The goal of this cluster-randomized controlled trial is to evaluate the effectiveness of tuberculosis preventive treatment (TPT) administered during the "window period" to prevent new Mycobacterium tuberculosis infections in children and adolescents.

The main question it aims to answer is:

Can immediate TPT reduce the incidence of IGRA conversions in children and adolescents who are household contacts of a newly diagnosed pulmonary tuberculosis patient?

Researchers will compare the incidence of new tuberculosis infections-measured by IGRA conversion at 12 weeks-between participants who receive immediate TPT while still uninfected (baseline IGRA-negative) and those who receive standard care, in which TPT is not offered to IGRA-negative contacts.

Participants will be:

1. Tested for M. tuberculosis infection using the Interferon-Gamma Release Assay (IGRA), specifically the QuantiFERON-TB Gold Plus, at enrollment and after 12 weeks of follow-up.

2. Take weekly isoniazid and rifapentine for 12 weeks if:

   1. They are assigned to the intervention arm (regardless of baseline IGRA result), or
   2. They are in the control arm and test IGRA-positive at baseline.

Additionally, participants from the control arm who experience an IGRA conversion at 12 weeks (following the primary outcome assessment) will also receive TPT, as per standard of care.

Mycobacterium tuberculosis acquisition following exposure is a common occurrence, but it remains challenging to diagnose, often requiring serial testing, as immunological responses (e.g., tuberculin skin test or interferon-gamma release assays) can take weeks to provide evidence of infection. Although tuberculosis infection is generally asymptomatic, research has shown that active mycobacterial replication and inflammation occur, and its long-term effects are not well understood due to the complexity of host-pathogen interactions and delayed disease progression. While antituberculosis prophylaxis has traditionally aimed at preventing the progression from established tuberculosis infection to active tuberculosis disease, recent studies suggest that prophylaxis administered during the "window period" after exposure may also prevent its acquisition, particularly in very young children.

This trial will help determine the effectiveness of tuberculosis prophylaxis administered during the window period in preventing the acquisition of tuberculosis infection in children and adolescents exposed in household settings. If successful, the findings may inform broader strategies for tuberculosis prevention, particularly in reducing reservoirs of Mycobacterium tuberculosis and contributing to the global tuberculosis elimination efforts.

Inclusion Criteria:

• Household contacts of patient (index case) with a new diagnosis of microbiologically confirmed pulmonary tuberculosis
• Age ≥5 to <18 years old

Exclusion Criteria:

• Suspected active tuberculosis in initial assessment (clinical or radiological)
• Current pregnancy or breastfeeding
• Immunocompromised
• Allergy or contraindication to isoniazid or rifapentine
• Chronic liver disease or alcohol use disorder
• History of previous treatment for active or latent tuberculosis infection
• Previous tuberculin skin test
• Household contacts of a tuberculosis index patient with a known or suspected drug-resistant M. tuberculosis strain
• Household contacts or a tuberculosis index patient currently living away from home for more than four weeks
• Household contacts of a tuberculosis index patient who have already received more than 15 daily doses of antituberculous treatment