A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis
A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis
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DOI：
10.1056/nejmoa1613306
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发表时间：
2017-06-15
影响因子：
158.5
通讯作者：
Wolbers, Marcel
中科院分区：
文献类型：
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作者：
Thuy Le;Nguyen Van Kinh;Wolbers, Marcel
背景马尔尼菲踝节菌感染是南亚和东南亚人类免疫缺陷病毒（HIV）相关死亡的主要原因。指南建议初始治疗采用两性霉素 B 脱氧胆酸盐，但这种药物副作用大、成本高且可用性有限。伊曲康唑有口服形式，与两性霉素相比，不可接受的副作用较少，并且广泛用于代替两性霉素；然而，缺乏比较这两种治疗方法的临床试验。 方法在这项开放标签、非劣效性试验中，我们随机分配 440 名患有踝部真菌病（经显微镜或培养证实）的 HIV 感染成年人接受静脉注射两性霉素 B 脱氧胆酸盐（两性霉素）（219 名患者），剂量为每公斤体重 0.7 至 1.0 毫克。 日，或伊曲康唑胶囊（221名患者），剂量为每天600毫克，持续3天，然后每天400毫克，持续11天；此后，所有患者均接受伊曲康唑维持治疗。主要结局是第 2 周的全因死亡率。次要结局包括第 24 周的全因死亡率、踝部真菌病临床缓解的时间、早期杀菌活性、踝部真菌病复发、免疫重建炎症综合征 (IRIS) 的发生以及副作用。 结果 两性霉素组第 2 周的死亡风险为 6.5%，而对照组为 7.4%。 伊曲康唑组（绝对风险差异，0.9 个百分点；95% 置信区间 [CI]，-3.9 至 5.6；非劣效性 P < 0.001）；然而，两性霉素组和伊曲康唑组在第 24 周时的死亡风险分别为 11.3% 和 21.0%（绝对风险差异，9.7 个百分点；95% CI，2.8 至 16.6；P = 0.006）。与伊曲康唑相比，两性霉素治疗可显着加快临床缓解和真菌清除速度，并显着降低复发率和 IRIS。接受两性霉素治疗的患者输注相关反应、肾功能衰竭、低钾血症、低镁血症和贫血的发生率显着高于伊曲康唑组患者。 结论 两性霉素作为踝部真菌病初始治疗在 6 个月死亡率、临床反应和杀菌活性方面优于伊曲康唑。 （由医学研究委员会和其他机构资助；IVAP 当前对照试验编号，ISRCTN59144167。）
BACKGROUNDTalaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking.METHODSIn this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile.RESULTSThe risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P < 0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P = 0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group.CONCLUSIONSAmphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167.)