therapy for 6 months with either a) Stribild®; elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; E/C/F/TDF)
  • Adequate renal function determined by the Cockcroft-Gault formula for creatinine clearance (>60 mL/min/1.73 m2
  • Controls: HIV negative as documented in prior tests and willing to undergo repeat HIV testing
  • Able and willing to communicate in English
  • Able and willing to provide written informed consent to take part in the study

Exclusion Criteria:

  • Exclusion criteria for all study participants:

Participants who meet any of the following criteria at screening will be excluded from the study:

  1. History of chronic inflammatory bowel disease, radiation proctitis or other chronic gastrointestinal disease, exclusive of functional bowel disease (irritable bowel syndrome)
  2. History of significant gastrointestinal bleeding
  3. History of a bleeding disorder
  4. History of colostomy
  5. History of auto-immune diseases
  6. Chronic viral hepatitis
  7. History of diabetes
  8. History of chemotherapy (for cancer or organ transplantation)
  9. The chronic or recent (~2 weeks) use of antimitotic drugs, sulfonamides or antibiotics
  10. History of or current coagulopathy and/or on anticoagulant therapy
  11. Anticipated use or unwillingness to abstain from use of aspirin, NSAIDS or any other drugs (including over the counter products) that are associated with the increased likelihood of bleeding
  12. Active rectal infection (gonorrhea, chlamydia trachomatis, or HSV)
  13. Positive STI at screening (urine NAAT)

    o Participants will be allowed one re-screening visit after appropriate STI treatment

  14. History of underlying cardiac arrhythmia or renal disease
  15. History of severe recent cardiac or pulmonary event
  16. > Grade 2 laboratory abnormality at baseline that can not be documented as stable /chronic for that individual
  17. Any other condition or prior therapy that, in the opinion of the investigator, would make the patient unsuitable for the study or unable to comply with study requirements. Such conditions may include, but are not limited to, current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological or cerebral disease.
  18. Pregnancy
  19. Breastfeeding
  20. Female of child-bearing potential unwilling to use acceptable form of contraception

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03251144


Contacts
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Contact: Theodoros Kelesidis, MD, PhD, Msc 3108257225 tkelesidis@mednet.ucla.edu

Locations
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United States, California
UCLA CARE Center Recruiting
Los Angeles, California, United States, 90035
Contact: Theodoros Kelesidis, MD, PhD, Msc    310-825-7225    tkelesidis@mednet.ucla.edu   
Sponsors and Collaborators
University of California, Los Angeles
Gilead Sciences
Investigators
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Principal Investigator: Theodoros Kelesidis, MD, PhD, Msc University of California, Los Angeles

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Responsible Party: Theodoros Kelesidis, MD, PhD, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT03251144     History of Changes
Other Study ID Numbers: CO-US-311-4393
CO-US-311-4393 ( Other Grant/Funding Number: GILEAD )
First Posted: August 16, 2017    Key Record Dates
Last Update Posted: April 16, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Theodoros Kelesidis, MD, PhD, University of California, Los Angeles:
HIV/AIDS
Tenofovir disoproxil fumarate (TDF)
Tenofovir alafenamide (TAF)
mitochondria
toxicity
Additional relevant MeSH terms:
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Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Tenofovir
Emtricitabine
Cobicistat
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors