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

摘要 坚持抗逆转录病毒治疗（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、客观的床旁检测可用于监测 无法准确识别依从性差的患者将导致更多的 HIV感染（来自失败的PrEP和非抑制性ART），更多的耐药病毒（通过失败的ART选择）， 和不必要的转换到昂贵的二线或三线ART（当一线方案具有病毒学疗效时， 但是不遵守被不适当地停止）。为了解决这一关键的知识差距，我们开发了一个 一种新的即时检测方法，用于检测替诺福韦（ART和PrEP中最常见的药物）的存在 全球范围内的治疗-在手指采血或尿液作为ART和PrEP依从性的客观指标。的 我们申请的目的是进行必要的下一步工作，以推进这种即时检测：我们将 在受控的药代动力学范围内评估我们在全血和尿液标本中的新型即时检测 研究健康志愿者维持受控的药物依从性，并进行我们的初步验证研究 对来自现有生物储存库的真实临床样本进行新的即时检测。我们的核心假设 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， 坚持客观的措施，我们的即时护理替诺福韦检测将有能力区分 不同的药物依从性水平。我们将通过以下两个具体问题来检验我们的中心假设： 目的：（1）评估我们的新型床旁替诺福韦（TFV）检测方法在全血和尿液标本中的应用， 接受富马酸替诺福韦酯（TDF）的HIV阴性成人的对照药代动力学研究， 中度和完美的遵守;和（2）为了验证我们的新的即时替诺福韦（TFV）检测血液 和尿液标本，使用来自真实世界临床HIV预防研究的现有生物储存库。这项工作 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， PrEP在临床护理点的依从性。我们的快速检测将帮助临床医生识别需要治疗的患者。 更多的坚持咨询，当实施时，将防止艾滋病毒感染，药物的出现， 耐药病毒和不必要的ART方案转换--这些措施将改善国家艾滋病规划 并帮助保护全球有效的艾滋病药物供应。

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.