Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)

 描述(申请人提供)：隐球菌性脑膜炎是在资源有限的情况下艾滋病患者死亡的主要原因。2014年，在非洲的艾滋病毒治疗方案中，约15%的死亡是由隐球菌脑膜炎造成的。这些死亡中的许多是可以预防的。此外，在撒哈拉以南非洲地区积极开展抗逆转录病毒治疗仅使隐球菌性脑膜炎发病率略有下降，例如，每一次南非国家监测的发病率为10-15%。在乌干达，2014年疑似脑膜炎住院患者中，隐球菌仍然比所有其他脑膜炎原因的总和更常见。在抗逆转录病毒治疗计划中预防早期死亡的一种策略是使用简单的血液测试(隐球菌抗原或CRAG)在无症状的艾滋病患者中筛查亚临床隐球菌感染。在36名未接受抗逆转录病毒治疗的非洲人群中，这种可检测到的亚临床隐球菌感染的流行率平均为7.2%(95%可信区间：6.8-7.6%)。如果确诊，这些无症状的ARG+患者可以给予“先发制人”的氟康唑抗真菌治疗，以防止脑膜炎的发展或死亡。我们的阶梯楔形随机“逆戟鲸”试验表明，在乌干达的18家诊所内，在HIV感染者中进行抗逆转录病毒治疗前的CRAG筛查，其CD4和100细胞/MCL的总体6个月死亡率相对降低了30%。在坦桑尼亚和赞比亚的一项单独的随机临床试验中也看到了类似的~30%的好处。然而，虽然CRAG筛查干预成功，但在两个试验中，CRAG阳性患者的存活率是CRAG阴性患者的2倍。基于我们团队之前的研究，乌干达和其他多个国家已经将艾滋病病毒携带者的抗逆转录病毒治疗前岩壁筛查纳入国家艾滋病毒指南。因此，需要进一步改进岩壁筛查和预防性治疗方案，以降低ART的早期死亡率。首先，我们将在一项随机比较有效性试验中评估，与目前世界卫生组织推荐的先发制人的CRAG+疗法相比，使用舍曲林的增强型先发制人抗真菌疗法是否可以改善CRAG+患者的6个月无隐球菌存活率。其次，我们将确定与6个月无隐球菌存活相关的先发制人CRAG+治疗失败的危险因素。总体而言，我们寻求创新艾滋病毒护理的交付，通过实施改进的一揽子护理方案来减少抗逆转录病毒治疗的早期死亡率。

 DESCRIPTION (provided by applicant): Cryptococcal meningitis is a leading cause of death among persons living with AIDS in resource-limited settings. In 2014, cryptococcal meningitis was responsible for approximately 15% of deaths in HIV treatment programs in Africa. Many of these deaths are preventable. Furthermore, the aggressive roll-out of ART in Sub-Saharan Africa has resulted in only slight decreases in cryptococcal meningitis incidence, e.g. 10-15% per South African national surveillance. In Uganda among hospitalized patients with suspected meningitis in 2014, Cryptococcus still remains more common than all other causes of meningitis combined. One strategy to prevent the early mortality in ART programs is to screen for sub-clinical cryptococcal infection among asymptomatic persons living with AIDS using a simple blood test (cryptococcal antigen or CrAg). The prevalence of this detectable sub-clinical cryptococcal infection averages 7.2% (95%CI: 6.8-7.6%) among 36 African cohorts with CD4<100 not receiving ART. If identified, these asymptomatic CrAg+ persons can be given "preemptive" fluconazole antifungal therapy to prevent the development of meningitis or death. Our stepped- wedge randomized "ORCAS" trial demonstrated that pre-ART CrAg screening among HIV- infected persons with CD4<100 cells/mcL led to a 30% relative reduction in overall 6-month mortality within 18 clinics in Uganda. A similar ~30% benefit was seen in a separate randomized clinical trial in Tanzania and Zambia. However, while the CrAg screening intervention was successful, the survival of CrAg+ persons was 2-fold worse than CrAg-negative persons in both trials. Based on our team's prior research, Uganda and multiple other countries have incorporated pre-ART CrAg screening of persons with CD4<100 into National HIV Guidelines. Therefore, further improvements in CrAg screening and preemptive therapy regimens are needed in order to reduce early ART mortality. First, we will evaluate in a randomized comparative effectiveness trial if 6-month cryptococcal-free survival of CrAg+ persons can be improved with enhanced preemptive antifungal therapy using adjunctive sertraline compared with the current WHO recommended preemptive CrAg+ therapy. Second, we will identify risk factors for failure of preemptive CrAg+ therapy with respect to 6-month cryptococcal-free survival. Overall we seek to innovate the delivery of HIV care to reduce early mortality on ART through implementation of an improved package of care for late presenters to care.