Clinic-based Screening to Prevent HIV-associated Cryptococcal Mortality

预防艾滋病毒相关隐球菌死亡的临床筛查

• 批准号: 8731612
• 负责人: Paul K Drain
• 金额: $ 18.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8731612
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Africa South of the Sahara; Antifungal Agents; Antigens; Applications Grants; Area; Bedside Testings; Biological Assay; Blood specimen; Boston; CD4 Lymphocyte Count; Caring; Cessation of life; Characteristics; Clinic; Clinical; Clinical Research; Clinical Treatment; Cost Effectiveness Analysis; Coupled; Cryptococcal Meningitis; Cryptococcus; Development; Diagnosis; Diagnostic tests; Disease; Dose; Early Diagnosis; Evaluation; Fingers; Fluconazole; Foundations; Goals; Gold; HIV; HIV Seropositivity; HIV diagnosis; Health; Immune; Immunosuppression; Incidence; Individual; Infection; Infection prevention; Intervention Trial; Knowledge; Laboratories; Lateral; Lead; Life; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Neurologic; Newly Diagnosed; Nurses; Oral; Outcome; Patients; Policy Maker; Positioning Attribute; Prevalence; Research; Research Infrastructure; Research Personnel; Resources; Risk; Sampling; Serum; South Africa; Specimen; Symptoms; Test Result; Testing; Time; Training; Tuberculosis; Urine; Whole Blood; Work; World Health Organization; antiretroviral therapy; base; career; clinical Diagnosis; cost; cost effective; cost effectiveness; design; education planning; experience; implementation science; improved; innovation; mortality; novel; point of care; point-of-care diagnostics; prevent; programs; prophylactic; prospective; public health relevance; reconstitution; screening; skills; tool

DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of AIDS-related mortality worldwide. Circulating cryptococcal antigens can be detected weeks before the onset of neurological symptoms, and pre-emptive anti-fungal therapy can prevent cryptococcal meningitis and death. Unfortunately, most clinics in cryptococcal endemic regions do not have access to laboratory-based testing for cryptococcal antigens. A newly-approved, rapid cryptococcal antigen test can facilitate implementing a clinic-based screening strategy in any resource-limited setting, which, when coupled with oral anti-fungal therapy, could save thousands of lives each year worldwide. However, evidence on the feasibility and impact of conducting point-of-care testing for cryptococcal antigens in a clinic-based setting is needed. My career goal is to become an independent investigator in clinical research with a focus on implementation science to improve clinical diagnosis and treatment of cryptococcal infections and prevention of cryptococcal meningitis in resource-limited settings. I will draw upon the methodological training of the K23 award and leverage the existing research infrastructure of my co-mentors and collaborators in Durban, South Africa to accomplish my scientific objective: to better understand the value of point-of-care testing, clinic-based screening, and implementation science for cryptococcal disease among HIV-infected adults in resource-limited settings. My hypothesis is that clinic-based, nurse-driven, point-of-care screening for cryptococcal antigens at the time of initial HIV diagnosis will be feasible and will improve patient outcomes. I will tes this hypothesis through the following four specific aims: (1) To estimate CD4-specific prevalence of cryptococcal antigenemia and cumulative incidence of cryptococcal meningitis and mortality for those with and without cryptococcal antigenemia within 12 months of HIV diagnosis in a standard-of-care, lab-based serum CrAg screening program, (2) To evaluate a rapid point-of-care LFA CrAg test by measuring test characteristics of whole blood and urine samples, compared with gold-standard serum-based tests, (3) To estimate cumulative incidence of cryptococcal meningitis and mortality within 12 months of HIV diagnosis when implementing an active, clinic-based screening program for CrAg in urine and/or whole blood among newly- diagnosed HIV-infected adults, and to compare cumulative incidence of cryptococcal meningitis and mortality to the standard-of-care, lab-based serum CrAg screening program (measured in Aim #1), and (4) To assess the long-term clinical outcomes, cost, and cost-effectiveness of intensified CrAg screening, compared to lab- based CrAg screening, among newly-diagnosed HIV-infected adults in South Africa. I am well positioned to accomplish these aims, based on my educational and mentorship plans, as well as my experience conducting a clinic-based, nurse-driven evaluation of a point-of-care diagnostic test for tuberculosis. I will draw upon the guidance of my renowned mentors and collaborators, who have extensive experience in HIV care, cryptococcal disease, clinical research, evaluating screening strategies, and cost-effectiveness analysis, while also developing my own distinct research trajectory. My approach is innovative by: (1) validating a point-of-care test in a clinical setting by nurses, (2) evaluatig the impact of clinic-based screening on patient outcomes, and (3) use of a novel, rapid cryptococcal antigen testing platform. The proposed research is significant because it will provide the tools to implement clinic-based screening for cryptococcus, a common and fatal disease in resource-limited settings, and provide a platform to launch my career as an independent investigator.

