BACKGROUND: The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS: We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) toisoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS:Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS: Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).
RCT Entities:
BACKGROUND: The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infectedchildren and uninfected children exposed to HIV during the perinatal period. METHODS: We randomly assigned 548 HIV-infected and 804 HIV-uninfectedinfants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infectedchildren had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infectedchildren and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfectedchildren within 96 to 108 weeks after randomization. RESULTS: Antiretroviral therapy was initiated in 98.9% of HIV-infectedchildren during the study. Among HIV-infectedchildren, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfectedchildren, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infectedchildren as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfectedchildren. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS: Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infectedchildren or tuberculosis-infection-free survival among HIV-uninfectedchildren immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infectedchildren. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).
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