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

项目总结 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 减少艾滋病毒携带者中的结核病发病率和死亡率，但总体上 由于我们依赖基于症状的筛查测试来排除活动性结核病，因此未得到充分利用。研究来自 非洲已表明，症状筛查对活动性结核病的特异性较低(10%-30%)，不符合 世界卫生组织为结核病制定的最低特异性(≥70%)要求 放映。低特异性是TB PT扩大的主要障碍，因为如果当前的结核病筛查指南 70%-90%的无活动性结核病的PLHIV不仅被拒绝立即开始TB PT，而且 还需要进行不必要且昂贵的确认性结核病检测。这个应用程序的总体目标是 评估可能更有效和更具成本效益的结核病筛查策略的影响，该策略是 下一步需要成功地吸收TBPT。我们的中心假设是，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，使用看护点测量 (POC)检测，将改善对TBPT的摄取，从而降低结核病发病率及其相关死亡率 PLHIV。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 满足世卫组织为结核病制定的最低敏感性(≥90%)和特异性(≥70%)目标的工具 放映。为了加快这一前景看好的结核病筛查战略的规模，从而扩大TB PT，我们 提出一项单中心个人随机试验，以评估基于POC-CRP的结核病筛查的影响。 1720名艾滋病毒感染者从乌干达3家典型的艾滋病毒诊所开始抗逆转录病毒治疗。参与者将是 随机接受POC-CRP或基于症状的结核病筛查，并跟踪2年。目标1将 确定基于POC-CRP的结核病筛查是否能改善两年的临床结果。主要结果是 目标1将是结核病发病率和全因死亡率的综合结果。关键的次要结果包括结核病-- 耐药结核病的特定死亡率和发病率。目标2将确定基于POC-CRP的结核病的影响 筛选与初步试验结果相关的中间结果。目标2的主要成果包括 艾滋病病毒感染者的比例(A)引发结核病，(B)被诊断为流行的结核病。次要结果包括 艾滋病病毒感染者的比例：(A)完成结核病治疗和(B)完成流行结核病的治疗。目标3将 比较有无POC的结核病筛查的成本效益和预计的流行病学影响 C反应蛋白。将使用低成本(每次2美元)、快速(3分钟)和简单(测量)的方法进行CRP检测 从毛细血管血)POC检测，增加了基于POC-CRP的结核病筛查将 即使在最外围的设置中也可实施。这项研究具有重要意义，因为除了 量化结核病筛查的预期临床、经济和流行病学益处，这项工作可能使 这一领域将超越无效的结核病筛查，成为结核病治疗和改善艾滋病病毒感染结果的障碍。

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.