Daily Isoniazid to Prevent Tuberculosis in Infants Born to Mothers With HIV

International Maternal Pediatric Adolescent AIDS Clinical Trials Group

Status and phase: Terminated; Phase 3; Phase 2

Conditions: Tuberculosis; HIV Infection; Pneumocystis Jiroveci Pneumonia

Treatments: Drug: Isoniazid (INH); Drug: Isoniazid Placebo (PL); Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)

Study type: Interventional

Funder types: Other; NETWORK; NIH

Identifiers

NCT00080119

U01AI068632 (U.S. NIH Grant/Contract)

PACTG P1041

Details and patient eligibility

About

Tuberculosis (TB) is highly endemic in sub-Saharan Africa. The increased burden of TB in settings with high prevalence of the Human Immunodeficiency Virus (HIV) is associated with high rates of transmission of Mycobacterium tuberculosis (M.tb) to both adults and children. Children infected with TB have a higher risk of developing severe disease than adults with TB. The purpose of this study was to determine if the antibiotic isoniazid (INH) prevented TB infection in infants born to HIV-infected mothers.

Full description

Tuberculosis (TB) and the Human Immunodeficiency Virus (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 Isoniazid (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 evaluated the effectiveness of INH prophylaxis in preventing TB infection in infants born to HIV-infected mothers in southern Africa.

Infants were 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 received daily trimethoprim/sulfamethoxazole (TMP/SMX) as Pneumocystis jiroveci pneumonia (PCP) prophylaxis until at least 1 year of age; HIV-uninfected infants received TMP/SMX until at least 6 months of age.

The study was to follow participants for 192 weeks. Study visits occurred at study entry and every 12 weeks until week 192. A physical exam and blood collection occurred at each study visit. Infants were assessed for peripheral neuropathy every 12 weeks until week 96 and for TB at weeks 96, 144, and 192. The study also assessed medication adherence.

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

Enrollment: 1,354 patients

Sex: All

Ages: 91 to 120 days old

Volunteers: Accepts Healthy Volunteers

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
• Physician assessment of age-appropriate neurodevelopment in which the chronological age is corrected for gestational age for prematurely born infants
• Parent or legal guardian able and willing to provide signed informed consent
• Plan to live in the study area for at least 4 years
• For inclusion in HIV-infected stratum, infant must have a positive HIV-1 DNA PCR; for inclusion in HIV-uninfected stratum, infant must have a negative HIV-1 DNA PCR performed at >= 4 weeks of age

Exclusion criteria

• Previous diagnosis of TB infection, TB disease or current treatment for TB infection or TB disease
• 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
• Failure to thrive
• Contraindications for use of INH or TMP/SMX
• 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

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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1,354 participants in 4 patient groups, including a placebo group

HIVneg/INH

Experimental group

Description:

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid (INH)10-20 mg/kg orally once a day for 96 weeks + Trimethoprim/Sulfamethoxazole (TMP/SMX) 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

Treatment:

Drug: Isoniazid (INH)

Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)

HIVneg/PL

Placebo Comparator group

Description:

Perinatally exposed, HIV-uninfected (HIVneg) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until HIV status is confirmed and child is no longer at risk of acquiring HIV through breastfeeding

Treatment:

Drug: Isoniazid Placebo (PL)

HIVpos/INH

Experimental group

Description:

HIV-infected (HIVpos) children receiving Isoniazid (INH) 10-20 mg/kg orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

Treatment:

Drug: Isoniazid (INH)

Drug: Trimethoprim/Sulfamethoxazole (TMP/SMX)

HIVpos/PL

Placebo Comparator group

Description:

HIV-infected (HIVpos) children receiving Isoniazid placebo (PL) orally once a day for 96 weeks + TMP/SMX 5 mg/kg of TMP component orally once a day until one year of age. TMP/SMX may have been continued after one year of age according to WHO guidelines.

Treatment:

Drug: Isoniazid Placebo (PL)