Cryptococcal Antigen Screening plus Sertraline (C-ASSERT)

隐球菌抗原筛查加舍曲林 (C-ASSERT)

• 批准号: 9914429
• 负责人: David R Boulware
• 金额: $ 11.66万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-10 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914429
• 关键词: Acquired Immunodeficiency Syndrome; Address; Africa; Africa South of the Sahara; African; Antifungal Therapy; Antigens; Blood; Blood Tests; Brain; C-reactive protein; CD4 Positive T Lymphocytes; Caring; Cause of Death; Cell Count; Cells; Cessation of life; Clinic; Country; Cryptococcal Meningitis; Cryptococcosis; Cryptococcus; Data; Development; Double-Blind Method; Evaluation of Risk Factors; Expert Opinion; Failure; Fluconazole; Goals; Guidelines; HIV; HIV therapy; Incidence; Infection; International; Intervention; Meningitis; Methods; Mycoses; Patients; Persons; Phase; Prevalence; Public Health; Publishing; Randomized; Randomized Clinical Trials; Recommendation; Regimen; Research; Resources; Risk; Risk Factors; Sertraline; Serum; Site; South African; Tanzania; Testing; Treatment Failure; Uganda; Zambia; antiretroviral therapy; base; cohort; comparative effectiveness; effectiveness trial; high risk; immunosuppressed; improved; individualized medicine; innovation; mortality; national surveillance; peripheral blood; prevent; preventable death; programs; prospective; public health relevance; randomized trial; screening; treatment program; tv watching

 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.

 描述（由适用提供）：隐球菌脑膜炎是在资源有限的环境中艾滋病患者中死亡的主要原因。 2014年，非洲的艾滋病毒治疗计划中约有15％的死亡人数造成了十五％的死亡。这些死亡中的许多是可以预防的。此外，撒哈拉以南非洲的艺术的积极推出导致隐球菌脑膜炎发病率的略有下降，例如每个南非国家监视10-15％。在乌干达，在2014年，住院治疗的脑膜炎患者中，隐孢子虫仍然比所有其他脑膜炎组合的其他原因更为普遍。预防艺术计划中早期死亡率的一种策略是使用简单的血液测试（加密局部抗原或crag）筛选出患有艾滋病的非对称人群中的次链链球菌感染。在36个非洲队列中，CD4 <100未接受ART的36个非洲队列中，这种可检测到的亚临床隐球菌感染的患病率平均为7.2％（95％CI：6.8-7.6％）。如果确定，这些不对称的crag+人可以给予“先发制人”氟康唑抗真菌疗法，以防止脑膜炎或死亡的发展。我们的阶梯楔随机“ Orcas”试验表明，在艾滋病毒感染者中，患有CD4 <100细胞/mcl的艾滋病毒感染者筛查导致乌干达18个诊所的总体6个月死亡率相对降低30％。在坦桑尼亚和赞比亚的一项单独的随机临床试验中，观察到了相似的〜30％益处。但是，尽管CRAG筛查干预成功，但在这两个试验中，Crag+人的生存比crag阴性人差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CD4 <100人群的人筛查纳入了国家艾滋病毒指南中。因此，为了降低早期艺术死亡率，需要进一步改善碎屑筛查和先发制人治疗方案。首先，我们将在一项随机比较有效性试验中评估crag+人的6个月无隐球菌存活率可以通过使用辅助性舍曲林进行增强的预先抗真菌治疗来改善与建议先发制性crag+治疗相比。其次，我们将确定相对于6个月无隐球菌生存期，先发制人crag+治疗失败的危险因素。总体而言，我们寻求创新的艾滋病毒护理，以通过实施改进的护理包装来降低艺术的早期死亡率，以供晚期主持人进行护理。