Point-of-care C-reactive protein-based tuberculosis screening in people living with HIV: a randomized trial

HIV 感染者基于 C 反应蛋白的即时结核病筛查：一项随机试验

• 批准号: 10026339
• 负责人: David Wesley Dowdy
• 金额: $ 96.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10026339
• 关键词: AIDS/HIV problem; Acute-Phase Proteins; Africa; Africa South of the Sahara; Area; Biological Assay; Blood capillaries; Blood specimen; C-reactive protein; CD4 Lymphocyte Count; Cells; Characteristics; Clinic; Clinical; Clinical Trials; Data; Detection; Diagnosis; Drug resistance in tuberculosis; Economics; Epidemic; Epidemiology; Fingers; Future; Generations; Grant; HIV; HIV Seropositivity; HIV diagnosis; HIV/TB; Incidence; Individual; Infection; Interleukin-6; Intervention; Lead; Life; Measures; Mediating; Microbiology; Modeling; Outcome; Participant; Patient-Focused Outcomes; Peripheral; Policies; Population; Preventive therapy; Public Health; Randomized; Recommendation; Regimen; Research; Resources; Risk; Savings; Specificity; Symptoms; Testing; Tuberculosis; Uganda; United States National Institutes of Health; Work; World Health Organization; antiretroviral therapy; base; comparative cost effectiveness; cost; cost effective; cost effective intervention; cost effectiveness; effectiveness evaluation; improved; improved outcome; incremental cost-effectiveness; innovation; mortality; point of care; prevent; primary endpoint; primary outcome; randomized trial; routine practice; scale up; screening; screening guidelines; secondary outcome; therapy outcome; tool; transmission process; uptake

PROJECT SUMMARY Tuberculosis preventive therapy (TBPT) is among the most efficacious and cost-effective interventions to reduce tuberculosis (TB) incidence and mortality among people living with HIV (PLHIV) but is grossly underutilized due to our reliance on a symptom-based screening test to rule-out active TB. Studies from Africa have shown that symptom screening has low specificity (10-30%) for active TB and does not meet the minimum specificity (≥70%) requirement established by the World Health Organization (WHO) for TB screening. The low specificity is a major barrier to TBPT scale-up because if current TB screening guidelines were followed, 70-90% of PLHIV without active TB would not only be denied immediate initiation of TBPT but would also require unnecessary and costly confirmatory TB testing. The overall objective of this application is to evaluate the impact of a potentially more effective and cost-effective TB screening strategy, which is the next step required for successful uptake of TBPT. Our central hypothesis is that compared to symptom screening, a TB screening strategy based on C-reactive protein (CRP) levels, measured using a point-of-care (POC) assay, will improve TBPT uptake, thereby reducing TB incidence and its associated mortality among PLHIV. The scientific premise for this hypothesis is based on our own work that identified POC CRP as the first tool to meet the minimum sensitivity (≥90%) and specificity (≥70%) targets established by the WHO for TB screening. To accelerate scale-up of this promising TB screening strategy, and thus scale-up of TBPT, we propose a single-center individual randomized trial to evaluate the impact of POC CRP-based TB screening in 1720 PLHIV initiating antiretroviral therapy from 3 prototypical HIV clinics in Uganda. Participants will be randomized to either POC CRP- or symptom-based TB screening and followed for 2-years. Aim 1 will determine whether POC CRP-based TB screening improves 2-year clinical outcomes. The primary outcome for Aim 1 will be a composite of TB incidence and all-cause mortality. Key secondary outcomes include TB- specific mortality and incidence of drug-resistant TB. Aim 2 will determine the impact of POC CRP-based TB screening on intermediate outcomes related to the primary trial outcome. Primary outcomes for Aim 2 include the proportion of PLHIV (a) initiating TBPT and (b) diagnosed with prevalent TB. Secondary outcomes include the proportion of PLHIV (a) completing TBPT and (b) completing treatment for prevalent TB. Aim 3 will compare the cost-effectiveness and projected epidemiologic impact of TB screening with and without POC CRP. CRP testing will be performed using a low-cost ($2 per test), rapid (3 minutes) and simple (measured from capillary blood) POC assay, increasing the likelihood that POC CRP-based TB screening will be implemented in even the most peripheral settings. This research is significant because in addition to quantifying the expected clinic, economic, and epidemiologic benefits of TB screening, this work may enable the field to move beyond ineffective TB screening as a barrier to TBPT and improved outcomes of PLHIV.

项目摘要 结核病预防治疗（TBPT）是最有效和最具成本效益的干预措施之一， 降低艾滋病毒感染者（PLHIV）的结核病发病率和死亡率，但 由于我们依赖于基于筛查的筛查测试来排除活动性结核病，因此未得到充分利用。研究从 非洲的研究表明，症状筛查对活动性结核病的特异性较低（10-30%）， 世界卫生组织（WHO）为结核病制定的最低特异性（≥70%）要求 筛选低特异性是TBPT扩大规模的主要障碍，因为如果目前的结核病筛查指南 在随访期间，70-90%没有活动性结核病的艾滋病毒感染者不仅被拒绝立即开始TBPT， 还需要进行不必要和昂贵的结核病确诊检测。本申请的总体目标是 评估一种可能更有效和更具成本效益的结核病筛查策略的影响， 成功吸收TBPT所需的下一步。我们的核心假设是，与症状相比， 筛查，一种基于C-反应蛋白（CRP）水平的结核病筛查策略，使用床旁测量 (POC)检测，将提高TBPT的吸收，从而降低结核病的发病率和相关的死亡率， 艾滋病毒感染者。这一假设的科学前提是基于我们自己的工作，即确定POC CRP是第一个 达到世卫组织确定的结核病最低灵敏度（≥90%）和特异性（≥70%）目标的工具 筛选为了加速扩大这一有前途的结核病筛查战略，从而扩大TBPT的规模，我们 提出一项单中心个体随机试验，以评估基于POC CRP的结核病筛查对 1720名艾滋病毒感染者在乌干达3个典型的艾滋病毒诊所开始抗逆转录病毒治疗。参与者将被 随机分配至POC CRP-或CRP-TB筛查组，并随访2年。目标1将 确定基于POC CRP的TB筛查是否改善2年临床结局。主要结局 目标1将是结核病发病率和全因死亡率的复合指标。关键次要结局包括结核病- 具体死亡率和耐药结核病发病率。目标2将确定基于POC CRP的结核病的影响 筛选与主要试验结局相关的中间结局。目标2的主要成果包括 艾滋病毒感染者（a）开始TBPT和（B）被诊断为流行结核病的比例。次要结局包括 艾滋病毒感染者（a）完成结核病预防治疗和（B）完成流行结核病治疗的比例。目标3将 比较有和没有POC的结核病筛查的成本效益和预计的流行病学影响 CRP. CRP检测将使用低成本（每次检测2美元）、快速（3分钟）和简单（测量 从毛细血管血）POC检测，增加了可能性，POC CRP为基础的结核病筛查将是 甚至在最外围的设置中实现。这项研究意义重大，因为除了 量化结核病筛查的预期临床、经济和流行病学效益，这项工作可能使 该领域将超越无效的结核病筛查作为TBPT的障碍，并改善艾滋病毒感染者的结果。