Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.
Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis.
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DOI：
10.1056/nejmoa1312884
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发表时间：
2014-06-26
期刊：
影响因子：
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通讯作者：
COAT Trial Team
中科院分区：
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作者：
Boulware DR;Meya DB;Muzoora C;Rolfes MA;Huppler Hullsiek K;Musubire A;Taseera K;Nabeta HW;Schutz C;Williams DA;Rajasingham R;Rhein J;Thienemann F;Lo MW;Nielsen K;Bergemann TL;Kambugu A;Manabe YC;Janoff EN;Bohjanen PR;Meintjes G;COAT Trial Team
隐球菌脑膜炎占非洲获得性免疫缺陷综合征相关死亡的20%至25%。抗逆转录病毒治疗（ART）是生存所必需的，然而，在隐球菌脑膜炎诊断后何时开始ART的问题仍然没有答案。我们评估了乌干达和南非177名患有隐球菌脑膜炎且以前未接受过ART的人类免疫缺陷病毒感染成人在26周时的生存率。我们将研究参与者随机分配接受早期ART启动（诊断后1至2周）或延迟ART启动（诊断后5周）。受试者接受了14天的阿替霉素B（每天每公斤体重0.7至1.0 mg）和氟康唑（每天800 mg），然后用氟康唑进行巩固治疗。较早开始ART治疗的26周死亡率显著高于延迟开始ART治疗的患者（45% [88例患者中的40例] vs. 30% [89例患者中的27例];死亡风险比为1.73; 95%置信区间[CI]为1.06 - 2.82; P = 0.03）。与早期ART启动相关的额外死亡发生在诊断后2至5周（组间比较P = 0.007）;此后两组的死亡率相似。在随机化时脑脊液中白色细胞较少（每立方毫米<5个）的患者中，与延迟ART相比，早期ART的死亡率特别高（风险比，3.87; 95%CI，1.41至10.58; P = 0.008）。早期ART组和延迟ART组的隐球菌免疫重建炎症综合征的发生率无显著差异（分别为20%和13%; P = 0.32）。所有其他临床、免疫学、病毒学和微生物学结局以及不良事件在两组之间相似。与1 - 2周开始ART相比，诊断隐球菌性脑膜炎后推迟ART 5周与生存率显著提高相关，尤其是在脑脊液中白色细胞缺乏的患者中。（由国家过敏和传染病研究所和其他机构资助; COAT ClinicalTrials.gov编号，NCT 01075152。
Cryptococcal meningitis accounts for 20 to 25% of acquired immunodeficiency syndrome–related deaths in Africa. Antiretroviral therapy (ART) is essential for survival; however, the question of when ART should be initiated after diagnosis of cryptococcal meningitis remains unanswered. We assessed survival at 26 weeks among 177 human immunodeficiency virus–infected adults in Uganda and South Africa who had cryptococcal meningitis and had not previously received ART. We randomly assigned study participants to undergo either earlier ART initiation (1 to 2 weeks after diagnosis) or deferred ART initiation (5 weeks after diagnosis). Participants received amphotericin B (0.7 to 1.0 mg per kilogram of body weight per day) and fluconazole (800 mg per day) for 14 days, followed by consolidation therapy with fluconazole. The 26-week mortality with earlier ART initiation was significantly higher than with deferred ART initiation (45% [40 of 88 patients] vs. 30% [27 of 89 patients]; hazard ratio for death, 1.73; 95% confidence interval [CI], 1.06 to 2.82; P = 0.03). The excess deaths associated with earlier ART initiation occurred 2 to 5 weeks after diagnosis (P = 0.007 for the comparison between groups); mortality was similar in the two groups thereafter. Among patients with few white cells in their cerebrospinal fluid (<5 per cubic millimeter) at randomization, mortality was particularly elevated with earlier ART as compared with deferred ART (hazard ratio, 3.87; 95% CI, 1.41 to 10.58; P = 0.008). The incidence of recognized cryptococcal immune reconstitution inflammatory syndrome did not differ significantly between the earlier-ART group and the deferred-ART group (20% and 13%, respectively; P = 0.32). All other clinical, immunologic, virologic, and microbiologic outcomes, as well as adverse events, were similar between the groups. Deferring ART for 5 weeks after the diagnosis of cryptococcal meningitis was associated with significantly improved survival, as compared with initiating ART at 1 to 2 weeks, especially among patients with a paucity of white cells in cerebrospinal fluid. (Funded by the National Institute of Allergy and Infectious Diseases and others; COAT ClinicalTrials.gov number, NCT01075152.)