• Time from randomization to development of tuberculosis (TB) disease or death among HIV infected children [ Time Frame: At Week 96 ] [ Designated as safety issue: Yes ]
  
• Time from randomization to development of TB infection or death among perinatally exposed, HIV uninfected children [ Time Frame: At Week 96 ] [ Designated as safety issue: Yes ]
  

• Time from randomization to development of TB infection, and time from randomization to development of TB disease among HIV infected and perinatally exposed, HIV uninfected children [ Time Frame: At Week 96 and Week 192 ] [ Designated as safety issue: Yes ]
  
• Time from randomization to death among HIV infected and perinatally exposed, HIV uninfected children [ Time Frame: At Week 96 and Week 192 ] [ Designated as safety issue: Yes ]
  
• Population pharmacokinetics (PK) model of isoniazid (INH) among HIV infected and perinatally exposed, HIV uninfected children at two dosing interval time points on two separate occasions (at Cape Town and Durban only) [ Time Frame: Throughout study ] [ Designated as safety issue: No ]
  
• Time from randomization to development of TB infection among HIV infected children [ Time Frame: At Week 96 ] [ Designated as safety issue: Yes ]
  
• Time from randomization to AIDS-defining illness or death among HIV infected children [ Time Frame: At Week 96 and Week 192 ] [ Designated as safety issue: Yes ]
  
• Time from randomization to development of TB disease among perinatally exposed, HIV uninfected children [ Time Frame: At Week 96 ] [ Designated as safety issue: Yes ]
  
• Time from randomization to new first Grade 3 or higher sign or symptom [ Time Frame: Throughout study ] [ Designated as safety issue: Yes ]
  

TB and HIV are major public health problems in southern Africa, and the incidence of TB in South Africa is among the highest in the world. TB is caused by the highly contagious bacterium Mycobacterium tuberculosis. The use of INH prophylaxis in adults has been associated with reduced risk of TB disease in high-risk populations. Delay in initiating INH prophylaxis in children has resulted in more cases of childhood TB infection. This study will evaluate the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV infected mothers in southern Africa.

Infants will be randomly assigned to receive either INH or placebo by mouth daily, beginning between the 91st and 120th day of life, and at least 90 days after Bacille Calmette-Guerin (BCG) vaccination. At sites in South Africa, HIV infected infants will receive daily sulfamethoxazole/trimethoprim (SMX/TMP) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV uninfected infants will receive SMX/TMP until at least 6 months of age. In Malawi, HIV exposed infants will be given SMX/TMP until they are confirmed HIV negative at 18 months of age; HIV infected infants will continue receiving prophylaxis.

This study will last 192 weeks. Study visits will occur at study entry and every 12 weeks until Week 192. A physical exam and blood collection will occur at each study visit. Infants will be assessed for peripheral neuropathy every 12 weeks until Week 96 and for TB at Weeks 96, 144, and 192. The study will also assess medication adherence.

As of November 12, 2008, Follow-up has been revised. All participants will be permanently discontinued from study follow-up by February 28, 2009 and no later than May 31, 2009. Only clinical evaluations will be performed for all participants. For HIV-infected participants, the study drug will be stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug is discontinued immediately.