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: 10260722
• 负责人: Angela D Kashuba
• 金额: $ 74.96万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10260722
• 关键词: Adherence; Anti-Retroviral Agents; Area; Behavior; Benchmarking; Blood Cells; Cells; Clinic; Clinical; Clinical Research; Clinical Trials; Communicable Diseases; Data; Detection; Dose; Double-Blind Method; Drug Kinetics; Drug Monitoring; Effectiveness; Electrospray Ionization; Enrollment; Evaluation; Exposure to; Feedback; Goals; Gold; Growth; HIV; HIV Seronegativity; Hair; Hair Color; Half-Life; Health; Image; Incubated; Individual; Ingestion; Instruction; Interview; Lasers; Length; Life; Mass Spectrum Analysis; Mathematics; Measures; Methods; Modeling; Monitor; Participant; Patient Self-Report; Patients; Pattern; Penetration; Performance; Personal Satisfaction; Pharmaceutical Preparations; Phase; Physiological; Placebos; Plasma; Plasma Cells; Population; Prevention; Protocols documentation; Provider; Publishing; RNA; Race; Research; Research Personnel; Resolution; Risk; Sampling; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; Standardization; Statistical Models; Structure; Techniques; Technology; Tenofovir; Therapeutic; Time; Tissues; Viral reservoir; Woman; Work; acceptability and feasibility; antiretroviral therapy; base; clinically relevant; drug efficacy; emtricitabine; healthy volunteer; imaging modality; inter-individual variation; medication compliance; men; novel; novel imaging technology; novel strategies; pre-exposure prophylaxis; prevent; response; therapeutic biomarker; tool

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 HIVnegative 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 IRMALDESI 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. RELEVANCE (See instructions): It is important to identify if someone is taking a medication regularly and as prescribed to optimize their health and wellbeing, but sometimes patients have trouble remembering if and when they miss doses; other times, even though patients are taking their medication, it is not getting into the body in the right amount. Quickly monitoring medications in 5-10 hair strands using our novel imaging technology called IR-MALDESI will allow patients and their doctors to see how much medication they are exposed to over 1 or more months, and help identify challenges to taking medication in both research and clinical settings. This proposal will optimize and explore the acceptability and feasibility of using IR-MALDESI for monitoring medications in hair.

坚持抗逆转录病毒（ARV）治疗对HIV感染者实现HIV RNA抑制至关重要。 患者和使用暴露前预防（PrEP）预防未感染个体获得HIV。 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HIV阴性个体，他们每天都没有感染HIV的风险。依从性差， 主要负责在多个最近的双盲，安慰剂对照的PrEP缺乏药物有效性 问题研究这些研究发现，计算产品退货率和使用患者自我报告显著高于 通过血浆或细胞中的ARV浓度测量预测的粘附。因为后果 的不良或间歇性的遵守是显着的，遵守的有效措施是至关重要的优化， 艾滋病毒治疗和预防的有效性，在诊所和研究环境。血浆或 细胞内浓度监测被认为是确定抗逆转录病毒药物是否 已被摄入，是治疗药物监测或临床试验依从性的常见标志物 监测.然而，这种方法有其自身的局限性，包括侵入性，需要 高级处理或储存（例如，细胞内测量），作为药物服用的短期测量 行为（取决于分析物的半衰期），并且需要长的周转时间或大量的 分析前的样品处理。我们建议使用红外（IR）基质辅助激光解吸 用于质谱成像（MSI）的电喷雾电离（MALDESI）技术， 头发中的抗逆转录病毒药物浓度。我们的假设是IR-MALDESI MSI可以快速定量ARV浓度， 提供非侵入性和纵向药物摄入的证据，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的反馈。提出了三个具体目标：1）发展 IR-MALDESI MSI毛发方案用于高灵敏度和准确性定量5种治疗药物中的11种ARV 2）进行3次结构化剂量比例研究，以制定真实的- 时间IR-MALDESI头发粘附监测在PrEP和HIV治疗应用，并验证 2期PrEP研究的基准，以及3）在真实的临床监测的背景下，研究 使用头发IRMALDESI MSI为HIV+患者提供 关于药物依从性的纵向模式的反馈。这项工作的目标是开发一个 简单、无创、纵向描述抗逆转录病毒药物依从性， 临床医生和患者。 相关性（参见说明）： 重要的是要确定某人是否定期服用药物，并按规定优化其健康状况 和幸福，但有时病人很难记住他们是否和何时错过剂量;其他时候， 即使病人正在服用药物，药物也没有以正确的量进入体内。迅速 使用我们称为IR-MALDESI的新型成像技术监测5-10根头发中的药物， 病人和他们的医生，看看他们有多少药物暴露超过1个月或更长时间，并帮助 确定在研究和临床环境中服用药物的挑战。该提案将优化和 探讨使用IR-MALDESI监测头发中药物的可接受性和可行性。

项目成果

Development and validation of an LC-MS/MS assay for the quantification of dolutegravir extracted from human hair.

开发和验证 LC-MS/MS 测定法，用于定量从人发中提取的多替拉韦。

• DOI: 10.1007/s00216-018-1394-y
• 发表时间: 2018
• 期刊: Analytical and bioanalytical chemistry
• 影响因子: 4.3
• 作者: Sykes,Craig;Blake,Kimberly;White,Nicole;Schauer,AmandaP;Guzman,BryanB;Cottrell,MackenzieL;Tamraz,Bani;Kashuba,AngelaDM
• 通讯作者: Kashuba,AngelaDM