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.