Targeted Treatment of Early Cryptococcal Infection in HIV-infected Patients

HIV感染者早期隐球菌感染的靶向治疗

• 批准号: 8779847
• 负责人: Ana-Claire Lew Meyer
• 金额: $ 6.14万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8779847
• 关键词: Targeted; Treatment; Early; Cryptococcal; Infection

DESCRIPTION (provided by applicant): In sub-Saharan Africa and southeast Asia, invasive cryptococcal disease is the second most common life- threatening opportunistic infection after tuberculosis and is responsible for up to 20% of deaths. As anti- retroviral and antifungal therapies become more available in resource-limited settings, there has been growing interest in developing new approaches to improve outcomes from invasive cryptococcal infection. Since invasive cryptococcal disease primarily affects HIV-individuals with advanced immunosuppression, one potential strategy to identify early cryptococcal infection in resource-limited settings is to screen asymptomatic individuals with advanced HIV-related immunosuppression for serum cryptococcal antigen (CrAg) as they enter outpatient HIV care and treatment programs. Several observational cohort studies have demonstrated that this approach clearly identifies a population at high risk of cryptococcal meningitis and death and is a feasible screening method for resource-limited settings. However, screening with serum CrAg alone without additional diagnostic studies identifies a heterogeneous clinical population with early cryptococcal infection, many of whom already have sub-clinical meningeal infection or fungemia. Although the mainstay of anti-cryptococcal therapy in resource-limited settings is monotherapy with oral fluconazole, preliminary evidence suggests this is not an effective treatment in a heterogeneous population of individuals with early cryptococcal infection. Thus, there is a critical need for potent therapies that are effective in a heterogeneous population of HIV-infected individuals with advanced immunosuppression and early cryptococcal infection and which can be safely administered in resource-limited settings. Although there are no randomized controlled trials of therapies for early cryptococcal infection, combination therapy with oral high-dose fluconazole and flucytosine has shown promise in small clinical trials for the treatment of cryptococcal meningitis. In this open-label Phase IIb randomized controlled clinical trial based at Family AIDS Care and Education Services (FACES) in Western Kenya, we will determine the safety and estimate the efficacy of combination therapy with oral flucytosine and fluconazole as compared to fluconazole monotherapy for the treatment of early cryptococcal infection in HIV-infected individuals with advanced immunosuppression who have no signs of meningitis or severe, systemic cryptococcal infection. In a sub-sample of trial participants, we will conduct additional diagnostic studies to further characterize the nature of early cryptococcal infection in our setting. Finally, through a new research collaboration which builds on existing relationships, we will conduct a series of activities intended to build research capacity in Kenya at the University of Nairobi and FACES.

描述（由申请人提供）：在撒哈拉以南非洲和东南亚，侵入性的加密秒性疾病是肺结核后第二大最常见的生命威胁机会感染，并负责多达20％的死亡。随着抗逆转录病毒和抗真菌疗法在资源有限的环境中变得越来越多，人们对开发新方法的兴趣越来越多，以改善侵入性的加密癌症感染的预后。由于侵入性的隐球菌疾病主要影响具有先进的免疫抑制的HIV个体，因此在资源有限的环境中鉴定早期隐球菌感染的一种潜在策略是筛查具有晚期HIV HIV相关免疫抑制的无症状患者，用于血清中的血清加密抗原（CRAG）（CRAG）（CRAG），以便他们输入型HIV和治疗方案。几项观察队列研究表明，这种方法清楚地识别了一个处于隐球菌脑膜炎和死亡高风险的人群，这是一种可用于资源限制环境的可行筛查方法。 但是，仅使用血清crag筛选而没有其他诊断研究，就会发现异质性临床人群具有早期的加密秒感染，其中许多人已经患有亚临床脑膜脑膜感染或真菌。尽管在资源有限的环境中，抗晶状体疗法的支柱是口服氟康唑的单一疗法，但初步证据表明，这不是早期加密赛感染的异构群体中的有效治疗方法。因此，对于有效的艾滋病毒感染者，具有先进的免疫抑制和早期加密秒感染的艾滋病毒感染者的有效疗法的有效疗法至关重要，并且可以在资源有限的环境中安全地施用。尽管没有针对早期隐球菌感染的疗法的随机对照试验，但与口服高剂量氟康唑和氟甲苯烷的联合疗法在小型临床试验中表现出了有望治疗隐孢菌脑膜炎的治疗。 在基于肯尼亚西部家庭艾滋病护理和教育服务（FAES）的这个开放标签的IIB期随机对照临床试验中，我们将确定与氟康唑一疗法相比，与氟康唑一体疗法相比，与氟康唑一体疗法相比，与氟康唑一体疗法相比，与早期无菌感染的患者相比，结合疗法与口服氟替辛和氟康唑的疗效相比全身性隐球菌感染。在试验参与者的子样本中，我们将进行其他诊断研究，以进一步表征早期隐球菌的性质 在我们的环境中感染。最后，通过建立在现有关系的新研究合作，我们将进行一系列旨在在内罗毕大学和面孔建立研究能力的活动。