描述（由申请人提供）：隐球菌脑膜炎是全球艾滋病相关死亡的主要原因。循环隐球菌抗原可以在神经系统症状发作前几周检测到，先发制人的抗真菌治疗可以预防隐球菌脑膜炎和死亡。不幸的是，隐球菌流行地区的大多数诊所无法获得基于实验室的隐球菌抗原检测。新批准的快速隐球菌抗原检测可以促进在任何资源有限的环境中实施基于临床的筛查策略，与口服抗真菌治疗相结合，每年可以挽救全球数千人的生命。然而，需要在临床环境中进行隐球菌抗原即时检测的可行性和影响的证据。我的职业目标是成为临床研究的独立研究者，专注于实施科学，以改善隐球菌感染的临床诊断和治疗，并在资源有限的环境中预防隐球菌脑膜炎。我将利用K23奖的方法学培训，并利用我在南非德班的共同导师和合作者的现有研究基础设施来实现我的科学目标：更好地了解护理点检测的价值，基于诊所的筛查，以及在资源有限的环境中感染艾滋病毒的成年人中隐球菌病的实施科学。我的假设是，以诊所为基础，护士驱动，在最初的HIV诊断时进行隐球菌抗原的即时筛查是可行的，并将改善患者的预后。我将通过以下四个具体目标来检验这一假设：（1）在标准护理、基于实验室的血清CrAg筛查项目中，评估HIV诊断后12个月内隐球菌抗原血症的CD 4特异性患病率、隐球菌脑膜炎的累积发病率和隐球菌抗原血症和非隐球菌抗原血症患者的死亡率，（2）通过测量全血和尿液样本的测试特征，与基于金标准血清的测试相比，评估快速床旁LFA CrAg测试，（3）当在新诊断的HIV感染的成人中实施针对尿液和/或全血中的CrAg的主动的、基于临床的筛查程序时，估计HIV诊断的12个月内隐球菌脑膜炎的累积发病率和死亡率，并将隐球菌脑膜炎的累积发病率和死亡率与护理标准、基于实验室的血清CrAg筛查程序（在目标#1中测量）进行比较，以及（4）在南非新诊断的HIV感染成人中，与基于实验室的CrAg筛查相比，评估强化CrAg筛查的长期临床结果、成本和成本效益。根据我的教育和指导计划，以及我对结核病护理点诊断测试进行基于诊所、护士驱动的评估的经验，我完全有能力实现这些目标。我将借鉴我著名的导师和合作者的指导，他们在艾滋病毒护理，隐球菌疾病，临床研究，评估筛查策略和成本效益分析方面拥有丰富的经验，同时也发展了我自己独特的研究轨迹。我的方法是创新的：（1）由护士在临床环境中验证床旁检测，（2）评估基于临床的筛查对患者结局的影响，以及（3）使用新型快速隐球菌抗原检测平台。这项拟议的研究意义重大，因为它将提供工具来实施基于临床的隐球菌筛查，这是一种在资源有限的环境中常见的致命疾病，并提供一个平台来启动我作为独立研究者的职业生涯。