Zhou Yihong, Qin Yuanyuan, Lu Yanqiu, Yuan Jing, Nie Jingmin, Liu Min, Tian Qun, Lan Ke, Zhou Guoqiang, Qin Yingmei, He Kaiyin, Yu Jianhua, Jiang Zhongsheng, Liu Jun, Liu Shuiqing, Harypursat Vijay, Chen Yaokai
Division of Infectious Diseases, Chongqing Public Health Medical Center, 109 Baoyu Road, Shapingba, Chongqing, 400036, China.
Division of Infectious Diseases, The Third People's Hospital of Guilin, Guangxi, China.
Infect Dis Ther. 2022 Aug;11(4):1575-1590. doi: 10.1007/s40121-022-00658-0. Epub 2022 Jun 11.
Current guidelines recommend amphotericin B as the preferred drug for induction therapy; however, amphotericin B is not available in certain settings. Induction therapy with amphotericin B deoxycholate or voriconazole has been shown to be an effective treatment for talaromycosis. However, prospective clinical trials comparing these two antifungal drugs are absent from the literature.
In this open-labeled, multicenter, prospective controlled trial, we enrolled patients at 15 hospitals in China from 2019 to 2020. Participants received induction treatment with either amphotericin B deoxycholate intravenously at a dose of 0.5 to 0.7 mg per kilogram per day or voriconazole at a dose of 6 mg/kg intravenously twice daily for the first day, followed by 4 mg/kg intravenously twice daily for 3 days, and then voriconazole was given either intravenously (4 mg/kg intravenously twice daily) or orally (200 mg twice daily) for the remaining 10 days. The primary outcome was all-cause mortality during 48 weeks after baseline. Secondary outcomes were mortality at week 2 or week 24, clinical resolution of talaromycosis, and fungal clearance at week 2. A propensity score (PS) matching analysis was performed to control confounding factors.
We observed no difference in the risk of death at week 2, at week 24, or at week 48 in either the unmatched cohort or the matched cohort. Both in the unmatched and the matched cohorts, logistic regression analysis revealed a significantly lower odds ratio of clinical resolution (OR 0.450, 95% CI 0.291-0.696, p < 0.001; OR 0.443, 95% CI 0.261-0.752, p = 0.003) and fungal clearance (OR 0.514, 95% CI 0.333-0.793, p = 0.003; OR 0.542, 95% CI 0.318-0.923, p = 0.024) in voriconazole users compared to amphotericin B deoxycholate users over the course of 2 weeks. In the induction therapy without ART subgroup patients in the amphotericin B deoxycholate group showed a significantly higher rate of clinical resolution and fungal clearance than those in the voriconazole group (56.1% vs. 30.4%, 95% CI 13.4-36.5, p = 0.000; 63.8% vs. 40.4%, 95% CI 11.1-34.7, p = 0.000), whereas there was no significant difference in clinical resolution and fungal clearance in the induction therapy combined with ART subgroup.
Induction therapy using voriconazole had a similar efficacy, in terms of all-cause mortality rate, to induction therapy using amphotericin B deoxycholate in HIV-infected patients with talaromycosis over a 48-week observation period. Amphotericin B deoxycholate contributed to earlier fungal clearance and earlier clinical resolution of symptoms in the induction therapy without ART subgroup, whereas amphotericin B deoxycholate use did not contribute to a significant difference in clinical resolution and fungal clearance in the induction therapy combination with ART subgroup.
ChiCTR1900021195. Registered 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .
当前指南推荐两性霉素B作为诱导治疗的首选药物；然而，在某些情况下无法获得两性霉素B。已证明使用两性霉素B脱氧胆酸盐或伏立康唑进行诱导治疗是治疗足分支霉病的有效方法。然而，文献中缺乏比较这两种抗真菌药物的前瞻性临床试验。
在这项开放标签、多中心、前瞻性对照试验中，我们于2019年至2020年在中国的15家医院招募患者。参与者接受诱导治疗，其中一组静脉注射两性霉素B脱氧胆酸盐，剂量为每日每千克0.5至0.7毫克；另一组接受伏立康唑治疗，首日静脉注射剂量为6毫克/千克，每日两次，随后3天为每日两次4毫克/千克，之后的10天伏立康唑改为静脉注射（每日两次4毫克/千克）或口服（每日两次200毫克）。主要结局是基线后48周内的全因死亡率。次要结局包括第2周或第24周的死亡率、足分支霉病的临床缓解情况以及第2周时真菌清除情况。进行倾向评分（PS）匹配分析以控制混杂因素。
在未匹配队列或匹配队列中，我们观察到第2周、第24周或第48周时死亡风险无差异。在未匹配和匹配队列中，逻辑回归分析均显示，与使用两性霉素B脱氧胆酸盐的患者相比，伏立康唑使用者在2周内临床缓解（比值比0.450，95%置信区间0.291 - 0.696，p < 0.001；比值比0.443，95%置信区间0.261 - 0.752，p = 0.003）和真菌清除（比值比0.514，95%置信区间0.333 - 0.793，p = 0.003；比值比0.542，95%置信区间0.318 - 0.923，p = 0.024）的比值比显著更低。在不联合抗逆转录病毒治疗（ART）的诱导治疗亚组中，两性霉素B脱氧胆酸盐组患者的临床缓解率和真菌清除率显著高于伏立康唑组（56.1%对3 .4%，95%置信区间13.4 - 36.5，p = 0.000；63.8%对40.4%，95%置信区间11.1 - 34.7，p = 0.000），而在联合ART的诱导治疗亚组中，临床缓解和真菌清除情况无显著差异。
在为期48周的观察期内，对于感染足分支霉病的HIV患者，使用伏立康唑进行诱导治疗在全因死亡率方面与使用两性霉素B脱氧胆酸盐进行诱导治疗的疗效相似。在不联合ART的诱导治疗亚组中，两性霉素B脱氧胆酸盐有助于更早清除真菌和更早实现症状的临床缓解，而在联合ART的诱导治疗亚组中，使用两性霉素B脱氧胆酸盐在临床缓解和真菌清除方面未产生显著差异。
ChiCTR1900021195。于2019年2月1日注册，http://www.chictr.org.cn/showproj.aspx?proj=35362 。
