But Botswana is often the exception to the African rule. Nevertheless, some developing countries have more resources than others, and in the question and answer session after his talk, Dr Reider was pressed about whether he thought better resourced NTPs should attempt IPT.
He responded, “I tell the national programme, implement first where it is simple, and if that works we go to the next [stage]... For example, we recommend preventive therapy for children under the age of five who live in the same household as a newly diagnosed smear-positive case. That is the easiest group to do. Everybody agrees, it’s simple, you give it to the patient, who gives it to the kid. Toxicity is minimal, they are under five, even if you miss a lymphadenopathy, no problem, the American Academy of Pediatrics has found this for years. It’s safe. It’s in every manual of the national TB programmes in Africa — I’ve seen it — but I have not seen a single country where they have systematically implemented it.”
“What I am hearing is, ‘I cannot do the simple things, please let me do the complicated things.’ And as long as I see that they don’t give their under fives who are exposed to smear-positive cases preventive therapy — where we don’t even need the tuberculin skin test just to decide are you healthy or are you sick. If this simple thing is not done, why should we try to complicate it?”
IPT is indeed standard of care for children living in same household as a smear-positive TB case because of the high risk of transmission. And yet in countries with a high burden of TB, children may be exposed to infection from other sources as well. In a session on contact tracing in children, Professor Nulda Beyers said that many children are actually infected outside of the home. According to a study using DNA fingerprinting, only 30% of children had the same strain as their parent, while 57% got the infection from someone else in the community, and in 13% the strain was unique and found in no one else in the community.
Children with HIV are at greatly increased risk of contracting TB and of developing severe forms of the disease so they would seem to be natural candidates for IPT treatment. However, many paediatricians and public health experts worry that it may be too difficult to exclude a diagnosis of active TB in children with HIV to recommend that IPT be more widely used in this population. The fear seems to be that there is too great a risk of missing subclinical disease and under treating more serious forms of TB that may develop in children with HIV.
But so far the clinical data look promising. At the World AIDS Conference in Bangkok last year, preliminary results a placebo-controlled South African study found that IPT halved risk of death for children with HIV
(see http://www.aidsmap.com/en/news/4346AD91-01A8-4760-AA4C-9D9B6C3BAC21.asp). Shortly afterwards, in an issue of HATIP, our advisory panel discussed the study (see http://www.aidsmap.com/cms1001025.asp ). The majority wanted to withhold judgment on the study’s public health consequences until final results were available.
The complete results were presented during a plenary at this year’s World Conference, and generally the results are consistent with what was reported in Bangkok, with the primary exception being that, in addition to the reduced mortality the treatment has now also been shown to reduce the incidence of culture-confirmed and probable TB.
In the initial results, the survival benefit was observed in an analysis of 148 subjects. At that point, the trial’s Data Safety and Monitoring Board recommended stopping the placebo arm and offering IPT to all participants. However, between the December 2003 analysis and the DSMB decision on May 17th 2004, 115 additional subjects had enrolled.
Final Results (intent-to-treat analysis)
INH
|
Placebo
|
HR
|
11/132 (8.3%)
|
21 /131 (16%)
|
0.46 [95%CI:0.22 to 0.95], p=0.0308
|
The children’s age or CDC classification had no influence on the difference between arms.
Overall, 32 children died: there were five confirmed cases of bacterial sepsis on placebo versus 6 (50%) on INH, pneumonia or diarrhoea or sepsis occurred in 4 (33%) on INH and 10 (50%) on placebo. No deaths were suspected to be due to having TB. The effect on survival was independent of previous TB but could be affected by current TB treatment.
Eighteen out of 263 patients developed tuberculosis or probable tuberculosis. There were no culture confirmed and five probable cases on IPT compared to five culture confirmed and eight probable cases on placebo.
Dr Cotton cited a number of potential concerns regarding more widespread use of INH prophylaxis in children with HIV, including the need to exclude active TB, what sort of infrastructure, resources would be needed to deliver it, and to encourage consistent adherence, and the potential for the development of resistance.
He’s also like to study the long-term effect of INH in these children. Unfortunately, the study’s sponsorship from the Rockefeller Foundation is finished, and Dr Cotton and colleage, Dr Heather Zar are looking for a new funder simply to help them conduct follow-up on the study participants.
But this will not be the last study to evaluate this IPT in children with HIV. Another, larger study (target enrolment 1300) has recently begun in infants born to HIV-infected mothers in South Africa.
However, many of the TB experts already seem ready to adopt IPT for children with HIV in areas with a high burden of coinfection. According to a presentation by Dr Robert Gie, of the University of Stellenbosch, and member of the Child TB subgroup of the DOTS Expansion Working Group, active TB “can be successfully screened by using symptoms.” According to one proposed treatment algorithm the subgroup is working on, children with HIV and without symptoms of active TB should be given nine months of IPT — at least until a better short course comes along.