Evaluating the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine and Isoniazid in HIV-1-Infected and HIV-1-Uninfected Pregnant and Postpartum Women With Latent Tuberculosis Infection

TB is a major cause of illness and death in women of reproductive age. Pregnant and
postpartum women with latent TB are at higher risk of developing active TB. This study will
evaluate the pharmacokinetics, tolerability, and safety of 12 once-weekly doses of RPT and
INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent TB.

This study will enroll HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and
their infants into two cohorts based on gestation. Cohort 1 participants will be enrolled in
their second trimester (greater than or equal to 14 to less than 28 weeks), and Cohort 2
participants will be enrolled in their third trimester (greater than or equal to 28 to less
than or equal to 34 weeks). All participants will receive 12 directly observed once-weekly
doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up
visits. Study researchers will perform an interim analysis during the study, and a dose
adjustment may be recommended based on this analysis.

Study visits will occur at days 0-3, once a week through week 11, and once a month until 24
weeks after delivery. Visits will include physical examinations, obstetrical exams, and blood
collection. Infants will be followed monthly until 24 weeks after birth.

Inclusion Criteria:

- Age greater than or equal to 18 years, or minimum age of consent according to locally
applicable laws or regulations at screening, verified per site standard operating
procedures (SOPs); and able and willing to provide written informed consent for study
at screening

- At screening, evidence by ultrasound of a viable singleton pregnancy with an estimated
gestational age at enrollment of greater than or equal to 14 weeks through less than
or equal to 34 weeks as per screening ultrasound (see protocol for more information)

- Has at least one of the following risk factors for TB:

- Per participant report, the participant is a household contact* of a known active
pulmonary TB patient

- Per medical records, confirmation of HIV-1 infection (see protocol for more
information) and a single positive tuberculin skin test (TST) or interferon gamma
release assay (IGRA) at any time in the past. If not available in medical record,
perform at screening.

- Note: A household contact is defined as a person who currently lives or lived in
the same dwelling unit and shares or shared the same housekeeping arrangements
and who reports exposure within the past two years to an adult index case with
pulmonary TB. Shared housekeeping arrangements are defined as sleeping under the
same roof as the index TB case for at least seven consecutive days during the one
month prior to the index case TB diagnosis.

- Documentation of HIV-1 infection status, or confirmation of HIV-1 infection status (if
unknown or undocumented). Confirmation of HIV-1 infection is defined as positive
results from two samples (described in the protocol) collected at different time
points. All samples tested must be whole blood, serum, or plasma. As this study is
being conducted under an IND, all test methods should be FDA-approved, if available.
If FDA-approved methods are not available, test methods should be verified according
to Good Clinical Laboratory Practice (GCLP) and approved by the IMPAACT Laboratory
Center. More information on this criterion is available in the protocol.

- If HIV-1-infected, documented current prescription of efavirenz (EFV) + 2 nucleoside
reverse transcriptase inhibitor (NRTI) regimen and reports taking regimen for at least
two weeks prior to enrollment (regimens containing protease, integrase, or entry
inhibitors are not permitted)

- Documented laboratory values obtained within 14 days prior to enrollment:

- Hemoglobin greater than or equal to 7.5 g/dL

- White blood cell count greater than or equal to 1,500 cells/mm^3

- Alanine transaminase (ALT) less than 2.5 times the upper limit of normal (ULN)

- Total bilirubin less than 1.6 times the ULN

- Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3

- Platelet count greater than or equal to 100,000/mm^3

- Per participant report at screening, intent to remain in the current geographical area
of residence for the duration of the study

- Per participant report at screening, able to swallow whole tablets

- Per participant report, intention to keep the pregnancy

- Per participant report, willingness to permit infant to participate in the study

Exclusion Criteria:

- Evidence of confirmed or probable active TB disease per World Health Organization
(WHO) symptom screen and confirmation by Gene Xpert, shielded chest x-ray, or sputum
sample

- Participant report of personal history of INH- or rifampin-resistant, multi-drug
resistant (MDR), or extensively drug-resistant (XDR) TB

- Participant report of personal history of active TB in the past 2 years

- Participant report of previous treatment for latent tuberculosis infection (LTBI)

- Household contact (as defined above) with known active MDR or XDR TB disease

- Known major fetal abnormality as detected on ultrasound

- Known allergy/sensitivity or any hypersensitivity to components of study drugs or
their formulation

- Known history of liver cirrhosis at any time prior to study entry

- Per participant report and/or medical records, evidence of acute clinical hepatitis,
such as a combination of abdominal pain, jaundice, dark urine, and/or light stools
within 90 days prior to entry

- Participant report and/or medical records of peripheral neuropathy Grade 2 or higher
within 90 days prior to entry

- Current use or history of active drug or alcohol use or dependence that, in the
opinion of the site investigator, would interfere with adherence to study requirements

- Participant report and/or clinical evidence of porphyria

- Any other condition that, in the opinion of the investigator of record (IoR)/designee,
would preclude informed consent, make study participation unsafe, complicate
interpretation of study outcome data, or otherwise interfere with achieving the study
objectives, including taking the study medication

- Planned or current participation in an interventional drug study

- Current use of any prohibited or precautionary medications (see protocol for more
information), including didanosine (DDI) or stavudine (D4T)