Impact of Weekly Administration of Rifapentine and Isoniazid on Steady State Pharmacokinetics of Tenofovir Alafenamide in Healthy Volunteers (YODA)

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 firstline 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.

- PARTICIPANT INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

1. Ages 18-65 years.

2. Weight greater than or equal to 45 kg and less than or equal to 120 kg OR body mass
index greater than or eqaul to 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) less than or equal
to upper limit of normal [ULN], SCr less than or equal to ULN, platelets (PLT) >
150,000/microL, hemoglobin (Hgb) > 13 g/dL (males); greater than or equal to 12g/dL
(females), C-reactive protein (CRP) less than or equal to ULN, CK less than or equal
to 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.

1. Male or female condom.

2. Diaphragm or cervical cap with a spermicide.

3. Intrauterine device without hormones.

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:

1. Latent or active TB infection.

2. 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).

3. 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).

4. Respiratory disease that is uncontrolled or requires daily treatment with
medication (eg, asthma or chronic obstructive pulmonary disease).

5. Cardiovascular disease (eg, hypertension [systolic blood pressure > 140 mm Hg or
diastolic blood pressure > 90 mm Hg], heart failure, or arrhythmia).

6. Metabolic disorders (eg, diabetes mellitus).

7. Hematologic or bleeding disorders (eg, anemia, hemophilia, serious/major bleeding
events, menorrhagia [female participants]).

8. Immunologic disorders.

9. Hormonal or endocrine disorders.

10. Psychiatric illness that would interfere with their ability to comply with study
procedures or that requires daily treatment with medication.

11. Seizure disorder, with the exception of childhood febrile seizures.

12. 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.

13. 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 patches, gum, electronic cigarettes, etc.

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.