A novel REverSe Transcriptase Chain Termination (RESTRICT) assay for near-patient, objective monitoring of long-term PrEP adherence

一种新型 REverSe 转录酶链终止 (RESTRICT) 测定，可用于患者附近长期 PrEP 依从性的客观监测

• 批准号: 10300073
• 负责人: Paul K Drain
• 金额: $ 77.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-09 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300073
• 关键词: Address; Adherence; Adult; Algorithmic Analysis; Biological Assay; Blood specimen; Client; Clinic; Clinical; Counseling; Data; Data Analyses; Data Collection; Diabetes Mellitus; Diphosphates; Drug Kinetics; Foundations; Fumarates; Glycosylated hemoglobin A; Goals; Gold; Guidelines; HIV; Half-Life; Human; Ingestion; Interview; Laboratories; Liquid Chromatography; Measurement; Measures; Medical center; Monitor; Oral; Outpatients; Patient Self-Report; Patients; Pharmaceutical Preparations; Population; Preparation; Procedures; Provider; RNA-Directed DNA Polymerase; Randomized; Reporting; Research; Resources; Sampling; Structure; Supportive care; Surveys; Tenofovir; Testing; Training; Universities; Urine; Validation; Visit; Washington; Whole Blood; acceptability and feasibility; base; cellular targeting; clinical efficacy; clinically relevant; emtricitabine; experience; follow-up; implementation science; implementation study; improved; in-vitro diagnostics; medication compliance; meetings; novel; novel strategies; pill; pre-exposure prophylaxis; prevent; prospective; tandem mass spectrometry; tool; transmission process; validation studies

ABSTRACT Oral pre-exposure prophylaxis (PrEP), composed of tenofovir disoproxil fumarate and emtricitabine, is effective for preventing HIV acquisition, but PrEP efficacy is highly dependent on drug adherence. In several trials and implementation studies, PrEP clients have difficulties maintaining adequate adherence and persistence, and monitoring their PrEP use is challenging. PrEP providers have relied on self-reported adherence, which is often inaccurate and unreliable. The lack of an objective PrEP adherence monitoring tool has led to inefficient counseling and poor supportive care. To address these issues, we completed a randomized pharmacokinetic study to determine drug levels during controlled directly-observed PrEP. Longer-term metabolites, such as tenofovir-diphosphate (TFV-DP) (~17-day half-life), provide a more accurate picture of long-term PrEP adherence. We recently developed a novel enzymatic assay that semi-quantitatively measures the concentration of TFV-DP by measuring inhibition of reverse transcriptase, which is the cellular target of oral PrEP drugs. In this proposal, our primary objectives are optimizing the REverSe TRanscrIptase Chain Termination (RESTRICT) assay to measure drug concentrations of PrEP clients, to establish validation for CLIA criteria when implemented in a near-patient clinical lab, and to evaluate the feasibility and acceptability of using the RESTRICT assay for drug level measurement among PrEP clients and providers. We will test our central hypotheses with three specific aims: (1) to calibrate and optimize the RESTRICT assay for measuring long-term TFV-DP drug concentrations, compared to gold-standard liquid chromatography tandem mass spectrometry (LC-MS/MS) measurement; (2) to validate the RESTRICT assay for meeting established CLIA criteria to enable clinical reporting of an objective near-patient measure for monitoring long-term TFV-DP drug concentrations; (3) to evaluate the feasibility and acceptability of near-patient TFV-DP testing among PrEP clients and providers at a major PrEP clinic in Seattle. Our proposed study will be the first to validate a rapid, near-patient long-term objective measure of oral PrEP adherence. This study will also provide crucial data on the feasibility and acceptability of a novel approach for improving PrEP delivery and monitoring to prevent HIV transmission. The results of this study will develop a new tool that may help improve PrEP delivery in the US and worldwide.

抽象的 由富马酸替诺福韦二吡呋酯和恩曲他滨组成的口服暴露前预防 (PrEP) 有效 预防 HIV 感染，但 PrEP 的疗效高度依赖于药物依从性。在多次试验和 实施研究，PrEP 客户难以保持足够的依从性和持久性，以及 监测他们的 PrEP 使用情况具有挑战性。 PrEP 提供者依赖自我报告的依从性，这通常是 不准确且不可靠。缺乏客观的 PrEP 依从性监测工具导致效率低下 咨询和支持性护理不佳。为了解决这些问题，我们完成了一项随机药代动力学研究 研究确定受控直接观察 PrEP 期间的药物水平。长期代谢物，例如 替诺福韦二磷酸 (TFV-DP)（约 17 天半衰期），提供更准确的长期 PrEP 图片 坚持。我们最近开发了一种新型酶测定法，可以半定量测量浓度 通过测量逆转录酶的抑制来检测 TFV-DP，逆转录酶是口服 PrEP 药物的细胞靶点。在这个 根据提案，我们的主要目标是优化反向转录酶链终止 (RESTRICT) 测定 PrEP 客户的药物浓度，在实施时建立 CLIA 标准的验证 在靠近患者的临床实验室中，并评估使用 RESTRICT 检测的可行性和可接受性 PrEP 客户和提供者之间的药物水平测量。我们将用三个方面来检验我们的中心假设 具体目标：（1）校准和优化用于测量长期 TFV-DP 药物的 RESTRICT 测定 浓度，与金标准液相色谱串联质谱 (LC-MS/MS) 相比 测量; (2) 验证 RESTRICT 测定是否满足既定的 CLIA 标准，以实现临床 报告用于监测长期 TFV-DP 药物浓度的客观近患者测量； (3) 至 评估 PrEP 客户和提供者之间近患者 TFV-DP 测试的可行性和可接受性 西雅图主要的 PrEP 诊所。我们提出的研究将是第一个验证快速、近患者长期治疗的研究 口服 PrEP 依从性的客观衡量。这项研究还将提供有关可行性和可行性的重要数据。 改善 PrEP 交付和监测以预防 HIV 传播的新方法的可接受性。这 这项研究的结果将开发出一种新工具，可能有助于改善美国和全世界的 PrEP 实施。