Phase 2
N=26
Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil Fumarate (TDF)
HIV/AIDS · Antiviral Toxicity · Antiviral Drug Adverse Reaction · Mitochondrial Alteration
Bottom Line
View on ClinicalTrials.gov: NCT03251144 ↗Enrolled (actual)
26
Serious AEs
0.0%
Results posted
May 2022
Primary outcome: Primary: Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals. — 50; 70 pmoles O2/min — p=<0.001
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- Switch to E/C/FTC/TAF daily (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- University of California, Los Angeles
- Primary completion
- Jul 2021
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Change in Mitochondrial Function [Cellular Oxygen Consumption (COC)] Over 12 Months After Switch of Antiretrovirals. |
50; 70 | <0.001 sig |
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.
Eligibility Criteria
Inclusion Criteria
- Inclusion criteria for HIV negative participants
All HIV negative participants must meet the following criteria:
- 18 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).
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 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:
- 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
- History of underlying cardiac arrhythmia or renal disease
- History of severe recent cardiac or pulmonary event
- > Grade 2 laboratory abnormality at baseline that can not be documented as stable /chronic for that individual
- 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.
- Pregnancy
- Breastfeeding
- Female of child-bearing potential unwilling to use acceptable form of contraception
Data sourced from ClinicalTrials.gov (NCT03251144). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.