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: 10548256
• 负责人: Tania A Thomas
• 金额: $ 24.72万
• 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/10548256
• 关键词: AIDS/HIV problem; Accounting; Acquired Immunodeficiency Syndrome; Address; Affinity; Africa South of the Sahara; Antigens; Antitubercular Agents; 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/TB; Hospitalization; Immunologic Deficiency Syndromes; Infrastructure; Intervention; Intervention Trial; Life; Lipopolysaccharides; Lung; Methods; Microbiology; Monoclonal Antibodies; Mycobacterium tuberculosis; Organ; Outcome; Parents; Patients; Performance; Persons; Pharmaceutical Preparations; Population; Process; Protocols documentation; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Reference Standards; Reporting; Research; Sensitivity and Specificity; Sepsis; Silver; Site; Specificity; Specimen; Specimen Handling; Sputum; Symptoms; Syndrome; Tanzania; Technology; Testing; Time; Tuberculosis; Tuberculosis diagnosis; Uganda; Undifferentiated; United States National Institutes of Health; Urine; Vulnerable Populations; Work; World Health Organization; accurate diagnosis; base; clinical implementation; clinical practice; clinically relevant; comparative; design; 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; 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.

项目概要/摘要 结核分枝杆菌是脓毒症的主要原因，也是艾滋病毒感染者的头号杀手 撒哈拉以南非洲地区的艾滋病感染者（PLWH）。在该人群中确诊结核病 (TB) 具有挑战性 由于少杆菌和播散性疾病状态，加上经常无法产生痰 即使是那些患有肺结核病灶的人。迫切需要改进结核病诊断， 特别是那些依赖尿液等现成样本的样本。 AlereLAM 就是这方面的一个例子 检测，从尿液中检测结核细胞壁碎片（阿拉伯脂甘露聚糖，或“LAM”）。 AlereLAM 已 自 2015 年起获得世界卫生组织 (WHO) 认可，在患有以下疾病的人群中表现相对较好 晚期 HIV/AIDS，但敏感性仍然较低，为 56%。 Fujifilm SILVAMP 是一款新型泌尿系统 LAM 测定使用高亲和力单克隆抗体和银扩增步骤来帮助解释。早期的 研究表明 PLWH 的敏感性提高了 71%，但该检测方法尚未经过测试 出现未分化败血症的 PLWH 子集。方面还有改进的余地 这些测定的准确性。因此，我们将使用以下方法评估约 30 分钟尿液处理步骤的能力 Ceres Nanotrap，以提高这些快速尿液 LAM 检测的产量。该项目作为子研究 ATLAS 试验是一项随机对照试验，采用 2x2 因子设计立即进行经验性抗结核治疗 治疗开始和脓毒症特异性抗结核治疗剂量以及居住者的护理标准 患有败血症的艾滋病毒感染者来到我们在坦桑尼亚和乌干达的合作地点。我们将比较 使用 Ceres 处理尿液之前和之后 AlereLAM 和 SILVAMP 检测的性能 Nanotrap 可浓缩尿液中的 LAM 并去除尿液中的干扰物质。我们还将 与相比，评估快速检测尿 LAM 的诊断准确性和增量产量 稳健的诊断参考标准（包括结核病血液/痰培养、痰涂片和结核病聚合酶链反应（TB-PCR） 测试、血液/痰/尿液细菌培养，以及新型多重 PCR 检测来确定病因 血液脓毒症和尿液 TB-PCR 检测），旨在识别脓毒症的结核病和非结核病病因， 以及部分来自 ATLAS 试验干预措施和结果的临床参考标准。 我们将利用介入性 ATLAS 试验设计并进行探索性分析来了解 更准确、更快速的结核病诊断对流行病学的影响以及更及时启动的临床影响 抗结核治疗对死亡率的影响。我们在这个独特的试验基础设施中的工作本质上可以加速 在结核病/艾滋病毒负担高的环境中将改进的尿结核诊断应用于临床实践 危重病人。