MICA: randomized trial of therapy shortening for minimal TB with new WHO-recommended doses and FDC drugs in African/Indian HIV+/HIV- children

Tuberculosis (TB) continues to be a major health problem in many countries. Of the estimated 9 million new TB cases every year across the world, about one million (11%) are in children with the majority in Africa and South East Asia. Based largely on research conducted only in adults, standard treatment for childhood TB is given for 6 months irrespective of how severe the disease is. Children often have mild forms of TB and it is likely that they could be successfully treated for less than 6 months. This would have major advantages for the child, their family and carers, and for over-burdened health systems, by reducing the number of clinic visits children need to make to take their drugs. Shorter treatment would be particularly advantageous for children who also have HIV and need to take seven or eight drugs at the same time, often leading to problems with drug side effects and difficulty taking all their pills at the right time. It could also reduce the cost of treating mild forms of TB in children, freeing up money to be used for treating other people and diseases. A trial in adult patients with mild TB disease in Hong Kong showed that they did equally well if they took four or six months of treatment. However, this study has not been repeated and no trial has studied the length of treatment needed for children with mild disease, which accounts for more than half the cases of TB worldwide in children. TB is a much neglected research area in children. In this trial, children aged twelve or younger with mild forms of TB disease who are considered by a doctor to need treatment for TB will be randomised (i.e. given by chance) to receive either the standard six months treatment recommended by international guidelines (the 'control group'), or the same drug regimen but given only for four months. We plan to use new dissolvable mini-pills containing three anti-TB drugs, at doses which have been recently recommended by the WHO. Pharmacokinetic studies (measuring levels of drug in the blood) will be performed at the start of the trial in order to confirm, as soon as possible, whether these new baby pills have the right doses of each drug, as well as whether the weight band tables suggested by the WHO, are correct (i.e. result in the right amount of drug in the blood). We will also check drug blood levels to ensure that the TB drugs are not causing the levels of HIV drugs to be too low, as we know these medicines interact with each other. This is an important research gap identified by the WHO HIV guidelines group. We will also do some research asking healthcare workers about how they use dosing tables for children, as the current ones for anti-TB drugs are different from the ones for anti-HIV drugs. This could help to harmonise these better, to make it easier for healthcare workers to treat children who have both HIV and TB. TB in children is most common in places where the resources available for health care are very restricted. This means the cost of different ways of treating TB is an important issue. The health economics work we are doing as part of this trial will help to show the budget impact of adopting a shorter regimen, if it is as good as the standard one, or, if it is not as good, then whether the 6 months treatment provides value for money. A total of 1200 children will be enrolled from clinical centres in Africa and Asia. Children with TB disease that is resistant to rifampicin, children with serious forms of TB or with advanced HIV disease will be excluded from the trial. We will follow all children for at least 18 months to check how many get TB again (relapse or get infected with a new strain of TB). The main objective of the trial is to determine whether treatment shortened to 4 months is as good as the 6 months current standard. We will also be able to analyse whether the levels of anti-TB drugs in the blood relate to both drug side effects and long-term response to TB and HIV treatment.