Enhanced Antifungal Therapy to Improve Survival in Early Disseminated Cryptococcal Infection

加强抗真菌治疗可提高早期播散性隐球菌感染的生存率

基本信息

批准号：
10621009
负责人：
Radha Rajasingham
金额：
$ 67.69万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-21 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621009
关键词：
Acquired Immunodeficiency Syndrome Adult Africa Africa South of the Sahara Amphotericin Amphotericin B Antifungal Agents Antifungal Therapy Antigens Blood CD4 Lymphocyte Count Cause of Death Cells Central Nervous System Infections Cessation of life Clinical Trials Cost Analysis Country Cryptococcal Meningitis Cryptococcosis Cryptococcus Data Data Reporting Development Disease Dose Enrollment Excess Mortality Fluconazole Flucytosine Guidelines HIV HIV therapy Hospital Costs Incidence Income Infection International Liposomes Meningitis Neurocognitive Neurologic Neurological outcome Outcome Participant Performance Persons Phase Plasma Prevention Prospective, cohort study Public Health Randomized Recommendation Regimen Testing Uganda Work World Health Organization antiretroviral therapy brain parenchyma comparative effectiveness trial cost cost effective cost effective intervention cost-effectiveness evaluation disability effective therapy efficacy evaluation efficacy testing high risk improved mortality phase III trial prevent randomized trial randomized, clinical trials recruit safety and feasibility screening standard of care survival outcome treatment guidelines

项目摘要

Abstract Cryptococcal meningitis is the most common adult neuroinfection in sub-Saharan Africa and causes ~15% of AIDS-related mortality globally. In the weeks prior to onset of meningitis, cryptococcal antigen (CrAg) is detectable in the blood, and is a predictor of meningitis and death. CrAg screening in plasma is an effective public health strategy to identify persons with CD4<200 cells/mcL at high risk of meningitis and death. In a randomized trial of 2000 persons with HIV, CrAg screening and preemptive fluconazole treatment yielded a 28% survival benefit over standard-of-care. As a result, the World Health Organization and U.S. guidelines recommend CrAg screening. Yet despite the survival benefit seen with CrAg screening and preemptive therapy, 25% of initially asymptomatic CrAg+ persons treated with fluconazole still die, even with HIV therapy. From 4 prospective cohort studies of CrAg+ persons in Africa, we have determined that as plasma CrAg titer increases, mortality increases, despite fluconazole therapy. Among asymptomatic CrAg+ persons, disseminated cryptococcosis is the most commonly identified cause of death. We posit that subclinical disseminated early neuroinfection in the brain parenchyma accompanies high CrAg titers, and fluconazole is inadequate therapy. More effective treatment is critically needed to reduce mortality in CrAg+ persons. For symptomatic cryptococcal meningitis, amphotericin B is the most effective antifungal; fluconazole alone is inadequate. Recent randomized trial data reported single dose of liposomal amphotericin (AmBisome) 10 mg /kg with flucytosine (5FC) and fluconazole is as effective and less toxic than the traditional 7-day amphotericin + 5FC for meningitis. We hypothesize that AmBisome (10mg/kg x1), when combined with fluconazole, will be more effective than fluconazole monotherapy for asymptomatic CrAg+ persons. We have enrolled 244 CrAg+ persons in the initial phase II of a phase II/III randomized trial to demonstrate safety and feasibility of this enhanced regimen in Uganda, and now we seek to complete the phase III trial in order to test efficacy. The objective of this application is to assess the efficacy of AmBisome plus fluconazole to prevent cryptococcal meningitis and death. We will complete a randomized clinical trial of 600 CrAg+ persons (i.e. 356 more participants) to determine if preemptive therapy with AmBisome (10mg/kg x1) plus fluconazole for CrAg+ persons will improve cryptococcal meningitis-free 6-month survival compared with the current standard of fluconazole monotherapy (Aim 1). In Aim 2, we will determine if neurocognitive outcomes in CrAg+ persons preemptively treated with AmBisome with fluconazole are superior to outcomes with fluconazole monotherapy. Finally, in Aim 3 we will evaluate the cost and cost-effectiveness of AmBisome with fluconazole preemptive treatment in CrAg+ persons. Findings from this trial will impact U.S. and international HIV guidelines on the optimal prevention of cryptococcal meningitis, in order to reduce mortality in persons living with HIV.

抽象的隐球菌性脑膜炎是撒哈拉以南非洲地区最常见的成人神经感染，约 15% 的患者患有隐球菌性脑膜炎全球与艾滋病相关的死亡率。在脑膜炎发病前几周，隐球菌抗原 (CrAg) 可在血液中检测到，是脑膜炎和死亡的预测因子。血浆 CrAg 筛查是一种有效的方法公共卫生战略，旨在识别 CD4<200 个细胞/mcL 的脑膜炎和死亡高风险人群。在一个对 2000 名 HIV 感染者、CrAg 筛查和先发性氟康唑治疗的随机试验得出了与标准护理相比，生存获益提高 28%。因此，世界卫生组织和美国的指导方针建议CrAg筛查。然而，尽管 CrAg 筛查和先发制人可以带来生存获益在接受氟康唑治疗的最初无症状 CrAg+ 患者中，即使接受 HIV 治疗，仍有 25% 死亡。从非洲 CrAg+ 人群的 4 项前瞻性队列研究中，我们确定，血浆 CrAg 尽管氟康唑治疗，滴度仍增加，死亡率增加。在无症状 CrAg+ 人群中，播散性隐球菌病是最常见的死亡原因。我们假设亚临床脑实质中的播散性早期神经感染伴随着高 CrAg 滴度，氟康唑是治疗不足。迫切需要更有效的治疗来降低 CrAg+ 患者的死亡率。对于有症状的隐球菌性脑膜炎，两性霉素 B 是最有效的抗真菌药物；单用氟康唑是不够的。最近的随机试验数据报告单剂量脂质体两性霉素 (AmBisome) 10 mg /kg 与氟胞嘧啶 (5FC) 和氟康唑联用与传统 7 天两性霉素一样有效且毒性较小 + 5FC 治疗脑膜炎。我们假设 AmBisome (10mg/kg x1) 与氟康唑联合使用时，将对于无症状 CrAg+ 患者，比氟康唑单一疗法更有效。我们已经登记了 244 名 CrAg+ 处于 II/III 期随机试验初始 II 期的人员，以证明该试验的安全性和可行性在乌干达加强了治疗方案，现在我们寻求完成III期试验以测试疗效。本申请的目的是评估 AmBisome 联合氟康唑预防的功效隐球菌性脑膜炎和死亡。我们将完成一项针对 600 名 CrAg+ 患者（即 356 名更多参与者）以确定是否使用 AmBisome（10mg/kg x1）加氟康唑抢先治疗 CrAg+ 与目前的标准相比，人们将提高无隐球菌性脑膜炎的 6 个月生存率氟康唑单药治疗（目标 1）。在目标 2 中，我们将确定 CrAg+ 患者的神经认知结果是否 AmBisome 联合氟康唑先发性治疗优于氟康唑单药治疗的结果。最后，在目标 3 中，我们将评估 AmBisome 与氟康唑先发制人的成本和成本效益 CrAg+ 患者的治疗。该试验的结果将影响美国和国际艾滋病毒指南最佳预防隐球菌性脑膜炎，以降低艾滋病毒感染者的死亡率。