Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis

描述（由申请人提供）：隐球菌脑膜炎（CM）是所有艾滋病相关机会性感染中的主要死因，估计每年在全世界造成100万例感染和625，000例死亡。即使有抗逆转录病毒治疗（ART），CM后6个月的生存率也很低，在资源有限的地区，生存率仅为30-40%。在两个非洲队列中，35-40%的死亡率发生在CM诊断后中位数5-6周开始门诊ART之前的间隔期间。目前，世界上大部分地区的标准做法是将抗逆转录病毒治疗的开始时间推迟到出院后，以便建立门诊治疗和艾滋病毒抗逆转录病毒治疗咨询。然而，这一间隔延长了免疫抑制的持续时间，并延迟了ART相关免疫重建发生的时间。关于CM患者ART最佳时机的现有数据有限且相互矛盾。因此，存在随机试验的治疗平衡。具体目标1：在隐球菌性脑膜炎患者中进行随机试验，以确定早期ART启动与标准ART启动相比，26周生存率是否有所改善。假设：CM后，与目前的标准治疗相比，在最初住院期间，在阿替霉素治疗的第二周，早期开始ART将改善生存率。设计图：服用阿替西汀7-10天后（研究入组），受试者将以1：1的比例随机分配至：（实验组）=研究入组后72小时内开始ART或-标准ART开始具体目标#2：确定早期ART相对于标准ART在以下方面的安全性和耐受性：IRIS、病毒学抑制、微生物清除、ART停药和不良事件的发生率。具体目标#3：确定IRIS和/或总体ART相关死亡率与隐球菌脑膜炎后ART时机相关的风险因素。该试验将招募420名参与者，以检测26周生存率的15%绝对（25%相对）差异。 相关性：在撒哈拉以南非洲，隐球菌脑膜炎是第二种最常见的艾滋病定义疾病，并导致约30%的艾滋病相关归因死亡率。据估计，全世界每年发生100万例隐球菌病。开始HIV治疗的最佳时间尚不清楚。这是一项明确的策略试验，以确定住院期间早期开始HIV治疗是否会导致更好的上级长期生存。

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.