• Culture-confirmed tuberculosis in persons > 18 years old AND Culture-confirmed or probable (clinical) tuberculosis in persons < 18 years old [ Time Frame: assessed both 33 months after enrollment, and 24 months after completion of therapy ] [ Designated as safety issue: No ]
  The rates of development of the primary endpoint will be compared: a) within 24 months of completing therapy, and b) given the possibility that TB can occur before treatment completion, within 33 months from the time of enrollment. Such an analysis is most appropriate for the determination of treatment effectiveness, including "intention-to-treat" analyses. Because "intention-to-treat" analyses can potentially increase the risk of falsely claiming non-inferiority (type I error), "per protocol" analyses will also be performed.
  
  

• 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 ]

  The maximum level of toxicity reached graded 3 or 4 as per the Common Toxicity Criteria (CTC ver. 2.0, Publish Date April 30, 1999, Cancer Therapy Evaluation Program).

  RELATED toxicity is defined as any AE occurring in a timely manner after administration of the study drug(s) that does or does not follow a known pattern of reaction and for which no other explanation is known. This category applies to those AEs that, after careful medical consideration at the time they are evaluated, are considered to be unlikely to be related but cannot be ruled out with certainty.

  
  
• Death [ Time Frame: during study therapy or within 60 days of the date of the last study dose ] [ Designated as safety issue: Yes ]
  Death due to any cause (grade 5 toxicity as per per the Common Toxicity Criteria [CTC ver. 2.0]).
  
  
• 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 ]
  Among participants concomitantly receiving methadone, the development of methadone withdrawal (defined as having > 3 new symptoms for > 7 days: nausea and vomiting, abdominal cramps, body aches, restlessness, irritability, dilated pupils, tremors, involuntary twitching, lacrimation, rhinorrhea, sneezing, yawning, excessive perspiration, goose flesh, or diarrhea).
  
  
• Discontinuation of therapy for any reason [ Time Frame: during study-phase therapy ] [ Designated as safety issue: Yes ]

  All patients who have not received at least 90% of the prescribed doses within the specified time periods:

  Patients on 3RPT/INH: considered to have incomplete therapy if they received less than 11 doses during a 16-week time period.

  Patients on 9INH: considered to have incomplete therapy if they received less than 240 doses (90%) during a 52-week period.

  
  
• Completion of the prescribed regimen [ Time Frame: Patients on 3RPT/INH: 16-week time frame. Patients on 9INH: 52-week time frame. ] [ Designated as safety issue: No ]

  Evidence of receipt of at least 90% of the prescribed doses within the specified time periods:

  Patients on 3RPT/INH: considered to have completed therapy if they received at least 11 doses (90%) during a 16-week time period.

  Patients on 9INH: considered to have completed therapy if they received at least 240 doses (90%) during a 52-week period.

  
  
• Development of culture (+) TB among HIV-infected patients [ Time Frame: assessed both 33 months after enrollment, and 24 months after completion of therapy ] [ Designated as safety issue: No ]
  The rates of development of the primary endpoint will be compared among people living with HIV: a) within 24 months of completing therapy, and b) given the possibility that TB can occur before treatment completion, within 33 months from the time of enrollment. Such an analysis is most appropriate for the determination of treatment effectiveness, including "intention-to-treat" analyses. Because "intention-to-treat" analyses can potentially increase the risk of falsely claiming non-inferiority (type I error), "per protocol" analyses will also be performed.
  
  
• Patterns of antibiotic resistance among Mycobacterium tuberculosis isolates in patients who develop TB [ Time Frame: among TB cases assessed both 33 months after enrollment, and 24 months after completion of therapy ] [ Designated as safety issue: Yes ]
  Development of resistance to study medications in isolates of M. tuberculosis from subjects who develop active TB.
  
  
• Discontinuation of study therapy due to adverse drug reactions [ Time Frame: during study-phase therapy ] [ Designated as safety issue: Yes ]

  Compare the rates of drug discontinuation due to adverse drug reactions associated with 3RPT/INH and 9INH.

  Development of a toxicity that warrants permanent discontinuation of any study drug as per the principal investigator's judgment.

  
  

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 (LTBI). 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.

Amendment of the study protocol to allow extension of enrollment to children < 12 years old and HIV-infected persons:

For assessment of the primary outcome, development of TB, a sample size of approximately 4,000 persons per arm will be required. To assess tolerability (one of the secondary outcomes) in sub-groups, children less than 12 years old and HIV-infected persons, a sample size of 644 per strata will be required. A sample size of 8,053 patients for the primary outcome was reached on February 15, 2008 (with expected follow-up completion time in 2010), leaving approximately 454 additional young children and 200 HIV-infected persons to be enrolled to achieve the targets of 644 for each group. The additional data on tolerability in those sub-groups will available for analysis in 2013.