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

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

Interventions

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.

Sponsors & Collaborators

• Gilead Sciences

  collaborator INDUSTRY

• University of California, Los Angeles

  lead OTHER

Principal Investigators

• Theodoros Kelesidis, MD, PhD, Msc · University of California, Los Angeles

Study Design

Allocation

NA

Purpose

BASIC_SCIENCE

Masking

NONE

Model

SINGLE_GROUP

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-04-01

Primary Completion

2021-07-01

Completion

2021-07-01

FDA Drug

Yes

Countries

• United States

Study Locations