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
基本信息
- 批准号:10395979
- 负责人:
- 金额:$ 62.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AIDS/HIV problemAcquired Immunodeficiency SyndromeAdultAfricaAfrica South of the SaharaAgeAlgorithmsAmphotericinAmphotericin BAntifungal AgentsAntigensAutopsyBiological AssayBrainCaringCarrier ProteinsCell WallCentral Nervous System InfectionsCessation of lifeClinicalClinical ResearchCoupledCryptococcal MeningitisCryptococcosisCryptococcusDataDevelopmentDiagnosisDiagnosticDiagnostic testsEnrollmentEnzymesEpidemiologyEtiologyFluconazoleFungal MeningitisGoalsHIVHIV InfectionsHIV antiretroviralHIV therapyIndividualInfectionLaboratoriesMeasuresMeningeal TuberculosisMeningitisMicrobiologyMorbidity - disease rateNeurocognitiveNeurologicNeurological outcomeOralOutcomePerformancePersonsPhase II Clinical TrialsPopulationProspective cohortProspective cohort studyProteinsResource-limited settingSafetySterilizationSurfaceTestingTherapeuticUgandaantiretroviral therapyattributable mortalitydeoxycholatediagnostic algorithmdiagnostic assaydisabilityexperienceimprovedin vivoinhibitorinnovationlateral flow assaymannoproteinsmolecular diagnosticsmortalitymycobacterialnext generation sequencingnovelnovel diagnosticsphase II trialpoint of careprospectivesurvival outcometuberculosis diagnosticsvalidation studies
项目摘要
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
总体而言。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。我们将使用护理点和分子
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.在撒哈拉以南非洲,通过使用以下方法确定HIV感染成人中CNS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,与氟康唑同时使用,达到非劣效的CSF率
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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David R Boulware其他文献
Management of advanced HIV disease in Africa
非洲艾滋病晚期的管理
- DOI:
10.1016/s2352-3018(23)00078-4 - 发表时间:
2023-06-01 - 期刊:
- 影响因子:13.000
- 作者:
Santiago Izco;Alberto L Garcia-Basteiro;David W Denning;David R Boulware;Adam Penn-Nicholson;Emilio Letang - 通讯作者:
Emilio Letang
Experiences, challenges, gaps, and strategies for counselling persons presenting with advanced HIV-associated meningitis in Uganda
- DOI:
10.1186/s12981-025-00705-z - 发表时间:
2025-02-19 - 期刊:
- 影响因子:2.500
- 作者:
Alisat Sadiq;Richard Kwizera;Tadeo K Kiiza;Peruth Ayebare;Cynthia Ahimbisibwe;Jane Frances Ndyetukira;David R Boulware;David B. Meya - 通讯作者:
David B. Meya
Randomized trial of mechanotherapy for the treatment of stress urinary incontinence in women
机械疗法治疗女性压力性尿失禁的随机试验
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:2
- 作者:
Nissrine A. Nakib;Suzette Sutherland;Kevin Hallman;Marcus Mianulli;David R Boulware - 通讯作者:
David R Boulware
Advancing the chemotherapy of tuberculous meningitis: a consensus view
推进结核性脑膜炎的化疗:共识观点
- DOI:
10.1016/s1473-3099(24)00512-7 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:31.000
- 作者:
Sean Wasserman;Joseph Donovan;Evelyne Kestelyn;James A Watson;Robert E Aarnoutse;James R Barnacle;David R Boulware;Felicia C Chow;Fiona V Cresswell;Angharad G Davis;Kelly E Dooley;Anthony A Figaji;Diana M Gibb;Julie Huynh;Darma Imran;Suzaan Marais;David B Meya;Usha K Misra;Manish Modi;Mihaja Raberahona;Robert J Wilkinson - 通讯作者:
Robert J Wilkinson
Nurse-targeted care for HIV positive persons with CD4<100 improved time to ART initiation and retention in Uganda
- DOI:
10.1186/1748-5908-10-s1-a81 - 发表时间:
2015-08-14 - 期刊:
- 影响因子:13.400
- 作者:
Agnes N Kiragga;Elizabeth Nalintya;Bozena Morawski;Joanita Kigozi;Benjamin J Park;Jonathan E Kaplan;David R Boulware;David B Meya;Yukari C Manabe - 通讯作者:
Yukari C Manabe
David R Boulware的其他文献
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{{ truncateString('David R Boulware', 18)}}的其他基金
Encochleated Oral Amphotericin for HIV-related Cryptococcal Meningitis Trial: Phase 3 Trial
包埋口服两性霉素治疗 HIV 相关隐球菌性脑膜炎试验:3 期试验
- 批准号:
10619788 - 财政年份:2023
- 资助金额:
$ 62.63万 - 项目类别:
11th International Conference on Cryptococcus and Cryptococcosis (ICCC)
第十一届隐球菌和隐球菌病国际会议(ICCC)
- 批准号:
10399173 - 财政年份:2022
- 资助金额:
$ 62.63万 - 项目类别:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
结核性脑膜炎:评估脑脊液免疫学以发现隐藏疾病和潜在的免疫调节疗法
- 批准号:
10335501 - 财政年份:2021
- 资助金额:
$ 62.63万 - 项目类别:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
结核性脑膜炎:评估脑脊液免疫学以发现隐藏疾病和潜在的免疫调节疗法
- 批准号:
10459614 - 财政年份:2021
- 资助金额:
$ 62.63万 - 项目类别:
TB Meningitis: Evaluating CSF Immunology to Discover Hidden Disease and Potential Immunomodulatory Therapies
结核性脑膜炎:评估脑脊液免疫学以发现隐藏疾病和潜在的免疫调节疗法
- 批准号:
10675513 - 财政年份:2021
- 资助金额:
$ 62.63万 - 项目类别:
Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial
包埋口服两性霉素治疗隐球菌性脑膜炎试验
- 批准号:
10163929 - 财政年份:2019
- 资助金额:
$ 62.63万 - 项目类别:
Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial
包埋口服两性霉素治疗隐球菌性脑膜炎试验
- 批准号:
10364704 - 财政年份:2019
- 资助金额:
$ 62.63万 - 项目类别:
Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)
隐球菌抗原筛查加舍曲林 (C-ASSERT)
- 批准号:
9271847 - 财政年份:2016
- 资助金额:
$ 62.63万 - 项目类别:
Phased Implementation of a Public Health Programme: Cryptococcal Screening and Treatment in South Africa
公共卫生计划的分阶段实施:南非的隐球菌筛查和治疗
- 批准号:
9232071 - 财政年份:2016
- 资助金额:
$ 62.63万 - 项目类别:
Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)
隐球菌抗原筛查加舍曲林 (C-ASSERT)
- 批准号:
9925177 - 财政年份:2016
- 资助金额:
$ 62.63万 - 项目类别:
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