Point-of-care Urine Monitoring of Adherence (PUMA): Testing a Real-Time Urine Assay of Tenofovir in PrEP

项目总结/摘要 暴露前预防（PrEP）临床试验的三个教训-坚持对有效性至关重要， 药物依从性指标比自我报告更可靠， 在临床护理点的依从性应改善依从性-必须解决，以便解释和 优化PrEP，因为它是在全球范围内推出。PrEP试验的定性证据，特别是VOICE研究， 缺乏依从性导致在血清不一致的年轻女性中发现PrEP无效 在非洲的夫妇，表明个人对PrEP会发现他们的PrEP药物水平的知识， 访视激励后续依从性。此外，有充分的证据表明， 实时监测所需药物的药物水平，然后向患者提供支持性反馈， 患者，增加依从性并改善结果。我们加州大学旧金山分校的研究小组帮助开拓了 小的头发样本（易于收集，储存和运输），以测量对PrEP的坚持;其他 坚持PrEP的药理学指标评估血浆或干血斑中的药物水平。然而，在这方面， 目前分析任何基质（包括尿液）中的PrEP药物的方法涉及液相色谱/串联色谱法， 质谱法（LC-MS/MS）是昂贵的并且不能实时进行。 我们的UCSF团队与Alere Rapid Diagnostics合作，后者是一家在以下方面拥有丰富专业知识的公司： 开发护理点（POC）诊断，现在已经开发出第一种免疫测定（基于抗体的 测定）以定量尿液中的TFV，这是一种易于用于POC检测的基质。免疫测定是高度 灵敏度（100%）、灵敏度（96%）和精确度;通过免疫测定法测定的TFV尿液水平高度相关 与LC-MS/MS的结果比较，相关系数r = 0.95。侧流免疫分析（LFA）允许低成本（每次测试<2.00美元） 监测.汇集了一个经验丰富的调查团队，这笔赠款将直接利用- 在泰国进行的TDF/FTC观察治疗研究，以确定用于包装 LFA成为一种临床上有用的，低成本的工具，表明高，中度，或低/无PrEP依从性（目标1）。目的 2将检查POC尿TFV水平与血浆TFV水平和HIV血清转换事件的相关性 在一项已完成的大型试验中（Partners PrEP）。目标3将评估真实的- 使用POC检测法对肯尼亚PrEP妇女随时间的依从性进行时间监测/反馈。 该提议具有高度创新性，因为我们已经开发了第一种TFV免疫测定法， POC依从性监测。这种新的检测方法对HIV治疗有进一步的意义。由于基于TFV 方案（TDF或替诺福韦艾拉酚胺（TAF））是HIV治疗的支柱， 可能有助于避免在更昂贵的病毒载量测量之间的病毒学失败和耐药性。这 低成本的工具有潜力提高PrEP和ART的有效性， 解释和加强依从性，帮助寻求结束全球新的艾滋病毒感染。

PROJECT SUMMARY/ ABSTRACT Three lessons of the pre-exposure prophylaxis (PrEP) clinical trials - that adherence is critical to effectiveness, that pharmacologic adherence measures are more reliable than self-report, and that a tool to measure adherence at the clinical point-of-care should improve adherence–must be addressed in order to interpret and optimize PrEP as it is rolled-out globally. Qualitative evidence from the PrEP trials, especially the VOICE study, where lack of adherence led to a finding of null efficacy for PrEP in young women not in serodiscordant couples in Africa, demonstrates that individuals on PrEP would find knowledge of their PrEP drug levels at a visit motivating for subsequent adherence. Moreover, there is ample evidence from other disease states that real-time monitoring of drug levels to the needed medication, followed by supportive feedback to the patient, increases adherence and improves outcomes. Our UCSF research group has helped pioneer the use of small hair samples (which are easy to collect, store and ship) to measure adherence to PrEP; other pharmacologic metrics of adherence to PrEP assess drug levels in plasma or dried blood spots. However, current methods to analyze PrEP drugs in any matrix, including urine, involve liquid chromatography/tandem- mass spectrometry (LC-MS/MS) which is expensive and cannot be performed in real-time. Our UCSF group, in collaboration with Alere Rapid Diagnostics, a company with vast expertise in developing point-of-care (POC) diagnostics, has now developed the first immunoassay (antibody-based assay) to quantitate TFV in urine, a matrix easily-accessible for POC testing. The immunoassay is highly sensitive (100%), sensitive (96%), and precise; TFV urine levels via the immunoassay are highly correlated with those from LC-MS/MS (r=0.95). Lateral flow immunoassays (LFA) allow for low-cost (<$2.00 per test) monitoring. Bringing together a highly experienced investigator team, this grant will leverage a directly- observed therapy study of TDF/FTC in Thailand to determine interpretive cut-offs for the assay to package the LFA into a clinically-useful, low-cost tool that indicates high, moderate, or low/no PrEP adherence (Aim 1). Aim 2 will examine the correlation of POC urine TFV levels with plasma TFV levels and HIV seroconversion events in a large completed trial (Partners PrEP). Aim 3 will evaluate the feasibility, acceptability, and impact of real- time monitoring/feedback using the POC assay on adherence over time among women on PrEP in Kenya. This proposal is highly innovative in that we have developed the first TFV immunoassay, allowing for POC adherence monitoring. This novel assay has further implications for HIV treatment. Since TFV-based regimens (TDF or tenofovir alafenamide (TAF)) are the backbone of HIV treatment, a low-cost POC TFV assay may help avert virologic failure and drug resistance between more expensive viral load measurements. This low-cost tool has the potential to improve PrEP and ART effectiveness during global expansion by both interpreting and enhancing adherence, aiding the quest to end new HIV infections worldwide.