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

项目摘要 结核病是艾滋病毒感染儿童死亡的主要原因，但现有数据不足 在儿童中新的HIV/TB联合治疗和TB预防策略的药代动力学（PK）。全球 将度鲁特韦扩大用于幼儿有可能显著改善艾滋病毒治疗 结果，但没有PK数据可以告知在含利福平的 为6岁以下儿童提供艾滋病毒/结核病联合治疗。此外，多项研究表明，目前 世卫组织推荐的利福平剂量在大多数儿童中导致低浓度， 利福平可改善成人和儿童的治疗结果并缩短治疗时间。然而， 尚未研究高剂量利福平对度鲁特韦暴露的影响。最后，众所周知， 治疗潜伏性结核感染（LTBI）可显著降低艾滋病毒感染者的结核病发病率， 这一战略在地方病流行的情况下远远没有得到充分利用。短期LTBI治疗方案增加 完成率，但尚未在接受度鲁特韦的艾滋病毒感染儿童中进行研究。解决 这些知识的差距，并提供所需的PK和安全性数据，以扩大使用这些有前途的 从成人到儿童的策略，我们将进行两项前瞻性PK研究，以检查：（1）每日两次 标准剂量和高剂量利福平期间的度鲁特韦，和（2）每周一次利福平治疗期间度鲁特韦的PK 利福喷丁/异烟肼用于TB预防/LTBI治疗。 为了进一步了解药物作用的潜在机制，我们还将研究 标准剂量和高剂量每日利福平和每周利福喷丁对4β-羟基胆固醇与胆固醇的影响 比值，CYP 3A 4活性的内源性生物标志物。这将提供关键药效学（PD）数据 用于群体PK/PD模型，以量化变异性，并告知这种脆弱人群的最佳药物剂量 儿童人口。 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 结核病的最大负担。自2004年以来，APIN公共卫生倡议提供艾滋病毒护理， 在尼日利亚，该公司为超过20，000名儿童提供治疗，因此在支持这项重要的PK研究方面具有独特的地位。 这一研究组合解决了关于新药PK和安全性知识的关键空白 艾滋病毒/结核病联合治疗和结核病预防的联合用药，这些发现可能为世卫组织关于在 儿童，以实现控制结核病在这一脆弱人群中造成的毁灭性死亡的目标。

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.