Clinical trial NCT03510468
Conditions: Healthy Volunteers
Keywords: Antiretroviral Therapy Human Immunodeficiency Virus Latent Tuberculosis Drug-Drug Interactions Rifamycin
Sponsor: National Institutes of Health Clinical Center (CC)
Start date: 2018-06-12; Completion date: 2022-12-21
Enrollment: 51 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

Human immunodeficiency virus (HIV) is treated with antiretroviral drugs. Many people with HIV also have the lung infection tuberculosis (TB). Most TB treatments are complicated. A simpler treatment of two TB drugs can be taken once a week. Researchers want to study how the HIV and TB drugs affect each other so people who take both can be treated safely.

Objective:

To study if rifapentine and isoniazid affect blood levels of the common antiretroviral TAF.

Eligibility:

Healthy adults ages 18-65 without HIV, TB, or hepatitis

Design:

Participants will fast before the screening visit. They will have a medical history, physical exam, and blood tests. Women may have a pregnancy test.

During the study, participants must:

Use effective birth control

Not take most medicine

Not drink alcohol

At the baseline visit, participants will repeat screening tests and get TAF tablets.

Participants will take TAF once a day for 31 days. They will keep track of doses and side effects.

Over 32 days, participants will have 4 long visits and 4 short.

At all visits, participants will:

Fast the night before

Get food

Take that day's TAF

Review their TAF supply

Have pregnancy and blood tests

Report side effects

At 3 visits, participants will also take the 2 TB drugs and vitamin B6.

At 3 long visits, participants will also have blood collected 8 times over 8 hours by plastic tube in an arm vein.

Around Day 46, participants will fast and have blood and pregnancy tests. Two weeks later, they will get a call to see how they are feeling.

Detailed description:
Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as a first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this regimen offers several potential benefits, the use of weekly RPT plus INH is limited in adults infected with human immunodeficiency virus (HIV) on antiretroviral therapy (ART) due to lack of drug interaction data with antiretrovirals (ARVs). Tenofovir alafenamide (TAF) is a preferred backbone agent by the current Department of Health and Human Services ARV guidelines and is a part of multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular TFV diphosphate (dp).

This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of TAF, TFV, and TFV-dp with coadministration of once-weekly RPT + INH administered at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily alone (days 1-14) and (2) TAF once daily + weight-based RPT + INH once weekly (days 15-31). Participants will undergo periodic serial ARV PK blood draws over 24 hours on days 14-15, 22-23, and 31-32.

TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.

Arms: arm 1: Healthy volunteers received Tenofovir alafenamide (TAF) 25 mg once daily for 14 days followed by TAF 25 mg once daily and Rifapentine (RPT) dosed by weight in 150-mg tablet increments (maximum oral dose of 900 mg) 750 or 900 mg (depending on weight) and Isoniazid (INH+ pyridoxine), 15 mg/kg (up to 900 mg) once weekly from days 15-31.
Interventions: intervention 1: Tenofovir alafenamide intervention 2: Rifapentine intervention 3: Isoniazid (INH) intervention 4: Pyridoxine
Intervention descriptions: intervention 1: Each tablet contains 25 mg of tenofovir alafenamide. intervention 2: Each tablet contains 150 mg of rifapentine. Participants who weigh 45 to \< 50 kg will take 750 mg (5 tablets), and participants who weigh (Bullet) 50 kg will take 900 mg (6 tablets). intervention 3: Each tablet is formulated as 100 or 300 mg of isoniazid. intervention 4: Each tablet contains 50 mg of pyridoxine

Protocol documents:
Prot_SAP_000.pdf: 
Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State 
Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)
NIAID Protocol Number:
18-CC-0087
Version Number:
6.0
Date:
August 3, 2021
Principal Investigator:
Joseph A. Kovacs, MD
Critical Care Medicine Dept. (CCMD)
NIH Clinical Center
Conducted by:
Clinical Center Pharmacy Department, NIH
National Institute of Allergy and Infectious Diseases (NIAID), 
NIH
Study Site:
NIH CC
10 Center Drive
Bethesda, MD 20814


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Table of Contents
Table of Contents.............................................................................................................................2
List of Abbreviations .......................................................................................................................5
Protocol Summary ...........................................................................................................................7
Précis................................................................................................................................................9
1
Background Information and Scientific Rationale ................................................................10
1.1
Background Information .............................................................................................10
1.2
Rifapentine ..................................................................................................................11
1.3
Isoniazid ......................................................................................................................11
1.4
Pyridoxine ...................................................................................................................12
1.5
ARV Agent of Interest: Tenofovir Alafenamide.........................................................12
1.6
Drug Interaction Studies Between LTBI Agents and ARVs.......................................13
1.7
Scientific Rationale .....................................................................................................14
2
Study Objectives....................................................................................................................15
2.1
Primary Objective........................................................................................................15
2.2
Secondary Objectives..................................................................................................15
3
Study Design..........................................................................................................................15
3.1
Description of the Study Design .................................................................................15
3.2
Study Endpoints ..........................................................................................................17
3.2.1
Primary Endpoint...................................................................................................17
3.2.2
Secondary Endpoints .............................................................................................17
4
Study Population....................................................................................................................17
4.1
Rationale of Participant Selection ...............................................................................17
4.2
Recruitment Plan .........................................................................................................17
4.3
Participant Inclusion Criteria.......................................................................................18
4.4
Participant Exclusion Criteria .....................................................................................19
4.5
Justification for Exclusion of Special Populations......................................................20
5
Study Agent/Interventions.....................................................................................................21
5.1
Disposition, Dispensation, and Accountability ...........................................................21
5.2
Formulation, Packaging, and Labeling........................................................................21
5.3
Assessment of Participant Compliance with Study Agents ........................................21
5.4
Study Agent Storage and Stability ..............................................................................21
5.5
Preparation, Administration, and Dosage of Study Agents.........................................21
5.6
Concomitant Medications and Procedures..................................................................22
5.7
Prohibited Medications and Procedures......................................................................22
6
Study Schedule ......................................................................................................................22
6.1
Screening (Day −89 to 0) ............................................................................................22
6.2
Baseline (Day −6 to 0).................................................................................................25
6.3
TAF Dosing Period (Days 1-14) .................................................................................25
6.4
TAF and RPT + INH Dosing Period (Days 15-32).....................................................26
6.4.1
First 24-hour PK (Trough).....................................................................................26
6.4.2
Second 24-hour PK................................................................................................26
6.4.3
Third Dose of RPT + INH + Pyridoxine ...............................................................27
6.4.4
Third 24-hour PK...................................................................................................28


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6.5
Safety Visit (Day 46 ± 3) and End-of-Study Phone Call (Day 60 ± 3).......................28
6.6
Early Termination Visit...............................................................................................28
6.7
Pregnancy and Follow-up Visit...................................................................................29
7
Study Procedures/Evaluations ...............................................................................................29
8
Potential Risks and Benefits ..................................................................................................29
8.1
Potential Risks.............................................................................................................29
8.2
Potential Benefits ........................................................................................................32
9
Research Use of Stored Human Samples, Specimens, and Data...........................................32
10
Data Sharing Plan ..................................................................................................................33
11
Remuneration Plan for Participants.......................................................................................33
12
Assessment of Safety.............................................................................................................34
12.1
Toxicity Scale..............................................................................................................34
12.2
Recording/Documentation...........................................................................................34
12.3
Definitions...................................................................................................................35
12.4
Reporting Procedures ..................................................................................................36
12.4.1
Expedited Reporting to the NIAID IRB ................................................................36
12.4.2
Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs, and 
Deaths
37
12.4.3
Annual Reporting to the NIAID IRB.....................................................................37
12.5
Pregnancy ....................................................................................................................37
12.6
Type and Duration of the Follow-up of Participants after Serious Adverse Events ...37
12.7
Pausing Rules for An Individual Participant...............................................................37
12.7.1
Reporting a Pause ..................................................................................................38
12.7.2
Resumption of a Paused Participant ......................................................................38
12.7.3
Discontinuation of Study Agent ............................................................................38
12.8
Halting Rules for the Protocol.....................................................................................38
12.8.1
Reporting a Study Halt ..........................................................................................39
12.8.2
Resumption of a Halted Study...............................................................................39
12.8.3
Discontinuation of Study Agent ............................................................................39
12.9
Study Discontinuation .................................................................................................39
12.10
Premature Withdrawal of a Participant .......................................................................39
12.11
Replacement of Withdrawn Participants or Participants Who Discontinue Study 
Treatment...................................................................................................................................39
12.12
Safety Monitoring Committee.....................................................................................39
13
Study Monitoring...................................................................................................................40
14
Statistical Considerations.......................................................................................................40
14.1
Primary Study Hypothesis...........................................................................................40
14.2
Sample Size Justification.............................................................................................40
14.3
Description of the Analyses ........................................................................................41
15
Ethics/Protection of Human Participants...............................................................................42
15.1
Informed Consent Process...........................................................................................42
15.1.1
Non-English–Speaking Participants ......................................................................42
15.2
Participant Confidentiality ..........................................................................................43
16
Data Handling and Record Keeping ......................................................................................43
16.1
Data Capture and Management ...................................................................................43
16.2
Record Retention.........................................................................................................43


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17
Scientific References .............................................................................................................44
Appendix A: Dosing Nomogram for Rifapentine and Isoniazid...................................................48
Appendix B: Schedule of Procedures/Evaluations........................................................................49
Appendix C: Blood Volumes for Specimen Collection ................................................................52
Appendix D: Study Initiation Calendar .........................................................................................53


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List of Abbreviations
ABCB1
ATP-binding cassette sub-family B member 1
AE
Adverse event
AIDS
Acquired Immunodeficiency Syndrome
ALT
Alanine transaminase
ART
Antiretroviral therapy
ARV
AntiretroviralAST
Aspartate transaminase
AUC
Area under the curve
AUC0-24hr
Area under the curve from the dosing interval of 0 to 24 hours
AUC0-12hr
Area under the curve from time 0 to 12 hours postdose
BTRIS
Biomedical Translational Research Information System
CBC/diff
Complete blood count with differential
CC
Clinical Center
CFR
Code of Federal Regulations
CK
Creatine kinase
CL/F
Apparent oral clearance
Cmax
Maximum total plasma concentration
Cmin
Minimum total plasma concentration
CPP
Clinical Pharmacology Program
CPRU
Clinical Pharmacokinetics Research Unit
CRIMSON
Clinical Research Information Management System of the NIAID
CRP
C-reactive protein
CYP
Cytochrome P450 isozymeDAIDS
DCR
Division of Clinical Research
DOT
Directly observed therapy
dp
Diphosphate
DPA
Durable power of attorney
DTG
Dolutegravir
EFV
Efavirenz
eGFR
Estimate glomerular filtration rate
EVG/c
Elvitegravir/cobicistat
FDA
Food and Drug Administration
FTC
Emtricitabine
GCP
Good Clinical Practice
GI
Gastrointestinal
GMR
Geometric mean ratio
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HRPP
Human Research Protections Program
ICH
International Council on Harmonisation
INH
Isoniazid
IRB
Institutional review board
ISM
Independent safety monitor
IV
Intravenous
LIR
Laboratory of Immunoregulation


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LTBI
Latent tuberculosis infection
NIAID
National Institute of Allergy and Infectious Diseases 
NIH
National Institutes of Health
OCRPRO
Office of Clinical Research Policy and Regulatory Operations
OHRP
Office for Human Research Protections
OHSRP
Office for Human Subjects Research Protections
OTC
Over-the-counter
sPBMC
Peripheral blood mononuclear cell
P-gp
P-glycoprotein
PK
Pharmacokinetic(s)
PLT
Platelet
RAL
Raltegravir
RFB
Rifabutin
RIF
Rifampin
RPT
Rifapentine
SAE
Serious adverse event
SCr
Serum creatinine
SMC
Safety monitoring committee
t½
Terminal half-life
TAF
Tenofovir alafenamide
TB
Tuberculosis
Tbili
Total bilirubin
TDF
Tenofovir disoproxil fumarate
TFV
Tenofovir
TFV-dp
Tenofovir diphosphate
tmax
Time to maximum plasma concentration
UGT1A1
UDP glucuronosyltransferase 1 family, polypeptide A1
ULN
Upper limit of normal
UP
Unanticipated problem
UPnonAE
Unanticipated problem that is not an adverse event


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Protocol Summary
Full Title:
Impact of weekly administration of rifapentine and isoniazid on 
steady state pharmacokinetics of tenofovir alafenamide in healthy 
volunteers
Short Title:
YODA
Sample Size:
N = 18
Accrual Ceiling:
N = 75
Study Population:
Healthy volunteers ages 18-65 years
Accrual Period:
2 years
Study Duration:
Start Date: 01 May 2018
End Date: 30 August 2023
Total length of individual participation: 2-5 months
Study Design:
This is an open-label, fixed sequence, intrasubject drug-drug 
interaction study designed to evaluate the steady state 
pharmacokinetics (PK) of tenofovir alafenamide (TAF) and 
tenofovir (TFV) when administered with and without once-weekly 
rifapentine (RPT) and isoniazid (INH). The study will be 
composed of two phases: (1) TAF 25 mg once daily alone (days 1-
14) and (2) TAF 25 mg once daily + weight-based RPT + INH 
once weekly (days 15-31).
Study Agent/
Intervention Description:
Participants will receive the following:
- TAF 25 mg by mouth once daily x 31 days
AND:
- RPT 750 or 900 mg by mouth once weekly (3 doses)
- INH 15 mg/kg (rounded to the nearest 50- or 100-mg dose, 
maximum dose of 900 mg) by mouth once weekly (3 doses)
- Pyridoxine 50 mg by mouth once weekly (3 doses)
Primary Objective:
To evaluate the effect of once-weekly administration of weight-
based RPT + INH (+ pyridoxine) on the steady-state plasma PK of 
TAF and TFV (administered as TAF 25 mg).
Secondary Objectives:
(1) To evaluate the effect of once-weekly administration of 
weight-based RPT + INH (+ pyridoxine) on the steady-state 
intracellular PK of TFV diphosphate (dp).


