Isoniazid treatment for prevention of active tuberculosis (TB) in children significantly reduces the risk of death in HIV-positive infants and small children according to results of a South African study presented as a late breaker on the final day of the Fifteenth International AIDS Conference in Bangkok.

The study was conducted in the Western Cape province of South Africa, a region with one of the highest incidences of TB in the world. Children have a 4.1% annualized risk of developing TB in the Western Cape.

Investigators undertook a prospective placebo-controlled trial involving children recruited from two treatment centres in Cape Town. The aim of the study was to see if isoniazid prophylaxis reduced mortality in HIV infected children. A secondary aim of the study was to establish the impact of isoniazid prophylaxis on the incidence of TB.

The study recruited HIV-positive children; asymptomatic infants infants below the age of 12 months and symptomatic infants aged 12 months and over. The median age of children enrolled to the study was 23.5 months.

All the children in the study were randomized to receive co-trimoxazole (TMP-SMX) prophylaxis (which is protective against PCP and certain other infections which individuals with immune suppression are vulnerable to) either daily or three times a week. The children in each TMP-SMX group were then randomised to receive either isoniazid prophylaxis or a placebo to be taken at the same dosing frequency as TMP-SMX. Isoniazid (INH) was dosed at 10mg/kg.

Enrollment started in January 2003 with the aim of recruiting 425 patients but the placebo arm of the study was discontinued after the Data Safety Monitoring Board reviewed the findings in May 2004.

By this point there had been a total of 32 deaths: 20 in the placebo group and 12 in the INH group, a statistically significant difference (p = 0.026). Isoniazid treatment was associated with a 53% reduction in mortality.

Survival benefit appeared early during prophylactic treatment with isoniazid (within 50 days), and was apparent in all CDC categories of HIV disease severity and at both treatment centres. Presenting the data, Dr Mark Cotton said he could not explain why isoniazid appeared to have such a rapidly protective effect.

This risk of death was nine times higher in children below the age of eight months when compared to children of 21 months age and over but there was no interaction between age and isoniazid treatment, suggesting that children below the age of 21 months had a higher risk of dying irrespective of which treatment they received.

Isoniazid prophylaxis also helped to prevent cases of tuberculosis. Of the 14 incident cases of tuberculosis which occurred during the study period nine were in the placebo group and five in the isoniazid group. This difference did not, however, reach statistical significance.

Reference

Zar H et al. Early and unexpected benefit of isoniazid in reducing mortality in HIV-infected children in an area of high tuberculosis prevelance. Fifteenth International AIDS Conference, Bangkok, late breaker abstract LbOrB12, 2004.

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