Background

Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB.

Methods

We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (C_trough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC_{0–24 h}), and maximum plasma concentration (C_max) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin C_max on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921).

Findings

Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for C_trough, 1·23 (0·99–1·53) for AUC_{0–24 h}, and 0·94 (0·76–1·16) for C_max. Individual dolutegravir C_trough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a C_max of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean C_max was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir.

Interpretation

Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB.

Funding

Penta Foundation, ViiV Healthcare, UK Medical Research Council.

中文翻译：

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多替拉韦每日两次用于治疗 HIV 相关结核病儿童：开放标签、多中心、随机、非劣效性 ODYSSEY 试验中的药代动力学和安全性研究

背景

患有艾滋病毒相关结核病 (TB) 的儿童几乎没有抗逆转录病毒治疗 (ART) 的选择。我们的目的是评估接受利福平治疗 HIV 相关结核病的儿童每日两次服用多替拉韦的安全性和药代动力学。

方法

我们在南非、乌干达和津巴布韦研究中心的开放标签、多中心、随机、对照、非劣效性 ODYSSEY 试验中进行了一项两期、固定顺序的药代动力学亚研究。接受利福平和每日两次多替拉韦治疗的患有 HIV 相关结核病的儿童（年龄 4 周至 <18 岁）符合纳入条件。我们对利福平和每日两次多鲁特韦进行了 12 小时药代动力学分析，并对每日一次多鲁特韦进行了 24 小时分析。使用谷血浆浓度（C_谷）、给药后 0 小时至 24 小时血浆浓度时间曲线下面积（AUC _{0-24 小时}）和最大血浆浓度（C _max）的几何平均比来比较多替拉韦浓度分学习日。我们在第一个亚研究日评估了利福平 C _{max 。}ODYSSEY 中所有患有 HIV 相关结核病且接受利福平和每日两次多替拉韦治疗的儿童均纳入安全性分析。我们描述了从开始每日两次多鲁特韦到恢复每日一次多鲁特韦后 30 天报告的不良事件。该试验已在 ClinicalTrials.gov (NCT02259127)、EudraCT (2014–002632-14) 和 ISRCTN 注册中心 (ISRCTN91737921) 注册。

发现

2016 年 9 月 20 日至 2021 年 6 月 28 日期间，有 37 名 HIV 相关结核病儿童（中位年龄 11·9 岁 [范围 0·4–17·6]，其中 19 名 [51%] 为女性，18 名 [49%]男性（非洲 36 名 [97%]，泰国 1 名 [3%]）接受利福平联合每日两次多替拉韦治疗，并纳入安全性分析。37 名儿童中有 20 名（54%）参加了药代动力学亚研究，其中 14 名儿童至少贡献了一条可评估的多替拉韦药代动力学曲线，其中 12 名进行了参与者内部比较。利福平和每日两次多鲁特韦与每日一次多鲁特韦的几何平均比率为：C 波谷为 1·51 (90% CI 1·08–2·11)，AUC 0 为 1·23 (0·99–1 _{· 53} ) _{–24 小时}，C _max为 0·94 (0·76–1·16) 。所有接受利福平和每日两次多替拉韦治疗的儿童中，个体多替拉韦 C_谷浓度均高于 90% 有效浓度（即 0·32 mg/L）。在 18 名可评估利福平浓度的儿童中，15 名 (83%) 的 C _max低于最佳目标浓度 8 mg/L。利福平几何平均C _max为5·1 mg/L（变异系数71%）。在中位随访 31 周（IQR 30-40）期间，37 名儿童中有 11 名（30%）发生了 15 起 3 级或以上不良事件，8 名（22%）儿童发生了 10 起严重不良事件，其中包括 2 名死亡（1例因肺结核死亡，1例因跌打损伤死亡）；没有考虑与多替拉韦相关的不良事件，包括死亡。

解释

每日两次的多替拉韦被证明是安全的，足以克服儿童中利福平酶的诱导作用，并且可以为患有 HIV 相关结核病的儿童提供实用的 ART 选择。

资金

Penta 基金会、ViiV Healthcare、英国医学研究委员会。