Mind the gaps: Pharmacokinetic research to advance pediatric HIV/TB cotreatment and TB prevention

项目总结 结核病是感染艾滋病毒的儿童的主要死亡原因，但数据不足。 儿童HIV/TB联合治疗和结核病预防策略的药代动力学(PK)。全球 扩大幼儿多洛替格列韦的使用有可能显著改善艾滋病毒的治疗 结果，但没有PK数据表明在含有利福平的过程中使用双剂量多洛替格列韦 为6岁以下儿童提供艾滋病毒/结核病共同治疗。此外，多项研究表明，目前 世卫组织推荐的利福平剂量导致大多数儿童的低浓度，而高剂量 利福平可能会改善成人和儿童的预后，缩短治疗时间。然而，它的影响 大剂量利福平对多洛替格韦暴露的影响尚未得到检查。最后，众所周知， 治疗潜伏性结核病感染(LTBI)显著减少了艾滋病毒感染者中的结核病发病率，但 在地方病流行的环境中，这一策略被大大低估了。短程LTBI治疗方案增加 完成率，但尚未在接受多洛替格韦治疗的艾滋病毒感染儿童中进行研究。致信地址 这些知识上的差距并提供了必要的PK和安全数据来扩展这些有希望的应用 从成人到儿童，我们将进行两项前瞻性PK研究：(1)每天两次 在标准剂量和大剂量利福平期间服用多洛替格韦，以及(2)每周服用多洛替格韦。 利福喷丁/异烟肼用于结核病预防/LTBI治疗。 为了促进我们对药物作用的潜在机制的理解，我们还将研究 标准剂量和大剂量每日利福平和每周利福喷丁对4β-羟基胆固醇的影响 Ratio是细胞色素P450 3A4活性的内源性生物标志物。这将提供关键的药效学(PD)数据 在人群PK/PD模型中使用，以量化变异性并为此脆弱人群提供最佳药物剂量 儿童的数量。 尼日利亚是世界上感染艾滋病毒的儿童最多的国家，也是世界上 突发结核病的最大负担。自2004年以来，APIN公共卫生倡议提供了艾滋病毒护理和 在尼日利亚为20,000多名儿童提供治疗，因此在支持这项重要的PK研究方面处于独特的地位。 这项研究的结合解决了关于PK和新药安全性的知识的关键差距 艾滋病毒/结核病共同治疗和结核病预防的组合，可能为世卫组织在以下方面的使用提供指导的发现 儿童，朝着遏制结核病在这一脆弱人群中造成的毁灭性损失的目标前进。

PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death among children with HIV, yet insufficient data are available on the pharmacokinetics (PK) of newer HIV/TB cotreatment and TB prevention strategies in children. Global expansion of dolutegravir use for young children has the potential to significantly improve HIV treatment outcomes, but there are no PK data to inform use of double-dose dolutegravir during rifampicin-containing HIV/TB cotreatment for children under 6 years of age. Further, multiple studies have shown that current WHO-recommended rifampicin dosages result in low concentrations in most children, and high-dose rifampicin may improve outcomes and shorten treatment duration in adults and children. Yet the impact of high-dose rifampicin on dolutegravir exposures has not been examined. Finally, it is well-established that treatment of latent TB infection (LTBI) significantly reduces incident TB among HIV-infected persons, yet this strategy is vastly underused in endemic settings. Short-course LTBI treatment regimens increase completion rates, but have not been studied among HIV-infected children receiving dolutegravir. To address these gaps in knowledge and provide needed PK and safety data to extend use of these promising strategies from adults to children, we will carry out two prospective PK studies to examine: (1) twice daily dolutegravir during both standard- and high-dose rifampicin, and (2) PK of dolutegravir during weekly rifapentine/isoniazid for TB prevention/LTBI treatment. To advance our understanding of underlying mechanisms of drug action we will also examine the impact of standard- and high-dose daily rifampicin and weekly rifapentine on the 4β-hydroxy-cholesterol to cholesterol ratio, an endogenous biomarker of CYP3A4 activity. This will provide critical pharmacodynamic (PD) data for use in population PK/PD models to quantify variability and inform optimal drug dosing in this vulnerable population of children. Nigeria is home to more children living with HIV than any other country in the world, and also bears one of the greatest burdens of incident TB. Since 2004, APIN Public Health Initiatives has provided HIV care and treatment to over 20,000 children in Nigeria and thus is uniquely positioned to support this vital PK research. This combination of studies addresses critical gaps in knowledge regarding PK and safety of newer drug combinations for HIV/TB cotreatment and TB prevention, findings that may inform WHO guidance on use in children, toward the goal of curbing TB’s devastating toll in this vulnerable population.