Effects of Biectegravir-Emtricitabine-Tenofovir Alafenamide on Coronary Flow Reserve in Stable HIV Patients (B/F/TAF-CFR) - Pilot Study
Phase: PHASE3
Conditions: HIV
Sponsor: Brigham and Women's Hospital

 
1
DETAILED PROTOCOL 
 
 
EFFECTS OF BICTEGRAVIR-EMTRICITABINE-TENOFOVIR ALAFENAMIDE ON CORONARY FLOW 
RESERVE IN STABLE HIV PATIENTS (B/F/TAF-CFR) – PILOT STUDY 
 
 
 
Open-label, multicenter, single-arm study to Evaluate the Safety and Efficacy of Switching from 
Regimens Consisting of Abacavir/Lamivudine/Dolutegravir (ABC/3TC/DTG) to the Bictegravir/ 
Emtricitabine/Tenofovir Alafenamide (B/F/TAF) Fixed-Dose Combination (FDC) in Virologically-
Suppressed HIV-Infected Adult Subjects 
 
Investigators: 
Marcelo F. Di Carli, MD, Paul E. Sax, MD, Nina Lin, MD, Laura Kogelman, MD 
 
 
Institution: 
Brigham and Women’s Hospital, Boston, MA 
Boston Medical Center, Boston, MA 
Tufts Medical Center, Boston, MA 
Massachusetts General Hospital, Boston, MA 
 
18 JUNE 2018 
07 August 2018 
20 December 2018 
January 4, 2019 
February 5, 2019 
March 22, 2019 
April 15, 2019 
April 30, 2019 
September 12, 2019 
 
 
 
 
 
 
 

 
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1.  
BACKGROUND AND SIGNIFICANCE  
The endothelium provides a permeability barrier for the vasculature, maintains a nonthrombogenic 
surface, regulates vascular tone and tissue flow, and inhibits vascular smooth muscle cell growth. In the 
presence of inflammatory cytokines, endothelial cells are activated which facilitates leukocyte adhesion 
and migration into the vessel wall, production of prothrombotic substances, and vasoconstriction, 
thereby creating a proatherogenic and procoagulant environment. Consequently, inflammation is a key 
mediator of a constellation of abnormalities that initiate and accelerate the progression of 
atherosclerosis. 
HIV-specific immune dysregulation promotes endothelial and immune cell activation. Indeed, 
antiretroviral (ART)-naive HIV positive patients have higher levels of endothelial immune activation 
markers (e.g., IL-6, VICAM-1 and others) than non-HIV controls. ART-naïve HIV positive patients also 
show evidence of endothelial-cell dysfunction, as assessed by brachial artery reactivity. Treatment with 
ART has been shown to reduce biomarker evidence of endothelial cell activation in observational and 
randomized trials, and some of these drugs also appear to improve endothelial function. However, most 
prior evidence of the direct biologic effect of HIV viral infection and its changes with therapy on 
coronary vascular function has been indirect through the measurement of circulating biomarkers or 
brachial artery reactivity. 
Positron emission tomography (PET) imaging allows precise and reproducible quantification of 
myocardial blood flow, thereby providing a direct assessment of coronary vascular health. Coronary flow 
reserve (CFR, calculated as the ratio of peak hyperemic myocardial blood flow over that at rest) is 
emerging as a powerful quantitative prognostic imaging marker of clinical cardiovascular risk. CFR 
provides a robust and reproducible clinical measure of the integrated hemodynamic effects of epicardial 
coronary artery disease (CAD), diffuse atherosclerosis, vessel remodeling, and microvascular dysfunction 
resulting from endothelial cell dysfunction on myocardial tissue perfusion across the entire coronary 
circulation. These processes have direct relevance to the underlying vascular pathobiology in patients 
with HIV infection. Consequently, quantitative CFR provides a unique opportunity to examine the 
potential impact of novel therapies on the biology of the disease and its association with cardiovascular 
outcomes. By testing the fundamental concept of whether novel ART therapies in HIV can lead to 
improved coronary blood flow and myocardial tissue perfusion, TAF-CFR would provide important 
mechanistic insights of the capabilities of TAF therapy to improve key determinants of clinical risk.  
 
JUSTIFICATION FOR THE USE OF CFR AS A SURROGATE MARKER OF CLINICAL RISK 
Noninvasive quantification of coronary flow reserve improves diagnosis and risk assessment in non-
HIV patients with CAD. Noninvasive quantification of coronary blood flow and flow reserve has been the 
research focus of our group for over 20 years. Our group has developed and validated methodology for 
flow quantification and disseminated this technology for broad access and use. We and others have 
demonstrated that CFR is a quantitative unique phenotyping tool to assess vascular health and pre-
clinical atherosclerosis which, in higher risk patients, can reveal flow-limiting coronary artery stenosis, 
thereby improving the accuracy of myocardial perfusion imaging in the diagnostic evaluation of known 
or suspected CAD 1-4. More recent data support the notion that coronary vascular dysfunction, as 
quantified by reduced CFR, is highly prevalent among patients with known or suspected CAD2, 5, 
increases the severity of inducible myocardial ischemia (beyond the effects of upstream coronary 
obstruction)6 and sub-clinical myocardial injury7, and identifies patients at high risk for serious cardiac 
adverse events, including cardiac death8-11. Thus, CFR is a robust measure of the integrated 
hemodynamic effects of epicardial CAD, diffuse atherosclerosis, vessel remodeling, and microvascular 
dysfunction on myocardial perfusion. In the presence of increased oxygen demand, a decreased CFR 

