aDepartment of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa bHarvard T.H. Chan School of Public Health/Frontier Science Foundation, Boston, Massachusetts cUniversity of Alabama at Birmingham, Birmingham, Alabama dEunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda eColumbiaUSA Technologies at the National Institute of Allergy and Infectious Diseases, Rockville, Maryland fFHI 360, Durham, North Carolina gFrontier Science & Technology Research Foundation, Inc, Amherst, New York hNational Institute of Allergy and Infectious Diseases, Rockville, Maryland iMerck & Co, Inc, Palo Alto, California, USA jPerinatal HIV Research Unit, University of the Witwatersrand kWits Reproductive Health and HIV Institute, Johannesburg lDesmond Tutu TB Centre, Western Cape mDepartment of Paediatrics and Child Health, FAM-CRU, Stellenbosch University, Cape Town, South Africa nDavid Geffen School of Medicine at the University of California Los Angeles, Los Angeles, California, USA.
AIDS. 2019 Nov 15;33(14):2197-2203. doi: 10.1097/QAD.0000000000002369.
Drug-drug interactions limit current antiretroviral treatment options for HIV-infected children with tuberculosis (TB). Rifampicin (RIF) induces UDP-glucuronosyltransferase activity, accelerating the clearance of raltegravir (RAL). We sought to establish an optimal and well tolerated dose of RAL when administered with RIF to HIV and TB co-infected children.
P1101 is a phase I/II open-label dose-finding study of RAL with RIF for children 2 to less than 12 years of age beginning treatment for HIV and active TB.
Four sites in South Africa.
Chewable RAL was given at 12 mg/kg per dose twice daily (twice the usual pediatric dose) with two nucleoside reverse transcriptase inhibitors. Intensive RAL pharmacokinetic sampling was conducted 5 to 8 days after antiretroviral therapy was initiated; a fourth antiretroviral agent was then added.
Children were recruited into two age-defined groups: cohort 1 (2 to <6 years old) and cohort 2 (6 to <12 years old). Pharmacological targets [geometric mean (GM) AUC12 h of 14-45 μmol/l h and GM C12 h ≥75 nmol/l) were reached in both cohort 1 (28.8 μmol/l h and 229 nmol/l) and cohort 2 (38.8 μmol/l h and 228 nmol/l). The RAL-based ART was well tolerated by most participants: one participant discontinued treatment because of grade 4 hepatitis that was possibly treatment-related. At week 8, 22 of 24 participants (92%) had HIV RNA concentrations below 400 copies/ml; 19 of 24 (79%) were below 50 copies/ml.
Giving 12 mg/kg twice daily of the chewable RAL formulation achieved pharmacokinetic targets safely in HIV-infected children receiving RIF for TB.
药物相互作用限制了 HIV 感染合并结核病（TB）儿童的现有抗逆转录病毒治疗选择。利福平（RIF）诱导 UDP-葡萄糖醛酸转移酶活性，加速拉替拉韦（RAL）的清除。我们旨在确定当 RIF 与 HIV 和 TB 合并感染的儿童联合使用时 RAL 的最佳且耐受良好的剂量。
P1101 是一项 I/II 期开放标签剂量探索研究，研究对象为开始接受 HIV 和活动性 TB 治疗的 2 岁至 12 岁以下的儿童，使用 RIF 联合 RAL。
南非四个地点。
咀嚼型 RAL 每天两次给予 12mg/kg，每次剂量（儿科常用剂量的两倍），联合两种核苷逆转录酶抑制剂。在开始抗逆转录病毒治疗后 5 至 8 天进行密集的 RAL 药代动力学采样；然后添加第四种抗逆转录病毒药物。
儿童被招募到两个年龄定义的组中：组 1（2 至 <6 岁）和组 2（6 至 <12 岁）。两组均达到了药理学目标[14-45μmol/l/h 的几何均数（GM）AUC12h 和 GM C12h≥75nmol/l]：组 1（28.8μmol/l/h 和 229nmol/l）和组 2（38.8μmol/l/h 和 228nmol/l）。大多数参与者均耐受良好的 RAL 为基础的 ART：一名参与者因可能与治疗相关的 4 级肝炎而停止治疗。在第 8 周，24 名参与者中的 22 名（92%）HIV RNA 浓度低于 400 拷贝/ml；24 名中的 19 名（79%）低于 50 拷贝/ml。
在接受 RIF 治疗 TB 的 HIV 感染儿童中，每天两次给予 12mg/kg 的咀嚼型 RAL 制剂可安全地达到药代动力学目标。
