College of Medicine and Emerging Pathogens Institute, University of Florida, Gainesville, Florida, USA
Department of Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Antimicrob Agents Chemother. 2018 Dec 21;63(1). doi: 10.1128/AAC.01657-18. Print 2019 Jan.
We compared efavirenz pharmacokinetic (PK) parameters in children with tuberculosis (TB)/human immunodeficiency virus (HIV) coinfection on and off first-line antituberculosis therapy to that in HIV-infected children. Children 3 to 14 years old with HIV infection, with and without TB, were treated with standard efavirenz-based antiretroviral therapy without any efavirenz dose adjustments. The new World Health Organization-recommended antituberculosis drug dosages were used in the coinfected participants. Steady-state efavirenz concentrations after 4 weeks of antiretroviral therapy were measured using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) assays. Pharmacokinetic parameters were calculated using noncompartmental analysis. Between groups, PK parameters were compared by Wilcoxon rank-sum test and within group by signed-rank test. Of the 105 participants, 43 (41.0%) had TB coinfection. Children with TB/HIV coinfection compared to those with HIV infection were younger, had lower median weight-for-age score, and received a higher median efavirenz weight-adjusted dose. Geometric mean (GM) efavirenz peak concentration (), concentration at 12 h (), , and total area under the curve from time 0 to 24 h (AUC) values were similar in children with HIV infection and those with TB/HIV coinfection during anti-TB therapy. Geometric mean efavirenz , , and AUC values were lower in TB/HIV-coinfected patients off anti-TB therapy than in the children with HIV infection or TB/HIV coinfection on anti-TB therapy. Efavirenz clearance was lower and AUC was higher on than in patients off anti-TB therapy. Reduced efavirenz clearance by first-line anti-TB therapy at the population level led to similar PK parameters in HIV-infected children with and without TB coinfection. Our findings do not support modification of efavirenz weight-band dosing guidelines based on TB coinfection status in children. (The study was registered with ClinicalTrials.gov under registration number NCT01704144.).
我们比较了正在接受一线抗结核治疗和未接受一线抗结核治疗的合并结核（TB）/人类免疫缺陷病毒（HIV）感染儿童的依非韦伦药代动力学（PK）参数与 HIV 感染儿童的依非韦伦 PK 参数。3 至 14 岁的 HIV 感染儿童，无论是否合并结核，均接受标准的依非韦伦为基础的抗逆转录病毒治疗，未调整依非韦伦剂量。合并感染的参与者使用新的世界卫生组织推荐的抗结核药物剂量。在抗逆转录病毒治疗 4 周后，使用经验证的液相色谱串联质谱（LC-MS/MS）测定法测量稳态依非韦伦浓度。使用非房室分析计算 PK 参数。组间比较 PK 参数采用 Wilcoxon 秩和检验，组内比较采用符号秩检验。在 105 名参与者中，43 名（41.0%）患有结核合并感染。与 HIV 感染儿童相比，TB/HIV 合并感染的儿童年龄较小，中位体重年龄评分较低，接受的依非韦伦剂量调整后体重中位数较高。在接受抗结核治疗期间，HIV 感染儿童和 TB/HIV 合并感染儿童的依非韦伦峰浓度（）、12 小时浓度（）、、和 0 至 24 小时总 AUC 值的几何均数（GM）相似。与 HIV 感染儿童或 TB/HIV 合并感染儿童在接受抗结核治疗时相比，TB/HIV 合并感染儿童在停止抗结核治疗时的依非韦伦、和 AUC 值较低。与停止抗结核治疗的患者相比，接受抗结核治疗的患者的依非韦伦清除率较低，AUC 较高。一线抗结核治疗在人群水平上降低了依非韦伦的清除率，导致合并和未合并结核的 HIV 感染儿童的 PK 参数相似。我们的研究结果不支持根据儿童合并结核的情况修改依非韦伦体重带剂量指南。（该研究在 ClinicalTrials.gov 上注册，注册号为 NCT01704144.）。