 
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reflects an imbalanced supply-demand relationship that may lead to myocardial ischemia, subclinical LV 
systolic and diastolic dysfunction, clinical symptoms and, ultimately, death. There is also emerging 
evidence that a reduced global CFR may help identify patients who benefit most from 
revascularization12.  
Systemic inflammation is associated with coronary vascular dysfunction. There is increasing evidence 
that coronary vascular dysfunction is associated with systemic inflammation and may precede or coexist 
with high-risk coronary atherosclerosis. Compared to healthy subjects, patients with rheumatoid 
arthritis or systemic lupus erythematosus, without significant CAD on invasive angiography, have 
impaired CFR to a degree directly related to disease duration13. In patients with cardiac syndrome X 
(CSX) with exertional angina and ST-segment depression on exercise stress testing but normal luminal 
coronary angiography, only those with elevated high sensitivity C-reactive protein (hsCRP, >3 mg/L) have 
reduced CFR14. Among patients presenting with acute coronary syndrome and nonobstructive CAD by 
angiography, reduced CFR (assessed by invasive Doppler flow velocity monitoring) is associated with 
higher frequency of thin-cap fibroatheroma, greater plaque burden, and significantly higher levels of 
hsCRP, despite similar amounts of epicardial disease by luminal area and fractional flow reserve 
measurements15. These results reinforce previous observations16-18 that inflammation is associated with 
impaired coronary vasoreactivity and, in the appropriate patient population, may be a better marker for 
poor outcomes related to diffuse and/or microvascular CAD than are conventional ischemic 
assessments.  
Anti-inflammatory therapies can modulate CFR. There is preliminary evidence that anti-inflammatory 
therapies lead to improved CFR.  Indeed, treatment with statins in patients with dyslipidemia has been 
shown to improve CFR in a way that is modified among carriers of a specific polymorphism that reduces 
IL-1beta expression19. Short-term inhibition of IL-1 activity with the IL-1 receptor antagonist anakinra in 
rheumatoid arthritis patients without perfusion abnormalities has been shown to improve 
echocardiographic measures of LV myocardial deformation (by speckle tracking) and CFR (by Doppler 
flow velocity in the left anterior descending artery (LAD))20. Finally, treatment with methotrexate led to 
reduced clinical scores of disease severity and improved CFR (as measured by echo Doppler flow velocity 
in the LAD) in patients with early rheumatoid arthritis, with no effect on common carotid intima-medial 
thickness21.  
Coronary vascular dysfunction is a powerful predictor of clinical risk. Emerging data have consistently 
shown that CFR measurements by PET can distinguish patients at high risk for serious adverse events, 
including cardiac death8-11. We recently reported that reduced global CFR is independently associated 
with higher rates of cardiac and all-cause mortality in a large cohort of patients with and without DM8, 22. 
Relatively preserved CFR identifies patients with known or suspected CAD who have significantly lower 
risk of cardiac death, regardless of traditional semi-quantitative measures of stress-induced ischemia. 
Conversely, reduced CFR identifies patients at significantly higher risk of cardiac death, even among 
those without objective evidence of ischemia, probably due to diffuse atherosclerosis and/or 
microvascular dysfunction. PET measures of CFR improved risk stratification beyond comprehensive 
clinical assessment, LVEF and semi-quantitative measures of myocardial ischemia and scar, and led to 
clinically meaningful risk-reclassification of ~50% of intermediate risk patients8. Diabetics with impaired 
vs. preserved CFR experienced substantially higher cardiac mortality (7.6%/year vs. 1.3%/year, relative 
to 4.2%/year vs. 0.4%/year in nondiabetics, respectively, both p<0.0001)22. Importantly, diabetic 
patients without known CAD and with impaired CFR experienced a rate of cardiac death comparable to, 
and possibly higher than, that for nondiabetic patients with known CAD (Fig. 3). Measures of CFR 
integrate the hemodynamic effects of focal epicardial coronary stenosis, fluid dynamic effects of diffuse 
atherosclerosis, and the effects of coronary microvascular dysfunction, all of which are prevalent among 
diabetics23-25, and affected by systemic inflammation. These observations have implications for the 

 
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classification of DM as a coronary disease risk equivalent26. Specifically, only among diabetics with 
impaired vascular function is prognosis comparable to nondiabetic patients with known CAD. Thus, 
differing levels of vascular health among previously studied cohorts may account for inconsistencies in 
relative mortality rates of diabetics without CAD and nondiabetics with CAD27-29.  
Quantitative CFR is a modifiable imaging biomarker of disease. There is consistent evidence supporting 
quantitative CFR as a powerful marker of vascular health and, as such, a useful marker to improve 
diagnosis and risk stratification and to monitor response to treatment, particularly in the context of 
clinical trials. The accuracy of quantitative noninvasive PET measures of myocardial blood flow and flow 
reserve by PET has been extensively validated in experimental animals30 and humans31-34. The 
reproducibility of this technique is also well-established33, 34. PET is considered the gold standard for 
quantifying coronary blood flow and flow reserve. There is extensive data supporting its use in diagnosis 
of CAD4, 35-37. The data discussed above demonstrate that the presence of abnormal CFR as measured by 
PET provides incremental risk stratification that leads to significant and meaningful risk-reclassification 
of intermediate risk patients5, 9-11, especially those with DM22. Furthermore, quantitative CFR as a 
measure of coronary vascular dysfunction is a modifiable imaging biomarker, which has been tested in 
the context of clinical trials 19, 38-46. 
 
Abacavir is a nucleoside reverse transcriptase inhibitor used as part of treatment regimens for HIV. An 
association between abacavir and increased myocardial infarction was first reported in 200847. Since 
then, most but not all studies have had similar findings48. As a result, HIV treatment guidelines state that 
ABC should be used with caution in patients with CV disease or at high CV risk. While the mechanism by 
which ABC increases CV risk is not definitively known, hypotheses include its effect on platelet 
aggregation, leukocyte adhesion, and systemic inflammation48. 
 
Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single pill regimen that was approved by 
the FDA in February 2018 for treatment of HIV. The marketed name of the drug is Biktarvy. In two phase 
3 comparative clinical trials, including one with ABC/3TC/DTG, it was found to be non-inferior to 
dolutegravir-containing regimens in terms of virologic outcomes49, 50. B/F/TAF was also well tolerated, 
with few discontinuations for adverse events. As a result, B/F/TAF is an ideal non-abacavir containing 
regimen to assess the effect of removing ABC on coronary flow reserve. 
 
