Enhanced Antifungal Therapy to Improve Survival in Early Disseminated Cryptococcal Infection

摘要 隐球菌脑膜炎是撒哈拉以南非洲最常见的成人神经感染， 全球艾滋病相关死亡率。在脑膜炎发作前的几周内，隐球菌抗原（CrAg） 在血液中可以检测到，并且是脑膜炎和死亡的预测因子。在血浆中筛选CrAg是一种有效的 制定公共卫生战略，以确定CD 4 <200个细胞/mcL的人患脑膜炎和死亡的高风险。中 对2000名HIV感染者进行随机试验，CrAg筛查和预先氟康唑治疗， 比标准治疗有28%的生存获益。因此，世界卫生组织和美国的指导方针 推荐CrAg筛查。然而，尽管CrAg筛查和先发制人的治疗可以带来生存益处， 然而，即使接受了HIV治疗，25%的最初无症状的CrAg+患者仍会死亡。 从非洲CrAg+人群的4项前瞻性队列研究中，我们已经确定， 滴度增加，死亡率增加，尽管氟康唑治疗。在无症状CrAg+患者中， 播散性隐球菌病是最常见的死亡原因。我们认为亚临床 脑实质中的弥散性早期神经感染伴随高CrAg滴度，氟康唑是 治疗不当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，阿替霉素B是最有效的抗真菌药;单用氟康唑 是不够的。最近的随机试验数据报告了单剂量脂质体阿霉素（AmBisome）10 mg 与传统的7天一次给药相比，氟胞嘧啶（5 FC）和氟康唑的疗效相同，毒性更低 + 5 FC治疗脑膜炎。我们假设AmBisome（10 mg/kg × 1）与氟康唑联合使用时， 对无症状CrAg+患者比氟康唑单药治疗更有效。我们已经招募了244名CrAg+ II/III期随机试验初始II期的受试者，以证明其安全性和可行性 我们在乌干达加强了方案，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 隐球菌性脑膜炎和死亡。我们将完成600名CrAg+患者（即356名 更多参与者），以确定AmBisome（10 mg/kg x1）联合氟康唑的抢先治疗是否适用于CrAg+ 与目前的标准相比， 氟康唑单药治疗（目的1）。在目标2中，我们将确定CrAg+患者的神经认知结果 预先用AmBisome联合氟康唑治疗上级氟康唑单药治疗。 最后，在目标3中，我们将评估AmBisome与氟康唑优先的成本和成本效果 CrAg+患者的治疗。这项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。

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.