Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Lancet Child Adolesc Health. 2019 Sep;3(9):636-645. doi: 10.1016/S2352-4642(19)30196-8. Epub 2019 Jul 16.
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.
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.
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 age-matched 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.
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.
Eunice Kennedy Shriver National Institute of Child Health and Human Development and UK Medical Research Council.
营养不良和幼儿特别容易患上严重形式的结核病，并且对治疗的反应较差。世界卫生组织（WHO）针对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用药剂量系统性不足，治疗效果不佳。我们旨在评估和量化 WHO 针对儿童药物敏感性结核病治疗指南在 20 个疾病负担最高国家的人群影响。
我们使用了一种综合模型，将 20 个疾病负担最高国家的个体特定人口统计学数据与药代动力学、结局和流行病学模型联系起来。我们根据世卫组织的指导原则（儿童根据固定剂量组合片剂的数量进行剂量分配，分别为 75mg 利福平、50mg 异烟肼、150mg 吡嗪酰胺），以及两种替代剂量方案，来估计 5 岁以下儿童的结核病治疗结局：一种方案基于一种使用年龄、体重和现有剂型的建议算法，其中体重不足的儿童将与同龄正常体重儿童接受相同的药物剂量；另一种方案基于没有剂量限制的个体化算法，其中推导剂量可使典型儿童达到目标暴露度。
我们估计，2017 年接受结核病治疗的 133302 名 5 岁以下儿童中，有 57234 名（43%）存在世卫组织剂量不足的情况，只有 47%的儿童能达到利福平的暴露目标。营养不良儿童的用药不足和治疗药物浓度低于治疗范围的情况比同龄健康儿童更为常见。建议的剂量方案将估计的利福平目标暴露度提高到 62%，并使营养状况相同的儿童的结局均等化。这种剂量方案可能解决三分之一的不良治疗结局，每年可在这些国家挽救至少 2423 名儿童的生命。通过个体化的剂量方案，几乎所有的儿童都能获得足够的药物浓度以达到治愈效果。
这项工作表明，简单地改变剂量方案，纳入年龄和营养状况，无需额外的测量或新的药物剂型，是改善儿童结核病治疗结局的一种方法，特别是对死亡率高的营养不良儿童。
美国国立卫生研究院儿童健康与人类发育研究所和英国医学研究理事会。