2.  
SPECIFIC AIMS  
2.1 
Hypothesis and Objectives 
The primary hypothesis of the B/F/TAF-CFR study is that reducing endothelial cell activation and 
dysfunction using bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) in place of 
abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) will quantitatively improve coronary flow reserve as 
measured by PET over 24 weeks, in stable higher risk asymptomatic patients with HIV.  
 
The primary objective of the B/F/TAF-CFR study is to test the hypothesis that in stable HIV patients 
treated with abacavir/lamivudine/dolutegravir STR regimens, a switch to a single tablet regimen 
(B/F/TAF) will improve coronary flow reserve and myocardial tissue perfusion, as assessed by 
quantitative PET imaging. This is a prospective, single arm study in which we will test that treatment 
B/F/TAF orally daily for 24 weeks will result in improved global coronary flow reserve in response to 
adenosine, reflecting coronary vasodilator function, as compared to baseline.  
 

 
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2.2 
Primary Endpoint: 
Change (from baseline) in global coronary flow reserve, as measured by PET imaging at 24 weeks after 
initiation of B/F/TAF therapy. 
 
2.3 
Secondary Endpoints: 
2.3.1. Change (from baseline) in peak-stress global myocardial blood flow (in mL/min/g) at 24 
weeks after initiation of B/F/TAF; 
2.3.2. Change (from baseline) in peak-stress global coronary vascular resistance (in mm 
Hg/mL/min/g) at 24 weeks after initiation of B/F/TAF; 
2.3.3. Change in serum biomarkers of inflammation (hs-CRP, IL-6, sCD163 and sCD14), myocyte 
injury and strain (hs Troponin, NT-proBNP) at 24 weeks after initiation of B/F/TAF. 
 
3.  
SUBJECT SELECTION  
3.1. 
Study Design 
Open label, multicenter, uncontrolled, single arm pilot study. Patients with stable HIV currently treated 
with abacavir/lamivudine/dolutegravir STR regimens will be eligible for the B/F/TAF-CFR study. PET 
scans will be performed after enrollment while on the abacavir/lamivudine/dolutegravir STR regimen 
and at 24 weeks after the switch to B/F/TAF regimen. Patients will be encouraged to remain on stable 
medical therapy throughout the enrollment period. 
 
3.2. 
Study group: HIV patients on stable therapy with abacavir/lamivudine/dolutegravir STR 
regimens. 
3.2.1. Inclusion criteria: 
We will recruit patients with HIV on abacavir/lamivudine/dolutegravir STR regimens for at least 
1 year fulfilling the following inclusion criteria: 
(1) 
age ≥ 45 years for men and ≥ 55 years for women; 
(2) 
at least one coronary risk factor including smoking, dyslipidemia, hypertension, obesity 
(BMI >30) or diabetes, or a calculated 10-year risk of heart attack of 7.5% or higher;  
(3) 
HIV RNA < 200 copies/mL at last clinical measurement, done within the past 12 months 
prior to screening, with no intervening HIV RNA > 200; 
(4) 
Screening HIV RNA < 50 copies/mL, HGB >10 g/dl, or Glomerular Filtration Rate (GFR) >30 
that do not preclude the use of Biktarvy. 
 
3.2.2. Exclusion criteria: 
(1) 
patients not fulfilling inclusion criteria; 
(2) 
unstable HIV disease or other medical condition that, in the opinion of the investigator, 
would interfere with the conduct of the study; 
(3) 
history of cardiomyopathy (LVEF <40%) or significant valvular heart disease; 
(4) 
cirrhosis; 
(5) 
end stage renal disease on dialysis; 
(6) 
uncontrolled hypertension (defined as SBP >200 or DBP >110); 
(7) 
pregnancy and breast-feeding;  

 
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(8) 
Patients requiring medications contraindicated with the components of B/F/TAF; 
(9) 
Patients on active treatment for severe asthma or severe COPD; 
(10) Hepatitis B; 
(11) Any reported use of methamphetamine, cocaine and heroin within the past 6 months; if 
such use has been reported, a negative toxicology screen will be required before entry. 
 
3.2. Source of subjects and recruitment methods 
A total of 30 evaluable patients will be required. This will be a collaborative effort between 4 sites in the 
Boston area: (1) Brigham and Women’s Hospital, BWH (PI: Paul Sax, MD), (2) Boston Medical Center (PI: 
Nina Lin, MD), (3) Tufts Medical Center (PI: Laura Kogelman, MD), and (4) Massachusetts General 
Hospital (PI: Virginia Triant, MD). All patients will be referred for PET imaging to BWH, with BWH serving 
as the Core Imaging Lab and Data Coordinating Center (PI: Marcelo Di Carli, MD).  
 
4. SUBJECT ENROLLMENT  
 
4.1.  
Procedures for obtaining informed consent  
The Principal Investigator, co-investigator, or qualified PI designee at each site will obtain consent during 
the study-related hospital visit prior to any study-related procedures.  Consent of subjects who do not 
speak English will be obtained and documented following the procedures outlined by IRB policy at each 
recruiting site. The informed consent process will also be documented and added to the research files 
for this study. 
 
4.2. 
Methods of Enrollment 
Potential study subjects will be recruited from medical clinics at BWH, MGH, BMC, and Tufts Medical 
Center. Screening procedures will include queries for potentially eligible subjects from lists of patients 
who are followed at each site.  Investigators at each site will evaluate whether a patient might be a 
candidate for the study and follow site-specific protocols for approaching patients and invite them into 
the study.  We will make every effort to mitigate any undue influence on patients to participate in this 
study, including providing the informed consent document to the patient to take home.  The patient will 
then be instructed to reach out to the study team or other healthcare providers with questions at any 
time.  The PI or PI designee at each site will review the informed consent form with the patient and 
answer any additional question the patient may have. All PET/CTs will occur at BWH.  Treatment 
assignment and monitoring will be performed by each site.  Additional procedures, particularly at the 
Baseline and End of Treatment visits may be performed at the local site or at BWH, for the convenience 
of the subjects. 
 
