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

MICA：在非洲/印度艾滋病毒/艾滋病毒儿童中使用世界卫生组织推荐的新剂量和 FDC 药物缩短最小结核病治疗的随机试验

• 批准号: MR/L004445/1
• 负责人: Diana Gibb
• 金额: $ 473.2万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL004445%2F1
• 关键词: MICA; randomized; trial; therapy; shortening

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.

结核病 (TB) 仍然是许多国家的主要健康问题。全球每年估计有 900 万新发结核病例，其中约 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时间为 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 个月的时间内就能得到成功治疗。通过减少儿童服药所需的就诊次数，这对儿童、其家人和护理人员以及负担过重的卫生系统来说将具有重大优势。较短的治疗时间对于同样感染艾滋病毒并需要同时服用七八种药物的儿童特别有利，这通常会导致药物副作用的问题以及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费用，从而腾出资金用于治疗其他人和疾病。在香港进行的一项针对患有轻度结核病的成年患者的试验表明，如果接受四到六个月的治疗，他们的效果同样好。然而，这项研究尚未重复，也没有试验研究轻症儿童所需的治疗时间，轻症儿童占全球儿童结核病病例的一半以上。结核病是一个经常被忽视的儿童研究领域。在这项试验中，医生认为需要治疗的十二岁或以下患有轻度结核病的儿童将被随机（即随机给予）接受国际指南推荐的标准六个月治疗（“对照组”），或接受相同的药物治疗方案但仅给予四个月。我们计划使用含有三种抗结核药物的新型可溶性迷你药丸，剂量符合世界卫生组织最近推荐的剂量。试验开始时将进行药代动力学研究（测量血液中的药物水平），以便尽快确认这些新婴儿药的每种药物剂量是否正确，以及世界卫生组织建议的体重带表是否正确（即血液中的药物量正确）。我们还将检查药物的血液水平，以确保结核病药物不会导致艾滋病毒药物的水平过低。 这些药物会相互作用。这是世界卫生组织艾滋病指南小组发现的一个重要的研究空白。我们还将做一些研究，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毒药物的剂量表不同。这有助于更好地协调这些因素，使医护人员更容易治疗同时患有艾滋病毒和结核病的儿童。儿童结核病在医疗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。作为本次试验的一部分，我们正在进行的卫生经济学工作将有助于显示采用较短治疗方案对预算的影响，如果它与标准治疗方案一样好，或者如果不如标准治疗方案，那么 6 个月的治疗是否物有所值。 总共将有 1200 名儿童从非洲和亚洲的临床中心入组。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的儿童将被排除在试验之外。我们将跟踪所有儿童至少 18 个月，以检查有多少人再次感染结核病（复发或感染新的结核病株）。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 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。

项目成果

Global estimates and determinants of antituberculosis drug pharmacokinetics in children and adolescents: a systematic review and individual patient data meta-analysis.

• DOI: 10.1183/13993003.01596-2022
• 发表时间: 2023-03
• 期刊: EUROPEAN RESPIRATORY JOURNAL
• 影响因子: 24.3
• 作者: Gafar, Fajri;Wasmann, Roeland E.;McIlleron, Helen M.;Aarnoutse, Rob E.;Schaaf, H. Simon;Marais, Ben J.;Agarwal, Dipti;Antwi, Sampson;Bang, Nguyen D.;Bekker, Adrie;Bell, David J.;Chabala, Chishala;Choo, Louise;Davies, Geraint R.;Day, Jeremy N.;Dayal, Rajeshwar;Denti, Paolo;Donald, Peter R.;Engidawork, Ephrem;Garcia-Prats, Anthony J.;Gibb, Diana;Graham, Stephen M.;Hesseling, Anneke C.;Heysell, Scott K.;Idris, Misgana I.;Kabra, Sushil K.;Kinikar, Aarti;Kumar, Agibothu K. Hemanth;Kwara, Awewura;Lodha, Rakesh;Magis-Escurra, Cecile;Martinez, Nilza;Mathew, Binu S.;Mave, Vidya;Mduma, Estomih;Mlotha-Mitole, Rachel;Mpagama, Stellah G.;Mukherjee, Aparna;Nataprawira, Heda M.;Peloquin, Charles A.;Pouplin, Thomas;Ramachandran, Geetha;Ranjalkar, Jaya;Roy, Vandana;Ruslami, Rovina;Shah, Ira;Singh, Yatish;Sturkenboom, Marieke G. G.;Svensson, Elin M.;Swaminathan, Soumya;Thatte, Urmila;Thee, Stephanie;Thomas, Tania A.;Tikiso, Tjokosela;Touw, Daan J.;Turkova, Anna;Velpandian, Thirumurthy;Verhagen, Lilly M.;Winckler, Jana L.;Yang, Hongmei;Yunivita, Vycke;Taxis, Katja;Stevens, Jasper;Alffenaar, Jan-Willem C.
• 通讯作者: Alffenaar, Jan-Willem C.

Evaluating pediatric tuberculosis dosing guidelines: A model-based individual data pooled analysis.

• DOI: 10.1371/journal.pmed.1004303
• 发表时间: 2023-11
• 期刊: PLoS medicine
• 影响因子: 15.8

Additional file 1: of Shorter treatment for minimal tuberculosis (TB) in children (SHINE): a study protocol for a randomised controlled trial

附加文件 1：儿童轻微结核病 (TB) 的短期治疗 (SHINE)：随机对照试验的研究方案

• DOI: 10.6084/m9.figshare.6164267
• 发表时间: 2018
• 作者: Chishala Chabala

Treating young children co-infected with tuberculosis and HIV

治疗同时感染结核病和艾滋病毒的幼儿

• DOI: 10.1016/s2352-3018(18)30326-6
• 发表时间: 2019
• 期刊: The Lancet HIV
• 作者: Turkova A

Inadequate Lopinavir Concentrations With Modified 8-Hourly Lopinavir/Ritonavir 4:1 Dosing During Rifampicin-based Tuberculosis Treatment in Children Living With HIV.

• DOI: 10.1097/inf.0000000000004047
• 发表时间: 2023-10-01
• 期刊: The Pediatric infectious disease journal