Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis

改善艾滋病毒/艾滋病相关脑膜炎的诊断和神经认知结果

• 批准号: 10395979
• 负责人: David R Boulware
• 金额: $ 62.63万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395979
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adult; Africa; Africa South of the Sahara; Age; Algorithms; Amphotericin; Amphotericin B; Antifungal Agents; Antigens; Autopsy; Biological Assay; Brain; Caring; Carrier Proteins; Cell Wall; Central Nervous System Infections; Cessation of life; Clinical; Clinical Research; Coupled; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Data; Development; Diagnosis; Diagnostic; Diagnostic tests; Enrollment; Enzymes; Epidemiology; Etiology; Fluconazole; Fungal Meningitis; Goals; HIV; HIV Infections; HIV antiretroviral; HIV therapy; Individual; Infection; Laboratories; Measures; Meningeal Tuberculosis; Meningitis; Microbiology; Morbidity - disease rate; Neurocognitive; Neurologic; Neurological outcome; Oral; Outcome; Performance; Persons; Phase II Clinical Trials; Population; Prospective cohort; Prospective cohort study; Proteins; Resource-limited setting; Safety; Sterilization; Surface; Testing; Therapeutic; Uganda; antiretroviral therapy; attributable mortality; deoxycholate; diagnostic algorithm; diagnostic assay; disability; experience; improved; in vivo; inhibitor; innovation; lateral flow assay; mannoproteins; molecular diagnostics; mortality; mycobacterial; next generation sequencing; novel; novel diagnostics; phase II trial; point of care; prospective; survival outcome; tuberculosis diagnostics; validation studies

Central nervous system (CNS) infections are common across all ages in Sub-Saharan Africa in people with or without HIV-infection. In persons with HIV, cryptococcal meningitis has historically been the second most common AIDS-defining illness in Africa and the most common cause of adult meningitis in Sub-Saharan Africa overall. The next most common cause of meningitis is likely TB meningitis, although CSF diagnostics are challenging. With the widespread availability of antiretroviral therapy (ART), long term survival in persons living with AIDS and CNS infections should be possible, but delayed or inaccurate diagnoses and limited therapeutic options contribute to poor outcomes. Furthermore, with the ‘test and treat’ strategy of immediate ART initiation, more people are presenting with CNS infections unmasked after starting ART, yet their outcomes are unclear. We propose to continue a prospective cohort study of 1200 new HIV-infected persons presenting with suspected CNS infection in Kampala and Mbarara, Uganda. We will use point-of-care and molecular diagnostics to rapidly determine the etiologies of CNS infections, with a specific focus on optimizing and validating new diagnostic tests, such as a semi-quantitative cryptococcal antigen (CrAg-SQ) lateral flow assay and the Xpert MTB/RIF Ultra for TB meningitis. Second, we propose to conduct phase II trial investigating the microbiologic effects of a novel oral antifungal agent (APX001) that inhibits fungal GWT1 enzyme blocking fungal mannoprotein transport to the cell wall surface and is synergistic with fluconazole. Finally, we will measure neurocognitive performance to investigate the effect of recent ART initiation on neurologic outcomes. Specific Aims 1. Determine the etiology of CNS infections in Sub-Saharan Africa among HIV-infected adults through use of a stepwise diagnostic algorithm coupled with next-generation sequencing and post-mortem exams. 2. Determine in HIV-related cryptococcal meningitis if oral APX001, a novel fungal GWT1 (GPI-anchored wall transport protein 1) inhibitor, achieves with concomitant fluconazole a non-inferior rate of CSF Cryptococcus clearance as compared with IV amphotericin B deoxycholate and fluconazole. 3. Determine if neurocognitive outcomes in HIV-infected persons presenting with CNS infections unmasked after recent ART initiation are worse than in ART-naïve persons presenting with CNS infections. Hypotheses: 1. We hypothesize in the ART era that cryptococcal and TB meningitis remain the two most common etiologies of meningitis in an HIV-infected population despite the ‘test and treat’ ART strategy. 2. We hypothesize that APX001, a novel broad spectrum oral antifungal agent is well tolerated and will have a non-inferior rate of CSF sterilization compared with IV amphotericin B in cryptococcal meningitis. 3. We hypothesize neurocognitive outcomes are worse in CNS infections unmasked on ART vs. ART-naïve.

中枢神经系统（CNS）感染在撒哈拉以南非洲的所有年龄段的人群中都很常见， 或者没有感染艾滋病毒。在艾滋病毒感染者中，隐球菌脑膜炎历来是第二大 非洲常见的艾滋病定义疾病和撒哈拉以南非洲成人脑膜炎的最常见原因 总的来说。脑膜炎的下一个最常见的原因可能是结核性脑膜炎，尽管CSF诊断是 挑战性随着抗逆转录病毒疗法（ART）的广泛应用， 与艾滋病和中枢神经系统感染应该是可能的，但延迟或不准确的诊断和有限的治疗 选择会导致糟糕的结果。此外，通过立即开始抗逆转录病毒治疗的“测试和治疗”战略， 更多的人在开始抗逆转录病毒治疗后暴露出中枢神经系统感染，但他们的结果尚不清楚。 我们建议继续对1200名新的HIV感染者进行前瞻性队列研究， 乌干达坎帕拉和姆巴拉拉疑似中枢神经系统感染。我们将使用即时和分子 诊断，以快速确定CNS感染的病因，特别侧重于优化和 验证新的诊断测试，如半定量隐球菌抗原（CrAg-SQ）侧流检测 和结核性脑膜炎的Xpert MTB/RIF Ultra。第二，我们建议进行第二阶段试验， 抑制真菌GWT 1酶阻断的新型口服抗真菌药（APX 001）的微生物学效应 真菌甘露糖蛋白转运到细胞壁表面，并与氟康唑协同。最后我们将 测量神经认知能力，以研究最近开始ART对神经学结果的影响。 具体目标 1.通过使用确定撒哈拉以南非洲艾滋病毒感染成年人中枢神经系统感染的病因 逐步诊断算法结合下一代测序和尸检。 2.确定在HIV相关隐球菌脑膜炎中是否口服APX 001，一种新的真菌GWT 1（GPI锚定壁 转运蛋白1）抑制剂，与氟康唑联合使用，达到了非劣效性的CSF 隐球菌清除率与IV阿替霉素B脱氧胆酸盐和氟康唑相比。 3.确定出现CNS感染的HIV感染者的神经认知结局是否未设盲 最近开始ART治疗后的CNS感染比ART初治患者更严重。 假设： 1.我们假设在ART时代隐球菌和结核性脑膜炎仍然是最常见的两种 尽管采取了“检测和治疗”ART策略，但HIV感染人群中的脑膜炎病因 2.我们假设APX 001，一种新型的广谱口服抗真菌药，耐受性良好， 在隐球菌性脑膜炎中，CSF灭菌率非劣效于IV阿替霉素B。 3.我们假设接受ART治疗的CNS感染患者的神经认知结局比未接受ART治疗的患者更差。