4.3. 
Treatment assignment 
Study subjects will all receive one tablet daily of bictegravir 50 mg/emtricitabine 200 mg/tenofovir 
alafenamide 25 mg. 
 
5. STUDY PROCEDURES 
 
 

 
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5.1.  Study visits and parameters to be measured 
This is a collaborative, multi-center, single arm trial. After giving written informed consent to participate 
in the study and fulfilling criteria for inclusion, patients will be switched to B/F/TAF and followed up for 
24 weeks. Patients will undergo rest and vasodilator-stress PET/CT scan for measurement of coronary 
flow reserve at baseline (before the switch to B/F/TAF), and again after completion of 24 weeks of 
B/F/TAF. Safety labs will be assessed at baseline at the 45-day study visit and at the end of the study at 
the Day 168 visit. There will be follow up phone calls at day 14, day 126, and one week after the end of 
study at day 174. Follow up calls will be used to assess changes in medical history and for any adverse 
event.  
Figure 1.  Outline of Procedures    
 
Table 1.  Schedule of Assessments   
Procedure 
Screening 
(-28 to -1 
days) 
Baseline 
(day 0) 
Tel F/U 1 
(day 14) 
Study 
Visit 
(day 45) 
Tel F/U 2 
(day 126) 
End of 
Treatment 
(day 168) 
Tel F/U 3 
(day 174) 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
Medical History 
 
X 
X 
X 
X 
X 
X 
Medication History 
 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
X 
 
X 
 
Physical Exam 
 
X 
 
X 
 
X 
 
Pregnancy Test + 
X 
X 
 
 
 
X 
 
Lab Tests (Clinical)  
X 
X 
 
X 
 
X 
 
Lab Tests – 
Research Only (to 
store) 
 
X 
 
 
 
X 
 
ECG 
 
X 
 
 
 
X 
 
PET/CT 
 
X 
 
 
 
X 
 

 
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Study Drug 
Dispensed 
 
X 
 
X 
 
 
 
Study Drug Pill 
Count / Diary 
Collection 
 
 
 
X 
 
X 
 
AE Monitoring 
 
X 
X 
X 
X 
X 
X 
*Telephone follow-up calls and study visits will be +/- 7 days to allow for scheduling flexibility.  
**Day 45 study visit will be +/- 14 days to allow for scheduling flexibility. 
***Day 168 study visit will be +/- 7 days to allow for scheduling flexibility and to ensure adequate 
supply of study drug.  
+Screening Pregnancy test may be urine or serum 
 
Screening (-28 to -1 days) 
• 
All screening assessments will occur within 28 days prior to start of medication switch  
• 
Obtain informed consent 
• 
Note whether subjects have fasted for 4 hours prior to the visit  
• 
Review inclusion and exclusion criteria to ensure the patient is eligible 
• 
Obtain vital signs, including weight and height, systolic and diastolic blood pressure (BP), heart 
rate (HR) 
• 
Perform laboratory tests, including pregnancy test (if WOCBP) and hepatitis B.  Laboratory tests 
(excluding pregnancy is WOCBP) are valid within one year of the screening visit).  
 
Baseline (Day 0, just prior to study medication initiation) 
• 
Verify clinical stability since screening evaluation 
• 
Confirm that subjects have withheld caffeine for 12 hours and fasted for 4 hours prior to 
imaging tests 
• 
Confirm that subjects have withheld beta blockers, calcium channel blockers and arterial 
vasodilators for 24 hours prior to the PET scan 
• 
Obtain interim medical history and concomitant medications review 
• 
Obtain vital signs, including weight and height, systolic and diastolic blood pressure (BP), heart 
rate (HR), and oxygen saturation (O2 sat) 
• 
Obtain 12-lead ECG 
• 
Complete physical exam  
• 
Perform laboratory tests, including serum pregnancy test prior to any imaging 
• 
Perform PET/CT scan 
• 
Study medication initiation must occur within 10 days of the baseline evaluation 
• 
Provide subjects with study drug and diary to take until next study visit (Day 45) 
• 
Monitor for AEs.  Educate patients on most common side effects of the new drug (Table 3).  
They are encouraged to immediately contact study investigators/staff by email and/or phone for 
any new or concerning symptoms.    
 

 
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Day 14 (Telephone follow-up call 1) 
• 
Contact all subjects by telephone approximately 2 weeks after medication switch 
• 
Assess changes in medical history or medication changes 
• 
Monitor for AEs 
 
Day 45 (study visit) 
• 
Assess drug compliance via pill count 
• 
Verify clinical stability since screening evaluation 
• 
Confirm that subjects have fasted for 4 hours prior to imaging tests 
• 
Obtain interim medical history and concomitant medications review 
• 
Obtain vital signs, including weight and height, systolic and diastolic blood pressure (BP), heart 
rate (HR), respiratory rate (RR), and oxygen saturation (O2 sat) 
• 
Complete physical exam  
• 
Perform laboratory tests 
• 
Collect drug remaining study drug and first diary to assess compliance 
• 
Prior to leaving, patients will be supplied with study drug and a new drug diary 
• 
Monitor for AE; subjects are again educated about the most common side effects.  They are 
encouraged to immediately contact study investigators/staff by email and/or phone for any new 
or concerning symptoms.   
 
