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: 10159767
• 负责人: Paul K Drain
• 金额: $ 76.78万
• 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/10159767
• 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; 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 口服预防前预防（PREP），由替诺福韦毒素毒素和伊姆特里滨组成，是有效的 为了预防艾滋病毒的获取，但是准备疗效高度依赖于药物依从性。在几个试验中 实施研究，准备客户难以维持足够的依从性和持久性，并且 监视他们的准备使用是具有挑战性的。准备提供者依靠自我报告的依从性，这通常是 不准确和不可靠。缺乏客观的准备依从性监控工具导致效率低下 咨询和不良的支持护理。为了解决这些问题，我们完成了一个随机的药代动力学 研究以确定在受控直接观察的PREP期间的药物水平。长期代谢产物，例如 Tenofovir-Diphosphate（TFV-DP）（〜17天半衰期），提供了更准确的长期准备情况 坚持。我们最近开发了一种新型的酶法测定 通过测量对逆转录酶的抑制，这是口服药物的细胞靶标。在这个 提案，我们的主要目标是优化逆转录酶链终止（限制） 测量药物的药物浓度的测定，实施时为CLIA标准建立验证 在接近患者的临床实验室中，并评估使用限制测定的可行性和可接受性 预备客户和提供者之间的药物水平测量。我们将用三个 具体目的：（1）校准和优化测量长期TFV-DP药物的限制测定法 与金色标准的液相色谱串联质谱法（LC-MS/MS）相比浓度 测量; （2）验证限制符合既定CLIA标准以实现临床的限制测定法 报告一项客观的接近患者测量，以监测长期TFV-DP药物浓度； （3）到 评估准备客户和提供商之间近亲TFV DP测试的可行性和可接受性 西雅图的主要预科诊所。我们提出的研究将是第一个验证快速，接近患者的长期的研究 口服准备依从性的客观度量。这项研究还将提供有关可行性和 一种新颖的方法可接受改善准备递送和监测以防止HIV传播的方法。这 这项研究的结果将开发一种新工具，可以帮助改善美国和全球的准备交付。