Background

Short-course preventive therapy with 12 doses of once-weekly rifapentine (900 mg) plus isoniazid (900 mg) could greatly improve tuberculosis control, especially in areas with high co-endemicity with HIV. However, a small previous trial of such therapy with dolutegravir in healthy, HIV-negative adults was halted early after two of the four patients developed serious adverse events. Because of the potential use of this therapy, and variable safety outcomes of tuberculosis drugs seen in patients with and without HIV, we aimed to characterise safety, pharmacokinetics, and virological suppression in adults who are HIV positive.

Methods

DOLPHIN was a phase 1/2, single-arm trial done at The Aurum Institute (Tembisa Clinical Research Site, Tembisa, South Africa), with pharmacokinetic visits done at VxPharma (Pretoria, South Africa). Adults (≥18 years) with HIV infection and undetectable viral load (<40 copies per mL) after at least 8 weeks of efavirenz-based or dolutegravir-based regimens were recruited in three consecutive groups, subject to approval by the independent safety monitoring committee. Participants received 50 mg of daily dolutegravir in place of efavirenz for 8 weeks, then began once-weekly rifapentine (900 mg)–isoniazid (900 mg) for 12 weeks. Groups 1A (n=12) and 1B (n=18) had intensive dolutegravir pharmacokinetic sampling at week 8 (before rifapentine–isoniazid), at week 11 (after the third dose of rifapentine)–isoniazid and at week 16 after the eighth dose. Group 2 (n=30) were treated with the same schedule and had sparse dolutegravir pharmacokinetic sampling at weeks 8, 11, and 16. Participants were followed 4 weeks after completion of prophylactic tuberculosis treatment. HIV viral loads were measured at baseline and at weeks 11 and 24. Primary endpoints were adverse events (grade 3 or higher) and dolutegravir population pharmacokinetics, assessed in participants who began rifapentine–isoniazid. This trial was registered at ClinicalTrials.gov, NCT03435146.

Findings

Between Jan 24, 2018, and Nov 25, 2018, 61 participants were enrolled into three groups; one participant withdrew (from group 1A). 43 (70%) of 60 participants were women and all participants were black African. Median age was 40 years (IQR 35–48), CD4 cell count was 683 cells per μL (447–935), and body-mass index was 28·9 kg/m² (24·0–32·9). Three grade 3 adverse events occurred; two elevated creatinine and one hypertension. Rifapentine–isoniazid increased dolutegravir clearance by 36% (relative standard error 13%) resulting in a 26% decrease in dolutegravir area under the curve. Overall geometric mean ratio of trough concentrations with versus without rifapentine–isoniazid was 0·53 (90% CI 0·49–0·56) though this ratio varied by day after rifapentine–isoniazid dose. All but one trough value was above the 90% maximal inhibitory concentration for dolutegravir and HIV viral loads were less than 40 copies per mL in all patients.

Interpretation

Our results suggest 12 doses of once-weekly rifapentine–isoniazid can be given for tuberculosis prophylaxis to patients with HIV taking dolutegravir-based antiretroviral therapy, without dose adjustments. Further exploration of the pharmacokinetics, safety, and efficacy in children and pharmacodynamics in individuals naive to antiretroviral therapy is needed.

Funding

UNITAID.

中文翻译：

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每周一次的利福喷汀和异烟肼用于预防接受基于多替拉韦的抗逆转录病毒治疗的 HIV 患者的结核病：1/2 期试验。

背景

使用 12 剂每周一次的利福喷丁（900 毫克）加异烟肼（900 毫克）的短期预防性治疗可以极大地改善结核病控制，特别是在与 HIV 共流行的地区。然而，在 4 名患者中有 2 名出现严重不良事件后，先前在健康的 HIV 阴性成人中使用多替拉韦进行此类治疗的小型试验被提前终止。由于这种疗法的潜在用途，以及在感染和未感染 HIV 的患者中观察到的结核病药物的不同安全性结果，我们旨在描述 HIV 阳性成人的安全性、药代动力学和病毒学抑制特征。

方法

DOLPHIN 是一项 1/2 期单臂试验，在 The Aurum Institute（Tembisa Clinical Research Site，Tembisa，南非）完成，药代动力学访问在 VxPharma（南非比勒陀利亚）完成。在接受至少 8 周基于依非韦伦或基于多替拉韦的方案后，感染 HIV 且病毒载量检测不到（<40 拷贝/mL）的成人（≥18 岁）被分为三个连续组，但须经独立安全监测委员会批准. 参与者每天服用 50 毫克多替拉韦代替依非韦伦，持续 8 周，然后开始每周服用一次利福喷丁 (900 毫克)– 异烟肼 (900 毫克)，持续 12 周。第 1A 组 (n=12) 和 1B (n=18) 在第 8 周（利福喷汀-异烟肼之前）、第 11 周（利福喷汀-异烟肼第三次给药后）和第 8 次给药后第 16 周进行密集的多替拉韦药代动力学采样. 第 2 组（n=30）接受相同的治疗，并在第 8、11 和 16 周进行稀疏的多替拉韦药代动力学取样。参与者在完成预防性结核病治疗后 4 周接受随访。在基线以及第 11 周和第 24 周时测量了 HIV 病毒载量。主要终点是不良事件（3 级或更高）和多替拉韦群体药代动力学，在开始使用利福喷汀-异烟肼的参与者中进行评估。该试验在 ClinicalTrials.gov 注册，NCT03435146。主要终点是不良事件（3 级或更高）和多替拉韦群体药代动力学，在开始使用利福喷汀-异烟肼的参与者中进行评估。该试验在 ClinicalTrials.gov 注册，NCT03435146。主要终点是不良事件（3 级或更高）和多替拉韦群体药代动力学，在开始使用利福喷汀-异烟肼的参与者中进行评估。该试验在 ClinicalTrials.gov 注册，NCT03435146。

发现

2018年1月24日至2018年11月25日期间，61名参与者被分为三组；一名参与者退出（从 1A 组）。60 名参与者中有 43 名 (70%) 是女性，所有参与者都是非洲黑人。中位年龄为 40 岁 (IQR 35–48)，CD4 细胞计数为 683 个细胞/μL (447–935)，体重指数为 28·9 kg/m ²(24·0–32·9)。发生了三个 3 级不良事件；两个升高的肌酐和一个高血压。利福喷丁-异烟肼使多替拉韦清除率增加 36%（相对标准误差 13%），导致多替拉韦曲线下面积减少 26%。有与没有利福喷汀-异烟肼的谷浓度的总体几何平均比值为 0·53（90% CI 0·49–0·56），尽管该比值在利福喷汀-异烟肼给药后随天数变化。除一个谷值外，所有患者的谷值均高于多替拉韦的 90% 最大抑制浓度，并且所有患者的 HIV 病毒载量均低于 40 拷贝/mL。

解释

我们的结果表明，对于接受基于多替拉韦的抗逆转录病毒治疗的 HIV 患者，每周一次的 12 剂利福喷汀-异烟肼可用于预防结核病，无需调整剂量。需要进一步探索儿童的药代动力学、安全性和有效性以及未接受过抗逆转录病毒治疗的个体的药效学。

资金

国际药品采购机制。