Trial for the Optimal Timing of HIV Therapy after Cryptococcal Meningitis

描述（由申请人提供）：隐球菌性脑膜炎（CM）是所有与艾滋病相关的机会性感染中导致死亡的主要原因，每年在全球造成约100万例感染和625,000例死亡。即使有抗逆转录病毒治疗（ART）， CM后的6个月生存率也很低，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5-6周开始门诊抗逆转录病毒治疗之前。目前世界上大部分地区的标准做法是将开始抗逆转录病毒治疗的时间推迟到出院后，以便建立提供艾滋病毒抗逆转录病毒治疗咨询的门诊护理。然而，这一间隔延长了免疫抑制的持续时间，并延迟了art相关免疫重建发生的时间。关于慢性粒细胞性白血病患者最佳抗逆转录病毒治疗时机的现有数据有限且存在矛盾。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一项随机试验，以确定与标准ART起始相比，早期ART起始是否能提高26周生存率。假设：CM后，与目前的标准治疗相比，在两性霉素治疗的第二周初次住院期间早期开始抗逆转录病毒治疗将提高生存率。设计：两性霉素治疗7-10天后（研究入组），受试者将按1:1的比例随机分配：-早期ART起始治疗（实验组）=研究入组后72小时内开始ART治疗，或-标准ART起始治疗（对照组）=研究入组后4周开始ART治疗。具体目标2：确定早期ART与标准ART治疗的安全性和耐受性：IRIS发生率、病毒学抑制、微生物清除率、ART停药和不良事件。具体目标#3：确定与隐球菌脑膜炎后抗逆转录病毒治疗时机相关的IRIS和/或总体抗逆转录病毒治疗相关死亡率的危险因素。该试验将招募420名参与者，以检测26周生存率的15%绝对差异（25%相对差异）。

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.