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

• 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
• 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

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 隐球菌脑膜炎是撒哈拉以南非洲最常见的成年神经感染，造成约15％ 全球与艾滋病有关的死亡率。在脑膜炎发作前的几周内，加密局局（CRAG）为 在血液中可检测，是脑膜炎和死亡的预测指标。等离子体中的crag筛查是有效的 公共卫生策略以识别患有脑膜炎和死亡的高风险CD4 <200细胞/MCL的人。在 2000人的HIV，crag筛查和先发制人氟康唑治疗的随机试验产生了 28％的生存益处与护理标准相比。结果，世界卫生组织和美国准则 推荐碎屑筛选。尽管在crag筛查和先发制人的情况下看到了生存益处 治疗，即使接受HIV疗法，接受氟康唑治疗的最初无症状crag+人仍会死亡。 在非洲的crag+人的4个前瞻性队列研究中，我们确定为等离子体crag 尽管氟康唑治疗，滴度增加，死亡率增加。在无症状的crag+人中， 传播的隐球菌病是最常见的死亡原因。我们认为那个亚临床 在脑实质中散布早期神经感染，伴随着高crag滴度，而氟康唑则是 治疗不足。需要更有效的治疗来降低Crag+人的死亡率。 对于有症状的隐球菌脑膜炎，两性霉素B是最有效的抗真菌蛋白。单独使用氟康唑 是不足的。最近的随机试验数据报道了单剂量的脂质体两性霉素（Ambisome）10 mg /kg氟替嗪（5FC）和氟康唑与传统的7天两性霉素一样有效且毒性较小 + 5FC用于脑膜炎。我们假设Ambisome（10mg/kg X1）与氟康唑结合使用时 对于无症状crag+人的氟康唑单一疗法比氟康唑单一疗法更有效。我们已经注册了244个crag+ 在II/III期随机试验的初始II阶段中的人员，以证明其安全性和可行性 乌干达增强的方案，现在我们寻求完成III期试验以测试功效。 该应用的目的是评估Ambisome和氟康唑的功效以防止 隐球菌脑膜炎和死亡。我们将完成600个crag+人的随机临床试验（即356 更多参与者）确定是否具有Ambisome（10mg/kg X1）和氟康唑的crag+ fluconazole是否进行预先治疗+ 与当前的标准相比 氟康唑单一疗法（AIM 1）。在AIM 2中，我们将确定crag+人的神经认知结果是否 用氟康唑的Ambisome先发治疗优于氟康唑单一疗法的结果。 最后，在AIM 3中，我们将通过氟康唑优先评估Ambisome的成本和成本效益 在crag+人中进行治疗。该审判的调查结果将影响美国和国际艾滋病毒的指南 为了减少艾滋病毒患者的死亡率，最佳预防隐球菌脑膜炎。