Day 126 (Telephone follow-up call 2) 
• 
Contact all subjects by telephone approximately 18 weeks after medication switch 
• 
Assess changes in medical history or medication changes 
• 
Monitor for AEs 
 
Day 168 (End of Treatment) 
• 
Assess drug compliance via pill count 
• 
Verify clinical stability since screening evaluation; including specific inquiry regarding common 
dose-related side effects associated with B/F/TAF 
• 
Confirm that subjects have withheld caffeine for 12 hours and fasted for 4 hours prior to 
imaging tests 
• 
Confirm that subjects have withheld beta blockers, calcium channel blockers and arterial 
vasodilators for 24 hours prior to the PET scan 
• 
Obtain interim medical history and concomitant medications review 
• 
Obtain vital signs, including weight and height, systolic and diastolic blood pressure (BP), heart 
rate (HR), and oxygen saturation (O2 sat) 
• 
Obtain 12-lead ECG 
• 
Complete physical exam  
• 
Perform laboratory tests, including serum pregnancy test prior to any imaging 
• 
Collect remaining study drug and second drug diary to assess compliance 
• 
Perform PET/CT scan 

 
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• 
Monitor for AEs 
 
Day 174 (Telephone follow-up call 3) 
• 
All patients will be contacted by telephone at approximately 7 days following administration of 
the last dose of study drug for AE monitoring. 
 
5.2. Drug to be used 
B/F/TAF is indicated for treatment of people with HIV-AIDS.  Patients enrolled in the study will be 
switched from a HIV regimen containing abacavir/lamivudine/dolutegravir to B/F/TAF for 24 weeks. In a 
comparative clinical trial, B/F/TAF was non-inferior to ABC/3TC/DTG in virologic outcomes and showed a 
significantly lower rate of patient-reported nausea. In Study GS-US-380-1489, a double-blind, 
multicenter, active-controlled, randomized controlled non-inferiority trial of ABC/3TC/DTG vs B/F/TAF in 
treatment naïve adults, both regimens were well tolerated. Adverse events leading to study 
discontinuation were noted in no participants in the bictegravir, emtricitabine, and tenofovir 
alafenamide group and 1% of participants in the dolutegravir, abacavir, and lamivudine group. Adverse 
events related to study drug were less common with bictegravir, emtricitabine, and tenofovir 
alafenamide than with dolutegravir, abacavir, and lamivudine (26% [n=82] vs 40% [n=127]), the 
difference being driven by a higher incidence of drug related nausea in the dolutegravir, abacavir, and 
lamivudine group (5% [n=17] vs 17% [n=55]; p<0.0001). 
 
5.3. Concomitant medications 
Only patients on stable HIV therapies will be included in the study. Because concurrent medications can 
potentially affect coronary blood flow and flow reserve (e.g., antihypertensive and oral hypoglycemic 
agents, statins), only patients on stable treatment for hypertension, diabetes and/or dyslipidemia will be 
included in the study. The following medications will be allowed provided they are neither initiated nor 
discontinued during the study period:  
• 
Aspirin; 
• 
Angiotensin-converting enzyme inhibitors and/or Angiotensin Receptor Blockers; 
• 
-blockers; 
• 
HMG –CoA Reductase Inhibitors (statins); 
• 
Nitroglycerin and long-acting nitrates; 
• 
Oral anti-diabetic medications and Insulin; 
• 
Stable hormone replacement therapy 
 
5.4. Procedures 
Positron Emission Tomography (PET): Regional and global myocardial blood flow will be assessed using 
PET imaging.  Clinical and research cardiac PET studies are routinely performed at BWH. The PET imaging 
team at BWH under Dr. Di Carli’s leadership consist of experienced imaging specialists and have a track 
record in research studies using PET. Di Carli has extensive experience in performing these procedures, 
quantifying myocardial blood flow and flow reserve, has published extensively on this topic, and runs an 
active core laboratory with experience in multi-center trials using imaging endpoints. PET scans will be 
performed using a whole body PET/CT scanner. Study participants will be asked to refrain from drinking 
caffeine-containing beverages and taking theophylline-containing medications for 12 hours before the 
PET study.  Calcium channel blockers, beta blockers, and arterial vasodilators will be withheld for 24 
hours prior to the PET scan.  Studies will be performed after 4 hours of fasting. 

 
11
Assessment of myocardial blood flow and coronary flow reserve: Regional myocardial blood flow (MBF) 
will be measured at rest and during vasodilator-stress with adenosine using 13N-ammonia as the flow 
tracer. 13N-ammonia is used in clinical and research studies and has been validated for the 
quantification of myocardial blood flow and coronary flow reserve. After transmission imaging and 
beginning with the intravenous bolus administration of 13N-ammonia (~20 mCi), list mode images will be 
acquired for 19 minutes. The patient will then undergo a standard infusion of adenosine (140 
mcg/kg/min) for 4 mins or regadenoson bolus injection (0.4 mg). Two mins into the adenosine infusion 
or one minute after the regadenoson bolus, a second dose of 13N-ammonia will be administered, and 
PET imaging collected in the same manner. Heart rate, blood pressure, and 12-lead electrocardiogram 
will be recorded at baseline, every minute during the infusion, and during 5 minutes after completion of 
the adenosine infusion or regadenoson injection.  
Analysis of PET data: Absolute MBF (in ml/g/min) will be computed from the dynamic rest and stress 
images using commercially available software (Corridor4DM; Ann Arbor, Michigan) and previously 
validated methods 33, 34. Automated factor analysis will be used to generate blood pool (arterial input 
function) and tissue time-activity curves. Regional and global rest and vasodilator-stress MBF will be 
calculated by fitting the 13N-ammonia time-activity curves to a two-compartment tracer kinetic model as 
described previously 33, 34. Per-patient global coronary flow reserve (CFR) will be calculated as the ratio 
of MBF at peak vasodilator-stress over that at rest for the entire left ventricle. This method for 
quantitation of MBF is highly reproducible. In the PET core laboratory at BWH, the intra-class correlation 
coefficient for CFR among four readers is 0.94 (95%CI 0.88-0.98), indicating excellent reproducibility5. 
 
