• Culture-confirmed tuberculosis in persons > 18 years old [ Time Frame: within 33 months of completion of LTBI therapy ] [ Designated as safety issue: No ]
• Culture-confirmed or probable (clinical) tuberculosis in persons < 18 years old [ Time Frame: within 33 months of completion of LTBI therapy ] [ Designated as safety issue: No ]

• Culture-confirmed tuberculosis in persons > 18 years old
• Culture-confirmed or probable (clinical) tuberculosis in persons < 18 years old
• OR

• Grade 3 or 4 drug-related toxicity [ Time Frame: during study therapy or within 60 days of the date of the last study dose ] [ Designated as safety issue: Yes ]
• Death [ Time Frame: during study therapy or within 60 days of the date of the last study dose ] [ Designated as safety issue: Yes ]
• Development of methadone withdrawal [ Time Frame: during study therapy or within 60 days of the date of the last study dose ] [ Designated as safety issue: Yes ]
• Discontinuation of therapy for any reason [ Time Frame: during study therapy ] [ Designated as safety issue: Yes ]
• Completion of the prescribed regimen [ Time Frame: within 33 months ] [ Designated as safety issue: Yes ]
• Development of culture (+) TB among HIV-infected patients [ Time Frame: within 33 months of completion of LTBI therapy ] [ Designated as safety issue: No ]
• Development of resistance to study medications in isolates during LTBI study therapy [ Time Frame: within 33 months ] [ Designated as safety issue: Yes ]
• Discontinuation of study therapy due to AE [ Time Frame: during study therapy phase ] [ Designated as safety issue: Yes ]

• *Discontinuation of study drugs due to AE *Grade 3 or 4 drug-related toxicity *Death
• *Development of methadone withdrawal *Discontinuation of therapy for any reason *Completion of the prescribed regimen *Culture (+) TB among HIV-infected *Resistance to study medications in isolates

The objectives of this open-label Phase III clinical trial is to compare the effectiveness and tolerability of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose)regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (TLI).

The PRIMARY objective of this open-label Phase III clinical trial is to compare the effectiveness of a three-month (12-dose) regimen of weekly rifapentine and isoniazid (3RPT/INH) to the effectiveness of a nine-month (270-dose) regimen of daily isoniazid (9INH) to prevent tuberculosis (TB) among high-risk tuberculin skin-test reactors, including children and HIV-infected persons, who require treatment of latent TB infection (TLI). The 3RPT/INH regimen will be given under direct observation and the 9INH regimen will be self-administered.

SECONDARY Objectives:

• Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.
• Compare the rates of drug discontinuation for any reason associated with 3RPT/INH and 9INH.
• Compare the rates of any grade 3, 4, or 5 drug toxicity associated with 3RPT/INH and 9INH.
• Compare treatment completion rates of 3RPT/INH and 9INH. Compare the efficacy (i.e., among persons who complete study-phase therapy) of 3RPT/INH and 9INH.
• Compare the effectiveness and tolerability of 3RPT/INH and 9INH in HIV-infected persons.
• Compare the effectiveness and tolerability of 3RPT/INH and 9INH in children < 18 years old.
• Compare the rates of methadone withdrawal associated with 3RPT/INH and 9INH among persons concomitantly receiving methadone.
• Describe patterns of antibiotic resistance among M. tuberculosis isolates in patients who develop TB despite treatment of latent infection.

• Drug: Rifapentine + Isoniazid once weekly for 3 months
• Drug: Isoniazid daily for 9 months

• Active Comparator: INH daily for 9 mo.
• Experimental: RPT/INH weekly for 3 months given by DOT

INCLUSION criteria:

• Males or nonpregnant, non-nursing females > 2 years old.

• Tuberculin (PPD) skin test reactors at high risk for developing TB but without evidence of active TB. High-risk reactors are defined as:

  1. Household and other close contacts of persons with culture-confirmed TB who are TST-positive as part of a contact investigation conducted within two years of the date of enrollment. Close contact is defined as > 4 hours in a shared airspace during a one-week period. Among close contacts, a positive TST is defined as > 5 mm induration after 5 TU of PPD placed intradermally using the Mantoux technique.
  2. TST converters--converting from a documented negative to positive TST within a two-year period. This is defined as persons with a tuberculin skin test of > 10 mm within two years of a nonreactive test or persons with an increase of > 10 mm within a two-year period.
  3. HIV-seropositive, TST positive (> 5 mm induration) persons.
  4. Persons with > 2 cm2 of pulmonary parenchymal fibrosis on chest X-ray, no prior history of TB treatment, > 5 mm induration on TST, and 3 sputum cultures negative for M. tuberculosis on final report.
• HIV-seropositive close contacts of persons with culture-confirmed TB, regardless of TST status. In addition, HIV-seropositive close contacts of persons with culture-confirmed TB who have a documented history of completing an adequate course of treatment for active TB or latent TB infection, are also eligible.
• Willing to provide signed informed consent, or parental consent and participant assent.

EXCLUSION criteria:

• Current confirmed culture-positive or clinical TB
• Suspected TB (as defined by the site investigator)
• Tuberculosis resistant to isoniazid or rifampin in the source case
• A history of treatment for > 14 consecutive days with a rifamycin or > 30 consecutive days with INH during the previous 2 years.
• A documented history of a completing an adequate course of treatment for active TB or latent TB infection in a person who is HIV-seronegative.
• History of sensitivity/intolerance to isoniazid or rifamycins
• Serum aminotransferase aspartate (AST, SGOT) > 5x upper limit of normal among persons in whom AST is determined
• Pregnant or nursing females
• Persons currently receiving or planning to receive HIV-1 protease inhibitors or nonnucleoside reverse transcriptase inhibitors in the first 90 days after enrollment.
• Weight < 10.0 kg