Evaluation of novel tuberculosis LAM assays among people living with HIV and sepsis

HIV 感染者和败血症患者中新型结核病 LAM 检测的评估

• 批准号: 10669787
• 负责人: Tania A Thomas
• 金额: $ 18.71万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10669787
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Affinity; Africa South of the Sahara; Antigens; Antitubercular Agents; Biological; Biological Assay; Blood; CD4 Lymphocyte Count; Case Fatality Rates; Cause of Death; Cell Wall; Cessation of life; Characteristics; Clinical; Coupled; Critical Illness; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Dose; Epidemiology; Etiology; Evaluation; Functional disorder; Genus Mycobacterium; Goals; HIV; HIV/AIDS; HIV/TB; Hospitalization; Immunologic Deficiency Syndromes; Infrastructure; Intervention; Intervention Trial; Life; Lipopolysaccharides; Lung; Methods; Monoclonal Antibodies; Mycobacterium tuberculosis; Nanotrap; Organ; Outcome; Parents; Patients; Performance; Persons; Pharmaceutical Preparations; Population; Process; Protocols documentation; Randomized; Randomized, Controlled Trials; Recommendation; Reference Standards; Reporting; Research; Sensitivity and Specificity; Sepsis; Silver; Site; Specificity; Specimen; Specimen Handling; Sputum; Symptoms; Syndrome; Tanzania; Technology; Testing; Tuberculosis; Tuberculosis diagnosis; Uganda; Undifferentiated; United States National Institutes of Health; Urine; Vulnerable Populations; Work; World Health Organization; accurate diagnosis; clinical implementation; clinical practice; clinically relevant; comparative; design; detection method; diagnostic accuracy; early phase clinical trial; improved; insight; lateral flow assay; lipoarabinomannan; mortality; multiplex assay; novel; particle; pathogen; performance tests; point of care; prospective; randomized trial; randomized, clinical trials; rapid test; standard of care; survival outcome; treatment arm; trial design; tuberculosis diagnostics; tuberculosis treatment; uptake; urinary

PROJECT SUMMARY/ABSTRACT Mycobacterium tuberculosis is a leading cause of sepsis and the leading killer among people living with HIV (PLWH) in sub-Saharan Africa. The diagnosis of tuberculosis (TB) is challenging to confirm in this population due to the paucibacillary and disseminated disease state, coupled with a frequent inability to produce sputum even among those with a pulmonary focus of TB. There is a pressing need for improved TB diagnostics, particularly those that rely on readily-available specimens such as urine. One example of this is the AlereLAM assay, which detects a TB cell-wall fragment (lipoarabinomannan, or “LAM”) from urine. The AlereLAM has been endorsed by the World Health Organization (WHO) since 2015 and performs relatively well among people with advanced HIV/AIDS, however the sensitivity is still modest at 56%. The Fujifilm SILVAMP is a newer urinary LAM assay that uses high affinity monoclonal antibodies and a silver amplification step to aid interpretation. Early studies have demonstrated improved sensitivity at 71% among PLWH, but the assay has not yet been tested among a subset of PLWH who present with undifferentiated sepsis. There is room for improvement in the accuracy of these assays. Therefore, we will evaluate the ability for a ~30 minute urine processing step, using the Ceres Nanotrap, to augment the yield of these rapid urinary LAM assays. This project serves as a substudy of the ATLAS Trial, a randomized controlled trial using a 2x2 factorial design of immediate empiric anti-TB therapy initiation and sepsis-specific doses of anti-TB therapy along with standard of care among people living with HIV who present with sepsis to our collaborative sites in Tanzania and Uganda. We will compare the performance between the AlereLAM and SILVAMP assays before and after processing the urine with the Ceres Nanotrap which concentrates urinary LAM and removes interfering substances within the urine. We will also evaluate the diagnostic accuracy and incremental yield of rapid assays to detect urinary LAM as compared to robust diagnostic reference standards (including blood/sputum culture for TB, sputum smear and TB-PCR testing, bacterial culture of blood/sputum/urine, as well as a novel multiplex PCR assay to identify the etiology of sepsis from blood and TB-PCR testing of urine) that are designed to identify TB and non-TB etiologies of sepsis, as well as a clinical reference standard that is partly informed by the ATLAS Trial interventions and outcomes. We will leverage the interventional ATLAS trial design and pursue exploratory analyses to understand the epidemiologic impact of a more accurate, rapid, TB diagnostic as well as the clinical impact of timelier initiation of anti-TB treatment on mortality. Our work within this unique trial infrastructure can inherently hasten the implementation of improved urinary TB diagnostics into clinical practice in settings with high TB/HIV burden for critically ill people.

项目总结/摘要 结核分枝杆菌是败血症的主要原因，也是艾滋病毒感染者的主要杀手 （PLWH）在撒哈拉以南非洲。在这一人群中，结核病的诊断具有挑战性 由于少菌性和播散性疾病状态，加上经常无法产生痰液， 即使是那些肺结核病灶的人。迫切需要改进结核病诊断， 特别是那些依赖于容易获得的样本如尿液的方法。这方面的一个例子是AlereLAM 本发明涉及一种用于检测来自尿液的TB细胞壁片段（脂阿拉伯甘露聚糖，或“LAM”）的方法。AlereLAM已被 自2015年以来得到世界卫生组织（WHO）的认可，在患有 晚期艾滋病毒/艾滋病，但敏感性仍然适中，为56%。Fujifilm SILVAMP是一种新的泌尿系统 LAM试验，使用高亲和力单克隆抗体和银扩增步骤辅助判读。早期 研究表明，PLWH的灵敏度提高了71%，但该检测方法尚未经过测试 在一个有未分化败血症的PLWH亚群中。有改进的余地， 这些分析的准确性。因此，我们将使用以下公式评估约30分钟尿液处理步骤的能力 Ceres Nanotrap，以增加这些快速尿LAM测定的产率。本项目作为子研究 ATLAS试验是一项随机对照试验，采用2x2析因设计， 治疗开始和脓毒症特异性剂量的抗结核治疗沿着标准治疗， 我们在坦桑尼亚和乌干达的合作点。我们将比较 用Ceres处理尿液前后AlereLAM和SILVAMP检测试剂盒之间的性能 Nanotrap浓缩尿液LAM并去除尿液中的干扰物质。我们还将 评价快速测定法检测尿LAM的诊断准确性和增量产率， 稳健的诊断参考标准（包括TB的血液/痰培养、痰涂片和TB-PCR 测试，血液/痰/尿的细菌培养，以及一种新的多重PCR检测，以确定病原学 血液中的脓毒症和尿液的TB-PCR检测），其设计用于鉴定脓毒症的TB和非TB病因， 以及部分由ATLAS试验干预和结局提供信息的临床参考标准。 我们将利用干预性ATLAS试验设计并进行探索性分析，以了解 更准确、快速的结核病诊断的流行病学影响以及更及时启动的临床影响 对死亡率的影响。我们在这一独特的试验基础设施内的工作可以内在地加速 在结核病/艾滋病毒负担高的环境中， 危重病人。