Coordination of ancillary study and central imaging analyses. BWH will serve as the coordinating center 
and central imaging core laboratory for the proposed PET scans in the pilot study. Dr. Di Carli runs a very 
active core laboratory and, as mentioned above, has extensive experience in managing multi-site 
imaging trials. In this investigator-initiated study, BWH will sub-contract all clinical centers in the 
ancillary study.  
For the central analysis of the PET images, all imaging data will be stripped of patient identifiers and 
assigned a trial-specific identifier to maintain compliance with US regulatory requirements regarding 
protection of patient privacy. Drs. Di Carli and Sax will organize a bi-monthly teleconference including 
investigators and research coordinators from each clinical site to monitor, discuss, and troubleshoot 
recruitment and other issues that may arise during the conduct of the clinical trial.  
 
5.5. Data to be collected and timing of data collection 
At each of the study visits, a medical history with symptom assessment, medication review, vital signs, 
physical exam, and blood samples will be obtained. As described above, additional data from the PET/CT 
scan as well as EKG assessment will be obtained at baseline and at the end of treatment period. One 
week after completion of the trial, telephone follow-up will be conducted to assess for any adverse 
events.  
 
Laboratory analysis:  Clinical labs will be collected at the Screening, Baseline, Day 45, and End of 
Treatment visits as follows: 
• 
Screening:  Comprehensive metabolic panel, lipid panel, hs-CRP, HbA1c, CBC, HIV RNA, D-Dimer, 
Hepatitis B Surface Antigen 
• 
Baseline:  hs-troponin and NT-proBNP 
• 
Day 45:  Comprehensive metabolic panel, lipid panel, hs-CRP, HbA1c, CBC, HIV RNA, D-Dimer 

 
12
• 
End of Treatment:  Comprehensive metabolic panel, lipid panel, hs-CRP, HbA1c, CBC, HIV RNA, 
D-Dimer, hs-troponin, NT-proBNP 
• 
In addition, pregnancy tests will be performed (for women of child-bearing potential) at 
Screening and before each PET scan. 
 
6. BIOSTATISTICAL ANALYSIS  
 
6.1.  Identification of clinical sites participating in the proposed ancillary study. BWH, MGH, Boston 
Medical Center and Tufts Medical Center will participate in this pilot study.  
Based on the power calculations above and assuming a 20% effect size, the study will need to recruit 
approximately 30 patients, approximately 10 patients per site.  BWH may recruit up to 20 patients.  We 
believe that the proposed  study is reasonable and attainable. Dr. Sax is an experienced clinical 
investigator with a successful track record in HIV clinical trials. Di Carli is a recognized expert in 
quantitative PET and nuclear cardiology imaging, has published widely on these topics, and has 
extensive experience in conducting clinical trials using imaging endpoints51-54.  
 
6.2.  Power Analysis:  
The table below shows the sample size needed to reach 85% power for an effect size of 20-30% relative 
improvement in coronary flow reserve from baseline using a standard deviation of 0.7 at baseline and 
follow-up and a correlation of 0.7 between baseline and follow-up measurements. Effect sizes were 
calculated from a baseline mean CFR of 1.74, which is a conservative value derived from our previous 
measurement of CFR in patients with HIV referred for myocardial perfusion imaging with PET: 
 
Table 2. Power calculation 
Effect Size Mean CFR difference 
(TAF – Baseline) 
SD 
Total Sample Size 
(80% power) 
Total Sample Size 
(85% power) 
Total Sample Size 
(90% power) 
20% 
0.35 
0.7 23 
26 
30 
25% 
0.43 
0.7 16 
18 
21 
30% 
0.51 
0.7 12 
14 
15 
 
Using a total sample size of 30 evaluable patients and a two-tailed alpha of 0.05, there will be 85% 
power to detect an effect size of 20% relative improvement in coronary flow reserve from baseline, 
estimating a ~15% attrition rate between time of baseline and final PET. The 20% relative improvement 
in CFR is the effect size previously demonstrated in statin trials. 
 
6.3. Study endpoints 
Primary Endpoint: Change (from baseline) in coronary flow reserve, as measured by PET imaging at 24 
weeks post medication switch. 
Secondary Endpoints: 
(1) Change (from baseline) in peak-stress global myocardial blood flow (in mL/min/g) at 24 weeks after 
initiation of B/FTAF; 

 
13
(2) Change (from baseline) in peak-stress global coronary vascular resistance (in mm Hg/mL/min/g) at 
24 weeks after initiation of B/FTAF; 
(3) Change in serum biomarkers of inflammation (hs-CRP, IL-6, sCD163 and sCD14), myocyte injury and 
strain (hs Troponin, NT-proBNP) at 24 weeks after initiation of B/F/TAF. 
  
 
6.4. Statistical methods 
To test the central hypothesis, that reducing endothelial cell activation and dysfunction by substituting 
B/F/TAF for ABC/3TC/DTG will quantitatively improve coronary flow reserve as measured by PET over 24 
weeks, we will perform a paired t-test to assess the ∆CFR between baseline and follow-up for each 
subject.   
If a significant change in CFR after the switch is observed, we will perform secondary analyses of 
association between other markers of inflammation also implicated in atherosclerosis (hs-CRP, IL-6, 
sCD163 and sCD14) with ∆CFR.  Significance of associations with other inflammatory markers and ∆CFR 
will be adjusted using the Bonferroni correction.  
 
 
7. RISKS AND DISCOMFORTS  
7.1.  Blood sampling and intravenous catheter 
The risks and discomforts of drawing blood from a vein include the possibility of discomfort, pain, 
redness, bruising, or bleeding at the site of the blood draw, occasional feeling of lightheadedness, and 
rarely, infection or fainting. 
 
There are minor risks and discomforts associated with placement of an intravenous line for the PET scan, 
including the possibility of bleeding, pain, inflammation (redness and swelling), and leaking of contrast 
agent outside of the vein at the site of the IV. These problems are usually self-limited or require only 
minor treatments, such as application of an ice-pack or slight pressure for a few minutes. 
 
