Clinical trial NCT03251144
Conditions: HIV/AIDS Antiviral Toxicity Antiviral Drug Adverse Reaction Mitochondrial Alteration
Keywords: HIV/AIDS Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF) mitochondria toxicity
Sponsor: University of California, Los Angeles
Start date: 2019-04-01; Completion date: 2021-07-01
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:
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.

Arms: arm 1: 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.
Interventions: intervention 1: Switch to E/C/FTC/TAF daily
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
Relative Mitochondrial Toxicity of Tenofovir Alafenamide (TAF) vs. Tenofovir Disoproxil 
Fumarate (TDF) 
 
 
 
Identifiers: 
NCT03251144 
 
March 22, 2022


 
 
STUDY SCHEMA 
 
HIV infected participants on stable antiretroviral therapy will be switched to newer antiretrovirals to evaluate the 
effect of these newer antiretrovirals on mitochondria. 
 
Primary Objective(s) Primary 
Endpoint(s) 
 
To assess in vivo the effects of TAF on mitochondrial health as assessed 
by several assays. Primary outcome will be cellular oxygen consumption 
(COC) and secondary outcomes the rest of measures of mitochondrial 
health as described in the study design.  
Study Regimen/Intervention 
 
There are 3 scenarios based on the possible TAF-based regimens 
A) Scenario 1: TAF based regimen is Stribild 
Study Switch (Stribild Genvoya. Intervention: Genvoya (elvitegravir 
150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 
mg; E/C/F/TAF)  
 
Emtricitabine 200 mg/tenofovir alafenamide 25 mg; E/C/F/TAF 1 tablet 
orally once daily. 
 
Optional switch to expedite recruitment (see study design) (any other 
ART  Stribild): Intervention: Stribild®; (elvitegravir 150 mg/cobicistat 
150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; 
E/C/F/TDF) 1 tablet orally once daily.  
 
B) Scenario 2: TAF based regimen is ODEFSEY 
Study Switch (Complera (Emtricitabine/Rilpivirine/Tenofovir 
Disoproxil Fumarate Tablets)  ODEFSEY® (emtricitabine, rilpivirine, 
and tenofovir alafenamide). Intervention: ODEFSEY (25 mg rilpivirine + 
200mg emtricitabine + 25mg tenofovir alafenamide fumarate)  
1 tablet orally once daily. 
 
C) Scenario 3: TAF based regimen is Descovy 
Study Switch (TRUVADA (emtricitabine/tenofovir disoproxil 
fumarate) + any other combination of antivirals --> Descovy 
(tenofovir alafenamide + emtricitabine) + any other combination of 
antivirals. Intervention: Descovy (200 mg emtricitabine + 10 mg 
tenofovir alafenamide fumarate)  
1 tablet orally once daily. 
 
After any ART switch safety labs will be done within 2 months (will 
aim for 1 month post switch) 
Study Duration  
 
There are a total of 3-5 study visits over a period of up to 9 months.  
Visit 0: (Optional) If not on Stribild, participant will switch from their current 
ART Stribild. Must stay on Stribild for 3 months before starting Visit 
1. 
Safety labs visit 0:  Follow up visit within 2 months after visit 0 (optional): 
Safety and early effects of Stribild (safety labs) will be assessed.  
Visit 1: Baseline visit: participant switched from TDF based regimen to 
TAF based regimen. A follow-up phone call will be made ~2 weeks 
after Entry.   
Visit 2: 2 month follow up visit: Safety and early effects of TAF based 
regimen on mitochondrial health will be assessed.  


 
Visit 3: 6 month follow up visit: differential in vivo effects of TAF based 
regimen on mitochondrial health will be assessed. 
Study Population 
30 participants will be enrolled  
 
Eligibilty criteria:  
• 
18 years of age or older  
• 
HIV infected and on anti-retroviral therapy with suppressed viremia for 
at least 3 months (viral RNA <50 copies per ml)  
• 
On stable antiretroviral therapy for ≥ 6 months with TDF based 
regimens: 1) Stribild®; elvitegravir 150 mg/cobicistat 150 
mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; 
E/C/F/TDF) OR 2) Complera (Emtricitabine 200 mg /Rilpivirine 25 
mg/Tenofovir Disoproxil Fumarate 300 mg Tablets OR 3) Truvada 
(Emtricitabine 200 mg /Tenofovir Disoproxil Fumarate 300 mg Tablets 
• 
On stable antiretroviral therapy for ≥ 6 months with ANY OTHER than 
Stribild antiretroviral therapy and willing to switch to Stribild for at least 
3 months. This optional switch (switch 1: old ART regimen to Stribild) 
will expedite recruitment and study completion (see study design). 
Once on 3 months of Stribild these participants would be eligible for 
switch from Stribild to Genvoya as described in the study design.  
• 
Adequate renal function determined by the Cockcroft-Gault formula for 
creatinine clearance (>60 mL/min/1.73 m2  
• 
Able and willing to communicate in English  
• 
Able and willing to provide written consent  
 
