DESIGN                   This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week daily rifapentine (RPT)/isoniazid (INH) regimen to a standard 9-month daily INH regimen for the prevention of tuberculosis (TB) in HIV-infected participants without evidence of active TB. The primary objective will be efficacy of TB prevention. The study will also assess safety and tolerability of the regimens, adherence to the treatments, and patterns of antibiotic resistance among Mycobacterium tuberculosis (MTB) isolates in participants who fail on these prophylactic regimens.

DURATION              Each participant will be followed for 3 years (156 weeks) after the last participant is enrolled.

SAMPLE SIZE         3000 participants

POPULATION         HIV-1 infected men and women ≥13 years old and ≥30 kg without evidence of active TB who:

1. Have tuberculin skin test (TST) reactivity ≥5 mm or a positive interferon gamma release assay (IGRA), OR

2. Live in high burden areas, defined as countries with all cases of TB prevalence ≥60 cases/100,000 population/year, according to the WHO (http://apps.who.int/globalatlas/predefinedreports/tb/index.asp).

If taking antiretroviral therapy (ART) and RPT, only nucleoside reverse transcriptase inhibitor (NRTI)- or non-NRTI (NNRTI)-based regimens are permitted for the first 4 weeks of study participation.

STRATIFICATION   Participants will be stratified based on (1) CD4+ cell count at entry (<100, 100-250, and >250 cells/mm³) and (2) ART use at entry (Yes/No).

REGIMEN                Participants will be randomized within strata in a 1:1 ratio to receive either:

Arm A: 4-week daily regimen of weight-based RPT and INH, plus pyridoxine (vitamin B₆)

OR

Arm B: 9-month (36-week) daily INH regimen, plus pyridoxine (vitamin B₆)