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)治疗对于实现艾滋病毒感染患者的艾滋病毒RNA抑制以及使用暴露前预防措施(PrEP)防止未感染的人感染艾滋病毒至关重要。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的艾滋病毒阴性者来说，高水平的坚持是具有挑战性的，他们没有每天感染艾滋病毒的风险。在最近的多项双盲、安慰剂对照的PrEP研究中，依从性差是导致药物缺乏有效性的主要原因。这些研究发现，计算产品退货和使用患者自我报告大大超过了通过血浆或细胞中ARV浓度衡量的依从性。由于不良或间歇性坚持的后果是重大的，有效的坚持措施对于优化临床和研究环境中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已摄入ARV的“金标准”，也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，包括具有侵入性，需要先进的处理或存储(例如细胞内测量)，是吸毒行为的短期衡量标准(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样品处理。我们建议使用红外线(IR)基质辅助激光解吸电喷雾电离(Maldesi)技术进行质谱仪成像(MSI)，以可视化和定量头发中的ARV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/研究参与者就依从性表现进行反馈。提出了三个具体目标：1)开发高灵敏度和准确性的IR-Maldesi MSI毛发方案，以量化5种治疗药物类别的11种抗逆转录病毒药物；2)进行3项结构性剂量比例研究，为PrEP和HIV治疗应用中的IR-Maldesi毛发黏附实时监测开发数学基准，并通过第二阶段PrEP研究验证基准；以及3)在实时临床监测的背景下，调查使用Hair IR-Maldesi MSI向HIV+患者提供有关用药依从性纵向模式的反馈的可接受性、适宜性和可行性。这项工作的目标是开发一种简单的、非侵入性的、纵向的ARV依从性描述，为临床医生和患者提供高清晰度的反馈。