 
 
STUDY DESIGN 
 
An open-label switch study will be conducted in virologically-suppressed, HIV-1 positive participants. The 
switch regiment will be: 1) 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 OR 2) Complera (Emtricitabine/Rilpivirine/Tenofovir Disoproxil 
Fumarate Tablets) to ODEFSEY (25 mg rilpivirine + 200mg emtricitabine + 25mg tenofovir alafenamide 
fumarate) OR 3) TRUVADA (emtricitabine/tenofovir disoproxil fumarate) + any other combination of antivirals 
to  Descovy (200 mg emtricitabine + 10 mg tenofovir alafenamide fumarate). 
 
Major eligibility criteria for study participants will be age > 18 years old, any CD4 T cell count, viral load <50 
copies/ml or undetectable on E/C/F/TDF for the previous 3 months prior to the onset of study, adequate renal 
function determined by the Cockcroft-Gault formula for creatinine clearance and no evidence of acute hepatitis 
in the prior 30 days. Major exclusion criteria will be pregnancy and diseases or use of other drugs known to 
affect mitochondrial function. Subjects will have three clinical visits: one at baseline prior to the TDF to TAF 
switch, and follow up visits at 2 and 6 months after the switch. We will also include the option to switch ANY 
HIV-infected person who meets the inclusion criteria and not on an antiretroviral regimen other than Stribild 
[(Elvitegravir (ELV)/cobicistat CO)/emtricitabine (FTC)/tenofovir (TDF)] to switch to Stribild for 3 months. This 
will allow for future switch (after these 3 months) from Stribild to GENVOYA. This approach can expedite 
recruitment since we can switch HIV infected persons to Stribild and then do another switch from Stribild to 
GENVOYA as per study protocol. In addition given the known clinical benefits (less toxicity) of Stribild and 
Complera compared to older antiretrovirals (such as protease inhibitors)[ Patient Prefer Adherence. 2015; 9: 
1213–1218.; J Acquir Immune Defic Syndr. 2014 Mar 1; 65(3):e118-20; Lancet. 2012 Jun 30;379(9835):2439-
48; J Acquir Immune Defic Syndr. 2014 Mar 1; 65(3):e121-4; AIDS. 2012;26:2315–2326; J Infect Dis. 
2015;212(3):345–354] and  the known clinical benefits of TAF compared to TDF (less bone and kidney toxicity) 
these ART switches are beneficial for the participant and they also allow us to study differential effects of TAF 


 
vs TDF on mitochondria. The participants who will undergo any ART switch will have a clinic visit or a phone 
call 1-2 weeks after the ART switch to check for side effects/tolerability of the new regimen and all subjects will 
have a clinic visit with blood tests to check viral load and safety labs (complete metabolic panel and complete 
blood count) within 2 months after any switch. Then after informed consent has been obtained ART will be 
switched as per protocol. 
 
During visits at baseline, month 2, 6, blood will be obtained for isolation of PBMC (measurement of 
mitochondrial function). This study design will account for confounders that may affect mitochondrial function 
among different subjects (given the intrinsic heterogeneity of mitochondria). All study participants will be 
recruited in outpatient clinics within UCLA. All HIV-1 infected participants will be recruited within the UCLA 
Center for AIDS Education and Research (UCLA CARE) Center which provides HIV care to over 1000 patients 
with HIV in Los Angeles and is regarded as one of the premier HIV care providers in the country. We anticipate 
recruiting 60 (30 HIV-1 infected and 30 uninfected) persons in total for all outlined experiments.  
 
 
STUDY POPULATION 
HIV-1-infected participants in the Los Angeles area will be recruited voluntarily through a UCLA IRB-approved 
protocol at UCLA Center for AIDS Research and Education (CARE).  
 
Enrollment will be open to men and women from all socioeconomic strata and all race and ethnic groups. We 
anticipate enrolling 30 HIV-1 infected individuals in total.  
 