7.2.  Vasodilator stress 
Vasodilator-stress with regadenoson and adenosine, as will be performed in this study, has been used 
routinely for many years for evaluation of known or suspected coronary artery disease in conjunction 
with myocardial perfusion imaging. During the infusion of the vasodilator stress agent, the patient may 
experience flushing, chest pain/pressure, nausea, or lightheadedness. If significant symptoms are 
present, patients will be given aminophylline (reversal agent) IV to relieve these symptoms. There will 
be continuous monitoring of heart rate, blood pressure, and 12-lead ECG throughout the infusion and 
recovery. These procedures are routinely performed in patients with CAD, as those in the CIRT trial, and 
are considered safe. 
Regadenoson stress as performed in this study has been used routinely for many years for evaluating 
patients with known or suspected CAD. The most common side effects associated with the regadenoson 
bolus include: flushing, chest pain/pressure, shortness of breath, palpitations, headache, mild 
hypotension and heart block. These side effects are usually mild and self-limiting. If they are severe in 
intensity, aminophylline IV (1 mg/kg) will be given as per standard protocol. 

 
14
Subjects with a history of seizures may receive adenosine. The side effects associated with this product 
include: facial flushing, headache, sweating, palpitations, chest pain, hypotension, shortness of 
breath/dyspnea, chest pressure, hyperventilation, head pressure, lightheadedness, dizziness, tingling in 
arms, numbness, apprehension, blurred vision, burning sensation, heaviness in arms, neck and back 
pain, nausea, metallic taste, tightness in throat, and pressure in groin. Adenosine is administered as a 
continuous infusion over 4 minutes and administered in a dose of 0.14mg/kg/min.  The half-life of 
adenosine is less than 10 seconds.  If the patient is having symptoms the infusion can be stopped, no 
further medication is administered, and the symptoms would stop within seconds because the 
medication would already be cleared from the heart. Therefore, no reversal medication is needed.   
Rarely, an aminophylline IV injection may be used to reverse side effects of regadenoson infusion. 
Aminophylline is generally well tolerated; possible side effects of aminophylline may include nausea, 
headache, restlessness, convulsions, rapid breathing, a rapid heart rate, and allergic reactions such as 
rash. 
7.3.  Radiation risk 
The estimated whole body effective radiation dose from each of the 13N-ammonia PET scan is ~3-4 
mSv55, comparable to the annual radiation dose from background radiation sources in North America. 
Each subject will undergo 2 PET studies during the trial for a total dose of ~6-7 mSv, significantly lower 
than the average radiation exposure associated with a single conventional myocardial perfusion imaging 
study using single-photon emission computed tomography (SPECT)55. 
 
7.4.  Drug side effects and toxicities 
The most common side effects with the use of B/F/TAF are nausea, diarrhea, and headache, as 
described in Table 3 which is based on the results of the phase III trials49, 50.   
 
Table 3. Drug side effects 
 
B/F/TAF group 
(n=314) 
DTF/ABC/3TC group 
(n=315) 
Any adverse event (AE) 
265 (84%) 
283 (90%) 
Grade 3 or 4 AE 
19 (7%) 
25 (8%) 
Drug-related AE 
82 (26%) 
127 (40%) 
Drug-related serious AE 
0 
4 (<1%) 
Any AE leading to study drug 
discontinuation 
0 
4 (1%)* 
AE occurring with 5% incidence in either group 
Nausea 
32 (10%) 
72 (23%) 
Diarrhea 
40 (13%) 
41 (13%) 
Headache 
36 (11%) 
43 (14%) 
Upper respiratory tract infection 
20 (6%) 
34 (11%) 
Nasopharyngitis 
23 (7%) 
29 (9%) 
Fatigue 
19 (6%) 
27 (9%) 
Syphilis 
12 (4%) 
25 (8%) 

 
15
Insomnia 
14 (4%) 
20 (6%) 
Arthralgia 
11 (4%) 
19 (6%) 
Vomiting 
12 (4%) 
17 (5%) 
Cough  
20 (^%) 
8 (3%) 
Bronchitis 
10 (3%) 
16 (5%) 
Abdominal pain 
9 (3%) 
16 (5%) 
Data are in n (%). B/F/TAF=bictegravir, emtricitabine, and tenofovir alafenamide. DTG/ABC/3TC= dolutegravir, 
abacavir, and lamiduvine. *Chronic pancreatitis and steatorrhea (n=1), nausea and generalized rash (n=1), 
depression (n=1), and thrombocytopenia (n=1).49, 50 
 
7.5.  Reproductive risks 
Pregnant or breastfeeding patients will be excluded from this study.   
 
A female is considered of child-bearing potential unless: 
• 
Permanently sterile (includes hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) 
• 
Medically documented ovarian failure 
• 
Post-menopausal, defined as ≥ 60 years of age with cessation of menses for ≥ 12 months. 
7.6.  Unknown Risks: 
There may be other risks and side effects that are not known at this time. 
 
8. POTENTIAL BENEFITS  
8.1.  Potential benefits to participating individuals 
There are no direct benefits for the patient from taking part in this study. The proposed study will test 
the important question of whether reducing endothelial cell activation and dysfunction using B/F/TAF 
will quantitatively improve coronary flow reserve, a sensitive measure of myocardial ischemia. Thus, this 
pilot study will provide important and unique mechanistic insights of the capabilities of novel HIV 
therapies to improve key determinants of clinical risk (improve coronary blood flow and reduce 
ischemia) and, in so doing, improve patient symptoms and quality of life, as well as outcomes.  
 
8.2. Potential benefits to society 
Data collected in this pilot trial may provide important mechanistic insights into presumed 
cardiovascular benefits from novel HIV therapies, as well as into the pathophysiology of microvascular 
dysfunction in HIV-AIDS. 
 
9.  MONITORING AND QUALITY ASSURANCE  
 
9.1.  Safety monitoring 
The PI of the study will monitor the overall safety of the study and will report any adverse events to the 
IRB, per local institutional guidelines.  The PI will also monitor this study to ensure that subjects’ human 
rights, safety, and well-being are protected, that the study is properly conducted in adherence to the 
current protocol, and study data reported by the investigator/subinvestigator are accurate, complete 
and verifiable with study-related records such as source documents. 

