Targeted Treatment of Early Cryptococcal Infection in HIV-infected Patients

描述（由申请人提供）：在撒哈拉以南非洲和东南亚，侵袭性隐球菌病是仅次于结核病的第二大威胁生命的机会性感染，导致高达20%的死亡。随着抗逆转录病毒和抗真菌治疗在资源有限的环境中变得越来越有效，人们对开发新方法来改善侵袭性隐球菌感染的结果越来越感兴趣。由于侵袭性隐球菌疾病主要影响晚期免疫抑制的HIV患者，因此在资源有限的环境中，识别早期隐球菌感染的一个潜在策略是在进入门诊HIV护理和治疗方案时，对晚期HIV相关免疫抑制的无症状患者进行血清隐球菌抗原（CrAg）筛查。几项观察性队列研究表明，这种方法清楚地确定了隐球菌脑膜炎和死亡高风险人群，是资源有限环境下可行的筛查方法。然而，在没有额外诊断研究的情况下，仅用血清CrAg进行筛查，确定了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。虽然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药治疗，但初步证据表明，这对早期隐球菌感染个体的异质人群不是有效的治疗方法。因此，迫切需要对具有晚期免疫抑制和早期隐球菌感染的异质艾滋病毒感染者群体有效的强效疗法，并且可以在资源有限的环境中安全使用。虽然没有早期隐球菌感染治疗的随机对照试验，但口服大剂量氟康唑和氟胞嘧啶联合治疗在小型临床试验中显示出治疗隐球菌性脑膜炎的希望。在肯尼亚西部的家庭艾滋病护理和教育服务（FACES）开展的这项开放标签ii期随机对照临床试验中，我们将确定口服氟康唑和氟康唑联合治疗早期隐球菌感染的安全性和有效性，并将其与氟康唑单药治疗相比，用于治疗晚期免疫抑制、无脑膜炎症状或严重系统性隐球菌感染的hiv感染者。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

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.