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(2) To evaluate the safety of coadministration of TAF with once-
weekly RPT +INH (+ pyridoxine) through documentation of 
adverse events (AEs) according to the Division of AIDS (DAIDS) 
AE Table for Grading the Severity of Adult and Pediatric 
Adverse Events Table and the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials AE table (total bilirubin [Tbili] only).
Primary Endpoint:
Plasma area under the curve during the dosing interval of 0 to 
24hours (AUC0-24hr), maximum total plasma concentration (Cmax), 
time to maximum plasma concentration (tmax), terminal half-life 
(t½), apparent oral clearance (CL/F), and minimum total plasma 
concentration (Cmin) for TAF and TFV.
Secondary Endpoints:
(1) Intracellular AUC0-24hr and t½ for TFV-dp. 
(2) AEs and abnormal laboratory values, as graded according to 
the DAIDS AE table and the Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials AE table (Tbili only). Key laboratory 
measures of interest include hepatic function (alanine 
transaminase [ALT], aspartate transaminase [AST], Tbili), renal 
function (serum creatinine [SCr], estimated glomerular 
filtration rate [eGFR]), complete blood count with differential 
(CBC/diff), creatine kinase (CK), and C-reactive protein (CRP).


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Précis
Rifapentine (RPT) is a long-acting rifamycin that can be used weekly with isoniazid (INH) as a 
first-line regimen in the treatment of latent tuberculosis infection (LTBI). Although this regimen 
offers several potential benefits, the use of weekly RPT plus INH is limited in adults infected with 
human immunodeficiency virus (HIV) on antiretroviral therapy (ART) due to lack of drug 
interaction data with antiretrovirals (ARVs). Tenofovir alafenamide (TAF) is a preferred backbone 
agent by the current Department of Health and Human Services ARV guidelines and is a part of 
multiple recommended first-line regimens for the treatment of HIV. However, the use of TAF with 
rifamycins, including RPT, is not recommended due to potential drug interactions. Thus, the 
purpose of this study is to determine the effects of concomitant RPT and INH administration on 
the steady state pharmacokinetics (PK) of plasma TAF, plasma tenofovir (TFV), and intracellular 
TFV diphosphate (dp).
This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate 
the steady state PK of TAF, TFV, and TFV-dp with coadministration of once-weekly RPT + INH 
administered at doses used to treat LTBI. The study will consist of two phases: (1) TAF once daily 
alone (days 1-14) and (2) TAF once daily + weight-based RPT + INH once weekly (days 15-31). 
Participants will undergo periodic serial ARV PK blood draws over 24 hours on days 14-15, 22-
23, and 31-32. 
TAF, TFV, and TFV-dp PK will be determined using non-compartmental methods. The following 
PK parameters will be compared between phases: area under the curve over the dosing interval, 
maximum plasma concentration, time to maximum plasma concentration, terminal half-life, 
apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and 
recorded.


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1
Background Information and Scientific Rationale
1.1
Background Information
Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, and up to one-third of 
the world’s population is estimated to be infected with this pathogen.1 The majority of infected 
individuals remain in an inactive state, referred to as latent TB infection (LTBI), which is 
characterized by a lack of symptoms or an ability to infect others. However, LTBI can be 
reactivated and develop into active disease. TB is particularly problematic in individuals infected 
with human immunodeficiency virus (HIV), as individuals are 26 times more likely to develop 
active TB infection than HIV-negative individuals,1 with increasing risk as CD4 T lymphocyte 
counts decline2 and viral loads increase.3 TB is one of the most common opportunistic infections 
in the HIV population worldwide, and in 2014, HIV-positive individuals accounted for 12% of 
newly developed TB cases.1 Furthermore, around 25% of all TB deaths were accounted for by 
those infected with HIV, and 33% of HIV/acquired immunodeficiency syndrome (AIDS) deaths 
were attributed to TB. The majority of TB cases and deaths are reported in developing countries 
in Africa and Asia. Higher-income countries, such as the United States, are associated with much 
lower incidence rates. Nevertheless, TB still poses a significant public health problem.
In order to reduce the morbidity and mortality observed in individuals with HIV, appropriate 
diagnosis and treatment of active and LTBI is essential. Currently, the first-line treatment 
recommendations for LTBI in HIV-positive individuals include (1) isoniazid (INH) 300 mg daily 
+ pyridoxine 25 mg daily for 9 months or (2) INH 900 mg twice weekly (as part of directly 
observed therapy [DOT]) + pyridoxine 25 mg daily for 9 months.4,5 Alternative treatment options 
include (1) rifampin (RIF) 600 mg given orally once daily for 4 months, or (2) rifabutin (RFB) 
(dose-adjusted for concomitant antiretroviral [ARV] drugs) for 4 months. INH-based therapies are 
highly effective for LTBI treatment. However, adherence and treatment completion is low in both 
HIV-infected and uninfected individuals due to long treatment courses and high pill burden.6-8 
Once weekly rifapentine (RPT) and INH is another more recently added option to available LTBI 
treatments in HIV. This regimen was found to be similar in efficacy to INH 300 mg daily for 6 
months8 and 9 months9 in HIV-infected individuals with LTBI not on antiretroviral therapy (ART), 
and noninferior to daily INH given for 9 months in a largely HIV-negative population.7 RPT + 
INH is an attractive therapeutic option for LTBI as it is dosed once weekly over 12 weeks, can be 
given as part of DOT treatment support, and is well tolerated by patients receiving this therapy. 
Collectively, these advantages translate into higher rates of adherence comparatively to INH 
therapy, which requires daily dosing and 6 to 9 months of therapy (82%-95% vs. 48%-85%, 
respectively).6-9 
Despite these potential benefits, the use of once weekly RPT with INH is limited in HIV-infected 
adults on ART in the US due to the lack of data on drug interactions between these agents.5 Once-
weekly RPT + INH is only recommended in patients receiving efavirenz (EFV)- or raltegravir 


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(RAL)-based regimens (in combination with either abacavir/lamivudine or tenofovir disoproxil 
fumarate/emtricitabine). As rifamycins can cause significant cytochrome P450 isozyme (CYP) 3A 
and P-glycoprotein (P-gp) transporter induction with daily administration,10,11 prospective drug 
interaction studies between RIF or RFB and ARV agents have informed clinicians of whether to 
avoid certain combinations or make appropriate dose adjustments. However, the extent of 
interaction that may be observed with once weekly RPT is unknown and should be further 
investigated. Furthermore, although INH is not suspected to interact significantly with ARVs, 
its role in modulating transporter-mediated drug interactions is unknown and should also be 
further investigated.
1.2
Rifapentine
RPT is a long-acting rifamycin used in combination with INH in the treatment of LTBI. Compared 
to RIF, RPT has a longer terminal half-life (t½ , 13-14 hours vs. 2-3 hours) and 4-to-5-fold higher 
intracellular concentrations, resulting in a long post-antibiotic effect.10 RPT is dosed by weight in 
150-mg tablet increments, with a maximum oral dose of 900 mg.12 Following oral administration 
of RPT at 600 mg, approximately 70% of the dose is absorbed, and the maximum concentration 
(Cmax) is reached within 5-6 hours under fed conditions. Administration with food increases Cmax 
and area under the curve (AUC) by 40%-51% comparatively to fasted conditions. RPT is primarily 
metabolized by esterases, which in turn leads to the formation of the active metabolite 25-desacetyl 
RPT.12,13 RPT and its 25-desacetyl metabolite contribute to 62% and 38% of the antibiotic activity 
against M tuberculosis, respectively. 
Similar to other rifamycins, RPT induces CYPs (most notably CYP3A4, 2C8, and 2C9), UDP 
glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), and P-gp/ATP-binding cassette sub-
family B member 1 (ABCB1) transporter.10-14 RIF’s effect on the CYP system and P-gp/ABCB1 
are well documented and characterized. RIF is the strongest CYP3A inducer of the rifamycin 
family, with RPT and RFB at 85% and 40% of RIF’s induction potency, respectively.10 CYP3A4 
turnover estimates range between 10-140 hours based on available in vivo studies,15,16 and 
maximal induction is typically observed after at least seven days of rifamycin therapy, with higher 
doses and shorter intervals demonstrating greater inductive effects.11 P-gp/ABCB1 is a 
transmembrane efflux protein responsible for the removal/transport of toxins and xenobiotics out 
of cells. Both RIF and RPT have shown to significantly upregulate or induce P-gp/ABCB1 in a 
concentration-dependent manner.14 In comparison to daily RIF, the inductive potential of once-
weekly RPT is not well understood. However, current data suggest this induction occurs in a 
concentration- and frequency-dependent manner. Due to RPT being administered once weekly 
rather than daily, it is difficult to predict the type and extent of interactions that may take place 
with ARVs.


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1.3
Isoniazid
INH is an antimycobacterial agent that can be used alone or in combination with RPT for the 
treatment of LTBI.17 A number of dosing regimens can be utilized for LTBI in adults, including 5 
mg/kg daily (maximum dose of 300 mg) for 6-9 months, 15 mg/kg 2-3 times per week (maximum 
dose of 900 mg per day) for 6-9 months if given alone, or 15 mg/kg once weekly (maximum dose 
of 900 mg) for 12 weeks if combined with RPT. Cmax is reached 1-2 hours following oral 
administration on an empty stomach. Administration of INH with food can decrease Cmax by 20%-
50% and AUC by 12%-43%; thus, it is recommended to administer INH 1 hour before or 2 hours 
after a meal.18-21 However, INH can be given with food for improved tolerability, and is usually 
administered concomitantly with other medications when given as part of DOT. INH is 
metabolized via acetylation and dehydrazination, and the rate at which acetylation takes place is 
dependent on the genetics of the individual receiving the medication.17 The t½ of INH is 1-1.8 hours 
in rapid acetylators, and 3-4 hours in slow acetylators.22 Rapid or slow acetylators do not show 
significant differences in the efficacy of INH therapy.17 However, slow acetylators may be at an 
increased risk of drug toxicity due to the decreased rate of elimination. INH is not described in the 
literature to be a victim or perpetrator in any transporter related drug-drug interactions. Due to this 
lack of data, the effects, if any, after combination of INH plus RPT will be difficult to predict.
1.4
Pyridoxine
Pyridoxine (vitamin B6) is an exogenous micronutrient obtained through various food sources in 
the human diet.23,24 During INH therapy, pyridoxine supplementation is recommended in certain 
patient populations considered to be at high risk of developing pyridoxine deficiency and 
subsequent peripheral neuropathy.17 These populations include alcoholics, diabetics, pregnant and 
lactating women, malnourished, the elderly, and HIV-infected individuals.17,23,24 INH-induced 
pyridoxine deficiency is believed to result from binding of INH and pyridoxine, which then results 
in the inability of nerve tissue to use pyridoxine, in addition to an increase in urinary excretion of 
the INH-pyridoxine complex.24
The onset of INH-induced peripheral neuropathy appears to be related to drug exposure, with 
higher doses (16-24 mg/kg/day) and decreased elimination (eg, slow acetylators) conferring a 
higher risk of developing this AE.23 Recommended doses of pyridoxine supplementation are 25 
mg daily in HIV-infected individuals,17 and range from 10-25 mg daily in HIV-negative 
populations.25 
1.5
ARV Agent of Interest: Tenofovir Alafenamide
Tenofovir alafenamide (TAF) is a preferred nucleotide analog backbone agent currently 
recommended as part of the initial treatment of HIV.4 TAF is dosed once daily in treatment-naïve 
individuals without evidence of pre-existing drug resistance mutations, has a high threshold for 
the development of resistance, and is overall well tolerated. For the treatment of HIV, TAF is 


