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

NCT03251144 | Completed Phase 1 Results FDA Drug

• 1 other identifier: CO-US-311-4393
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

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.

Conditions

HIV/AIDS; Antiviral Toxicity; Antiviral Drug Adverse Reaction; Mitochondrial Alteration

Keywords

HIV/AIDS; Tenofovir disoproxil fumarate (TDF); Tenofovir alafenamide (TAF); mitochondria; toxicity

Outcome Measures

Primary Outcomes (1)

• Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals.

  Change in mitochondrial function \[abnormal mitochondrial dynamics \[(cellular oxygen consumption (COC)\] over 12 months after switch of antiretrovirals.

  12 month visit after switch

Study Arms (1)

Switch to E/C/FTC/TAF daily

EXPERIMENTAL

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

Interventions

Switch to E/C/FTC/TAF daily DRUG

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.

Also known as: E/C/FTC/TDF 1 tablet once daily

Switch to E/C/FTC/TAF daily

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All HIV negative participants must meet the following criteria:
• years of age or older
• Understands and agrees to local STI reporting requirements
• HIV negative at screening by self-report, with no significant medical diagnoses
• HIV negative by both HIV antibody and HIV PCR in blood (samples obtained during Visit 1)
• Able and willing to communicate in English
• Able and willing to provide written informed consent to take part in the study
• Able and willing to provide adequate information for locator purposes
• Able and willing to provide medical/surgical history
• Availability to return for all study visits, barring unforeseen circumstances
• 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
• Negative pregnancy test
• Post-menopausal or using and acceptable form of contraception (e.g. barrier method, IUD, hormonal contraception, or surgical sterilization).
• years of age or older

You may not qualify if:

• Participants who meet any of the following criteria at screening will be excluded from the study:
• History of chronic inflammatory bowel disease, radiation proctitis or other chronic gastrointestinal disease, exclusive of functional bowel disease (irritable bowel syndrome)
• History of significant gastrointestinal bleeding
• History of a bleeding disorder
• History of colostomy
• History of auto-immune diseases
• Chronic viral hepatitis
• History of diabetes
• History of chemotherapy (for cancer or organ transplantation)
• The chronic or recent (\~2 weeks) use of antimitotic drugs, sulfonamides or antibiotics
• History of or current coagulopathy and/or on anticoagulant therapy
• 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
• Active rectal infection (gonorrhea, chlamydia trachomatis, or HSV)
• Positive STI at screening (urine NAAT)
• o Participants will be allowed one re-screening visit after appropriate STI treatment

Sponsors & Collaborators

• University of California, Los Angeles: lead
• Gilead Sciences: collaborator

Study Sites (1)

UCLA CARE Center

Los Angeles, California, 90035, United States

Location

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Theodoros Kelesidis
• Organization: University of California Los Angeles

tkelesidis@mednet.ucla.edu

3108257875

Study Officials

• Theodoros Kelesidis, MD, PhD, Msc

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: August 6, 2017
• First Posted: August 16, 2017
• Study Start: April 1, 2019
• Primary Completion: July 1, 2021
• Study Completion: July 1, 2021
• Last Updated: May 10, 2022
• Results First Posted: May 10, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)