Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)

 描述（由申请人提供）：隐球菌脑膜炎是资源有限环境中艾滋病感染者死亡的主要原因。2014年，隐球菌脑膜炎导致非洲艾滋病毒治疗项目中约15%的死亡。其中许多死亡是可以预防的。此外，抗逆转录病毒疗法在撒哈拉以南非洲的积极推广仅导致隐球菌脑膜炎发病率略有下降，例如，根据南非国家监测，发病率下降了10-15%。在乌干达，2014年疑似脑膜炎的住院患者中，隐球菌仍然比脑膜炎的所有其他原因加起来更常见。 在ART项目中预防早期死亡的一种策略是使用简单的血液检测（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个CD 4 <100未接受抗逆转录病毒治疗的非洲队列中，这种可检测的亚临床隐球菌感染的患病率平均为7.2%（95%CI：6.8-7.6%）。如果发现，这些无症状的CrAg+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“ORCAS”试验表明，在乌干达的18个诊所内，在CD 4 <100个细胞/mcL的HIV感染者中进行ART前CrAg筛查导致总体6个月死亡率相对降低30%。在坦桑尼亚和赞比亚进行的一项单独的随机临床试验中也观察到了类似的~30%的获益。然而，虽然CrAg筛查干预是成功的，但在两项试验中，CrAg+患者的生存率比CrAg阴性患者差2倍。根据我们团队先前的研究，乌干达和其他多个国家已将CD 4 <100的人的ART前CrAg筛查纳入国家艾滋病毒指南。 因此，需要进一步改进CrAg筛查和抢先治疗方案，以降低早期ART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WHO推荐的CrAg+先发制人治疗相比，使用舍曲林加强先发制人抗真菌治疗是否可以改善CrAg+患者6个月的无隐球菌生存率。其次，我们将确定与6个月无隐球菌生存率相关的抢先CrAg+治疗失败的风险因素。总的来说，我们寻求创新艾滋病毒护理的提供，以减少早期死亡率的抗逆转录病毒治疗，通过实施一个改进的一揽子护理晚介绍照顾。

 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.