HIV infected women in South 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 South Africa.

Condition	Treatment or Intervention	Phase
HIV Infections Tuberculosis Pneumocystis carinii Pneumonia	Drug: Isoniazid  Drug: Sulfamethoxazole-Trimethoprim	Phase II Phase III

TB and HIV are major public health problems in South 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 South African infants born to HIV infected mothers.

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. HIV infected infants will receive daily sulfamethoxazole-trimethoprim (SMX/TMP) as Pneumocystic carinii pneumonia (PCP) prophylaxis until at least 1 year of age; HIV uninfected infants will receive SMX/TMP until at least 6 months of age.

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.

Ages Eligible for Study:  91 Days   -   120 Days,  Genders Eligible for Study:  Both

Accepts Healthy Volunteers

Criteria

Inclusion Criteria:

• Mother is HIV infected
• Received Bacille Calmette-Guerin (BCG) vaccine during the first week of life
• 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
• Use of 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 2 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 interefere with the study

South Africa
      Chris Hani Baragwanath Hospital, Johannesburg,  South Africa
      University of Cape Town, Red Cross Children's Hospital, Cape Town,  South Africa
      University of Stellenbosch, Tygerberg Hospital, Cape Town,  South Africa

Study chairs or principal investigators

Shabir Madhi, MD,  Study Chair,  University of the Witwatersrand   
George McSherry, MD,  Study Chair,  UMD - New Jersey Medical School   
Charles D. Mitchell, MD,  Study Chair,  University of Miami School of Medicine   

Study ID Numbers:  PACTG P1041
Record last reviewed:  August 2004
Record first received:  March 23, 2004
ClinicalTrials.gov Identifier:  NCT00080119
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-20