Novel Mass Spectrometry Imaging Methods to Quantify Antiretroviral Adherence

量化抗逆转录病毒依从性的新型质谱成像方法

• 批准号: 9040663
• 负责人: Angela D Kashuba
• 金额: $ 80.33万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040663
• 关键词: Adherence; Anti-Retroviral Agents; Area; Behavior; Benchmarking; Blood; Blood Cells; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Data; Detection; Dose; Double-Blind Method; Drug Monitoring; Effectiveness; Electrospray Ionization; Enrollment; Evaluation; Feedback; Goals; Gold; Growth; HIV; Hair; Hair Color; Half-Life; Health; Image; Imaging technology; Incubated; Individual; Ingestion; Interview; Lasers; Length; Life; Mass Spectrum Analysis; Measures; Methods; Modeling; Monitor; Participant; Patient Self-Report; Patients; Pattern; Penetration; Performance; Pharmaceutical Preparations; Phase; Placebo Control; Plasma; Plasma Cells; Population; Prevention; Process; Prophylactic treatment; Protocols documentation; Provider; Publishing; RNA; Race; Research; Research Personnel; Resolution; Risk; Sampling; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; Statistical Models; Structure; Techniques; Technology; Tenofovir; Therapeutic; Time; Tissues; Viral reservoir; Woman; Work; antiretroviral therapy; base; clinically relevant; emtricitabine; healthy volunteer; imaging modality; medication compliance; men; novel; novel strategies; physiologic model; prevent; public health relevance; response; therapeutic biomarker; tool

 DESCRIPTION (provided by applicant): Adherence to antiretroviral (ARV) therapy is critical for achieving HIV RNA suppression in HIV-infected patients and for preventing HIV acquisition in uninfected individuals using pre-exposure prophylaxis (PrEP). Yet a high level of adherence is challenging for HIV-infected individuals on life-long ARVs, and for HIV-negative individuals using daily PrEP who are not at daily risk for HIV acquisition. Poor adherence was primarily responsible for a lack of drug effectiveness in multiple recent double-blind, placebo-controlled PrEP studies. These studies found that counting product returns and using patient self-report significantly over predicted adherence as measured by ARV concentrations in blood plasma or cells. Since the consequences of poor or intermittent adherence are significant, valid measures of adherence are critical for optimizing the effectiveness of both HIV treatment and prevention, in both the clinic and research settings. Blood plasma or intracellular concentration monitoring have been considered the "gold standard" for determining if an ARV has been ingested, and is a common marker for therapeutic drug monitoring or clinical trial adherence monitoring. However, this approach has its own set of limitations, including being invasive, requiring advanced processing or storage (e.g. intracellular measures), being a short-term measure of drug taking behavior (depending on the half-life of the analyte), and requiring long turn-around times or substantial sample processing prior to analysis. We propose the use of infra-red (IR) matrix-assisted laser desorption electrospray ionization (MALDESI) technology for mass spectrometry imaging (MSI) to visualize and quantify ARV concentrations in hair. Our hypothesis is that IR-MALDESI MSI can rapidly quantify ARV concentrations, provide evidence of drug ingestion non-invasively and longitudinally, and allow for clinician/researcher and patient/study participant feedback on adherence performance. Three specific aims are proposed: 1) Develop IR-MALDESI MSI hair protocols for high sensitivity and accuracy to quantify 11 ARVs in 5 therapeutic drug classes, 2) Conduct 3 structured dose proportionality studies to develop mathematical benchmarks for real-time IR-MALDESI hair adherence monitoring in both PrEP and HIV treatment applications, and validate the benchmarks with a Phase 2 PrEP study, and 3) In the setting of REAL TIME clinical monitoring, investigate the acceptability, appropriateness, and feasibility of using hair IR-MALDESI MSI to provide HIV+ patients with feedback regarding longitudinal patterns of medication adherence. The goal of this work is to develop a simple, noninvasive, longitudinal depiction of ARV adherence that will provide high clarity feedback for both clinicians and patients.

 描述（由申请人提供）：坚持抗逆转录病毒 (ARV) 治疗对于实现 HIV 感染者的 HIV RNA 抑制以及使用暴露前预防 (PrEP) 预防未感染者感染 HIV 至关重要。然而，对于终生服用抗逆转录病毒药物的艾滋病毒感染者和每天使用 PrEP 且不存在日常感染艾滋病毒风险的艾滋病毒阴性者来说，高水平的依从性具有挑战性。在最近的多项双盲、安慰剂对照 PrEP 研究中，依从性差是导致药物有效性缺乏的主要原因。这些研究发现，计算产品退货和使用患者自我报告显着超过通过血浆或细胞中的抗逆转录病毒浓度测量的预测依从性。由于依从性差或间歇性依从性的后果很严重，因此有效的依从性测量对于在临床和研究环境中优化艾滋病毒治疗和预防的有效性至关重要。血浆或细胞内浓度监测被认为是确定是否摄入抗逆转录病毒药物的“金标准”，并且是治疗药物监测或临床试验依从性监测的常见标志。然而，这种方法有其自身的局限性，包括侵入性、需要先进的处理或存储（例如细胞内测量）、作为吸毒行为的短期测量（取决于分析物的半衰期）以及在分析之前需要较长的周转时间或大量的样品处理。我们建议使用红外（IR）基质辅助激光解吸电喷雾电离（MALDESI）技术进行质谱成像（MSI）来可视化和量化头发中的抗逆转录病毒浓度。我们的假设是 IR-MALDESI MSI 可以快速量化 ARV 浓度，提供非侵入性和纵向的药物摄入证据，并允许临床医生/研究人员和患者/研究参与者对依从性表现进行反馈。提出了三个具体目标：1) 开发 IR-MALDESI MSI 头发协议，以实现高灵敏度和准确性，以量化 5 种治疗药物类别中的 11 种抗逆转录病毒药物，2) 进行 3 项结构化剂量比例研究，为 PrEP 和 HIV 治疗应用中的实时 IR-MALDESI 头发粘附监测制定数学基准，并通过 2 期 PrEP 研究验证基准，以及 3) 在实时临床环境中 监测，调查使用头发 IR-MALDESI MSI 为 HIV+ 患者提供有关药物依从性纵向模式的反馈的可接受性、适当性和可行性。这项工作的目标是开发一种简单、无创、纵向的抗逆转录病毒药物依从性描述，为临床医生和患者提供高度清晰的反馈。