4.1 Inclusion Criteria 
• 
18 years of age or older  
• 
Cases: Chronically infected and on anti-retroviral therapy with suppressed viremia for at least 3 
months (viral RNA <50 copies per ml)  
• 
On stable antiretroviral therapy for >6 months with TDF based regimens: 1) Stribild®; elvitegravir 150 
mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg; E/C/F/TDF) OR 2) 
Complera (Emtricitabine 200 mg /Rilpivirine 25 mg/Tenofovir Disoproxil Fumarate 300 mg Tablets OR 
3) Truvada (Emtricitabine 200 mg /Tenofovir Disoproxil Fumarate 300 mg Tablet.  
• 
On stable antiretroviral therapy for ≥ 6 months with ANY OTHER than Stribild antiretroviral therapy 
and willing to switch to Stribild for at least 3 months. This optional switch (switch 1: old ART regimen 
to Stribild) will expedite recruitment and study completion (see study design). Once on 3 months of 
Stribild these participants would be eligible for switch from Stribild to Genvoya as described in the 
study design.  
• 
Adequate renal function determined by the Cockcroft-Gault formula for creatinine clearance 
(>60 mL/min/1.73 m2  
• 
Able and willing to provide written consent  
 
4.2 Exclusion Criteria 
• 
History of taking medications that are known to have a major effect on mitochondrial function such 
as cyclosporine, mitochondrial antioxidants.  
• 
History of mitochondrial disease  
• 
Pregnancy  
• 
Hepatitis; no evidence of acute hepatitis in the prior 30 days 
• 
History of severe renal impairment  (eGFR < 30 ml/min/1.73 m2) 
• 
History of severe or recent cardiac event  
• 
Current alcoholism or IV drug abuse  
• 
Use of systemic immunomodulatory medications (e.g. steroids) within 4 weeks of enrollment  
• 
Anemia precluding safe donation of blood (For men, anemia is typically defined as hemoglobin level 
of less than 13.5 gram/100 ml and in women as hemoglobin of less than 12.0 gram/100 ml).  
• 
Use of any investigational products within 4 weeks of enrollment  
• 
Any other clinical condition or prior therapy that, in the opinion of the investigator, would make the 
patient unsuitable for the study or unable to comply with the 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.  
• 
Subjects who are on medications that are strong inducers of CYP3A (as these may decrease the 
efficacy of Stribild or Genvoya). Examples include phenobarbital, phenytoin, carbamazepine, and 
rifampin. 
• 
Subjects who are on medications that are cleared by CYP3A and that may be toxic with elevated 
drug levels (examples include Cisapride, ergotamine, Pimozide, Lurasidone, Lovastatin, and 
Simvastatin). 
 
 
INTERVENTIONS  
 
Regimen (dose, schedule, route, administration) 
 
Scenario 1: TAF based regimen is Genvoya 
 
Study Switch (Stribild Genvoya)  
Intervention: Genvoya (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 
mg; E/C/F/TAF) (1 tablet orally once daily for 6 months) 
 
Scenario 2: TAF based regimen is ODEFSEY 
 
Study Switch (Complera (Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Tablets)  ODEFSEY® 
(emtricitabine, rilpivirine, and tenofovir alafenamide). Intervention: ODEFSEY (25 mg rilpivirine + 200mg 
emtricitabine + 25mg tenofovir alafenamide fumarate)  
 
Scenario 3: TAF based regimen is Descovy 
 
Study Switch (TRUVADA (emtricitabine/tenofovir disoproxil fumarate) + any other combination of antivirals --> 
Descovy (tenofovir alafenamide + emtricitabine) + any other combination of antivirals. Intervention: Descovy 
(200 mg emtricitabine + 10 mg tenofovir alafenamide fumarate)  
 
 Alternative switch to expedite recruitment (see study design) (any other ART  Stribild) 
Intervention: Stribild® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil 
fumarate 300 mg; E/C/F/TDF) 1 tablet orally once daily for 3 months. 
 
Study Product Formulation and Preparation 
 
• 
Genvoya (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 
mg; E/C/F/TAF) 1 tablet, taken orally, daily (FDA approved).  
• 
Odefsey (25 mg rilpivirine + 200mg emtricitabine + 25mg tenofovir alafenamide fumarate) 1 tablet, 
taken orally, daily (FDA approved). 
• 
Descovy (200 mg emtricitabine + 10 mg tenofovir alafenamide fumarate) 1 tablet, taken orally, 
daily (FDA approved). 
• 
Stribild®; (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil 
fumarate 300 mg; E/C/F/TDF) 1 tablet, taken orally, daily (FDA approved). 
 
