The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis
The efficacy of dihydroartemisinin-piperaquine and artemether-lumefantrine with and without primaquine on Plasmodium vivax recurrence: A systematic review and individual patient data meta-analysis
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DOI：
10.1371/journal.pmed.1002928
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发表时间：
2019-10-01
期刊：
影响因子：
15.8
通讯作者：
Price, Ric N.
中科院分区：
文献类型：
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作者：
Commons, Robert J.;Simpson, Julie A.;Price, Ric N.
作者摘要 为什么要做这项研究？在许多疟疾流行地区，对氯喹的敏感性正在下降。在新出现的氯喹耐药领域，推荐使用基于青蒿素的联合疗法（ACT）；然而，最佳的 ACT 尚不清楚。了解不同地区的比较优势和劣势将有助于指导国家政策制定者。研究人员做了什么并发现了什么？经过系统回顾，汇集了 2017 名患者的个人数据，这些数据来自 2000 年 1 月 1 日至 2018 年 1 月 31 日期间进行的 19 项研究。Cox 回归分析显示，与双氢青蒿素哌喹 (DP) 治疗相比，单独使用蒿甲醚-本芴醇 (AL) 治疗后第 42 天的复发风险是双氢青蒿素-哌喹 (DP) 治疗后的 12 倍，尽管到第 63 天时，DP 后的复发风险也增加了 12 倍。高。哌喹剂量每增加 5 毫克/公斤，第 42 天的复发风险就会下降 37%。症状复发时间的延迟与血红蛋白的增加有关。与伯氨喹联合用药可使 AL 后第 42 天的复发风险降低 80%，DP 后第 63 天的复发风险降低 92%。这些发现意味着什么？ AL 或 DP 后复发的风险很高，除非与伯氨喹合用。与 AL 相比，接受 DP 治疗的患者早期罹患 AL 的风险降低。复发。延迟复发时间与更好的血液学恢复有关，这有可能通过预防贫血的累积风险来预防与多次快速复发相关的发病率。 背景 在出现氯喹耐药性的地区，建议对无并发症的间日疟原虫疟疾采用基于青蒿素的联合疗法 (ACT)。我们进行了系统回顾和个体患者数据荟萃分析，以比较双氢青蒿素-哌喹 (DP) 和蒿甲醚-本芴醇 (AL) 联合或不联合伯氨喹 (PQ) 对间日疟原虫复发风险的疗效。方法和结果 2000 年 1 月 1 日至 2018 年 1 月 31 日期间发表的用 DP 或 AL 治疗的无并发症间日疟原虫的临床疗效研究是通过在国际前瞻性系统评价注册库 (PROSPERO) 注册的系统评价来确定的：CRD42016053310。合格研究的研究者被邀请提供使用标准化方法汇总的个体患者数据。根据先验分析计划，通过 Cox 回归分析研究了哌喹/苯芴醇的 mg/kg 剂量、ACT 给药和 PQ 对开始治疗后第 7 天至第 42 天之间间日疟原虫复发率的影响。次要结果是在第 28 天和第 63 天评估的复发风险。分析中纳入了 19 项研究，纳入了 2,017 名患者。与仅接受 DP 治疗的 812 名患者 (9.3%, 95% CI 7.1-12.2) 相比，仅接受 AL 治疗的 384 名患者在第 42 天时间日疟原虫复发的风险显着更高 (44.0%, 95% CI 38.7-49.8)：调整后风险比 (AHR) 12.63 (95% CI) 6.40-24.92)，p < 0.001。第 42 天和第 63 天评估的复发率与哌喹剂量成反比：每增加 5 mg/kg，AHR (95% CI) 分别增加 0.63 (0.48-0.84)，p = 0.0013 和 0.83 (0.73-0.94)，p = 0.0033。苯芴醇的剂量与复发率没有显着相关性（每增加 5 mg/kg，复发率增加 1.07，95% CI 0.99-1.16，p = 0.0869）。在事后分析中，在 AL 后有症状复发的患者中，复发每延迟 5 天，平均血红蛋白增加 0.13 g/dL (95% CI 0.01-0.26)，p = 0.0407。联合使用 PQ 显着降低了 AL 后第 42 天（AHR = 0.20，95% CI 0.10-0.41，p < 0.001）和 DP 后第 63 天（AHR = 0.08，95% CI 0.01-0.70，p = 0.0233）评估的复发率。结果受到患者随访时间为 63 天或更短以及非随机治疗组的限制。结论 在本研究中，我们观察到与 AL 相比，DP 治疗后第 42 天时间日疟原虫复发的风险显着降低，反映出治疗后预防的时间更长；通过与 PQ 联合用药可大大降低这种风险。我们发现，延迟间日疟原虫复发与血红蛋白的小幅但显着的改善有关。这些结果强调了 PQ 根治的好处，以及提供血液阶段抗疟药物和长期治疗后预防的好处。
Author summaryWhy was this study done? The susceptibility of to chloroquine is decreasing in many malaria-endemic locations. Artemisinin-based combination therapies (ACTs) are recommended in areas of emerging chloroquine resistance; however, the optimal ACT is not clear. Knowledge of the comparative advantages and disadvantages of different ACTs will help guide national policy makers. What did the researchers do and find? Following a systematic review, individual data from 2,017 patients were pooled from 19 studies undertaken between January 1, 2000, and January 31, 2018. Cox regression analysis showed that the risk of recurrence at day 42 was 12-fold greater following treatment with artemether-lumefantrine (AL) alone compared with dihydroartemisinin-piperaquine (DP), although by day 63 the risk of recurrence following DP was also high. For every 5-mg/kg increase in the dose of piperaquine, the risk of recurrence at day 42 fell by 37%. A delay in the time to symptomatic recurrence was associated with an increase in haemoglobin. Coadministration with primaquine reduced the risk of recurrence at day 42 after AL by 80% and at day 63 after DP by 92%. What do these findings mean? There is a high risk of recurrence following AL or DP unless they are combined with primaquine. Compared with AL, patients treated with DP have a reduced risk of early . recurrence. Delaying the time to recurrence was associated with greater haematological recovery, and this has potential to prevent morbidity related to multiple rapid recurrences by preventing a cumulative risk of anaemia.Background Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax. Methods and findings Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups. Conclusions In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis.