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

在撒哈拉以南非洲，中枢神经系统(CNS)感染在所有年龄段的人中都很常见 或者没有感染艾滋病毒。在艾滋病毒携带者中，隐球菌性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 总体而言。脑膜炎的下一个最常见的原因可能是结核脑膜炎，尽管脑脊液诊断是 很有挑战性。随着抗逆转录病毒疗法(ART)的广泛应用，生活在 与艾滋病和中枢神经系统感染应该是可能的，但延误或不准确的诊断和有限的治疗 选项会导致糟糕的结果。此外，在立即启动艺术的“测试和治疗”策略下， 越来越多的人在开始抗逆转录病毒治疗后出现CNS感染，但他们的结果尚不清楚。 我们建议继续对1200名新的艾滋病毒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。我们将使用护理点和分子 诊断以快速确定中枢神经系统感染的病因，特别侧重于优化和 验证新的诊断试验，如半定量隐球菌抗原(CRAG-SQ)侧向流动试验 和Xpert MTB/RIF Ultra治疗结核病脑膜炎。第二，我们建议进行第二阶段试验，调查 新型口服抗真菌药APX001抑制真菌GWT1酶阻断的微生物学效应 真菌甘露糖蛋白转运到细胞壁表面，并与氟康唑有协同作用。最后，我们会 测量神经认知表现，以调查最近ART启动对神经学结果的影响。 具体目标 1.通过使用以下方法确定撒哈拉以南非洲艾滋病毒感染者中中枢神经系统感染的病原学 结合下一代测序和尸检的分步诊断算法。 2.在HIV相关性隐球菌性脑膜炎中检测口服APX001，一种新的真菌GWT1(GPI-锚定壁) 转运蛋白1)抑制剂，与氟康唑联合使用可达到非劣化的脑脊液疗效 隐球菌清除率与IV、两性霉素B、脱氧胆酸盐和氟康唑的比较。 3.确定表现为中枢神经系统感染的艾滋病毒感染者的神经认知结果是否未被掩盖 在最近的ART启动后，比ART天真的人更糟糕，呈现出CNS感染。 假设： 1.我们假设在ART时代，隐球菌和结核脑膜炎仍然是最常见的两种 尽管采取了“检测和治疗”的抗逆转录病毒治疗策略，但HIV感染人群中脑膜炎的病原学。 2.我们推测APX001是一种新型广谱口服抗真菌药，耐受性良好，将有 隐球菌性脑膜炎脑脊液灭菌率与静脉注射两性霉素B的比较。 3.我们假设，与单纯使用ART相比，未经ART治疗的中枢神经系统感染患者的神经认知结果更差。

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.