• 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 tuberculosis (TB) disease among HIV infected children, as observed at Week 96
• time from randomization to development of TB disease among perinatally-exposed, HIV uninfected children, as observed at Week 96

• 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 ]

• Time from Week 96 to development of TB infection, and time from Week 96 to development of TB disease among HIV infected and perinatally-exposed, HIV uninfected children
• time from randomization to death as observed at Week 96, and time from Week 96 to death among HIV infected and perinatally-exposed, HIV uninfected children
• population pharmacokinetics (PK) model of isoniazid (INH) among HIV infected and perinatally-exposed, HIV uninfected children
• time from randomization to development of TB infection among HIV infected children, as observed at Week 96
• time from randomization to a new AIDS-defining illness or death as observed at Week 96, and time from Week 96 to AIDS-defining illness or death among HIV infected children
• time from randomization to development of TB disease among perinatally-exposed, HIV uninfected children, as observed at Week 96

HIV infected women in southern Africa have a high risk of tuberculosis (TB) infection. Children born to HIV infected mothers may be more likely to be exposed to and become infected with TB, and children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study is to determine if the antibiotic isoniazid (INH) will prevent TB infection in infants born to HIV infected mothers in southern Africa.

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.

• HIV Infections
• Tuberculosis
• Pneumocystis Jirovecii Pneumonia

• Drug: Isoniazid
• Drug: Sulfamethoxazole/Trimethoprim

• Experimental: HIV-infected infants receiving INH and SMX/TMP
• Placebo Comparator: HIV-infected infants receiving INH placebo and SMX/TMP
• Experimental: HIV-exposed infants receiving INH and SMX/TMP
• Placebo Comparator: HIV-exposed infants receiving INH placebo and SMX/TMP

• Chintu C, Mwaba P. Tuberculosis in children with human immunodeficiency virus infection. Int J Tuberc Lung Dis. 2005 May;9(5):477-84. Review.
• Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med. 2003 May 12;163(9):1009-21. Review.
• de Jong BC, Israelski DM, Corbett EL, Small PM. Clinical management of tuberculosis in the context of HIV infection. Annu Rev Med. 2004;55:283-301.
• Toossi Z. Virological and immunological impact of tuberculosis on human immunodeficiency virus type 1 disease. J Infect Dis. 2003 Oct 15;188(8):1146-55. Epub 2003 Sep 30. Review.

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 HIV-infected participants, the study drug will be stopped at the next scheduled visit. For HIV-uninfected subjects, the study drug is discontinued immediately.

Inclusion Criteria:

• Mother is HIV infected. Hard copy documentation of the mother's HIV infection is unnecessary if a positive DNA PCR from her infant is available.
• Received Bacille Calmette-Guerin (BCG) vaccine up to and including the 30th day of life and at least 90 days prior to study entry
• Able to complete all study requirements
• Normal truncated Denver Developmental Test for peripheral neuropathy at study entry
• Normal deep tendon reflexes and muscle bulk, tone, and strength at study entry
• Plan to live in the study area for at least 4 years

Exclusion Criteria:

• Previous diagnosis of TB infection
• Previous receipt of INH
• Contact with a known acid fast bacilli (AFB) sputum smear or culture-positive case of TB before study entry
• Current acute or recurrent (3 or more prior episodes) lower respiratory tract disease
• Chronic persistent diarrhea
• Significant drop in weight or failure to gain weight appropriately during a 2- to 3-month period
• Contraindications for use of INH or SMX/TMP
• Require certain medications
• Known or suspected immune system diseases other than HIV
• Current or previous diagnosis of or treatment for cancer
• Current immunosuppressive therapy greater than 1 mg/kg/day of prednisone or equivalent
• Anticipated long-term oral or intravenous corticosteroid therapy (greater than 3 weeks). Those receiving nonsteroidal anti-inflammatory agents and inhaled corticosteroids are not excluded.
• Grade 3 or greater AST/SGOT, ALT/SGPT, ANC, hemoglobin, platelet count, rash, neuropathy, or myopathy at screening
• Any Grade 4 clinical or laboratory toxicity within 14 days prior to study entry
• Other acute or chronic conditions that, in the opinion of the investigator, may interfere with the study

• Comprehensive International Program of Research on AIDS
• Secure the Future Foundation