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available in multiple coformulations including with the nucleoside analog emtricitabine, the 
integrase inhibitor elvitegravir/cobicistat (EVG/c), and the non-nucleoside analog rilpivirine. 
However, potential drug interactions between TAF and RPT are of concern. TAF is a prodrug that 
is preferentially taken up or loaded into peripheral blood mononuclear cells (PBMCs), where it is 
further phosphorylated to its major intracellular metabolite of interest, tenofovir-diphosphate 
(TFV-dp).16 This selective intracellular uptake and cleavage of TAF allows for prolonged systemic 
exposure of TAF as intact prodrug and less conversion of TAF to tenofovir (TFV) in plasma. 
Higher and prolonged exposure of plasma TFV is reported to result in its uptake into various off 
target sites such as kidney and bone.26 In fact, renal impairment including Fanconi syndrome and 
proximal renal tubulopathy as well as perturbations in bone metabolism has been described with 
an alternate prodrug, tenofovir disoproxil fumarate (TDF, marketed as Viread). 
TAF is a substrate for the efflux drug transporter, P-gp.15 P-gp is expressed variably throughout 
the body including intestinal enterocytes, blood-brain barrier, as well as in PBMCs.27 RPT is 
capable of inducing drug transport in a dose- and frequency-dependent manner,14 thereby affecting 
the transport of TAF from the gut to the plasma during the absorption phase as well as its uptake 
into PBMCs. This induction of transport may potentially result in lower plasma and intracellular 
concentrations of TAF and TFV-dp, respectively. RPT has not been evaluated with regard to how 
many days it would take to reach maximal induction effect of P-gp transport of TAF. However, a 
maximum of 3 weekly doses of RPT at 900 mg was studied with TDF in people with HIV infection 
and showed an overall decrease in the plasma minimum concentration (Cmin) of TFV with minimal 
change in AUC.28 This decrease was deemed to be clinically insignificant.  
1.6
Drug Interaction Studies Between LTBI Agents and ARVs
To date, the full pharmacokinetic (PK) profile of RPT and ARVs has only been described with 
EFV,29 a substrate of CYP2B6 and 3A4, and RAL,30 a UGT1A1 substrate. Once-daily RPT at 
10 mg/kg and INH at 300 mg administered with EFV at 600 mg over 4 weeks revealed that 88% 
of HIV-infected patients were able to maintain EFV trough concentrations > 1 µg/mL, and 97% 
remained virally suppressed.29 In this study, inhibition of CYP2B6 by INH was hypothesized as a 
possible reason that significant induction with daily RPT was not observed. In a separate healthy 
volunteer study, RAL with once-weekly RPT at 900 mg (without INH) resulted in a 71% and 89% 
increase in AUC from time 0 to 12 hours postdose (AUC0-12hr) and Cmax, respectively, and a 
decrease in Cmin by 12%. RAL with once-daily RPT at 600 mg revealed no change in AUC0-12hr or 
Cmax, but did demonstrate a decrease in Cmin by 41%.30 A drug interaction study conducted in 
healthy volunteers with dolutegravir (DTG) and weekly RPT + INH was initiated recently by our 
group but was terminated early due to a serious unexpected AE.31 Although PK data were derived 
from only 4 patients, significant induction of DTG was observed with weekly RPT + INH. Given 
the variability of published PK data, it is difficult to predict the significance of drug interactions 
that may result between RPT and other ARV agents, particularly when RPT is given as a once-
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Table 1
Summary of Drug Interaction Studies with Rifamycins
ARV 
ARV Dose
ARV 
Metabolism/Transport 
LTBI Agent & 
Dose
ARV PK 
Results 
Rifamycins
EFV29
600 mg dailya
3A4, 2B6 (minor)
RPT 10 mg/kg QD 
+ INH 300 mg QD
Cmin > 1 mg/L 
maintained in 
88% 
RPT 900 mg QW
AUC0-12hr ↑ 71%
Cmax ↑ 89%
Cmin ↓ 12%
RAL30
400 mg 
Q12hrsb
UGT1A1 
RPT 600 mg QD
AUC0-12hr ↔
Cmax ↔
Cmin ↓ 41%
TDF32
300 mg QDc
P-glycoprotein
RIF 600 mg QD
AUC0-24hr ↓12%
Cmin ↓ 15%
Cmax ↓ 16%
TDF29
300mg QDd
P-glycoprotein
RPT 900 mg QW
AUC0-24hr ↓ 9%
Cmin ↓ 13%
Cmax ↔
50 mg QD
RPT 900 mg QW + 
INH 900 mg QW
Day 14:
AUC0-24hr ↓ 46%
Cmin ↓ 74%
Cmax ↓ 34%
Day 19:
AUC0-24hr ↓ 15%
Cmin ↓ 38%
Cmax ↓ 12%
50 mg QD
RFB 300 mg QD
AUC0-24hr ↓ 5%
Cmax ↑ 16%
Cmin ↓ 30%
50 mg BIDe
AUC0-24hr ↓ 54%
Cmax ↓ 43%
Cmin ↓ 72%
DTG31,33
50 mg BIDf
UGT1A1 (major), 3A4 
(minor)
RIF 600mg QW
AUC0-24hr ↑ 33%
Cmax ↑ 18%
Cmin ↑ 22%
ARV = antiretroviral; AUC0-12hr = area under the curve from time 0 to 12 hours postdose; 
AUC0-24hr = area under the curve from time 0 to 24 hours postdose; BID = twice per day; 
Cmax = maximum concentration; Cmin = minimum concentration; DTG = dolutegravir; EFV = 
efavirenz; INH = isoniazid; LTBI = latent tuberculosis infection; PK = pharmacokinetic(s); 
Q12hrs = once every 12 hours; QD = once per day; QW = once per week; RAL = raltegravir; 
RFB = rifabutin; RIF = rifampin; RPT = rifapentine; TDF = tenofovir disoproxil fumarate; 
UGT1A1 = uridine diphosphate glucuronosyl transferase 1A1.
a
RPT 10 mg/kg QD + INH 300 mg QD concomitantly administered with EFV.


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ARV 
ARV Dose
ARV 
Metabolism/Transport 
LTBI Agent & 
Dose
ARV PK 
Results 
b
RAL 400 mg Q12hrs + RPT 900 mg QW x 3 and RAL 400 mg Q12hrs + RPT 600 mg QD 
vs. RAL 400 mg Q12hrs alone. 
c
TDF 300 mg + RIF 600 mg QD vs. TDF 300 mg alone.
d
TDF 300 mg + RPT 900 mg QW x 3 vs. TDF 300 mg daily.
e
PK results for DTG 50 mg BID + RIF 600 mg QD vs. DTG 50 mg BID.
f
PK results for DTG 50 mg BID + RIF 600 mg QD vs. DTG 50 mg QD.
1.7
Scientific Rationale
TAF is a substrate for P-gp that RPT may induce.34 Although INH (+ pyridoxine) is not thought 
to play a role in this P-gp–mediated drug-drug interaction, it is included as part of this study to 
provide data with the full LTBI regimen. Additionally, although INH is not suspected to interact 
significantly with ARVs, its role in modulating transporter-mediated drug interactions is 
unknown and should also be further investigated. Thus, the effects of once-weekly RPT + INH 
regimen on the PK of TAF may result in lower overall plasma exposures of TAF and TFV, and 
intracellular (TFV-dp) exposure. Decreased exposure may result in subtherapeutic ARV levels and 
potentially loss of virologic control. Thus, studies are needed to determine the effects of once-
weekly RPT + INH (+ pyridoxine) on the steady state PK of TAF, TFV, and TFV-dp. In order to 
avoid the risk of subtherapeutic ARV levels and virologic failure in HIV-infected individuals, this 
study will be conducted in healthy HIV-negative volunteers to assess whether a significant 
decrease in ARV drug levels may take place. Ultimately, the results of these studies will guide 
clinicians as to whether the once-weekly RPT + INH (+ pyridoxine) can be used in HIV-infected 
patients receiving TAF as part of their ARV regimen.
2
Study Objectives
2.1
Primary Objective
To evaluate the effect of once-weekly administration of weight-based RPT + INH (+ pyridoxine) 
on the steady-state plasma PK of TAF and TFV (administered as TAF 25 mg).
2.2
Secondary Objectives
1. To evaluate the effect of once-weekly administration of weight-based RPT + INH (+ 
pyridoxine) on the steady-state intracellular PK of TFV-dp.
2. To evaluate the safety of coadministration of TAF with once-weekly RPT + INH (+ 
pyridoxine) through documentation of AEs according to the DAIDS AE Table for Grading 
the Severity of Adult and Pediatric Adverse Events Table and the Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine 
Trials AE table (total bilirubin [Tbili] only).


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3
Study Design
3.1
Description of the Study Design
This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate 
the steady state PK of TAF, TFV, and TFV-dp with and without coadministration of once-weekly 
RPT + INH (+ pyridoxine) given at doses used to treat LTBI. Fifteen healthy volunteers will enroll 
in and complete this study. A schematic of the study design is presented in Figure 1.
This study will be comprised of two phases: (1) TAF 25 mg once daily alone (days 1-14) and (2) 
TAF 25 mg once daily + weight-based RPT and INH (+ pyridoxine) once weekly (days 15-31) 
(Figure 1). Participants will undergo serial 24-hour PK blood draws after reaching steady state 
within each phase on days 14-15, 22-23, and 31-32. The phase 1 period lasts a total of fifteen days 
in order to assess PK parameters under plasma steady-state conditions. Steady state is typically 
reached after 3-5 half-lives (ie, > 90% of steady state), and the half-lives of plasma TAF, TFV, 
and intracellular TFV-dp are approximately 30 minutes, approximately 40 hours, and 
approximately 100 hours, respectively. Thus, steady state in plasma would be reached after 
approximately 150 minutes for TAF, approximately 200 hours (8 days) for TFV, and steady state 
intracellularly would be reached after approximately 500 hours (20 days).34-36
With the initiation of RPT dosing, subsequent PK visit days are scheduled to assess the degree of 
induction that is occurring across the RPT dosing interval. The first 24-hour PK assessment is 
scheduled to take place after 14 days of TAF administration. This visit will assess the steady-state 
plasma PK of TAF and TFV prior to the start of weekly administration of RPT. The second PK 
assessment is scheduled to take place 7 days after the first weekly dose of RPT. Rifamycins have 
been shown to reach maximal induction after 7 days of drug therapy. However, these observations 
have been made with daily administration of rifamycins, and thus it is unclear whether this same 
degree and pattern of induction will be observed with RPT when given once weekly. As the half-
life of RPT is only approximately 14 hours, the majority of the drug will be eliminated from 
systemic circulation after 3-5 half-lives (ie, 2-3 days), and thus it is unclear to what extent 
induction will be observed with regard to potency or duration of effects. The second PK visit will 
assess the effects of weekly RPT on the steady-state plasma and intracellular PK of TAF, TFV and 
TFV-dp when given simultaneously (day 22). The third and last 24-hour PK assessment is 
scheduled 2 days following the final weekly dose of RPT and will assess the presumed maximal 
inductive effects of RPT on the steady state PK of TAF, TFV, and TFV-dp. Maximal induction is 
expected at this time point as the inductive potential of RPT is described to be dose- and 
frequency-dependent. Furthermore, PK data derived from a similar study performed by our group 
evaluating the impact of once-weekly RPT on the steady state PK of DTG revealed maximal 
induction occurred 48-72 hours after the second weekly dose compared to same day dosing of RPT 
and DTG.31


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Figure 1 Study Schematic
Screening: Day -89 to 0.
Baseline visit: Day -6 to 0.
PK Visits: Days 14/15, 22/23, 31/32
• 9 blood samples for plasma PK (TAF, TFV) at 0 (predose), 0.25, 
0.5, 1, 2, 4, 6, 8, and 24 hours postdose.
• 6 blood samples for PBMCs at 0 (predose), 1, 2, 6, 8, and 24 hours 
postdose.
• Study drugs administered with standardized breakfast and after time 0 sample collection.
• Safety labs drawn with predose sample.
Safety visit and end of study phone call: Safety visit: 14 ± 3 days after administration of final 
study dose. End of study phone call: 28 ± 3 days after administration of final study dose.
3.2
Study Endpoints
3.2.1
Primary Endpoint
The primary endpoints of this study are plasma AUC during the dosing interval of 0 to 24 hours 
(AUC0-24hr), total plasma Cmax, time to maximum plasma concentration (tmax), t½, apparent oral 
clearance (CL/F), and total plasma Cmin for TAF and TFV.
3.2.2
Secondary Endpoints
1. Intracellular AUC0-24hr and t½ for TFV-dp.
2. AEs and abnormal laboratory values, as graded according to the DAIDS AE table and the 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Trials AE table (Version 2.1, July 2017).
3. Tbili only. Key laboratory measures of interest include hepatic function (alanine 
transaminase [ALT], aspartate transaminase [AST], Tbili), renal function (serum creatinine 
[SCr], estimated glomerular filtration rate [eGFR]), complete blood count with differential 
(CBC/diff), creatine kinase (CK), and C-reactive protein (CRP).
Total Study Duration 
(excluding screening): 
43-63 days
Phase 1
Phase 2
DOT and 1 hour 
observation


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4
Study Population
4.1
Rationale of Participant Selection
Healthy volunteers will be studied, as opposed to patients with HIV infection, in order to reduce 
the risk of subjecting participants to subtherapeutic ARV exposure and virologic failure in the 
event that RPT causes induction of TAF transport. In addition, HIV patients are often on 
concomitant medications, which may interact with the study drugs being examined, and thus the 
final interpretation of study results could be affected. The presence or magnitude of this interaction 
may differ between healthy volunteers and HIV-infected individuals on the basis of previous PK 
and interaction studies.37-39 However, the benefit of assessing this interaction in an HIV-infected 
population does not outweigh the risk of subtherapeutic drug exposure and possible virologic 
rebound at this time. Given the dose and duration of study drugs, the risks to healthy volunteers 
do not outweigh the benefit of data. 
4.2
Recruitment Plan
This study is being conducted at a single site, the NIH CC. Up to 75 participants will be screened 
for a total of up to 18 healthy HIV-negative volunteers to enroll and complete this open-label study. 
Participation of all ethnic groups and genders will be actively encouraged. This will be done 
through the Office of Patient Recruitment, which recruits participants for volunteer studies 
conducted at the NIH CC. There is an active effort to recruit minorities and women through 
outreach programs in the Washington, DC metropolitan area. This study is not designed to assess 
the influence of gender, age, and/or ethnicity on the drug-drug interaction (if observed) between 
TAF + RPT + INH.
Recruitment of NIH employees: NIH employees and members of their immediate families may 
participate in this protocol. We will follow the Guidelines for the Inclusion of Employees in NIH 
Research Studies and will give each employee a copy of the “NIH Information Sheet on Employee 
Research Participation.”
For NIH employees:

NIH staff may be a vulnerable class of participants.

