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.

在撒哈拉以南非洲的所有年龄段的患者中，中枢神经系统（CNS）感染很常见 或没有HIV感染。在患有艾滋病毒的人中，隐球菌脑膜炎历史上是第二大的 定义非洲的常见艾滋病和撒哈拉以南非洲成人脑膜炎的最常见原因 全面的。脑膜炎的下一个最常见原因可能是结核病脑膜炎，尽管CSF诊断是 具有挑战性的。抗逆转录病毒疗法的宽度可用性（ART），长期生存 有可能使用艾滋病和中枢神经系统感染，但延迟或不准确的诊断和有限的治疗 选择会导致结果不佳。此外，采用即时艺术倡议的“测试和治疗”策略， 越来越多的人出现在开始艺术后揭露的中枢神经系统感染，但他们的结果尚不清楚。 我们建议继续对1200名介绍的新的HIV感染者进行一项前瞻性队列研究 坎帕拉和乌干达姆巴拉拉的可疑中枢神经系统感染。我们将使用即可和分子 诊断迅速确定中枢神经系统感染的病因，具体侧重于优化和 验证新的诊断测试，例如半定量的加密秒抗原（CRAG-SQ）侧向流量测定法 以及用于TB脑膜炎的XPERT MTB/RIF Ultra。其次，我们建议进行II阶段试验调查 新型口服抗真菌剂（APX001）的微生物学作用，该抗真菌剂抑制真菌GWT1酶阻断 真菌甘露蛋白转运到细胞壁表面，并与氟康唑协同。最后，我们会的 测量神经认知性能，以研究最近的ART计划对神经系统结局的影响。 具体目标 1。通过使用，确定撒哈拉以南非洲中枢神经系统感染的病因 逐步诊断算法，再加上下一代测序和验尸考试。 2。确定与HIV相关的隐球菌脑膜炎，如果口服APX001，一种新型真菌GWT1（GPI锚定壁） 转运蛋白1）抑制剂，与氟康唑伴随的CSF速率相同 与IV两性霉素B脱氧胆酸盐和氟康唑相比，隐孢子菌清除率。 3。确定在CNS感染的艾滋病毒感染者中是否产生神经认知结果 在最近的艺术倡议之后，比未来有CNS感染的艺术人更糟。 假设： 1。我们假设在艺术中擦除了隐球菌和TB脑膜炎仍然是最常见的两个 尽管采用了“测试和治疗”策略，但艾滋病毒感染人群中脑膜炎的病因。 2。我们假设APX001是一种新型的广泛的口服抗真菌剂，耐受性良好，将具有一个 与静脉内脑膜炎中的IV两性霉素B相比，CSF灭菌的速率是非内部率。 3。我们假设神经认知结果在中枢神经系统感染中遭到的抗辩与艺术与艺术不受欢迎。