 
16
Safety data will be obtained at each study visit from the spontaneous reports by patients of adverse 
events, vital sign monitoring, physical examinations, 12-lead ECGs and clinical laboratory tests. In 
addition, telephone follow-up will be conducted to assess for any adverse events. All safety data will be 
reviewed by an HIV physician investigator (Dr. Paul Sax). 
Patients with unexpected abnormalities on the baseline PET scan will be discussed with the patient’s 
PCP/ID physician to decide whether the patient should participate in this pilot trial. The findings will be 
discussed with the patient and the patient’s primary physician in order to facilitate an appropriate 
management plan. If a patient is excluded on safety grounds, we do not think that this will affect our 
ability to determine the effect of B/F/TAF on myocardial blood flow. 
The safety of B/F/TAF will be assessed with respect to the following end points: (1) death from any 
cause, (2) the composite of death from any cause or any cardiovascular hospitalization, (3) frequency of 
symptomatic documented arrhythmia, (4) serious adverse events related to the study drug and clinically 
significant laboratory abnormalities.  
 
9.2. Treatment Compliance 
Subject compliance to treatment regimen will be assessed at each study visit by a count of remaining 
medication in each bottle.  Subjects will be asked to complete a medication diary for additional 
compliance assessment.  The diary will be compared to the drug count.  A threshold of ≥80% will be 
used to define compliance with treatment assignment. Subjects determined to be noncompliant (<80% 
compliance) will be counseled regarding the importance of following dosing instructions but not 
withdrawn from the study.  
 
9.3. Discontinuation criteria for individual subjects  
Discontinued subjects are those who are enrolled in the study and for whom study treatment is 
terminated prematurely for any reason. The subject is free to withdraw from the study treatment 
and/or study for any reason and at any time without giving reason for doing so and without penalty or 
prejudice.  The investigator is also free to terminate a subject’s involvement in the study at any time if 
the subject’s clinical condition warrants it.  
Subjects will be discontinued if: 
• 
Subject experiences a serious or intolerable adverse event 
• 
Subject has severe disease and has to be intervened upon based on the imaging tests 
• 
In the Investigator’s opinion, the subject is non-compliant with the protocol requirements 
• 
Subject’s health would be jeopardized by continued participation 
• 
Subject wishes to withdraw consent 
• 
Investigator elects to end the study 
 
 
9.4. Adverse event reporting guidelines 
 
   9.4.1    Definition of Adverse Events (AEs) 
An adverse event (AE) is defined as any untoward medical occurrence in a subject administered a 
study drug, and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 

 
17
symptom, or disease temporally associated with the use of a study drug, whether or not related to 
the study drug. 
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG data, 
physical exam) should be defined as an AE only if the abnormality meets one or more of the 
following criteria: 
• Induces clinical signs or symptoms 
• Requires active intervention 
• Requires interruption or discontinuation of study medication 
• The abnormality or investigational value is clinically significant in the opinion of the 
investigator 
 
   9.4.2    Definition of Serious Adverse Events (SAEs) 
A serious AE is any untoward medical occurrence that, at any dose: 
• Results in death, 
• Is life threatening (an event in which the subject is at risk of death at the time of the event; 
it does not refer to an event which hypothetically might have caused death if it was more 
severe), 
• Results in persistent or significant disability/incapacity, 
• Results in congenital anomaly, or birth defect, 
• Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
• Other medically important events 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above. These events, 
including those that may result in disability, should also usually be considered serious.  
 
   9.4.3    Criteria for Causal Relationship to the Study Drug 
Adverse events that fall under either "Possible" or "Probable" should be defined as "adverse 
events whose relationship to the study drugs could not be ruled out." 
 
Causal relationship 
to the study drug 
Criteria for causal relationship 
 
Not Related 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying 
disease provide plausible explanations. 
Possible 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, but which 

 
18
could also be explained by concurrent disease or other drugs or 
chemicals.  Information on drug withdrawal may be lacking or unclear. 
Probable 
A clinical event, including laboratory test abnormality, with a 
reasonable time sequence to administration of the drug, unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and 
which follows a clinically reasonable response on re-administration (re-
challenge) or withdrawal (de-challenge). 
 
   9.4.4    Criteria for Defining the Severity of an Adverse Event 
The following standard with 3 grades is to be used to measure the severity of adverse events, 
including abnormal clinical laboratory values. 
• Mild: No disruption of normal daily activities 
• Moderate: Affect normal daily activities 
• Severe: Inability to perform daily activities 
 
   9.4.5    Reporting of Serious Adverse Events (SAEs) 
In the case of a serious adverse event (SAE), the investigator should submit a report to the IRB per 
local institutional guidelines of the date the investigator first becomes aware of the problem as 
per Partners policy.  
 
   9.4.6    Follow-up to Adverse Events 
All adverse events occurring during the study are to be followed up until resolved or judged to be 
no longer clinically significant, or until they become chronic to the extent that they can be fully 
characterized. 
If during adverse event follow-up, the adverse event progresses to an "SAE," or if a subject 
experience a new SAE, the investigator must immediately report the information to the sponsor. 
 
   9.4.7    Procedure in Case of Pregnancy 
If a woman becomes pregnant during the study dosing period or within 30 days from the 
discontinuation of dosing, the investigator will report the information to the IRB as if it is an SAE. 
The expected date of delivery or expected date of the end of the pregnancy, last menstruation, 
estimated fertility date, pregnancy result and neonatal data etc., should be included in this 
information. 
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE.  
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the investigator should respond in accordance with the report procedure for 
SAEs. Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below: 
• "Spontaneous abortion" includes abortion and missed abortion. 
• Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug. 

 
19
• If an infant dies more than 1 month after the birth, it should be reported if a 
relationship between the death and intrauterine exposure to the study drug is judged as 
"possible" by the investigator. 
• In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth. "Normality" of the miscarried fetus is evaluated by visual examination unless 
test results which indicate a congenital anomaly are obtained prior to miscarriage. 
 
 
 

 
20
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