背景:用于儿童和青少年药物易感结核病(DS-TB)治疗的一线药物的最佳剂量仍不确定。我们旨在确定使用WHO推荐或更高剂量的一线药物治疗的儿童是否取得了成功的结果和足够的药代动力学暴露。
方法:标题,摘要,并对全文文章进行了筛选。我们搜索了Pubmed,EMBASE,中部,和2010年至2021年的试验登记处。我们纳入了18岁以下儿童的研究,正在用利福平治疗DS-TB,吡嗪酰胺,异烟肼,还有乙胺丁醇.结果是治疗成功率和药物暴露。系统审查的方案已在PROSPERO中预先注册,CRD42021274222。
结果:在确定的304项研究中,46项研究有资格进行全文审查,包括12篇和18篇文章进行疗效和药代动力学分析,分别。在纳入疗效分析的1,830名儿童中,82%有良好的结果(范围25%-95%)。在世卫组织推荐的剂量下,暴露于利福平,吡嗪酰胺,与成人相比,儿童的乙胺丁醇较低。≤6岁的儿童的AUC比年龄较大的儿童低35%(14.4(9.9-18.8)比22.0(13.8-30.1)μg。h/mL)和HIV感染儿童(CWHIV)的利福平AUC比HIV阴性儿童低35%(17.3(11.4-23.2)比26.5(21.3-31.7)μg。h/mL)。异质性和小样本量是主要限制。
结论:结果差异很大,平均有82%的有利结果。儿童的药物暴露低于成人。年幼的儿童和CWHIV对利福平的影响不足。需要药代动力学儿科研究和个体患者数据分析的标准化以及安全性评估,以告知最佳剂量。
Optimal doses of first-line drugs for treatment of drug-susceptible tuberculosis in children and young adolescents remain uncertain. We aimed to determine whether children treated using World Health Organization-recommended or higher doses of first-line drugs achieve successful outcomes and sufficient pharmacokinetic (PK) exposures.
Titles, abstracts, and full-text articles were screened. We searched PubMed, EMBASE, CENTRAL, and trial registries from 2010 to 2021. We included studies in children aged <18 years being treated for drug-susceptible tuberculosis with rifampicin (RIF), pyrazinamide, isoniazid, and
ethambutol. Outcomes were treatment success rates and drug exposures. The protocol for the systematic
review was preregistered in PROSPERO (no. CRD42021274222).
Of 304 studies identified, 46 were eligible for full-text
review, and 12 and 18 articles were included for the efficacy and PK analyses, respectively. Of 1830 children included in the efficacy analysis, 82% had favorable outcomes (range, 25%-95%). At World Health Organization-recommended doses, exposures to RIF, pyrazinamide, and
ethambutol were lower in children than in adults. Children ≤6 years old have 35% lower areas under the concentration-time curve (AUCs) than older children (mean of 14.4 [95% CI 9.9-18.8] vs 22.0 [13.8-30.1] μg·h/mL) and children with human immunodeficiency virus (HIV) had 35% lower RIF AUCs than HIV-negative children (17.3 [11.4-23.2] vs 26.5 [21.3-31.7] μg·h/mL). Heterogeneity and small sample sizes were major limitations.
There is large variability in outcomes, with an average of 82% favorable outcomes. Drug exposures are lower in children than in adults. Younger children and/or those with HIV are underexposed to RIF. Standardization of PK pediatric studies and individual patient data analysis with safety assessment are needed to inform optimal dosing.