Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study
Alternative dosing guidelines to improve outcomes in childhood tuberculosis: a mathematical modelling study
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DOI：
10.1016/s2352-4642(19)30196-8
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发表时间：
2019-09-01
影响因子：
36.4
通讯作者：
Savic, Radojka M.
中科院分区：
文献类型：
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作者：
Radtke, Kendra K.;Dooley, Kelly E.;Savic, Radojka M.
背景营养不良的儿童和幼儿特别容易患上严重的结核病，而且治疗效果不佳。世卫组织结核病治疗药物的剂量指南仅基于体重，这可能导致这些儿童的系统性剂量不足和不良结果。我们的目的是评估和量化的人口效应世卫组织的药物敏感结核病的儿童在20个国家的最高疾病burner.Methods的指导方针，我们使用了一个综合的模型，连接国家特定的人口数据在个人层面上从20个国家的最高疾病负担的药代动力学，结果和流行病学模型。我们根据WHO指南评估了5岁以下儿童的结核病治疗结果（儿童按与固定剂量复方片剂[75 mg利福平、50 mg异烟肼、150 mg吡嗪酰胺]数量对应的体重范围给药）和两种替代给药策略：一种是基于使用年龄、体重和可用配方的建议算法，其中体重不足的儿童将接受与同龄正常体重儿童相同的药物剂量;另一种基于没有剂量限制的个性化算法，其中，导出的剂量导致典型儿童达到目标暴露量。结果我们估计，57 234（43%）2017年接受结核病治疗的133，302名5岁以下儿童中，世卫组织剂量不足，只有47%的儿童能够达到利福平暴露目标。剂量不足和亚治疗暴露在营养不良儿童中比在年龄匹配的健康儿童中更常见。拟定的给药方法将估计的利福平目标暴露量达到率提高至62%，并通过营养状态实现了均衡结局。估计三分之一的不利治疗结果可能通过这种给药策略得到解决，每年在这些国家挽救至少2423名儿童的生命。通过个体化给药方法，几乎所有的儿童都可以达到足够的暴露量来治愈。解释这项工作表明，简单地改变给药程序，包括年龄和营养状况，不需要额外的测量或新的药物配方，是改善儿童结核病治疗效果的一种方法，特别是营养不良的儿童，他们有很高的死亡风险。
Background Malnourished and young children are particularly susceptible to severe forms of tuberculosis and poor treatment response. WHO dosing guidelines for drugs for tuberculosis treatment are based only on weight, which might lead to systematic underdosing and poor outcomes in these children. We aimed to assess and quantify the population effect of WHO guidelines for drug-susceptible tuberculosis in children in the 20 countries with the highest disease burden.Methods We used an integrated model that linked country-specific demographic data at the individual level from the 20 countries with the highest disease burden to pharmacokinetic, outcome, and epidemiological models. We estimated tuberculosis treatment outcomes in children younger than 5 years following WHO guidelines (children are dosed by weight bands corresponding to the number of fixed-dose combination tablets [75 mg rifampicin, 50 mg isoniazid, 150 mg pyrazinamide]) and two alternative dosing strategies: one based on a proposed algorithm that uses age, weight, and available formulations, in which underweight children would receive the same drug doses as would normal weight children of the same age; and another based on an individualised algorithm without dose limitations, in which derived doses results in target exposure attainment for the typical child.Findings We estimated that 57 234 (43%) of 133 302 children younger than 5 years who were treated for tuberculosis in 2017 were underdosed with WHO dosing and only 47% of children would reach the rifampicin exposure target. Underdosing and subtherapeutic exposures were more common among malnourished children than among agematched healthy children. The proposed dosing approach improved estimated rifampicin target exposure attainment to 62% and equalised outcomes by nutritional status. An estimated third of unfavourable treatment outcomes might be resolved with this dosing strategy, saving the lives of a minimum of 2423 children in these countries annually. With individualised dosing approaches, almost all children could achieve adequate exposure for cure.Interpretation This work shows that a simple change in dosing procedure to include age and nutritional status, requiring no additional measurements or new drug formulations, is one approach to improve tuberculosis treatment outcomes in children, especially malnourished children who are at high risk of mortality.