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

结核病在许多国家仍然是一个主要的健康问题。据估计，全世界每年新增结核病病例900万例，其中约100万例(11%)是儿童，其中大部分在非洲和东南亚。主要基于仅在成人中进行的研究，儿童结核病的标准治疗时间为6个月，无论疾病有多严重。儿童通常患有轻微形式的结核病，他们很可能在不到6个月的时间内成功治疗。这将减少儿童服用药物所需的诊所次数，从而对儿童、他们的家人和照顾者以及负担过重的卫生系统有重大好处。对于同样感染艾滋病毒并需要同时服用七到八种药物的儿童来说，较短的治疗时间将特别有利，这往往会导致药物副作用的问题，并难以在正确的时间服用所有药物。它还可以降低治疗儿童轻度结核病的成本，腾出资金用于治疗其他人和疾病。在香港对患有轻度结核病的成年患者进行的一项试验表明，如果他们接受四个月或六个月的治疗，他们的效果同样好。然而，这项研究没有重复进行，也没有试验研究患有轻度疾病的儿童需要接受多长时间的治疗，这种疾病占全球儿童结核病病例的一半以上。结核病是一个被严重忽视的儿童研究领域。这是世界卫生组织艾滋病毒指南小组发现的一个重要研究空白。我们还将进行一些研究，询问医护人员他们如何使用儿童剂量表，因为目前的抗结核病药物与抗艾滋病毒药物不同。这可能有助于更好地协调这些因素，使医护人员更容易治疗同时感染艾滋病毒和结核病的儿童。结核病在可用于医疗保健的资源非常有限的地方最为常见。这意味着治疗结核病的不同方法的成本是一个重要的问题。患有对利福平耐药的结核病的儿童、患有严重结核病或晚期艾滋病毒疾病的儿童将被排除在试验之外。我们将对所有儿童进行至少18个月的跟踪调查，以检查有多少儿童再次感染结核病(复发或感染一种新的结核病菌株)。试验的主要目标是确定缩短到4个月的治疗是否与目前6个月的标准一样好。我们还将能够分析血液中抗结核药物的水平是否既与药物副作用有关，也与结核病和艾滋病毒治疗的长期反应有关。

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.