A multicenter, randomized, stratified, open-label, phase IV trial among HIV-positive persons (PLHIV) on antiretroviral therapy (ART), or HIV-negative household contacts of patients with rifampicin-sensitive pulmonary tuberculosis (TB), who do not have evidence of active TB.

Participants will be stratified by indication for tuberculosis (TB) preventive treatment (TPT) - HIV seropositive persons or HIV-negative household contact of person with infectious TB - and will receive either one of two TB preventive therapy regimens:

Group 1: People living with HIV infection without active TB

Arm A: isoniazid (300mg) and rifapentine (600mg) daily for 4 weeks (1HP)

Arm B: isoniazid (900mg) and rifapentine (900mg) weekly for 12 weeks (3HP)

Arm A (n=250): 250 participants age ≥13 years of age who are HIV seropositive and taking ART who do not have evidence of active TB will be recruited from local clinics. After being consented, screened, and randomized, participants in Arm A will receive the 1HP regimen once daily for 4 weeks (28 doses).

Study events include a health history, physical exam, TB symptom screen, symptom screen for adverse events (AEs), adherence checks during 1HP, and clinic visits at months 1, 2, and 6, at the least. Safety labs for liver function will be checked as clinically indicated.

Arm B (n=250): 250 participants age ≥13 years of age who are HIV seropositive and taking ART who do not have evidence of active TB will be recruited from local clinics. After being consented, screened, and randomized, participants in Arm B will receive the 3HP regimen once weekly for 12 weeks (12 doses).

Study events include a health history, physical exam, TB symptom screen, symptom screen for adverse events (AEs), adherence checks during 3HP, and clinic visits at months 1, 2, 3, and 6, at the least. Safety labs for liver function will be checked as clinically indicated.

Group 2: HIV-negative household contacts of newly diagnosed adults with rifampicin-sensitive pulmonary TB.

Arm A: isoniazid (300mg) and rifapentine (600mg) daily for 4 weeks (1HP)

Arm B: isoniazid (900mg) and rifapentine (900mg) weekly for 12 weeks (3HP)

Arm A (n=250): 250 participants age ≥13 years of age who are HIV-negative household contacts of adults with rifampicin-sensitive pulmonary TB who do not have evidence of active TB will be recruited from local clinics and households of active cases. After being consented, screened, and randomized, participants in Arm A will receive the 1HP regimen once daily for 4 weeks (28 doses).

Study events include a health history, physical exam, TB symptom screen, symptom screen for adverse events (AEs), adherence checks during 1HP, and clinic visits at months 1, 2, and 6, at the least. Safety labs for liver function will be checked as clinically indicated.

Arm B (n=250): 250 participants age ≥13 years of age who are HIV-negative household contacts of adults with rifampicin-sensitive pulmonary TB who do not have evidence of active TB will be recruited from local clinics and households of active cases. After being consented, screened, and randomized, participants in Arm B will receive the 3HP regimen once weekly for 12 weeks (12 doses).

Study events include a health history, physical exam, TB symptom screen, symptom screen for adverse events (AEs), adherence checks during 3HP, and clinic visits at months 1, 2, 3, and 6, at the least. Safety labs for liver function will be checked as clinically indicated.

Group 1: HIV-positive adolescents and adults in South Africa and India

Inclusion criteria:

1. Age ≥ 13 years
2. Weight > 30 kg
3. HIV-seropositive
4. HIV viral load <400 copies/mL, defined as "virally suppressed," on an EFV or DTG-based ART regimen (see Section 3.6.2)
5. Candidates must meet WHO criteria for receiving TPT

Exclusion criteria:

1. Confirmed or suspected TB disease (evidenced by symptoms and/or clinical exam findings and/or chest radiographic findings suggestive of TB, positive mycobacterial culture or molecular TB testing or currently on TB treatment for active TB disease)
2. Likely to move from the study area during the study period
3. Known recent exposure to a TB case with resistance to isoniazid or rifampicin.
4. Previous treatment for active or latent TB for more than 30 days within the past 2 years
5. On nevirapine, etravirine, rilpivirine, PI-based, or raltegravir-containing ART regimens
6. Known sensitivity or intolerance to isoniazid or rifamycins
7. Suspected acute hepatitis or known chronic or unstable liver disease^
8. ALT > 3 times the upper limit of normal (ULN)
9. Total bilirubin > 2.5 times the ULN
10. Pregnancy or breastfeeding Females of childbearing potential who are unable or unwilling to use two forms of contraception**
11. On prohibited medications (see Appendix I)

Group 2: HIV-negative household contacts of an adult with confirmed pulmonary TB in Mozambique and Indonesia

Inclusion criteria:

1. Age ≥ 13 years
2. Weight > 30 kg
3. HIV-negative
4. Household contact of an adult with confirmed rifampicin-sensitive pulmonary TB
5. Candidates must meet WHO criteria for receiving TPT

Exclusion criteria:

1. Confirmed or suspected TB disease (evidenced by symptoms and/or clinical exam findings and/or chest radiographic findings suggestive of TB, positive mycobacterial culture or molecular TB testing or currently on TB treatment for active TB disease)
2. Likely to move from the study area during the study period
3. Known exposure to TB cases with resistance to isoniazid or rifampicin in the source case
4. Previous treatment for active or latent TB for >30 days within the past 2 years
5. Known sensitivity or intolerance to isoniazid or rifamycins
6. Suspected acute hepatitis or known chronic or unstable liver disease^
7. ALT > 3 times the upper limit of normal (ULN)
8. Total bilirubin > 2.5 times the ULN
9. Pregnancy or breastfeeding Females of childbearing potential who are unable or unwilling to use two forms of contraception**
10. On prohibited medications