The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs.

中文翻译：

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开发和验证具有稳定同位素内标的多重 UHPLC-MS/MS 分析，用于监测 HIV 感染者中抗逆转录病毒药物 bictegravir、cabotegravir、doravirine 和 rilpivirine 的血浆浓度。

高效抗逆转录病毒治疗的广泛使用极大地改变了艾滋病毒感染者 (PLWH) 的预后。然而，此类治疗必须终生进行，这会引发有关维持治疗效果和长期耐受性的问题。最近批准或研究的抗逆转录病毒药物具有相当大的优势，允许每日一次口服剂量以及对抗耐药变异体（例如，比替拉韦和多拉韦林）的活性以及促进治疗依从性的肠胃外肌肉注射（例如，长效注射制剂，例如卡博替拉韦和利匹韦林）。尽管如此，由于吸收问题、异常消除、药物-药物相互作用等原因，仍然存在循环暴露不足或夸大的风险。在这种情况下，已开发出一种多重超高效液相色谱与串联质谱联用 (UHPLC-MS/MS) 生物测定法，用于监测 PLWH 中 bictegravir、cabotegravir、doravirine 和 rilpivirine 的血浆水平。进行简单方便的蛋白质沉淀，然后将上清液直接注入 UHPLC-MS/MS 系统。使用反相色谱法与三重四极杆质谱检测相结合，四种分析物在不到 3 分钟的时间内被洗脱出来。该生物测定按照国际指南进行了充分验证，并在临床相关浓度范围内的真实度 (94.7%-107.5%)、重复性 (2.6%-11%) 和中间精密度 (3.0%-11.2%) 方面取得了良好的性能（ bictegravir、cabotegravir、30 至 9000 ng/mL 和多拉韦林以及 10 至 1800 ng/mL 的利匹韦林）。这种灵敏、准确和快速的 UHPLC-MS/MS 分析目前在我们的实验室中用于口服药物比克替拉韦和多拉韦林的常规治疗药物监测，也打算用于监测来自 PLWH 的血浆中卡博特韦/利匹韦林水平每月或每 2 个月接受一次这些长效抗逆转录病毒药物的肌肉注射。