Neither participation nor refusal to participate will have an effect, either beneficial or 
adverse, on the participant’s employment or work situation.

The NIH information sheet regarding NIH employee research participation will be 
distributed to all potential participants who are NIH employees.

The employee participant’s privacy and confidentiality will be preserved in accordance 
with NIH CC and NIAID policies, which define the scope and limitations of the 
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
For NIH employee participants, consent will be obtained by an individual independent of 
the employee’s team. Those in a supervisory position to any employee and co-workers of 
the employee will not obtain consent.

The importance of maintaining confidentiality when obtaining potentially sensitive and 
private information from co-workers or subordinates will be reviewed with the study staff 
at least annually and more often if warranted.
4.3
Participant Inclusion Criteria
Individuals must meet all of the following criteria to be eligible for study participation:
1. Ages 18-65 years. 
2. Weight ≥ 45 kg and ≤ 120 kg OR body mass index ≥ 18.0 and < 30.
3. Judged to be healthy based on medical history, physical examination, vital signs, and 
clinical laboratory tests: liver function tests (AST, ALT, Tbili) ≤ upper limit of normal 
[ULN], SCr ≤ ULN, platelets (PLT) > 150,000/µL, hemoglobin (Hgb) > 13 g/dL (males); 
> 12g/dL (females), C-reactive protein (CRP) < ULN, CK < 2x ULN, fasting total 
cholesterol < 240 mg/dL, or fasting triglycerides < 240 mg/dL, urine glucose < grade 2 (per 
DAIDS AE table), urine protein < grade 2 (per DAIDS AE table).
4. Negative QuantiFERON-TB Gold test at screening. 
5. HIV-negative, as determined by standard serologic assays for HIV infection. 
6. No laboratory evidence of active or chronic hepatitis A, B, or C infection.
7. Willing to abstain from alcohol consumption throughout the study period.
8. Agrees to genetic testing and storage of specimens for future research. 
9. Able to provide informed consent.
10. Negative serum or urine pregnancy test for females of child-bearing potential.
11. Participants must agree not to become pregnant or impregnate a partner for the duration of 
the study.  The use of hormonal contraceptives will not be permitted.  Study participants 
must use one of the following methods of birth control when engaging in sexual activities 
that can result in pregnancy, beginning at screening until the final study visit.   Male 
vasectomy and females who have undergone hysterectomy are acceptable forms of birth 
control.
a) Male or female condom.
b) Diaphragm or cervical cap with a spermicide.
c) Intrauterine device without hormones.
4.4
Participant Exclusion Criteria
Individuals meeting any of the following criteria will be excluded from study participation:
1. Known hypersensitivity to TAF, TDF, INH, RPT, and other rifamycin analogues.
2. History or presence of any of the following:


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a.
Latent or active TB infection.
b. Gastrointestinal (GI) disease that is uncontrolled, requires daily treatment with 
medication, or would interfere with a participant’s ability to absorb drugs (eg, diarrhea, 
pancreatitis, or peptic ulcer disease).
c.
Renal impairment (chronic renal insufficiency of any chronic kidney disease stage, or 
acute renal failure not induced by drug therapy defined as eGFR < 90 mL/min or SCr 
> ULN).
d. Respiratory disease that is uncontrolled or requires daily treatment with medication 
(eg, asthma or chronic obstructive pulmonary disease).
e.
Cardiovascular disease (eg, hypertension [systolic blood pressure > 140 mm Hg or 
diastolic blood pressure > 90 mm Hg], heart failure, or arrhythmia).
f.
Metabolic disorders (eg, diabetes mellitus).
g. Hematologic or bleeding disorders (eg, anemia, hemophilia, serious/major bleeding 
events, menorrhagia [female participants]).
h. Immunologic disorders.
i.
Hormonal or endocrine disorders.
j.
Psychiatric illness that would interfere with their ability to comply with study 
procedures or that requires daily treatment with medication.
k. Seizure disorder, with the exception of childhood febrile seizures.
l.
Any current or history of malignancy, with the exception of cutaneous basal cell 
carcinoma, non-invasive squamous cell carcinoma, or any other malignancies not 
requiring systemic therapy.
m. Current or history of osteopenia and osteoporosis.
3. Current participation in an ongoing investigational drug protocol or use of any 
investigational drug within 30 days (based on last dose received) prior to receipt of any 
study drugs.
4. Therapy with any prescription, over-the-counter (OTC), herbal, or holistic medications, 
including hormonal contraceptives by any route, within 5 half-lives of the agent prior to 
receipt of any study medications will not be permitted with the following exception: 
Intermittent or short-course therapy (< 14 days) with prescription or OTC medications, 
herbals, or holistic medications within the screening period prior to starting study drugs 
may be permitted, and will be reviewed by investigators on a case-by-case basis for 
potential drug interactions. Receipt of influenza vaccination will be allowed prior to, 
during, and/or after the study.
5. Inability to obtain venous access for sample collection.
6. Inability to swallow whole capsules and/or tablets.
7. Pregnant or breastfeeding.
8. Drug use that may impair safety or adherence.
9. Use of nicotine-containing products, including cigarettes and chewing tobacco, nicotine 
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10. Organ or stem cell transplant recipient.
11. Uncorrected and persistent electrolyte abnormalities (eg, potassium, magnesium, and 
calcium).
12. Current alcohol use disorders (DSM-5 criteria).
13. Fasting total cholesterol > 240 mg/dL or fasting triglycerides > 240 mg/dL at screening.
14. Any condition that, in the opinion of the investigator, contraindicates participation in this 
study.
Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than enrollment on 
observational studies. Study staff should be notified of co-enrollment as it may require the approval 
of the investigator. 
4.5
Justification for Exclusion of Special Populations
Exclusion of pregnant women: Pregnant participants are excluded from this study to reduce the 
confounding effects of physiological changes during pregnancy on PK parameters of interest. 
Furthermore, the effects of RPT and INH on the developing human fetus are unknown with the 
potential for teratogenic or abortifacient effects. There are no human data of the use of TAF during 
pregnancy, but animal data studies show no developmental effects after TAF administration.  
Exclusion of breastfeeding women: Because there is an unknown but potential risk for AEs in 
nursing infants secondary to exposure of the mother with TAF, RPT, or INH, breastfeeding 
participants are excluded from study participation.
Exclusion of children and persons > 65 years old: This study is intended to investigate the PK 
and safety profiles of agents in an adult population, as opposed to children, as age-related 
metabolic and transport processes in children differ from those of adults. TAF is not approved for 
use in pediatric populations.34 However once-weekly RPT + INH regimen for LTBI has been found 
to be safe and effective in children 2-17 years of age.40 However, as this is a preliminary study, 
there is no potential benefit to children, as a population, to justify their participation at this time. 
As in children, changes in metabolic processes as a result of aging may confound findings from 
participants older than 65 years. Again, as this is a preliminary study, there is no potential benefit 
as a population to justify their participation. However, future investigators may include this 
population as well.
5
Study Agent/Interventions
5.1
Disposition, Dispensation, and Accountability
Study agents will be distributed and accounted for by the NIH pharmacy according to standard 
pharmacy procedures.


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5.2
Formulation, Packaging, and Labeling
Each bottle will be individually labeled with the patient ID number, dosing instructions, 
recommended storage conditions, the name and address of the manufacturer, and that the agent 
should be kept out of reach of children.
5.3
Assessment of Participant Compliance with Study Agents
Participants will receive a memory aid card to log their doses of TAF and record AEs between 
study visits. This memory aid card will not be used as a source document. Each participant will 
receive telephone contact to remind them of appropriate adherence and/or of upcoming 
appointments. Additionally, participants will be instructed to bring all study agent bottles to each 
study visit for pill count.
5.4
Study Agent Storage and Stability
All study agents should be stored and dispensed from the NIH CC Pharmacy according to standard 
pharmacy procedures.  
5.5
Preparation, Administration, and Dosage of Study Agents
Participants will receive once-daily dose of TAF (25 mg) for 31 days, and once-weekly doses of 
RPT (750 or 900 mg, depending on weight), INH (15 mg/kg, up to 900 mg), and pyridoxine (50 
mg) from study days 15 to 29 (total of 3 doses of RPT, INH, and pyridoxine). 
Each tablet of Vemlidy (Gilead Sciences, Inc [Foster City, CA]) contains 25 mg of TAF. 
Participants will be instructed to take one tablet daily at the same time (0800 + 2 hours) every day 
with food on non-study days. At the 24-hour PK visit days, participants will be instructed to bring 
their study agent supply to the NIH Day Hospital or OP-8 Infectious Diseases Clinic for DOT 
administration.
Each tablet of Priftin (Sanofi-Aventis [Bridgewater, NJ]) contains 150 mg of RPT. Participants 
who weigh 45 to < 50 kg will take 750 mg (5 tablets), and participants who weigh ≥ 50 kg will 
take 900 mg (6 tablets). These tablets will be administered with food via DOT (NIH Day Hospital 
or OP-8 Infectious Diseases Clinic) once weekly on days 15, 22, and 29. 
Each tablet of generic INH is formulated as 100 or 300 mg of the drug. Participants will be 
administered INH with food via DOT (NIH Day Hospital or OP-8 Infectious Diseases Clinic) 
based on weight, at approximately 15 mg/kg (up to 900 mg) with RPT on days 15, 22, and 29. 
A dosing nomogram for RPT and INH is provided in Appendix A.


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Each tablet of pyridoxine contains 50 mg of Vitamin B6. Participants will be administered B6 with 
food via DOT (NIH Day Hospital or OP-8 Infectious Diseases Clinic) with RPT + INH on days 
15, 22, and 29.  
5.6
Concomitant Medications and Procedures
All concomitant prescription and nonprescription (including OTC) medications taken during study 
participation will be recorded in the Clinical Research Information Management System of the 
NIAID (CRIMSON). For this protocol, a prescription medication is defined as a medication that 
can be prescribed only by a properly authorized/licensed clinician.
5.7
Prohibited Medications and Procedures
To minimize potential drug interactions or AEs in healthy volunteers, therapy with any 
prescription, OTC, herbal, or holistic medications, excluding occasional use of acetaminophen (no 
more than 2 g/24 hrs), ibuprofen, naproxen, loperamide, or antihistamines (on non-PK days), will 
not be permitted throughout the study period unless discussed with and approved by the 
investigator.
6
Study Schedule
A flowchart of the study schedule is provided in Figure 2. A table of the study schedule is provided 
in Appendix B, and blood volumes are listed in Appendix C. 
6.1
Screening (Day −89 to 0)
The participant will be required to fast for at least 8 hours before the screening visit. Screening 
evaluations to determine eligibility for this study are listed below. The participant will sign the 
informed consent form before undergoing any screening procedure. Blood draws and urine for 
labs may be repeated as clinically indicated at the discretion of the medically responsible 
investigator within 14 days of initial screening.
1. Physical exam with vital signs and weight.
2. Medical history review.
3. Serum or urine pregnancy test (for participants who are able to become pregnant).
4. Blood draw for screening labs:
a.
HIV-1/2 antigen/antibody testing.
b. QuantiFERON-TB Gold tuberculosis testing.
c.
Viral markers hepatitis screen (hepatitis B surface antigen, anti-hepatitis C antibody, 
anti-hepatitis A IgM).
d. Acute care, hepatic, and mineral panels.
e.
CRP.
f.
Creatine kinase.


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g. Lipid panel.
h. CBC/diff.
i.
Amylase
j.
Lipase
5. Urine for screening labs:
a.
Protein.
b. Glucose.