Study Product Supply and Accountability 
 
The study medications Genvoya and Stribild will be provided to all study participants for the whole 
duration of the study by Gilead Biosciences as described in the agreement. The medications Odefsey 
and Descovy will be provided to all study participants in the setting of clinical care (switch by the 
primary care physician). The participants will remain on the appropriate antiretroviral therapy as per 
clinician’s care/decision after the study and their ART outside the scope of the study will be covered 


 
within the standard practices of clinical care. 
 
Permitted Medications and Procedures 
Any medications not listed as contraindicated in package insert 
 
Prohibited Medications and Procedures 
See package insert 
 
 
SCHEDULE OF EVENTS 
There are up to 5 study visits total (screening visit excluded). Participants not on Stribild before study 
enrollment will have 4 visits (screening visit excluded)); those already on Stribild will have 3 visits.  
 
Day -90: switch from any other ART  Stribild. Must stay on Stribild for 3 months before starting Visit 1. Two 
weeks after this visit Dr Kelesidis or the study coordinator will contact the participant over the phone to see if 
the participant is handling the switch to Stribild okay. 
 
Day -60 or up to -30: Follow up visit within 2 months after visit 0 (optional): Safety and early effects of Stribild 
(safety labs) will be assessed. 
Day 0: Baseline visit: prescription given for Genvoya; begin switch from TDF based regimen to TAF based 
regimen. 
Day 60 (2 month follow up visit): Safety follow-up and early (2 month post switch) differential in vivo effects 
of TAF based regimen on mitochondrial health will be assessed.  
Day 180 (6 month follow up visit): Late (6 month post switch) differential in vivo effects of TAF based 
regimen on mitochondrial health will be assessed.  
 
Blood draws will be done at Day -90, Day 0, Day 60, Day 180 for laboratory testing. Approximately 100mL will 
be collected at each visit, with no more than 400 mL total over the course of the study.  
 
Screening 
Medical records will be accessed and reviewed for:  
• 
HIV status (e.g. CD4 count, viral load) 
• 
Age 
• 
Underlying condition and comorbidities 
• 
Medications 
• 
Labs e.g. creatinine to determine kidney and liver function 
 
Switch to Stribild: switch from any other ARTStribild. No additional blood draw.  
 
Participants will undergo a blood draw (100mL) and then be given a prescription for TAF based regimen for 6 
months (switch from TDFTAF). 
 
Entry/Day 0 
 
 
Follow-up phone call 
 
2 weeks after the Entry visit, a brief phone call from the PI or study coordinator will be made to  
 
participants to ensure they are adjusting to the switch okay.  The following questions will be asked: 
• 
Are you tolerating the new medication okay? 
• 
Have you experienced any new symptoms since you started the new drug? (expected side 
effects from switching antivirals should have already been addressed at the initial study visit).  
• 
Have you been taking all your pills? 
• 
Do you have any questions we could answer for you?  


 
 
If new symptoms appear, the participant will be instructed to schedule a visit with their care provider 
for standard evaluations.   
 
Day 60 post-switch 
Blood draw (100mL) 
 
Day 180 post-switch 
Blood draw (100mL) 
 
Laboratory Evaluations 
Mitochondrial function assays: The Seahorse method measures function through the COC (increased COC 
indicates reduced bioenergetic capacity and mitochondrial dysfunction).  
 
Specimen Preparation, Handling and Shipping 
Whole blood will be collected using standard phlebotomy and placed in standard heparin green top tubes. All 
tubes per participant will be placed in a biohazard bag and shipped at room temperature to Kelesidis Lab for 
further processing.  
 
Ship to: Kelesidis Lab/Infectious Diseases 
37-121 CHS 10833 Le Conte Avenue 
Los Angeles CA 90095 
Total Blood Volume 
100 mL of blood will be collected during Day -90, Day 0, Day 60, and Day 180.  No more than 400mL of blood 
will be collected for this study.  
 
