Phased Implementation of a Public Health Programme: Cryptococcal Screening and Treatment in South Africa

 描述(申请人提供)：隐球菌性脑膜炎是在资源有限的情况下导致艾滋病人死亡的主要原因，约占非洲艾滋病毒治疗计划死亡人数的20%。这些死亡中的许多是可以预防的。尽管南非积极推出抗逆转录病毒疗法，但根据国家传染病研究所(NICD)的国家监测，隐球菌性脑膜炎的发病率仅略有下降10%-15%。隐球菌仍然是南非成年人脑膜炎的最常见原因。最近的研究表明，在接受抗逆转录病毒治疗计划的无症状患者中，使用简单的血液测试(隐球菌抗原或CRAG)进行亚临床早期感染的常规筛查可以确定哪些患者具有发展为脑膜炎或死亡的高风险。这种可检测到的亚临床隐球菌感染在南非患者中的流行率为4.1%。如果被发现，这些无症状的人可以给予“先发制人”的抗真菌氟康唑治疗，以防止脑膜炎和/或死亡。我们的研究合作表明，这样的筛查策略将具有极高的成本效益，估计每节省一个质量调整的生命年(QALY)就能节省10美元。在南非，这样的岩壁筛查将在总体上节省医疗体系的成本，并导致更好的生存。根据我们团队之前的成本效益研究，南非已将对艾滋病毒感染者进行CRAG筛查作为其2015年国家艾滋病毒治疗指南的一部分，但尚未广泛实施。我们建议使用基于实验室的反射测试对CD4&lt；100细胞/MCL患者的剩余血浆样本进行CRAG筛查。我们将在南非各地的CD4检测实验室采用阶梯式楔形设计分阶段实施，以评估对公众健康的影响。首先，我们将确定在HIV感染者的CD4&lt；100细胞/MCL(目标1)中，实施基于实验室的反射测试的CRAG筛查是否比提供者发起的测试提供更好的吸收。其次，我们将实施增强的指标和评估监测队列，以确定CRIG+预防性治疗的护理障碍，并确定那些在6个月无隐球菌生存(目标2)中治疗失败的高风险患者。最后，我们将确定，在目前世界卫生组织推荐的CRIG+预防性治疗(目标3)的情况下，定制基于CRIG滴度和1：160的目标腰椎穿刺点是否可以提高6个月的存活率，并降低目前25%的失败率(即脑膜炎或死亡)。

 DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of death among persons with AIDS in the resource-limited settings, responsible for approximately 20% of deaths in HIV treatment programs in Africa. Many of these deaths are preventable. Despite the aggressive roll out of ART in South Africa, the incidence of cryptococcal meningitis has only slightly decreased by 10- 15% per the National Institute of Communicable Diseases (NICD) national surveillance. Cryptococcus remains the most common cause of meningitis among adults in South Africa. Recent research has shown that routine screening for sub-clinical early infection among asymptomatic patients presenting to ART programs using a simple blood test (cryptococcal antigen or CRAG) can identify which patients are at high risk of developing meningitis or death. The prevalence of this detectable sub-clinical cryptococcal infection is 4.1% among South Africans with CD4<100. If identified, these asymptomatic persons can be given "preemptive" anti-fungal fluconazole therapy to prevent meningitis and/or death. Our research collaboration has demonstrated that such a screening strategy would be highly cost-effective, at an estimated <$10 per quality-adjusted life year (QALY) saved. In South Africa, such a CRAG screening would be cost-saving overall to the healthcare system and result in better survival. Based on our team's previous cost-effectiveness research, South Africa has included CRAG screening of HIV-infected persons with CD4<100 cells/mcL as part of their 2015 National HIV Treatment Guidelines, yet broad implementation has not yet occurred. We propose to implement CRAG screening using lab-based reflex testing of leftover plasma specimens in persons with CD4<100 cells/mcL. We will implement at CD4 testing labs across South Africa using a stepped wedge design phased implementation in order to assess the public health impact. First, we will determine if implementation of CRAG screening using lab- based reflex testing provides better uptake as compared with provider initiated testing in HIV- infected persons with CD4<100 cells/mcL(Aim 1). Second, we will implement an enhanced metrics and evaluation surveillance cohort to determine the barriers for care of CrAg+ preemptive therapy and determine those at high risk of treatment failure for 6 month cryptococcal-free survival (Aim 2). Lastly, we will determine if customization of care with target lumbar punctures based of CrAg titer >1:160 will improve 6-month survival and decrease the current 25% failure rate (i.e. meningitis or death) with current WHO recommended CrAg+ preemptive therapy (Aim 3).