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Figure 2 Study Schedule and Procedures
Screening (Day −89 to 0)
Vital signs, medical history, physical examination, and fasting blood 
samples and urine for screening labs (including QuantiFERON-Gold 
testing, HIV ELISA, and a viral markers hepatitis screen).
Baseline (Day -6 to 0)e
Vital signs, weight, and baseline safety labsa & TAF supply dispensed.
Days 1-14: TAF Dosing Days 
TAF 25 mg once daily at 0800 hrs (± 2 hrs) with food. 
Administration recorded on provided dosing log.
Day 14: Serial (24-hr) PK Sampling
AE assessment, safety labsa and serial (24-hr) blood PK samplesc.
TAF 25 mg at 0800 (± 2 hrs) with a well-balanced meald. 
Day 15: TAF + RPT & INH Dosing Dayd,e
Collection of 24-hr postdose PK sample and safety labs.
Weight-based RPT and INHb, and TAF 25 mg after collection of 24-hr 
PK sample.
Day 16: TAF Dosing & Safety Labs 
Vital signs, weight,Safety labsa then TAF 25 mg at 0800 (± 2 hrs) with 
food. 
Administration will be recorded on the provided dosing log.
Days 16-21: TAF Dosing Days
TAF 25 mg once daily at 0800 (± 2 hrs) with food. 
Administration recorded on provided dosing log.
Day 22: TAF + RPT & INH Dosing Dayd,e
Weight-based RPT and INHb, and TAF 25 mg at 0800 (± 2 hrs) with 
well-balanced meal. Administration recorded on the provided dosing log. 
AE assessment, safety labsa, and serial (24-hr) blood PK samplesc.
Day 23: TAF Dosing Day & Safety Labs 
Collection of 24-hr postdose PK sample .
TAF 25 mg administered with food after collection of 24-hour PK. 
Days 24-28: TAF Dosing Day
TAF 25 mg once daily at 0800 (± 2 hrs) with food. 
Administration recorded on provided dosing log.
Day 29: TAF + RPT & INH Dosing Day and Observation Periodd
Weight-based RPT and INHb, and TAF 25 mg at 0800 (± 2 hrs). DOT 
administration of RPT and INH and 1-hour observation period. 
Collection of safety labs.
Day 30: TAF Dosing Daye
TAF 25 mg once daily at 0800 (± 2 hrs) with food.
Administration recorded on provided dosing log.
Day 31: Serial (24-hr) PK Samplinge
AE assessment, safety labsa, and serial (24-hr) blood PK samplesc.
TAF 25 mg at 0800 (± 2 hrs) with a well-balanced meald.
Day 32: No Dosing Day
Collection of 24-hour postdose PK sample. 
Collection of safety labsa.
Day 46 ± 3: Safety Visit
Day 60 ± 3: End of Study Phone Calle 
a Safety laboratory assessments will be collected at 
baseline, with the time 0 (predose) measure on 
each PK day, 24 hours after 1st and 2nd doses of 
RPT + INH + pyridoxine, and 48 hours after the 
final dose of RPT + INH + pyridoxine. Assessments 
will include serum or urine pregnancy test for 
females of child-bearing potential; a basic 
chemistry [acute care panel including Na, K, CO2, 
anion gap, BUN, serum creatinine, estimated 
glomerular filtration rate, glucose, albumin], 
hepatic [including AST, ALT, alkaline phosphatase, 
total bilirubin, direct bilirubin], and mineral panel 
[Ca, Mg, Phos]; C-reactive protein, creatine kinase, 
amylase/lipase (at baseline and Day 16 only), and 
complete blood count with differential [WBC, RBC, 
Hgb, HCT, platelets, differential]
b RPT dosed by weight of participant (ie, 750 mg 
[5 x 150-mg tablets] if 45 to < 50 kg, 900 mg 
[6 x 150-mg tablets] if ≥ 50 kg). INH dosed by 
weight (15 mg/kg rounded to nearest 50- or 
100-mg dose, max 900-mg dose).
c 24-hr plasma PK sampling times will occur at 
time: 0 (predose), 0.25, 0.5, 1, 2, 4, 6, 8, and 
24 ( ± 2) hours postdose. Blood will be collected 
for PBMCs at 0 (predose), 1, 2, 6, 8, and 24 hours 
postdose. The participant will be discharged after 
collection of the 8-hour postdose sample, to then 
return for the 24-hour postdose sample collection 
the following day.
d TAF + RPT and INH (with pyridoxine) 
administered in clinic setting. 
e Telephone contact to remind participant on day 0 
(Monday) to start taking TAF on day 1 (Tuesday) of 
study. Telephone contact on day 10 + 1, 
day 18 ± 3, and day 30 to remind the participant of 
upcoming PK visits on days 14, 22, and 31, 
respectively. On day 25 ± 3, telephone contact to 
remind participant of 8-10-hour observation 
period on day 29. On day 60 + 3, telephone 
contact to assess side effects.
Phase 1
Phase 2


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6.2
Baseline (Day −6 to 0)
Participants will return to the NIH CC after eligibility has been confirmed for medical 
history/medication review, vital signs, weight, and to receive a 34-day course of TAF. The TAF 
regimen for this study only requires 31 tablets (a 31-day supply), but participants will be provided 
with three additional days of study agent to allow for possible minor scheduling variances. 
Participants will be counseled on the importance of study agent adherence throughout the study, 
and will be instructed to take their TAF doses at approximately the same time each day 
(0800 ± 2 hours) with a food at home. They will also receive a phone call on day 0 to remind them 
to start their course of TAF on day 1.
Participants will receive a memory aid to serve as a reminder of the appropriate drug administration 
schedule, and to also serve as a memory aid during visit interviews regarding any AEs they may 
have experienced. Participants will be instructed to bring their memory aid cards and all bottles of 
study agent to each study visit to assess for study agent adherence and self-reported AEs. 
If the screening visit happened more than 6 days before the first dose of TAF, then participants 
will be instructed to fast for at least 8 hours before the baseline visit so blood can be collected for 
baseline evaluation (same as screening labs, and excluding urine, HIV, TB, and hepatitis tests, 
which will not be done again). Additional blood will not be collected (and fasting will not be 
required) if screening happens within 6 days of the first dose of TAF.
Participants of childbearing potential will always have their baseline visit scheduled for day 0 so 
a serum or urine pregnancy test can be done within 24 hours of the first dose. The pregnancy test 
must be negative for the participant to proceed with the study.
6.3
TAF Dosing Period (Days 1-14)
Day 1, which is the first dose of TAF, will always be scheduled for a Tuesday to ensure that other 
study visits also occur on weekdays (Appendix D). Participants will self-administer 25-mg TAF 
once per day with food for days 1-13. Participants will receive a phone call around day 10 to 
remind them of their upcoming visit on day 14. In preparation for this visit, they will be instructed 
to fast for 8 hours and refrain from eating or drinking any beverage besides water after midnight 
prior to the day 14 PK visit (NIH Day Hospital or OP-8 Infectious Diseases Clinic). They will also 
be instructed to not take any study agent prior to arrival to the NIH Day Hospital clinic, and to 
instead bring their study agent supply with them to the day 14 PK visit for administration following 
the predose (time 0) blood draw. At the day 14 visit, participants will have the following 
evaluations:

AE assessment and memory aid review.

Medical/medication history.

Pill count/study agent adherence review.


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
Measurement of vital signs and weight. 

Serum or urine pregnancy test (if of childbearing potential, which must be negative to 
proceed with the study). 

Insertion of intravenous (IV) catheter to collect blood for safety labs, pharmacogenomic 
testing, and the time 0 (predose) plasma and PBMC PK samples. 

Urine sample for safety labs: urine protein and glucose.
Participants will then be provided with a standardized breakfast that consists of a well-balanced, 
moderate fat meal containing > 500 calories, which will be provided by the NIH metabolic unit 
kitchen. During breakfast, participants will be administered a single dose of TAF with 240 mL of 
water by nursing staff. Serial blood PK samples will be collected at 0.25, 0.5, 1, 2, 4, 6, and 8 
hours postdose. Blood for PBMCs will be collected at 1, 2, 6, and 8 hours postdose. Participants 
will be provided with lunch no sooner than 4 hours after the standardized breakfast. Participants 
will also be given the option of dinner, which they may accept or decline per individual preference. 
The participant will be dismissed from the clinic after collection of the 8-hour postdose sample 
and removal of the IV catheter. 
6.4
TAF and RPT + INH Dosing Period (Days 15-32)
6.4.1
First 24-hour PK (Trough)
In anticipation of the PK visit on day 15 (24-hour trough), participants will be instructed to fast 
for 8 hours and refrain from eating or drinking any beverage besides water after midnight prior to 
the day 15 PK visit (NIH Day Hospital or OP-8 Infectious Diseases Clinic). Participants will also 
be instructed to not take any study drug prior to arrival to the NIH Day Hospital clinic, and to 
instead bring their study agent supply with them to the day 15 PK visit. At this visit, participants 
will do the following:

AE assessment and memory aid review.

Medical/medication review.

Pill count/study agent adherence review.

Measurement of vital signs and weight.

Blood draw for safety labs and 24-hour (± 2 hours) postdose plasma and PBMC PK sample 
collections.

Serum or urine pregnancy test (if of childbearing potential, which must be negative to 
proceed with the study). 
After these procedures, participants will be provided with breakfast and administered their daily 
dose of TAF and first weekly weight-based dose of RPT and INH (and pyridoxine), as described 
in section 5.5. Participants will return again on day 16 for AE assessment, medical/medication 
history, vital signs and weight, pill count, pregnancy test, and blood draw for safety labs before 


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administration of TAF. Participants must fast for 8 hours and refrain from eating or drinking any 
beverage besides water after midnight prior to the day 16 visit.
6.4.2
Second 24-hour PK
Daily self-administered dosing of TAF will continue between days 17 and 21, and participants will 
be contacted by phone on day 18 (± 3 days) for remote AE assessment and reminder for the day 
22 PK visit. The second 24-hour PK visit will be on day 22 when the second weekly dose of RPT 
+ INH (+ pyridoxine) will be administered (+ TAF); participants will have been instructed to fast 
for 8 hours prior to this visit and refrain from eating or drinking any beverage besides water after 
midnight prior to day 22. The following evaluations will be done at this visit:

AE assessment and memory aid review.

Medical/medication history.

Pill count/study agent adherence review.

Measurement of vital signs and weight.

Serum or urine pregnancy test (if of childbearing potential, which must be negative to 
proceed with the study). 

Insertion of IV catheter to collect blood for safety labs and predose plasma and PBMC PK. 
Participants will then be provided with a standardized breakfast, during which they will be 
administered TAF and RPT + INH (+ pyridoxine). Participants will be provided with lunch no 
sooner than 4 hours after the standardized breakfast. Participants will also be given the option of 
dinner, which they may accept or decline per individual preference.  Serial blood PK samples will 
be collected at 0.25, 0.5, 1, 2, 4, 6, and 8 hours postdose, with extra blood collected for PBMCs at 
1, 2, 6, and 8 hours postdose. 
The visit on day 23 will be similar to the day 15 visit. Participants will be instructed to fast for 
8 hours and refrain from eating or drinking any beverage besides water after the preceding 
midnight. Participants will also be instructed to not take any study drug prior to arrival to the NIH 
Day Hospital clinic, and to instead bring their study agent supply with them. Day 23 procedures 
are the following:

AE assessment and memory aid review.

Medical/medication review.

Pill count/study agent adherence review.

Measurement of vital signs and weight.

Blood draw for safety labs and 24-hour (± 2 hours) postdose PK and PBMC sample 
collections.

Serum or urine pregnancy test (if of childbearing potential, which must be negative to 
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After these procedures, participants will be provided with breakfast and administered their daily 
dose of TAF. 
Daily self-administered dosing of TAF will continue again between days 24 and 28. Participants 
will receive a phone call around day 25 to remind them of their upcoming visit on day 29.
6.4.3
Third Dose of RPT + INH + Pyridoxine
Participants will return to the NIH OP8 Clinic on day 29. Participants will be instructed to fast for 
8 hours and refrain from eating or drinking any beverage besides water after the preceding 
midnight. Day 29 procedures are the following:

AE assessment and memory aid review.

Medical/medication review.

Pill count/study agent adherence review.

Measurement of vital signs and weight.

Blood draw for safety labs.

Serum or urine pregnancy test (if of childbearing potential, which must be negative to 
proceed with the study). 
After these procedures, participants will receive their third and final weekly dose administration 
of RPT + INH (+ pyridoxine), and will be observed for 1- hour postdose. 
In an earlier study conducted by our group that evaluated INH + RPT and a different antiretroviral, 
dolutegravir, 2 out of 4 enrolled participants experienced SAEs including elevations in liver 
function tests and flu-like syndrome approximately 8 hours after study drug administration after 
the third weekly dose of INH + RPT. Although a different antiretroviral is under investigation in 
this study, participants will still receive RPT + INH. Therefore, to ensure the safety of the 
participants, a 8-10-hour observation period was included to check vitals and safety labs. This 8-
10 hour observation period was conducted for the first three participants who reached this 
point in the study, after which time the need for this observation period was re-assessed and 
revised by the study team in consultation with the SMC for the remainder of potential study 
participants.
6.4.4
Third 24-hour PK
The third PK sampling visit is days 31 and 32, and participants will receive a phone call on day 30 
to remind them of this visit. The schedule for these days is the same as days 22 and 23 
(section 6.4.2) but without administration of RPT + INH (+ pyridoxine). In anticipation of this PK 
visit, participants will be instructed to fast for 8 hours and refrain from eating or drinking any 
beverage besides water after midnight prior to the visits on days 31 and 32 (NIH Day Hospital or 
OP-8 Infectious Diseases Clinic). Day 31 is also the final dose of TAF, so the participants will not 


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receive another dose on day 32 after assessments and collection of the 24-hour PK, blood for safety 
labs, and pregnancy test.
6.5
Safety Visit (Day 46 ± 3) and End-of-Study Phone Call (Day 60 ± 3)
Participants will return to the NIH CC for a final follow-up visit on day 46, approximately 2 weeks 
after the end of third PK visit. AEs will be assessed, vital signs and weight measured, and blood 
drawn and urine collected for safety labs. Participants who can become pregnant will have a blood 
or urine pregnancy test. A follow-up phone call for remote AE assessment will be scheduled 
approximately 2 weeks later (4 weeks after the end of the third PK visit). Participation ends after 
the phone call.
6.6
Early Termination Visit
If participants terminate the study early, they will be asked to return for drawing end-of-study labs 
(14 ± 3 days after the final dose of any study drug[s]) and will receive a physical exam and AE 
assessment.
6.7
Pregnancy and Follow-up Visit
Participants who become pregnant while on study will discontinue study agents and procedures, 
and will be instructed to follow-up with their physician for prenatal care; they will also be followed 
to delivery for purposes of safety monitoring for this study.
7
Study Procedures/Evaluations
Blood draw: The amount of blood drawn for research purposes will be within the limits allowed 
for adult research participants by the NIH CC (Medical Administrative Policy 95-9, Guidelines for 
Limits of Blood Drawn for Research Purposes in the Clinical Center: http://cc-
internal.cc.nih.gov/policies/PDF/M95-9.pdf). Blood samples will be used for the following:

Screening labs (see section 6.1). 

24-hour plasma PK of TAF and TFV.

Collection of PBMCs for measurement of intracellular PK of TFV-dp.

