尽管历史上有较差的耐受性,目前还缺乏关于抗利什曼钠化疗安全性的全面审查.我们对1980年至2019年所有已发表的内脏利什曼病(VL)临床试验进行了更新,以记录任何报告的严重不良事件(SAE)。
对于此更新的系统评价,我们从2016年1月1日至2019年5月2日搜索了以下数据库:PUBMED,Embase,Scopus,WebofScience,科克伦,clinicaltrials.gov,世卫组织ICTRP,和全球指数Medicus。我们纳入了随机和非随机介入研究,旨在评估治疗效果,并提取了治疗开始前30天内报告的SAE数量。使用随机效应Poisson回归进行荟萃分析,将各个治疗组的死亡率(IRD)进行组合。
我们确定了157项已发表的研究,在347个治疗组中招募了35,376名患者。在74(21.3%)中施用了五价锑,多剂量脂质体两性霉素B(L-AmB)在52(15.0%),两性霉素b脱氧胆酸51(14.7%),米替福辛33人(9.5%),两性霉素B脂肪/脂质/胶体/胆固醇31(8.9%),和单剂量L-AmB在17(4.9%)组中。总共有804例SAE报告,其中793例(包括428例死亡)在研究组水平被提取(11例SAE仅在研究水平被报告)。在最初的30天,有285例(66.6%)死亡,总IRD估计为0.068[95%置信区间(CI):0.041-0.114;I2=81.4%;95%预测区间(PI):0.001-2.779]在东非,风险为0.628[95%CI:0.368-1.021;I2=82.5%],和0.041[95%CI:0.021-0.081;I2=68.1%]在印度次大陆。在明确表明允许纳入HIV共感染患者的21个研究组中,IRD为0.575[95%CI:0.244-1.355;I2=91.9%],而在排除HIV共感染的160个组中,IRD为0.043[95%CI:0.020-0.090;I2=62.5%]。
开始VL治疗的前30天内的死亡率是临床试验中很少报道的事件,总体估计死亡率为每1000人天有风险的0.068例。尽管它因地区和患者人群而异。这些估计可以作为未来试验的基准,可以与前瞻性和药物警戒研究的死亡率数据进行比较。我们的综述暴露的方法学局限性支持需要收集个体患者数据(IPD)以进行可靠的IPD荟萃分析,并从现有试验中产生更强有力的证据来支持治疗指南和指导未来的研究。
Despite a historical association with poor tolerability, a comprehensive
review on safety of antileishmanial chemotherapies is lacking. We carried out an update of a previous systematic
review of all published clinical trials in visceral leishmaniasis (VL) from 1980 to 2019 to document any reported serious adverse events (SAEs).
For this updated systematic
review, we searched the following databases from 1st Jan 2016 through 2nd of May 2019: PUBMED, Embase, Scopus, Web of Science, Cochrane, clinicaltrials.gov, WHO ICTRP, and the Global Index Medicus. We included randomised and non-randomised interventional studies aimed at assessing therapeutic efficacy and extracted the number of SAEs reported within the first 30 days of treatment initiation. The incidence rate of death (IRD) from individual treatment arms were combined in a meta-analysis using random effects Poisson regression.
We identified 157 published studies enrolling 35,376 patients in 347 treatment arms. Pentavalent antimony was administered in 74 (21.3%), multiple-dose liposomal amphotericin B (L-AmB) in 52 (15.0%), amphotericin b deoxycholate in 51 (14.7%), miltefosine in 33 (9.5%), amphotericin b fat/lipid/colloid/cholesterol in 31 (8.9%), and single-dose L-AmB in 17 (4.9%) arms. There was a total of 804 SAEs reported of which 793 (including 428 deaths) were extracted at study arm level (11 SAEs were reported at study level only). During the first 30 days, there were 285 (66.6%) deaths with the overall IRD estimated at 0.068 [95% confidence interval (CI): 0.041-0.114; I2 = 81.4%; 95% prediction interval (PI): 0.001-2.779] per 1,000 person-days at risk; the rate was 0.628 [95% CI: 0.368-1.021; I2 = 82.5%] in Eastern Africa, and 0.041 [95% CI: 0.021-0.081; I2 = 68.1%] in the Indian Subcontinent. In 21 study arms which clearly indicated allowing the inclusion of patients with HIV co-infections the IRD was 0.575 [95% CI: 0.244-1.355; I2 = 91.9%] compared to 0.043 [95% CI: 0.020-0.090; I2 = 62.5%] in 160 arms which excluded HIV co-infections.
Mortality within the first 30 days of VL treatment initiation was a rarely reported event in clinical trials with an overall estimated rate of 0.068 deaths per 1,000 person-days at risk, though it varied across regions and patient populations. These estimates may serve as a benchmark for future trials against which mortality data from prospective and pharmacovigilance studies can be compared. The methodological limitations exposed by our
review support the need to assemble individual patient data (IPD) to conduct robust IPD meta-analyses and generate stronger evidence from existing trials to support treatment guidelines and guide future research.