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

基本信息

批准号：
8255248
负责人：
Ana-Claire Lew Meyer
金额：
$ 12.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8255248
关键词：
Acquired Immunodeficiency Syndrome Adult Adverse event Affect Africa South of the Sahara Anti-Retroviral Agents Antifungal Therapy Antigens CD4 Lymphocyte Count CD4 Positive T Lymphocytes Caring Cause of Death Cells Cerebrospinal Fluid Cessation of life Characteristics Chest Clinical Clinical Research Clinical Treatment Clinical Trials Cohort Studies Collaborations Combined Modality Therapy Cox Proportional Hazards Models Cryptococcal Meningitis Data Diagnostic Diagnostic tests Disease Dose Early treatment Education Evaluation Faculty Family Fluconazole Flucytosine Fungemia HIV Human Resources Immune Immunosuppression Incidence Individual Infection Inflammatory Kenya Laboratories Life Logistic Regressions Medicine Meningeal Meningitis Methods Nature Opportunistic Infections Oral Organism Outcome Outpatients Participant Patients Phase Physicians Population Population Heterogeneity Procedures Province Randomized Randomized Controlled Clinical Trials Randomized Controlled Trials Recruitment Activity Research Resources Safety Sampling Screening procedure Series Serious Adverse Event Serum Services Southeastern Asia Spinal Puncture Survival Rate Symptoms Syndrome Testing Time Tuberculosis Universities antiretroviral therapy base career design effective therapy efficacy testing high risk improved interest member mortality nervous system disorder novel strategies open label prevent randomized trial reconstitution skills standard care treatment program

项目摘要

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. PUBLIC HEALTH RELEVANCE: Cryptococcal meningitis is a leading cause of death in HIV-infected individuals. In this study we will test a new combination of medicines for the treatment of early cryptococcal infection in individuals with advanced HIV. We will determine if this treatment is at least as safe as standard treatments in preventing death from cryptococcal meningitis.

描述（由申请人提供）：在撒哈拉以南非洲和东南亚，侵袭性隐球菌病是继结核病之后第二常见的危及生命的机会性感染，导致高达 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可用，人们越来越有兴趣开发新方法来改善侵袭性隐球菌感染的结果。由于侵袭性隐球菌病主要影响患有高级免疫抑制的 HIV 个体，因此在资源有限的环境中识别早期隐球菌感染的一种潜在策略是，在患有高级 HIV 相关免疫抑制的无症状个体进入门诊 HIV 护理时筛查血清隐球菌抗原 (CrAg)和治疗方案。几项观察性队列研究表明，这种方法可以清楚地识别隐球菌性脑膜炎和死亡的高风险人群，并且对于资源有限的环境来说是一种可行的筛查方法。然而，仅用血清 CrAg 筛查而不进行额外的诊断研究即可识别出早期隐球菌感染的异质临床人群，其中许多人已经患有亚临床脑膜感染或真菌血症。尽管在资源有限的情况下，抗隐球菌治疗的主要方法是口服氟康唑单一疗法，但初步证据表明，这对于早期隐球菌感染的异质人群来说并不是一种有效的治疗方法。因此，迫切需要有效的治疗方法，该治疗方法对具有高级免疫抑制和早期隐球菌感染的异质性 HIV 感染个体群体有效，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治疗的随机对照试验，但口服大剂量氟康唑和氟胞嘧啶的联合治疗在治疗隐球菌脑膜炎的小型临床试验中显示出了希望。在这项基于肯尼亚西部家庭艾滋病护理和教育服务 (FACES) 的开放标签 IIb 期随机对照临床试验中，我们将确定口服氟胞嘧啶和氟康唑联合治疗与氟康唑单药治疗相比的安全性并评估其疗效。治疗患有晚期免疫抑制但没有脑膜炎或严重全身性隐球菌感染迹象的艾滋病毒感染者的早期隐球菌感染。在试验参与者的子样本中，我们将进行额外的诊断研究，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基础上的新研究合作，我们将开展一系列活动，旨在增强肯尼亚内罗毕大学和 FACES 的研究能力。公共卫生相关性：隐球菌性脑膜炎是 HIV 感染者死亡的主要原因。在这项研究中，我们将测试一种新的药物组合，用于治疗晚期艾滋病毒个体的早期隐球菌感染。我们将确定这种治疗在预防隐球菌性脑膜炎死亡方面是否至少与标准治疗一样安全。