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（由申请人提供）：隐球菌性脑膜炎是资源有限环境中艾滋病患者死亡的主要原因。2014 年，隐球菌性脑膜炎导致非洲艾滋病毒治疗项目中约 15% 的死亡。此外，在撒哈拉以南非洲积极推广抗逆转录病毒疗法仅导致隐球菌性脑膜炎的发病率略有下降。 2014 年，南非国家监测显示，在疑似脑膜炎住院患者中，隐球菌仍然比所有其他脑膜炎病因加起来更为常见。 ART 项目中预防早期死亡的一项策略是筛查亚型脑膜炎。使用简单的血液检测（隐球菌抗原或 CrAg）可检测无症状艾滋病患者的临床隐球菌感染情况。在 36 个未接受 ART 的 CD4<100 的非洲队列中，感染率平均为 7.2%（95%CI：6.8-7.6%）。如果确诊，这些无症状 CrAg+ 患者可以接受“先发制人”氟康唑抗真菌治疗，以预防脑膜炎的发展或死亡。我们的阶梯楔形随机“ORCAS”试验表明，对 CD4<100 的 HIV 感染者进行 ART 前 CrAg 筛查。细胞/mcL 使乌干达 18 家诊所的 6 个月总体死亡率相对降低了 30%，在坦桑尼亚和赞比亚的一项单独随机临床试验中也看到了类似的约 30% 的益处，尽管 CrAg 筛查干预措施取得了成功。根据我们团队之前的研究，在两项试验中，CrAg+ 患者的生存率比 CrAg 阴性患者差 2 倍，乌干达和其他多个国家已对患者进行了 ART 前 CrAg 筛查。 CD4<100 纳入国家 HIV 指南，因此，需要进一步改进 CrAg 筛查和先发制人的治疗方案，以降低早期 ART 死亡率。首先，我们将在随机比较有效性试验中评估 6 个月的无隐球菌生存率。与目前世界卫生组织推荐的先发性 CrAg+ 治疗相比，使用辅助舍曲林的强化先发性抗真菌治疗可以改善 CrAg+ 患者的病情。 其次，我们将确定导致 CrAg+ 治疗失败的危险因素。总体而言，我们寻求创新 HIV 护理服务，通过对晚期就诊者实施改进的护理方案来降低 ART 的早期死亡率。