Pregnancy testing

Safety labs: safety panels (acute care, hepatic, mineral), CRP, amylase (study day 16), 
lipase (study day 16), CBC/diff, CK.  
o
Results of safety lab assessments will be reviewed as they become available, with 
appropriate clinical follow-up through resolution as necessary for any abnormal results.
Pharmacogenomics: A single blood sample (10 mL) on day 14 will be collected for 
pharmacogenomic testing (targeted sequencing).  


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Urine: Urine samples will be used for the following:

Screening labs (urine protein and urine glucose).

Safety labs: urine protein and glucose on study day 14 and end of study visit.

Pregnancy testing.
8
Potential Risks and Benefits
8.1
Potential Risks
TAF: In clinical trials of TAF in people with hepatitis B infection, the AEs (all grades) observed 
in more than 5% of study participants were headache, abdominal pain, fatigue, cough, nausea, and 
back pain.34
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported 
with use of TFV prodrugs in animal toxicology and human trials.34 In clinical trials of TAF alone 
(in patients with hepatitis B) or in combination with FTC and EVG/c (in patients with HIV 
infection), there have been no reports of patients experiencing proximal renal tubulopathy or 
Fanconi syndrome.41,42 In a 24-week trial in HIV-infected adults (n = 248) with baseline renal 
impairment (eGFR = 30-60 mL/min), FTC/TAF + EVG/c was discontinued for 2 patients who 
experienced worsening renal function.43 
Lactic acidosis (including life-threatening cases) as well as hepatic steatosis have been reported 
with the use of nucleoside analogs including FTC and TDF. This is a rare but recognized AE of 
nucleoside analogues and is described to occur as a result of mitochondrial toxicity. The incidence 
of lactic acidosis varies based on the case definition and has a reported incidence in HIV-infected 
patients of 1.9/1000 to 14.8/1000.44 Described characteristic symptoms in patients reported to have 
experienced lactic acidosis include elevated lactate levels (> 5 mmol/L), elevated liver function 
tests, and abdominal pain. 
In a 96 week trial, three percent of patients with chronic hepatitis B experienced elevations in 
amylase (> 2 x ULN).  Eight out of 866 participants receiving TAF experienced elevated amylase 
with associated symptoms of nausea, low back pain, abdomninal tenderness; and biliary 
pancreatitis and pancreatitis.34  Of these eight, two participants discontinued TAF.  Amylase and 
lipase will both be assessed in healthy volunteers receiving TAF during the study.
TAF, TDF, and TFV have been associated with bone mineral density loss in clinical trials of HIV-
infected participants.41,42 This has also been observed in clinical trials of TAF in patients with 
hepatitis B.34 The long-term clinical significance of these changes is not known.
RPT: In clinical trials and post-marketing surveillance, the most frequent AEs (> 1%) with 
prolonged RPT-based treatment of active TB included hematologic changes (anemia, 
lymphopenia, neutropenia, leukocytosis, thrombocytosis, thrombocytopenia, lymphadenopathy), 


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GI symptoms (dyspepsia, vomiting, nausea, diarrhea), back and abdominal pain, fever, anorexia, 
increases in ALT and AST, arthralgia, headache, dizziness, hemoptysis, coughing, rash, increased 
sweating, pruritus, and maculopapular rash.12 AEs were less common with once-weekly 
administration of RPT compared to the twice-weekly regimen. Hypersensitivity reactions were the 
most common AE (≥ 1%) observed in treatment of LTBI. RPT may produce a red-orange 
discoloration of body tissues and/or fluids (eg, skin, teeth, tongue, urine, feces, saliva, sputum, 
tears, sweat, and cerebrospinal fluid). 
Other serious warnings and precautions for RPT include hepatotoxicity, hypersensitivity reactions 
(hypotension, urticaria, angioedema, acute bronchospasm, conjunctivitis, thrombocytopenia, 
neutropenia, or flu-like syndrome), discoloration of bodily fluids, Clostridium difficile-associated 
diarrhea, and contraindication to use in patients with porphyria. Rifamycins can also cause 
transient increases in direct bilirubin as a result of inhibition of the major bile salt exporter pump 
and/or dose-dependent competition with bilirubin clearance.45,46
Studies in HIV-negative and HIV-infected patients have revealed higher rates of hepatotoxicity 
with daily INH therapy for 9 months vs. weekly RPT + INH.7,9 However, greater discontinuation 
rates in the RPT + INH group because of hypersensitivity or flu-like reactions were observed in 
the study with a largely HIV-negative population.7 The flu-like reaction was characterized by 
symptoms of headache, nausea, chills, fatigue, and myalgia.47 In post hoc analyses of patients 
experiencing these reactions with RPT + INH, risk factors for the development of this AE included 
being 35 years of age older, female sex, lower body mass index, and white non-Hispanic 
race/ethnicity. In a more recent study in HIV-infected individuals, 2/207 (1%) study participants 
developed this AE with RPT + INH, compared to none in the INH-only arm.9 However, these 
hypersensitivity reactions were not observed in a separate study comparing weekly RPT + INH 
therapy to daily INH in HIV-infected individuals,8 or in studies looking at RPT + INH for active 
TB treatment.48,49 
Because healthy volunteers will be limited to three doses of RPT given at weekly intervals, the 
risk to participants in this study is expected to be significantly less than in the long-term treatment 
studies.
INH: In clinical trials and post-marketing surveillance, the most frequent AEs with daily INH 
administration included peripheral neuropathy (dose- and risk factor–related) and mild elevation 
of serum transaminase levels (10%-20%).17 Transaminase elevations are more common with 
concomitant use of RIF, usually occur within 1 to 3 months of initiating therapy, and typically 
normalize with continued treatment. Mild increases do not require treatment discontinuation. Other 
AEs include GI symptoms (nausea, vomiting, epigastric distress, and pancreatitis), hematologic 
changes (agranulocytosis; hemolytic, sideroblastic or aplastic anemia; thrombocytopenia; and 
eosinophilia), hypersensitivity reactions (fever, skin reactions, lymphadenopathy, toxic epidermal 
necrolysis, and drug reaction with eosinophilia syndrome), metabolic and endocrine reactions 


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(pyridoxine deficiency, pellagra, hyperglycemia, metabolic acidosis, and gynecomastia), 
rheumatic syndrome, and systemic lupus erythematosus-like syndrome. Other serious AEs, which 
are uncommon with conventional doses, are convulsions, toxic encephalopathy, optic neuritis and 
atrophy, memory impairment, and toxic psychosis. 
INH carries a black box warning for severe and sometimes fatal hepatitis that can develop after 
several months of therapy, and development of this AE is related to increased age and daily 
consumption of alcohol. In clinical trials comparing once-weekly RPT and INH to daily INH 
therapy, once-weekly therapy was associated with lower rates of grade 3 or 4 transaminase 
elevations (0.3% vs. 2.0% in Sterling et al,7 and 1.5% vs. 5.5% in Martinson et al8 for RPT + INH 
vs. daily INH). Drug discontinuation as a result of hepatotoxicity was significantly higher with 
daily INH therapy (1% for RPT + INH vs. 4% for daily INH, p = 0.05). However, as discussed 
previously, there were greater discontinuation rates in the RPT + INH group as a result of 
hypersensitivity reactions in a largely HIV-negative population.7 These hypersensitivity reactions 
were not observed in a separate study comparing weekly RPT-based therapy to daily INH in HIV-
infected individuals.8 As healthy volunteers will be limited to three doses of INH given at weekly 
intervals, and patients will be counseled to abstain from alcohol consumption during the study 
period, the risk to participants in this study is expected to be less in frequency and severity than in 
the clinical trials with daily INH therapy. 
Pyridoxine: In the studies examining once-weekly RPT + INH for LTBI, pyridoxine was 
coadministered once weekly with the LTBI regimen at a dose of 25 mg8 or 50 mg.7 The risk of 
pyridoxine toxicity is very low as this vitamin is water-soluble, and doses up 100 mg/day are 
considered a safe upper limit for supplementation.24 However, toxic sensory peripheral neuropathy 
has been observed in individuals taking pyridoxine at doses > 200 mg/day for several months at a 
time. As participants in this study will be healthy volunteers, and INH therapy will be limited to 
three doses at once weekly intervals, the risk of peripheral neuropathy due to INH in this study 
population is considered low. The addition of pyridoxine at clinically utilized doses is an added 
safety measure to further reduce the risk of INH-induced deficiency and subsequent AEs.
Blood draw and IV catheter: The risks of drawing blood include pain, bruising, bleeding, and, 
rarely, fainting or infection. Insertion of an IV catheter for collection of blood can also result in 
inflammation of the skin and vein.
Pharmacogenomic testing: There are no foreseeable risks with pharmacogenomic testing. 
Results of pharmacogenomic testing will not become a part of the participant’s medical record at 
the NIH. Records containing this information are maintained in a secure manner. Genetic 
information about the participant will not be revealed to others, including the participant’s 
relatives, without the participant’s permission. We will not release any information about the 
participant to any insurance company or employer unless they sign a document allowing release 
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8.2
Potential Benefits
This is not a therapeutic trial; therefore, study participants will not experience direct benefits from 
their participation. However, the results of this study may help in the care of patients receiving 
these or similar medications in the future.
9
Research Use of Stored Human Samples, Specimens, and Data
Intended Use: Samples, specimens, and data collected under this protocol will be used to assess 
plasma and intracellular concentrations of TAF, TFV and TFV-dp. Genetic testing may be 
performed.  Method development for drug assays (TAF, TFV, TFV-dp) and sample processing 
will be performed by Drs. William Figg and Cody Peer.  
Storage: Samples collected for PK assessments will be stored at −80°C in a locked freezer in the 
NCI Clinical Pharmacology Program (CPP) under the management of the director (Dr. William 
Figg). Other samples collected under this study may be stored at the Frederick National Laboratory 
for Cancer Research. Samples and data will be stored using codes assigned by the investigators or 
their designees. All stored computer data will be password protected. Only investigators will have 
access to the samples and data.
Tracking: Samples acquired under this protocol will be tracked using a database located on a 
password-protected computer. Data will be stored and maintained in CRIMSON database.
Disposition at the Completion of the Protocol:

In the future, other investigators (both at NIH and outside) may wish to study these samples 
and/or data. Before any sharing of samples, data, or clinical information, either institutional 
review board (IRB) approval must be obtained or the NIH Office of Human Subjects 
Research Protections (OHSRP) must determine that the research is exempt from IRB 
oversight. OHSRP can make this determination for some research where the samples or 
data have no personal identifying information about the study participant and the researcher 
is not able to ascertain it.

At the time of protocol termination, samples will either be destroyed, or after IRB approval, 
transferred to another existing protocol. Data will be archived by the study team in 
compliance with requirements for retention of research records; alternatively, after IRB 
approval, the data may be either destroyed or transferred to another repository.
Loss or Destruction:

Any loss or unanticipated destruction of samples (for example, due to freezer malfunction) 
or data (for example, misplacing a printout of data with identifiers) that meets the definition 
of a protocol deviation or unanticipated problem (UP), and/or compromises the scientific 
integrity of the data collected for the study, will be reported to the IRB. 


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
Additionally, participants may decide at any point not to have their samples stored. In this 
case, the principal investigator will destroy all known remaining samples and report what 
was done to both the participant and to the IRB. This decision will not affect the 
individual’s participation in this protocol or any other protocols at NIH.
10
Data Sharing Plan
Human data generated in this study will be shared for future research as follows:

De-identified data in an NIH-funded or approved public repository.

Identified data in the Biomedical Translational Research Information System (BTRIS, 
automatic for activities in the CC).

De-identified or identified data with approved outside collaborators under appropriate 
agreements.

Through publications and/or public presentations.
Data will be shared before, at the time of or shortly after publication.
11
Remuneration Plan for Participants
Participants will be compensated for their time and inconvenience per study visit as described in 
the following table:
Compensation schedule 
Screening
$50
Baseline
$50
Days 14-15
$400
Day 16
$50
Days 22-23
$400
Day 29
$200
Days 31-32
$400
Day 46
$50
Total
$1600
If the participant requires additional clinical follow-up outside of scheduled study visits based on 
medical advisory investigator discretion, then the participant may be compensated an amount 
consistent with NIH CC policies and guidelines for additional follow-up visits/procedures. 
Payment will be issued after the final study visit. Travel and/or lodging expenses may be provided 
as per PI discretion.


