Isoniazid Prophylaxis With Concomitant Cotrimoxazole in HIV-infected Children
Condition: Tuberculosis
MeSH terms: Tuberculosis
Study type: Interventional
Phase: Phase 3

Summary: 
      The study involves use of isoniazid and cotrimoxazole as strategies for preventing infections
      in HIV-infected children and reducing mortality. Cotrimoxazole is well known to reduce
      mortality and infections in HIV-infected children and is currently the recommended standard
      of care. However, isoniazid has only been studied in HIV-infected adults (in whom it has been
      shown to substantially reduce the incidence of tuberculosis). In a randomised controlled
      study of isoniazid in HIV-infected children, the investigators found that INH reduced
      mortality and tuberculosis incidence in excess of 50%; the data safety monitoring board
      recommended termination of the placebo arm given the beneficial effects of INH. The
      investigators therefore aim to follow-up these children to compare the long term impact of
      two different INH and CTX preventive regimens (daily versus thrice weekly) on morbidity,
      mortality, adherence and incidence of adverse reactions. The investigators also aim to
      investigate the efficacy, safety and tolerability of INH compared with placebo for prevention
      of TB in children receiving HAART as the benefit in this group is unknown.
    

Detailed description: 
      Tuberculosis (TB) and HIV are dual pandemics occurring in South Africa. Prevention of TB and
      the subsequent decline in immune function in HIV-infected children is an important strategy
      to reduce mortality. Isoniazid (INH) prophylaxis reduces TB incidence in HIV-infected adults,
      but the efficacy in HIV-infected children has not been studied. In 2003, the investigators
      therefore began a double blind placebo controlled trial to investigate the impact of INH
      prophylaxis on mortality, morbidity and TB incidence in HIV-infected children. Interim
      analysis found a striking reduction in mortality and TB with a decrease in mortality in
      excess of 50% and 60% respectively, in children on INH. Based on this, the placebo arm was
      terminated; the study continued as a trial of thrice versus daily INH and cotrimoxazole
      (CTX). Although the results indicate an important benefit in children on INH, it is unknown
      what the long term efficacy and safety of INH prophylaxis is, what the optimal regime is and
      whether this pertains to children on HAART (who formed a minority of the cohort but who are
      still at risk for TB).

      Aim To investigate the efficacy, safety and tolerability of INH and CTX as prophylactic
      strategies for HIV-infected children in a high TB prevalence area.

      Objectives

        1. To compare the long term impact of two different INH preventive regimens (daily versus
           thrice weekly) on TB incidence, occurrence of INH resistance in patients with
           culture-confirmed TB, mortality, incidence of adverse reactions and adherence

        2. To compare the long term impact of two different CTX prophylactic regimens (daily versus
           thrice weekly) on mortality, frequency and duration of hospitalization, type of serious
           infections, nasopharyngeal carriage of bacteria and development of antimicrobial
           resistance, adherence and incidence of adverse reactions

        3. To investigate the efficacy, safety and tolerability of INH compared with placebo for
           prevention of TB in children receiving HAART

      Methods A prospective randomized double blind placebo controlled study of INH versus placebo
      in newly recruited HIV-infected children who are stable on HAART. In addition, an extended
      follow-up study of children already randomised to thrice weekly or daily INH and CTX.
      Children will be followed for 2 years with regular clinical evaluation, adherence assessment
      and laboratory monitoring. Outcomes measured will be mortality, TB incidence, morbidity,
      adherence and tolerability.
    

Intervention name(s): Isoniazid; Cotrimoxazole; isoniazid; placebo
Intervention type(s): Drug; Drug; Drug; Other
Intervention description(s): isoniazid 10mg/kg orally, daily, for study period; Cotrimoxazole given 3 times a week or daily, orally, for study period; Isoniazid, 10mg/kg daily for study period; Placebo tablet identicle in appearance to intervention: isoniazid table
Intervention MeSH terms: Isoniazid; Trimethoprim, Sulfamethoxazole Drug Combination
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: Double
Primary purpose: Prevention
Keywords: Tuberculosis; Child; HIV; prophylaxis; mortality