Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis

描述(申请人提供)：隐球菌性脑膜炎(CM)是所有与艾滋病相关的机会性感染中的主要死亡原因，每年在全球范围内造成约100万人感染和62.5万人死亡。即使有抗逆转录病毒治疗(ART)，CM后6个月的存活率也很低，在资源有限的地区，存活率只有30%-40%。在两个非洲队列中，35-40%的死亡率发生在开始门诊抗逆转录病毒治疗之前的时间段，中位数为CM诊断后5-6周。目前世界大部分地区的标准做法是将抗逆转录病毒疗法的启动推迟到出院后，以允许建立带有艾滋病毒抗逆转录病毒药物咨询的门诊护理。然而，这一间隔延长了免疫抑制的持续时间，并推迟了ART相关免疫重建发生的时间。现有的关于心肌梗塞患者最佳抗逆转录病毒治疗时机的数据是有限的，而且相互矛盾。因此，随机试验的治疗平衡是存在的。具体目标#1：在隐球菌性脑膜炎患者中进行一项随机试验，以确定与标准ART治疗相比，早期ART治疗是否可以改善26周的存活率。假设：在CM后，与目前的治疗标准相比，在两性霉素治疗的第二周内，在最初住院期间尽早开始ART将提高存活率。设计：在服用两性霉素7-10天(研究项目)后，受试者将按1：1随机分配到：-早期ART启动(试验组)=在研究进入后72小时内启动ART或-标准ART启动(控制组)=ART在研究进入后4周具体目标2：确定早期ART与标准ART在以下方面的安全性和耐受性：IRIS的发生率、病毒学抑制、微生物学清除、ART终止和不良事件。具体目标#3：确定与隐球菌性脑膜炎后抗逆转录病毒治疗的时间相关的IRIS和/或总体ART相关死亡率的风险因素。这项试验将招募420名参与者，以检测26周存活率的15%绝对差异(25%相对差异)。 相关性：在撒哈拉以南非洲，隐球菌性脑膜炎是第二种最常见的艾滋病定义疾病，占艾滋病相关可归因性死亡的约30%。据估计，全世界每年发生100万例隐球菌病。开始艾滋病毒治疗的最佳时间尚不清楚。这是一项明确的策略试验，旨在确定在住院期间早期开始艾滋病毒治疗是否会带来更好的长期存活率。

DESCRIPTION (provided by applicant): Cryptococcal meningitis (CM) is a leading cause of death among all AIDS-related opportunistic infections, causing an estimated 1 million infections and 625,000 deaths worldwide annually. Even with availability of antiretroviral therapy (ART), the 6-month survival after CM is poor, with survival being only 30-40% in resource-limited areas. In two African cohorts, 35-40% mortality occurred during the interval before initiating outpatient ART at a median of 5-6 weeks after CM diagnosis. The current standard practice throughout much of the world is to delay initiation of ART until after hospital discharge to allow the establishment of outpatient care with HIV ART counseling. However, this interval prolongs the duration of immunosuppression and delays the time until ART-associated immune reconstitution occurs. Existing data about the optimal timing of ART in persons with CM are limited and conflicted. Thus, therapeutic equipoise for a randomized trial exists. Specific Aim #1: Conduct a randomized trial among persons with cryptococcal meningitis, to determine whether 26-week survival is improved with early ART initiation compared with standard ART initiation. Hypothesis: After CM, early initiation of ART during initial hospitalization during the second week of amphotericin therapy will improve survival as compared to the current standard of care. Design: After 7-10 days of amphotericin (study entry), subjects will be randomized in 1:1 allocation to: - Early ART Initiation (Experimental Group) = ART initiated within 72 hours after study entry OR - Standard ART Initiation (Control Group) = ART at >4 weeks after study entry Specific Aim #2: Determine the safety and tolerability of early ART versus standard ART with respect to the: incidence of IRIS, virologic suppression, microbiologic clearance, ART discontinuation, and adverse events. Specific Aim #3: Determine risk factors for IRIS and/or overall ART-related mortality with respect to the timing of ART after cryptococcal meningitis. The trial will enroll 420 participants to detect a 15% absolute (25% relative) difference in 26-week survival. RELEVANCE: In Sub-Saharan Africa, cryptococcal meningitis is the second most common AIDS-defining illness, and causes ~30%) of the AIDS-related attributable mortality. An estimated 1 million cases of cryptococcosis occur worldwide annually. The optimal time to start HIV therapy is unknown. This is a definitive strategy trial to determine if early initiation of HIV therapy while hospitalized results in superior long term survival.