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

结核病仍然是许多国家的主要健康问题。在全世界每年估计的900万新发结核病例中，约有100万（11%）是儿童，其中大多数在非洲和东南亚。主要基于仅在成人中进行的研究，儿童结核病的标准治疗是6个月，无论疾病有多严重。儿童通常患有轻度结核病，他们很可能在不到6个月的时间内得到成功治疗。这将对儿童、其家庭和照料者以及负担过重的卫生系统产生重大好处，因为减少了儿童为服药而需要去诊所就诊的次数。较短的治疗时间对那些同时感染艾滋病毒并需要同时服用七种或八种药物的儿童特别有利，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。香港一项针对轻度结核病成年患者的试验显示，如果他们接受四个月或六个月的治疗，效果同样良好。然而，这项研究没有重复，也没有试验研究轻度疾病儿童所需的治疗时间，这占全球儿童结核病病例的一半以上。在本试验中，将对12岁或12岁以下患有轻度结核病并被医生认为需要接受结核病治疗的儿童进行随机分组（即偶然给予）接受国际准则建议的标准六个月治疗（“对照组”），或相同的药物方案，但只给予四个月。我们计划使用新的可溶性小药丸含有三种抗结核药物，按照世界卫生组织最近推荐的剂量。药代动力学研究（测量血液中的药物水平）将在试验开始时进行，以尽快确认这些新的婴儿药丸是否具有每种药物的正确剂量，以及是否符合世界卫生组织建议的体重范围表，是正确（即在血液中产生适量的药物）我们也会检查血液中药物的含量，以确保结核病药物不会导致艾滋病毒药物的含量过低，因为我们知道这些药物会相互作用。这是世卫组织艾滋病指南小组确定的一个重要研究空白。我们还将进行一些研究，询问医护人员如何使用儿童剂量表，因为目前的抗结核药物与抗艾滋病药物的剂量表不同。这可能有助于更好地协调这些问题，使卫生保健工作者更容易治疗同时感染艾滋病毒和结核病的儿童。儿童结核病在卫生保健资源非常有限的地方最常见。这意味着治疗结核病的不同方法的成本是一个重要问题。作为本试验的一部分，我们正在进行的卫生经济学研究将有助于显示采用较短方案的预算影响，如果它与标准方案一样好，或者，如果它不如标准方案好，那么6个月的治疗是否物有所值。对利福平耐药的结核病儿童、严重结核病儿童或晚期艾滋病儿童将被排除在试验之外。我们将对所有儿童进行至少18个月的随访，以检查有多少人再次患上结核病（复发或感染新的结核病菌株）。该试验的主要目的是确定缩短至4个月的治疗是否与目前的6个月标准一样好。我们还将能够分析血液中抗结核药物的水平是否与药物副作用以及对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.