Laboratoire de Pharmacocinétique et Toxicologie, Aix Marseille Univ, APHM, INSERM, CNRS, CRCM SMARTc, Hôpital La Timone, Marseille, F-13005, France.
APHP, Hôpital Bichat-Claude Bernard, Laboratoire de Pharmacologie-Toxicologie, IAME, UMR 1137, Université Paris Diderot, Sorbonne Paris Cité and INSERM, Paris, F-75018, France.
Br J Clin Pharmacol. 2020 Dec;86(12):2404-2413. doi: 10.1111/bcp.14344. Epub 2020 Jun 1.
The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine.
A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration.
Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%).
This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.
本研究旨在评估利匹韦林/恩曲他滨/替诺福韦二吡呋酯联合制剂的抗病毒活性，并描述利匹韦林的药代动力学及其与临床常规耐药的相关性。
对接受每日一次利匹韦林/恩曲他滨/替诺福韦二吡呋酯治疗的初治和经治 HIV 患者进行回顾性多中心队列研究。在随访期间收集免疫病毒学和耐药数据以及利匹韦林的血药浓度。进行统计学分析以评估利匹韦林药代动力学与病毒学应答之间的关系。进行受试者工作特征（ROC）曲线分析以确定最佳目标利匹韦林血药浓度。
共纳入 379 例患者。中位随访 28 个月后，26%的患者因毒性而停药，病毒学成功率为 65.7%。5%的患者发生病毒学失败。在 M6（28%）和 M12（31%）时，大多数 HIV-RNA>40 拷贝/mL的患者的利匹韦林血药浓度低于目前使用的 50ng/mL 疗效阈值，与病毒学抑制的患者相比，利匹韦林血药浓度明显较低。半数发生利匹韦林耐药突变的病毒学失败患者至少有一次利匹韦林血药浓度不理想。利匹韦林血药浓度的最佳目标为 70ng/mL（灵敏度 75.4%；特异性 61.5%）。
本研究表明利匹韦林血药浓度对病毒学应答和利匹韦林耐药突变的出现都有影响。此外，我们的结果表明，在临床实践中可以提出更高的利匹韦林血药浓度目标。