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12
Assessment of Safety
12.1
Toxicity Scale
The Investigator will grade the severity of each AE according to the “DAIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events” most recent Version 2.1, July 2017, which 
can be found at: https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-
for-grading-the-severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf?sfvrsn=2. 
Some Grade 1 lab parameters on the DAIDS Toxicity Table fall within the NIH lab reference range 
for normal values. These normal values will not be reported as Grade 1 AEs.
Total bilirubin will be graded according to the “Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Trials”, as indicated in the table below. The 
full 
table 
can 
be 
accessed 
through 
the 
following 
link: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/ucm091977. Only the total bilirubin 
measure (not direct or indirect bilirubin individually) will be used to determine whether pausing 
rules have been met. Direct and indirect bilirubin measures will still be collected as AEs. 
Serum Test
Mild (Grade 1)
Moderate 
(Grade 2)
Severe (Grade 
3)
Potentially 
Life 
Threatening 
(Grade 4)
Total bilirubin – when 
accompanied by any 
increase in LFTs (eg, 
AST, ALT) increase by 
factor.
1.1-1.25 x ULN
1.26-1.5 x ULN
1.51-1.75 x 
ULN
> 1.75 x ULN
Total bilirubin – when 
LFTs (eg, AST, ALT) 
are all normal; increase 
by factor.
1.1-1.5 x ULN
1.6-2.0 x ULN
2.0-3.0 x ULN
> 3.0 x ULN
ALT = alanine transaminase; AST = aspartate transaminase; LFT = liver function test; ULN = 
upper limit of normal.
12.2
Recording/Documentation
At each contact with the participant, starting from the time the informed consent form is signed 
through the end of the final study visit, information regarding AEs will be elicited by appropriate 
questioning and examinations. All events, both expected/unexpected and related/unrelated, will be 
recorded on a source document. Source documents will include progress notes, laboratory reports, 
consult notes, phone call summaries, survey tools, and data collection tools. Source documents 
will be reviewed in a timely manner by the research team. All reportable AEs that are identified 


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will be recorded in CRIMSON. The start date, the stop date, the severity of each reportable event, 
and the principal investigator’s judgment of the AE’s relationship and expectedness to the study 
agent/intervention will also be recorded in CRIMSON.
12.3
Definitions

Please refer to Policy 801 and Policy 802 for definitions
NOTE: The following hospitalizations are not considered SAEs in this clinical study:

A visit to the emergency room or other hospital department lasting less than 24 hours that 
does not result in admission (unless considered an “important medical event” or a 
life-threatening event).

Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical/surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative).
1.  
 
12.4
Reporting Procedures 
AE and SAE reporting to the NIH IRB will be done as per Policy 801 and Policy 802.
12.4.1
Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs, 
and Deaths
Anticipated deviations in the conduct of the protocol will not be reported to the IRB unless they 
occur at a rate greater than anticipated by the study team. Expected AEs will not be reported to the 
IRB unless they occur at a rate greater than that known to occur in a healthy population. If the rate 
of these events exceeds the rate expected by the study team, then the events will be classified and 
reported as though they are UPs. 
12.5
Pregnancy
Although pregnancy itself is not an AE, events occurring during pregnancy, delivery, or in the 
neonate (eg, congenital anomaly/birth defect) may be AEs or SAEs.


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In the event  a participant or female partner of a participant becomes pregnant, prenatal care will 
not be provided by the study and the following steps will be taken:

Discontinue the study agents and procedures but continue to follow-up until delivery for 
safety.

Enroll in antiretroviral pregnancy registry.

Report to safety oversight committee and/or the IRB.

Advise research participant to notify the obstetrician of study participation and study agent 
exposure.
12.6
Type and Duration of the Follow-up of Participants after Serious Adverse 
Events
SAEs that have not resolved by the end of the follow-up period will be followed until final outcome 
is known. If it is not possible to obtain a final outcome for an SAE (eg, the participant is lost to 
follow-up), then the reason a final outcome could not be obtained will be recorded by the 
investigator in CRIMSON.
12.7
Pausing Rules for An Individual Participant
Pausing is the suspension of administration of study agent to a single participant until a decision 
is made whether or not to resume administration of the study agent.
The pausing criteria for a single participant in this study include any of the following:

A participant experiences a > Grade 3 AE that is unexpected and possibly, probably, or 
definitely related to a study agent (except absolute lymphocyte count);

A participant experiences a Grade 2 AE of transaminase elevations that are possibly, 
probably, or definitely related to the study agents.
Any safety issue that the site investigator determines should pause administration of a study agent 
to a single participant.
12.7.1
Reporting a Pause
If a pausing criterion is met, then a description of the AE(s) or safety issue must be reported by the 
principal investigator within 1 business day to the IRB and the safety monitoring committee (SMC) 
by fax or email.
12.7.2
Resumption of a Paused Participant
A participant who experiences an SAE will not be permitted to resume the study agents but will 
continue to be followed for safety.  


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12.7.3
Discontinuation of Study Agent
A participant who does not resume study agent will continue to be followed for safety.
12.8
Halting Rules for the Protocol
Halting the study requires immediate discontinuation of study agents administered for all 
participants and suspension of enrollment until a decision is made whether or not to continue 
enrollment and study agent administration.
The halting rules are:

2 or more participants experience the same or similar ≥ Grade 3 AEs that are possibly, 
probably, or definitely related to the study agents (except for absolute lymphocyte count);
OR

2 or more participants experience Grade 2 events of transaminase elevations that are 
possibly, probably, or definitely related to the study agents;
OR

Any safety issue that the principal investigator and/or the safety oversight committee 
determines should halt the study.
The principal investigator and SMC will determine if the study should be halted.
12.8.1
Reporting a Study Halt
If a halting rule is met, then a description of the AE(s) or safety issue must be reported by the 
principal investigator within 1 business day to the IRB and SMC by fax or email.
12.8.2
Resumption of a Halted Study
The principal investigator and safety oversight committee will determine if it is safe to resume the 
study. The principal investigator will notify the IRB and safety oversight committee of the decision 
on resumption of the study.
12.8.3
Discontinuation of Study Agent
Participants who do not resume study agent will continue to be followed for safety.
12.9
Study Discontinuation
The IRB, the NIAID, the SMC, and other oversight bodies as applicable, as part of their duties to 
ensure that research participants are protected, may discontinue the study at any time. Subsequent 
review of serious, unexpected, and related AEs by the IRB may also result in suspension of 
enrollment and further trial interventions/administration of study agent.


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12.10
Premature Withdrawal of a Participant
An individual participant will be withdrawn for any of the following:

An individual participant’s decision. (The investigator should attempt to determine the 
reason for the participant’s decision.)

Participant loses ability to provide ongoing informed consent.

Non-compliance with study procedures to the extent that it is potentially harmful to the 
participant or to the integrity of the study data.

The investigator determines that continued participation in the study would not be in the 
best interest of the participant.
12.11
Replacement of Withdrawn Participants or Participants Who Discontinue Study 
Treatment
Participants who withdraw or are withdrawn from the study prior to day 31 will be replaced. If a 
participant is replaced, all the data collected from that participant will still be included for the 
safety assessment. 
12.12
Safety Monitoring Committee
An independent SMC consisting of 3 individuals will review the study prior to initiation and at 
specific time points as agreed upon by the SMC. The SMC will focus on participant safety and 
will include subject matter experts. The independent experts do not have direct involvement in the 
conduct of the study and have no significant conflicts of interest as defined by NIAID policy.
Prior to each SMC review, the principal investigator will submit data as requested by the SMC. 
After each SMC review, a recommendation as to whether the study is to continue, be modified, or 
be terminated will be provided in a summary report. All SAEs and all UPs will be reported by the 
principal investigator to the SMC at the same time they are submitted to the IRB. The SMC will 
be notified within 1 business day if pausing or halting rules are met, and the SMC will provide a 
recommendation for continuation, modification, or termination of the study. The principal 
investigator will submit the written SMC summary reports with recommendations to the IRB.
13
Study Monitoring
Accrual and safety data will be monitored by the PI, who will provide oversight to the conduct of 
this study. The PI will continuously evaluate implementation of the protocol for any unusual or 
unpredicted complications that occur and will review the data for accuracy and completeness. 
The NIH CC’s Quality Assurance Program will conduct study monitoring at least annually or more 
frequently as required. Participant consent documents, primary outcome and safety laboratory 
results, and diagnostic test results will be monitored for accuracy, correct dating, and agreement 


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between case report forms and source documents. All regulatory reports, reviews and amendments, 
AEs and problem reports related to study, along with investigator credentials, training records, and 
the delegation of responsibility log will also be reviewed during monitoring visits. The PI will be 
responsible for reporting any problems to the IRB as defined in Section 12.4, Reporting 
Procedures. .
14
Statistical Considerations
14.1
Primary Study Hypothesis
In healthy volunteers receiving TAF concomitantly with RPT + INH (+ pyridoxine), significant 
RPT induction of P-gp will not be observed, and thus levels of TAF, TFV and TFV-dp will not be 
significantly decreased. A significant decrease in TAF and TFV levels is defined as a 25% or 
greater decrease in the AUC geometric mean ratio (GMR) of phase 2 comparatively to phase 1. 
14.2
Sample Size Justification
As described above, power calculations were performed to estimate the probability of declaring 
that there is less than a 25% interaction for different sample sizes assuming there is no interaction. 
Intrasubject variability (CV%) was assumed as 27% for TFV based on available PK data.36,50 If θ 
denotes the phase 2:phase 1 GMR, the procedure we use may be viewed in either of the following 
equivalent ways:
1. Test the null hypothesis that θ ≤ 0.75 versus the alternative hypothesis that θ > 0.75 using 
a log transformation and a one-tailed test at α = 0.05. If the test rejects the null hypothesis, 
then declare the interaction effect to be less than 25%. 
2. Compute the lower confidence limit of a 2-sided, 90% confidence interval for θ (again by 
log transforming and then transforming back at the end). If the lower limit is > 0.75, then 
declare the interaction effect to be less than 25%.
From the tables below, a sample size of 15 participants provides an 88% chance of correctly 
declaring that the interaction effect is less than 25% (ie, θ > 0.75). Equivalently, the probability 
that the lower limit of the confidence interval exceeds 0.75 is 88%. If the test is not significant 
(equivalently, the lower confidence limit is less than 0.75), AND if the upper limit of the 
confidence interval is less than 1, then we will have demonstrated that there is a statistically 
significant, nonzero interaction. If the truth is that there is a 25% interaction (phase 2:phase 1 GMR 
θ = 0.75), then the probability that the upper interval is less than 1 is given in the table below. 
Thus, for example, with a sample size of 15, if the truth is that there is a 25% interaction, then the 
probability that the upper limit of the confidence interval is less than 1 is 88%. 
Power and Sample Size (n) Tables for TFV 
n
6
7
8
9
10
11
12
13
14
15
16
17
18
Power
0.49
0.560
0.621
0.676
0.723
0.765
0.800
0.831
0.858
0.880
0.990
0.916
0.930


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Power is the same whether we define it as P (declare θ > 0.75) when θ is actually 1, or P 
(declare θ < 1) when θ is actually 0.75.
Power and Sample Size (n) Tables for TAF
n
6
7
8
9
10
11
12
13
14
15
16
17
18
Power
0.366
0.420
0.470
0.517
0.560
0.600
0.638
0.672
0.703
0.732
0.759
0.783
0.805
Power is the same whether we define it as P (declare θ > 0.75) when θ is actually 1, or P 
(declare θ < 1) when θ is actually 0.75.
14.3
Description of the Analyses
TAF, TFV, and TFV-dp PK parameters will be determined using noncompartmental methods with 
Phoenix WinNonlin (version 6.03; Pharsight Corporation, Mountain View, CA). Cmax, tmax, and 
Cmin for TAF, TFV, and TFV-dp will be obtained directly by visual inspection of the plasma 
concentration vs. time profiles. The apparent elimination rate constant (λZ) will be determined by 
calculating the absolute value of the slope of the log-linear regression of at least 3 points of the 
plasma concentration-time plot. The t½ will be calculated as 0.693/λZ. The AUC0–24hr will be 
calculated using the linear trapezoidal rule. CL/F will be calculated as CL/F = 25 mg/AUC0-24hr 
for TAF.
Steady-state PK parameters (AUC0-24hr, Cmax, tmax, t½, CL/F, and Cmin) for TAF 25 mg daily will 
be compared alone and in combination with once weekly RPT and INH (dose-adjusted by 
participant weight). GMRs (in combination vs alone) with 90% confidence intervals will be 
calculated using paired t-tests. A p-value less than 0.05 will be accepted as statistically significant.
A paired t-test and confidence interval will be conducted on log-transformed values of PK 
parameters. The confidence interval for GMR will be obtained by exponentiating the limits 
of the log-transformed interval.
The primary analysis will be conducted in patients who report no missing doses.  Sensitivity 
analysis will also be conducted in all participants.
15
Ethics/Protection of Human Participants
15.1
Informed Consent Process
Informed consent is a process where information is presented to enable persons to voluntarily 
decide whether or not to participate as a research participant. It is an ongoing conversation between 
the human research participant and the researchers which begins before consent is given and 
continues until the end of the participant’s involvement in the research. Discussions about the 
research will provide essential information about the study and include: purpose, duration, 


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experimental procedures, alternatives, risks, and benefits. Participants will be given the 
opportunity to ask questions and have them answered.
The participants will sign the informed consent document prior to undergoing any research 
procedures. The participants may withdraw consent at any time throughout the course of the trial. 
A copy of the informed consent document will be given to the participants for their records. The 
researcher will document the signing of the consent form in the participant’s medical record. The 
rights and welfare of the participants will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study.
15.1.1
Non-English–Speaking Participants
If a nonEnglish-speaking participant is unexpectedly eligible for enrollment, the participant will 
be provided with the CC Short Written Consent Form for NonEnglish-speaking Research 
Participants in the participant’s native language and a verbal explanation of the purpose, 
procedures, and risks of the study as described in Medical Administrative Series Policy M77-2, 
NIH HRPP Standard Operating Procedure 12, and Title 45 of the United States Code of Federal 
Regulations (CFR) Part 46.117(b)(2). The IRB-approved English consent form will serve as basis 
for the verbal explanation of the study. The investigator will obtain an interpreter unless the 
investigator is fluent in the prospective participant’s language. Preferably, the interpreter will be 
someone who is independent of the participant (ie, not a family member). Interpreters provided by 
the CC will be used whenever possible. The interpreter will interpret all oral communications 
(English to target language and conversely) between the investigator and a limited 
English-proficient participant, facilitate discussions, and clarify information as necessary.
The IRB-approved English consent form will be signed by the investigator obtaining consent and 
a witness to the oral presentation. The CC Short Written Consent Form will be signed by the 
participant and a witness who observed the presentation of information. The interpreter may sign 
the consent document as the witness and, in this case, will note “Interpreter” under the signature 
line. A copy of both signed forms will be provided to the participant to take home.
The investigator obtaining consent will document the consent process in the participant’s medical 
record (CRIMSON), including the name of the interpreter. Further, all instances of use of the CC 
Short Written Consent Form will be reported to the IRB at the time of annual review. 
15.2
Participant Confidentiality
All records will be kept confidential to the extent provided by federal, state, and local law. The 
study monitors and other authorized individuals may inspect all documents and records required 
to be maintained by the investigator, including but not limited to, medical records. Records will 
be kept locked and all computer entry and networking programs will be done with coded numbers 