CARE Clinic will draw and collect blood to be sent to Kelesidis lab via courier. Kelesidis lab will handle all blood 
processing, including peripheral blood mononuclear cells (PBMCs), 
 
Entry visit  
• 
Fasting Lipid Profile  
 
The following labs are to be done only if they have not been done within the last  
3 months: 
• 
CBC 
• 
Complete metabolic panel 
• 
HIV RNA PCR  
• 
CMV antibody  
 
Safety labs for Visit 2:  
• 
HIV viral load 
• 
T-cell subset 
• 
CBC 
• 
CMP 
• 
Fasting Lipid Profile  
• 
 
Safety labs for Visit 3: 
• 
CBC 
• 
CMP 
• 
Fasting lipid profile 
 
100 ml of blood will be drawn per visit/phlebotomy. Out of this volume standard tubes for the standard clinical 


 
labs (fasting lipid profile, complete metabolic panel, HIV RNA PCR, CMV antibody, T- cell subset) will be sent 
to the clinical laboratory as per standard clinic procedure. The rest of the whole blood will be placed in EDTA or 
green top tubes and will be shipped to Kelesidis lab via courier. It is expected that 1 million cells will be 
obtained per ml of whole blood and cells will be isolated and cryopreserved at Kelesidis lab. 
 
ASSESSMENT OF SAFETY 
 
Adverse Event Reporting and monitoring. 
 
An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
diagnosis that occurs in a study participant during the conduct of the study REGARDLESS of the attribution 
(i.e., relationship of event to medical treatment/study product/device or procedure/intervention). This includes 
any occurrence that is new in onset or aggravated in severity or frequency from the baseline condition.  
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), corrected Version 2.1, July 2017, must be used for grading the adverse events in this protocol and is 
available on the DAIDS RSC Web site at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables. 
 
The AEs/SAEs should immediately be reported to the Principal Investigator. All events should be reported to 
the local IRB if they are reportable per the local IRB’s reporting criteria.  
This study will be internally monitored biannually. 
 
A Data Safety Monitoring Board is not needed for this single-center open-label Phase I clinical trial (safety 
related to mitochondrial toxicity) since the local investigator will have access to all data. Dr. Kelesidis will be 
available to provide direct evaluation of any clinically-related concerns that might arise during the study. The 
principal investigator will directly discuss with assigned independent persons appointed by Gilead any 
concerns for adverse events (mitochondrial toxicity) and make recommendations for continuing or stopping the 
study. It is important to emphasize that the clinical safety of the described antiretrovirals has already been 
established within large scale clinical trials. This exploratory study will investigate subtle molecular readouts of 
mitochondrial toxicity that have been associated with adverse clinical outcome in some settings (e.g. diabetes). 
However the exact clinical significance of the findings from this small exploratory study will need to be 
validated in further larger scale trials. Thus, given the nature and scope of this study we do not anticipate any 
major clinical side effects and stopping the study early if subtle effects of antiretrovirals on mitochondria are 
detected.  
 
 
CLINICAL MANAGEMENT 
Not Applicable.  
 
Criteria for Discontinuation 
The study may be discontinued at any time by the IRB, OHRP, or other government agencies when 
necessary to ensure the protection of research subjects. 
Completion of study product(s)/intervention(s) as defined in the protocol  
 
Criteria for Premature Study Discontinuation for an Individual Participant 
• 
Participant repeatedly non-compliant with study product/intervention as prescribed 
• 
Pregnancy or breastfeeding  
• 
Request by participant to withdraw 
• 
Participant judged by the investigator to be at significant risk of failing to comply with the provisions 
of the protocol as to cause harm to self or seriously interfere with the validity of study results 
• 
Participants will be taken off of study in the event of virologic failure or in the event of grade 3 or higher 
adverse effects or intolerable grade 2 adverse effects 


 
 
 
STATISTICAL CONSIDERATIONS 
 
 
Study Endpoints 
 
Primary Endpoint 
Cellular oxygen consumption (COC): From all the measures of mitochondrial function cellular oxygen 
consumption (COC) will be considered the “gold standard” given it is a measure of the most important 
mitochondrial function (oxidative phosphorylation) that relates to clinical outcome. It is accepted that two 
independent measures of mitochondrial function can more reliably predict mitochondrial dysfunction compared 
to each one of the measures separately. Thus, 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 compared to baseline measurement will be done. 
Primary endpoint is continuous variables (measured in pmoles O2/min) and it will be compared 
 between the 2 groups on different antiretrovirals (TAF based vs TDF based) cross sectionally using unpaired 
t-test. Changes in primary outcome within the same person will be determined by paired t-test (baseline and 
after switch). Statistical p value <0.05 will be considered statistically significant.