A Point-of-Care Assay to Measure Tenofovir for Monitoring PrEP and ART Adherence

摘要 坚持抗逆转录病毒疗法(ART)和暴露前预防(PrEP)是成功的关键 艾滋病毒治疗和治疗性预防。没有准确、客观的护理点检测可用来监控 坚持ART或PrEP。无法准确识别依从性差的患者将导致更多 艾滋病毒感染(来自失败的PrEP和非抑制性ART)，更多的抗药性病毒(由失败的ART选择)， 以及不必要地转向昂贵的二线或三线抗逆转录病毒疗法(当一线疗法具有病毒学疗效时 但不遵守被不适当地停止)。为了解决这一关键的知识差距，我们开发了一种 用于检测抗逆转录病毒治疗和PrEP中最常见药物替诺福韦存在的新型护理点测试 全球范围内的治疗--用手指抽血或尿液作为ART和PrEP依从性的客观衡量标准。这个 我们申请的目标是进行必要的下一步工作，以推进这一护理点测试：我们将 在受控药代动力学范围内评估我们新的全血和尿样护理点检测方法 健康志愿者维持受控用药依从性的研究和我们的初步验证研究 对来自现有生物仓库的真实世界临床样本进行的新的护理点分析。我们的中心假设 替诺福韦在血液和尿液中的药代动力学将支持护理点替诺福韦检测作为 客观地衡量依从性，我们的护理点替诺福韦测定法将有能力区分 不同的药物依从性水平。我们将通过追求以下两个具体假设来测试我们的中心假设 目的：(1)评估我们的新的护理点替诺福韦(TFV)在全血和尿样中的检测 HIV阴性成人服用富马酸替诺福韦(TDF)的对照药代动力学研究 中度和完美的依从性；以及(2)验证我们新的护理点替诺福韦(TFV)血液分析 以及使用来自真实世界临床艾滋病毒预防研究的现有生物库的尿样。这部作品 是创新的，因为它开发了一种全新的快速诊断测试类别，用于监测ART和 在临床护理点准备坚持。我们的快速检测将帮助临床医生识别有需要的患者 更多的依从性咨询，当实施时，将防止艾滋病毒感染，毒品的出现- 抗药性病毒和不必要的抗逆转录病毒治疗方案转换--这些措施将改善国家艾滋病毒规划 并帮助保持有效的艾滋病毒药物的全球供应。

ABSTRACT Adherence to antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are critical to the success of HIV treatment and therapeutic prevention. No accurate, objective point-of-care test is available to monitor adherence to either ART or PrEP. The inability to accurately identify poorly adherent patients will lead to more HIV infections (from failed PrEP and non-suppressive ART), more drug-resistant virus (selected by failing ART), and unnecessary switching to costly second- or third-line ART (when first-line regimens with virologic efficacy but non-adherence are stopped inappropriately). To address this critical knowledge gap, we have developed a novel point-of-care test to detect the presence of tenofovir—the most common drug in both ART and PrEP treatments worldwide—in fingerprick blood or urine as an objective measure of ART and PrEP adherence. The objective of our application is to conduct essential next-step work to advance this point-of-care test: we will assess our novel point-of-care assay in whole blood and urine specimens within a controlled pharmacokinetic study of healthy volunteers maintaining controlled drug adherence and conduct a pilot validation study of our novel point-of-care assay on real-world clinical samples from an existing biorepository. Our central hypothesis is that the pharmacokinetics of tenofovir in blood and urine will support point-of-care tenofovir detection as an objective measure of adherence, and that our point-of-care tenofovir assay will have the ability to discriminate different drug adherence levels. We will test our central hypotheses by pursuing the following two specific aims: (1) To assess our novel point-of-care tenofovir (TFV) assay in whole blood and urine specimens within a controlled pharmacokinetic study of HIV-negative adults receiving tenofovir disoproxil fumarate (TDF) with low, moderate, and perfect adherence; and (2) To validate our novel point-of-care tenofovir (TFV) assay on blood and urine specimens using an existing biorepository from a real-world clinical HIV prevention study. This work is innovative because it develops an entirely new category of rapid diagnostic testing for monitoring ART and PrEP adherence at the clinical point of care. Our rapid assay will help clinicians identify patients in need of more adherence counseling, which when implemented will prevent HIV acquisition, emergence of drug- resistant virus, and unnecessary ART regimen switching—measures that will improve national HIV programs and help preserve the global supply of an effective HIV medication.