title: Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children.
abstract: 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) 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-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.).
authors: Department of Science and Technology/National Research Foundation: Vaccine Preventable Diseases and the Medical Research Council: Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa. madhis@rmpru.co.za
authors: Shabir A
authors: SA
authors: Madhi
authors: Sharon
authors: S
authors: Nachman
authors: Avy
authors: A
authors: Violari
authors: Soyeon
authors: S
authors: Kim
authors: Mark F
authors: MF
authors: Cotton
authors: Raziya
authors: R
authors: Bobat
authors: Patrick
authors: P
authors: Jean-Philippe
authors: George
authors: G
authors: McSherry
authors: Charles
authors: C
authors: Mitchell
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000517:prevention & control*; D000995:Antitubercular Agents / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D024881:Drug Resistance, Bacterial; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007223:Infant; D057194:Intention to Treat Analysis; D007538:Isoniazid / Q000009:adverse effects / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D008297:Male; D014376:Tuberculosis / Q000175:diagnosis / Q000517:prevention & control*; D019562:Viral Load
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid