These data are preliminary and restricted to two sites. The investigators certainly are not trying to suggest that guidelines be adapted. Yet HATIP has recognised a tendency in HIV/AIDS medicine to change clinical practice on the basis of a ten-minute conference presentations of incomplete trial data. At the same time, it can be problematic to run more placebo-controlled studies when a survival benefit has been demonstrated. We are aware that some clinicians plan to implement isoniazid prophylaxis on the basis of the evidence presented. It's a catch 22 situation.
The study investigators themselves urge caution:
Professor Heather Zar commented: "I think one needs to be quite careful... really one should wait for publication of the study before reporting this as potentially very important with widespread public health implications."
Dr. Cotton believes that the final findings eventually could warrant that "INH prophylaxis could be considered for HIV-infected children in regions of high prevalence" However: "What is most important is to stress that the findings are still preliminary and await analysis of our full data set.
HATIP then asked a cross-section of experts and care providers for children with HIV in resource limited settings the following questions:
1) Should clinical guidelines be adjusted so that children with HIV are offered INH or should more placebo-controlled studies be conducted in other settings?"
2) Should ALL children with HIV now be offered isoniazid prophylaxis or should it only be given to those in areas with a high incidence of TB?"
3) Is this preliminary analysis enough to make you consider changing how you treat children in your practice, or will you wait for a) publication of the final analysis of the complete data set or b) other confirmatory trials in your setting, or c) until formal WHO or national guidelines are changed?"
Almost all the responses we received agreed on the need for caution and further analysis of the complete data set (and possibly further study) before even considering changing clinical practice.
Says Dr. Haruna Jabril: "The result of the impact of INH prophylaxis on the mortality as reported is quite impressive but my feeling is that we need to complete the data analysis and take it up from there.
"I think that it is time to have another look at the question of INH prophylaxis in children. It may just be that we are denying children with HIV/AIDS something that will make a difference to their survival or even an improvement in their quality of life."
"If we improve our yield of AFB positivity in a given setting enough to develop an acceptable degree of confidence in its sensitivity, we should be able to use it to rule out TB disease with some degree of confidence. We are looking at gastric washings (in combination with other diagnostic parameters) now in children in an attempt to do this. Perhaps we will be able to develop that confidence in diagnosing TB disease."
"Most importantly however we need to replicate it elsewhere. Perhaps a multicentre collaborative study may be the way to go. We will be quite happy to participate."
Dr. Siobhan Crowley of WHO commented: "I think this work could be of relevance to practitioners in resource constrained settings where there is a large burden of TB, but we need further data and analysis and other studies to determine at this stage whether to change international guidelines."
Also we need to look at the impact of greater access to ARVs and improved diagnostic capability for HIV infection in infants and children as in many countries practitioners are unable to diagnose infections prior to 15-18 months, except in those who are very unwell or have an AIDS defining diagnosis, and it may well be that in these children INH is necessary and beneficial but in those who are symptomatic it is not as protective, and that in infants on ARVs the need for INH is outweighed by its interference with ART."
"We need to look more closely at this data set first and see if this gives us enough data to at least then introduce in areas where TB prevalence is the same or higher, then need some studies in TB less burden settings, but agree we need to try to avoid placebo controls otherwise we may be withholding survival benefit."
Others were concerned that the strategy might be harmful to children.
Dr Françoise Railhet, Manager of the LLL France Medical Associate Program said: "TB is more and more resistant. It seems to me that a "prophylactic" treatment is not a very good idea : this sort of treatment increases resistance. And isoniazid has iatrogenic effects (beginning with hepatic toxicity)."
Others questioned the high death rate, particularly those who work on breastfeeding issues in children. Jackie Nutt, a colleague of Dr. Railhet, works with women trying to achieve exclusive breastfeeding in South Africa:
"I am intrigued to see that there is no mention of adjusting for feeding method of infants in the report of the study. Perhaps in a setting with a lot more support for breastfeeding than the Western Cape, the death rates might have been different, or of different causes [since] bacterial sepsis is something that breastfeeding protects against. I would assume that these children were not breastfed [or] some of the children might have been orphans already, or perhaps the mothers were already too ill to breastfeed."
"I am also interested in the balance between drug benefits and the counter-productive effects they have on an infant's immature gut (e.g. gut irritation by co-trimoxazole). How well is isoniazid tolerated - any information? How sure are the researchers that some of the adverse effects were not due to drug side effects?"
She thinks the placebo arm may have been dropped prematurely:
"In HIV treatment we have to weigh up the pros and cons of every intervention. It appears that dropping the placebo arms from recent MTCT trials of AZT vs NVP might have been premature. It seems that many researchers focus entirely on transmission rates and not on eventual `health outcomes.`
"The apparent synergistic effects of isoniazid outside the context of TB is thought provoking - another reason why I think it would be important to continue with a placebo arm in a non-TB area."
"Where TB is a non-issue, will survival be improved by adding a drug (which has serious side effects) "just in case"? And even in the Western Cape, what will we see a few months hence - perhaps children "saved" from TB, yet with non-functioning livers? Or greater resistance? The placebo needs to be there for the next trial, I firmly believe."