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only. Clinical information will not be released without written permission of the participant, except 
as necessary for monitoring by the IRB, NIAID, and OHRP.
16
Data Handling and Record Keeping
16.1
Data Capture and Management 
Study data will be maintained in CRIMSON and collected directly from participants during study 
visits and telephone calls, or will be abstracted from participants’ medical records. Source 
documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary to confirm the data abstracted for this study. Data entry into CRIMSON will 
be performed by authorized individuals. The investigator is responsible for assuring that the data 
collected are complete, accurate, and recorded in a timely manner.
16.2
Record Retention
The investigator is responsible for retaining all essential documents listed in the ICH GCP 
guidelines. Study records will be maintained by the principal investigator according to the 
timelines specified in 45 CFR 312.62 or a minimum of 5 to 7 years, and in compliance with 
institutional, IRB, state, and federal medical records retention requirements, whichever is longest. 
All stored records will be kept confidential to the extent required by federal, state, and local law.
17
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Post FA, Tebas P, Clarke A, et al. Brief Report: Switching to Tenofovir Alafenamide, 
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44.
Claessens YE, Chiche JD, Mira JP, Cariou A. Bench-to-bedside review: severe lactic 
acidosis in HIV patients treated with nucleoside analogue reverse transcriptase inhibitors. 
Critical care. 2003;7(3):226-232.
45.
Byrne JA, Strautnieks SS, Mieli-Vergani G, Higgins CF, Linton KJ, Thompson RJ. The 
human bile salt export pump: characterization of substrate specificity and identification 
of inhibitors. Gastroenterology. 2002;123(5):1649-1658.
46.
Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of 
antituberculosis therapy. Am J Respir Crit Care Med. 2006;174(8):935-952.
47.
Sterling TR, Moro RN, Borisov AS, et al. Flu-like and Other Systemic Drug Reactions 
Among Persons Receiving Weekly Rifapentine Plus Isoniazid or Daily Isoniazid for 
Treatment of Latent Tuberculosis Infection in the PREVENT Tuberculosis Study. 


YODA
Protocol Version 6.0
August 3, 2021
Page 48 of 58
Clinical infectious diseases : an official publication of the Infectious Diseases Society of 
America. 2015;61(4):527-535.
48.
Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week 
versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary 
tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet. 
2002;360(9332):528-534.
49.
Bock NN, Sterling TR, Hamilton CD, et al. A prospective, randomized, double-blind 
study of the tolerability of rifapentine 600, 900, and 1,200 mg plus isoniazid in the 
continuation phase of tuberculosis treatment. Am J Respir Crit Care Med. 
2002;165(11):1526-1530.
50.
United States Food and Drug Administration. Clinical Pharmacology Review: Descovy 
(emtricitabine/tenofovir alafenamide). 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208215Orig1s000ClinPharm
R.pdf. Published December 30, 2016. Accessed July 3, 2017.


YODA
Protocol Version 6.0
August 3, 2021
Page 49 of 58
Appendix A: Dosing Nomogram for Rifapentine and Isoniazid
Rifapentine
Isoniazid
Quantitya
Quantitya,b
Weight (kg)
Dose
150-mg 
tablet
Dose
300-mg 
tablet
100-mg 
tablet
45 to < 48.4
750 mg
5
700 mg
2
1
48.4 to < 50
750 mg
5
750 mg
2.5
0
50 to < 51.7
900 mg
6
750 mg
2.5
0
51.7 to < 55
900 mg
6
800 mg
2
2
55 to < 58.4
900 mg
6 
850 mg
2.5
1
≥ 58.4
900 mg
6 
900 mg
3
0
a
Quantity of tablets per dose. For the total quantity of tablets required for the entire study 
period, multiply the quantity per dose by 3.  
b
If the total quantity of tablets required for the entire study period contains a half-tablet dose, 
then round up to the nearest whole number.


YODA
Protocol Version 6.0
August 3, 2021
Page 50 of 58
Appendix B: Schedule of Procedures/Evaluations
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
Informed 
Consent
X
Medical/Medi
cation History
X
X
X
X
X
X
X
X
X
X
X
Vital 
Signs/Weight
X
X
X
X
X
X
X
Xa
X
X
X
X
Case Manager 
Assessmentb
X
X
X
X
X
X
X
X
X
X
LIP Clinical 
Assessmentb
X
X
X
X
Telephone 
Reminder/
Assessmentc
X
(day 0 
remin
der)
X
X
X
X
X
Acute Care 
Panel
4 mL 
Li-Hep
arin
X
Xd
X
X
X
X
X
Xe
X
X
X
X
Hepatic Panel
4 mL 
Li-Hep
arin
X
Xd
X
X
X
X
X
Xe
X
X
X
X
Mineral Panel
4 mL 
Li-Hep
arin
X
Xd
X
X
X
X
X
Xe
X
X
X
X
CBC/diff
3 mL 
purple
X
Xd
X
X
X
X
X
Xe
X
X
X
X


YODA
Protocol Version 6.0
August 3, 2021
Page 51 of 58
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
Lipid Panel
4 mL 
Li-Hep
arin
X
Xd
CRP
4 mL 
Li-Hep
arin
X
Xd
X
X
X
X
X
Xe
X
X
X
X
CK
4 mL 
Li-Hep
arin
X
Xd
X
X
X
X
X
Xe
X
X
X
X
Amylase
4 mL 
Li-Hep
arin
X
Xd
X
Lipase
4 mL 
Li-Hep
arin
X
Xd
X
Pregnancy 
Testingf
Blood 
or 
Urine
X
X
X
X
X
X
X
X
X
X
X
X
Anti-HIV-1/2
X
QuantiFERON
-Gold TB 
Testing
X
Viral Markers 
Hepatitis 
Screen
X


YODA
Protocol Version 6.0
August 3, 2021
Page 52 of 58
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
Urine Safety 
Labs:
Protein and 
Glucose
X
X
X
X
Study Labs:        
TAF Serial 
plasma PK 
collection
6 mL 
purple 
top
Xg
Xh
Xg
Xh
Xg
Xh
Study Labs: 
Serial PBMC 
collection
8 mL 
CPT 
tube
Xg
Xh
Xg
Xh
Xg
Xh
Study Labs:        
Pharmacogeno
mics
10 mL 
purple 
top
Xi
Study Drugs 
(TAF) 
Dispensed
Xj
Study Drugs 
(TAF): DOT 
Administration
k
X
X
X
X
X
X
X


YODA
Protocol Version 6.0
August 3, 2021
Page 53 of 58
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
Study Drugs 
(RPT, INH, 
Vit B6) 
Dispensed and 
DOT 
Administration
l
X
X
X


YODA
Protocol Version 6.0
August 3, 2021
Page 54 of 58
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
CBC/diff = complete blood cell count with differential; CK= creatine kinase; CRP= C-reactive protein; DOT = directly observed therapy; INH = 
isoniazid; LIP= licensed independent practitioner; PBMC = peripheral blood mononuclear cell; PK = pharmacokinetics; RPT = rifapentine; 
TAF= tenofovir alafenamide; TB= tuberculosis; Vit B6 = vitamin B6; X = to be performed.
a Vital signs will be collected at the time of study drug administration and at the discretion of the medically advisory investigator as clinically 
indicated throughout the Day 29 observation period.
b LIP assessments will take place at the screening (Day −89 to 0), baseline (Day −6 to 0) and end-of-study (Day 46 ± 3) visits, and as clinically 
indicated during the study period. The remaining clinical assessments refer to case manager assessments during which AE assessments, 
medication reconciliations, and adherence assessments will be completed.
c Phone call on Day 0 to remind participant to start taking TAF study medication starting Day 1. Reminder phone calls for long study visit days 
14, 22, 29, and 31. Assessment of study medication tolerability will also be performed. Follow-up phone call assessment for side effects at day 
60 ± 3.
d Blood will only be collected at baseline if the baseline visit is more than 6 days after screening.
e Safety labs will be repeated during the Day 29 observation period at the discretion of the medically advisory investigator as clinically indicated.
f Pregnancy test must be negative to proceed in the study. Pregnancy test will be performed at every visit prior to study drug administration. 
Pregnancy test may be conducted with blood and/or urine.
g Blood for serial PK time points (plasma) are 0 (predose), 0.25, 0.5, 1, 2, 4, 6, and 8 hours postdose. Blood for serial PK time points (PBMCs) 
are 0 (predose), 1, 2, 6, and 8 hours postdose. Samples will be processed and stored by the Figg Laboratory Clinical Pharmacology Program 
Page: 102-11964.  Phone: 240-760-6180 or 240-760-6190.
h 24 hour postdose trough collection (plasma and PBMC). Samples will be processed and stored by the Figg Laboratory Clinical Pharmacology 
Program:102-11964.  Phone: 240-760-6180 or 240-760-6190.
i Sample collection for pharmacogenomics will be drawn PK time point 0.  Send to Frederick as whole blood to be frozen and stored. NIH 
Contact: Cathy Rehm. Frederick Contact: Ven Natarajan 301-846-1258.
j A 31-day supply (+ 3 additional tablets) will be dispensed to the participant at the baseline visit. Participant will be reminded to bring the TAF 
study medication supply to each visit.
k On study day visits 14, 15, 16, 22, 23, 29, and 31, participants will be reminded to bring in their TAF study medication supply to the NIH to be 
administered at the clinic or Day Hospital under DOT.


YODA
Protocol Version 6.0
August 3, 2021
Page 55 of 58
Evaluation
Scree
ning
(Day 
−89 to 
−0)
Baseli
ne
(Day 
−6 
to 0)
Da
y 
10 
(+ 
1)
Da
y 
14
Da
y 
15
Da
y 
16 
Da
y 
18 
(+ 
3)
Da
y 
22
Da
y 
23
Da
y 
25 
(+ 
3)
Da
y 
29
Da
y 
30
Da
y 
31
Da
y 
32
Da
y 
46 
(+ 
3)
Da
y 
60 
(+ 
3)
Early 
Termin
ation 
Visit
l On study day visits 15, 22, and 29, study drugs RPT, INH, and vitamin B6 will be dispensed from the pharmacy and administered to the 
participant at the clinic or Day Hospital under DOT.
 


YODA
Protocol Version 6.0
August 3, 2021
Page 56 of 58
Appendix C: Blood Volumes for Specimen Collection
Study day
Evaluation
Screening
(days −89 to 
0)
Baselinea
(day −6 to 
0)
14
15
16
22
23
29
31
32
46 
(± 3)
Early 
terminati
on visit
HIV-1/2 
antigen/antibody 
testing
8
QuantiFERON Gold
3
Viral markers 
hepatitis screen
8
Acute care panelb
4
4
4
4
4
4
4
4
4
4
4
4
Hepatic panelb
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
Mineral panelb
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
Creatine kinaseb
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
Lipaseb
(4)
(4)
Amylaseb
(4)
(4)
Lipid panelb
(4)
(4)
CRPb
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
Serum pregnancy testb
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
(4)
CBC/diff
3
3
3
3
3
3
3
3
3
3
3
3
PK blood
48
6
48
6
48
6
PBMCs
40
8
40
8
40
8
Pharmacogenomicsc
10
Daily volume (mL)
26
7
105
21
7
95
21
7
95
21
7
7
Cumulative volume 
(mL)
26
33
138
159
166
261
282
289
384
405
412


YODA
Protocol Version 6.0
August 3, 2021
Page 57 of 58
CBC/diff = complete blood count with differential; CRP = C-reactive protein; PBMC = peripheral blood mononuclear cell; PK = 
pharmacokinetics.
a
Blood will only be collected at baseline if this visit is more than 6 days after screening.
b
A single volume of blood will be collected for acute care, hepatic, mineral, and lipid panels, amylase, lipase, CRP, creatine kinase, and 
pregnancy test.
c
Sample collection for pharmacogenomics. Send to Frederick as whole blood to be frozen and stored. NIH Contact: Cathy Rehm. 
Frederick Contact: Ven Natarajan 301-846-1258.


YODA
Protocol Version 6.0
August 3, 2021
Page 58 of 58
Appendix D: Study Initiation Calendar
Sunday
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
 
Day 0
Day 1 
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 12
Day 13
Day 14
Day 15
Day 16
Day 17
Day 18
Day 19
Day 20
Day 21
Day 22
Day 23
Day 24
Day 25
Day 26
Day 27
Day 28
Day 29
Day 30
Day 31
Day 32
Day 33
Day 34
Day 35
Day 36
Day 37
Day 38
Day 39
Day 40
Day 41
Day 42
Day 43
Day 44
Day 45
Day 46
Day 47
Day 48
Day 49
Day 50
Day 51
Day 52
Day 53
Day 54
Day 55
Day 56
Day 57
Day 58
Day 59
Day 60
Days with study visits to the NIH are bolded.