Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial
Comparison of artemether-lumefantrine and chloroquine with and without primaquine for the treatment of Plasmodium vivax infection in Ethiopia: A randomized controlled trial
复制标题
DOI：
10.1371/journal.pmed.1002299
复制
发表时间：
2017-05-01
期刊：
影响因子：
15.8
通讯作者：
Price, Ric N.
中科院分区：
文献类型：
--
作者：
Abreha, Tesfay;Hwang, Jimee;Price, Ric N.
背景近年来在疟疾控制方面的努力在减轻恶性疟原虫负担方面取得了很大进展，但间日疟原虫的耐受性更强。它能够形成休眠的肝脏阶段，混淆了控制和消除的努力。为了比较伯氨喹治疗根治性肺炎的有效性和安全性，我们在埃塞俄比亚进行了一项随机对照试验。方法和结果：选择有症状的间日疟原虫感染患者，随机分为氯喹(CQ)和蒿甲醚-鲁米芬(AL)两组，分别给予氯喹(CQ)或蒿甲醚-鲁米芬(AL)，或联合用药14d(总剂量为3.5 mg/kg)。共对398例患者(CQ组104例，AL组100例，CQ+PQ组102例，AL+PQ组92例)进行为期1年的随访，复发患者的治疗与入选时分配的相同。主要终点是第28天和第42天间日疟原虫复发的风险。CQ+PQ治疗后第28天间日疟原虫复发的风险为4.0%(95%CI 1.5%~10.4%)，CQ+PQ治疗后为0%(95%CI 0%~4.0%)。单纯AL组和AL+PQ组的风险分别为12.0%(95%CI 6.8%~20.6%)和2.3%(95%CI 0.6%~9.0%)。在42天，CQ后的风险为18.7%(95%CI 12.2%~28.0%)，CQ+PQ后为1.2%(95%CI 0.2%~8.0%)，AL后为29.9%(95%CI 21.6%~40.5%)，AL+PQ后为5.9%(95%CI 2.4%~13.5%)(P<；0.001)。在那些没有开PQ处方的患者中，AL治疗后第42天复发的风险比CQ治疗更大(HR=1.8[95%CI1.0-3.2]；p=0.059)。随访结束时，CQ组间日疟的发病率为2.2次/人年，CQ+PQ组为0.4次/人年(比率比：5.1[95%CI 2.9~9.1]；P<；0.001)；AL组为2.3次/人年，AL+PQ组为0.5次/人年(比率比：6.4[95%CI 3.6~11.3]；P<；0.001)。两个治疗组之间的不良事件发生率没有差异。该研究的主要局限性是试验提前终止，42天后遗漏了血红蛋白测量，导致无法估计贫血的累积风险。结论尽管有证据表明间日疟原虫耐药，但除非与PQ监督疗程相结合，否则本研究中AL治疗后复发的风险更大。PQ联合CQ或AL耐受性良好，1年后间日疟疾复发率降低5倍。
BackgroundRecent efforts in malaria control have resulted in great gains in reducing the burden of Plasmodium falciparum, but P. vivax has been more refractory. Its ability to form dormant liver stages confounds control and elimination efforts. To compare the efficacy and safety of primaquine regimens for radical cure, we undertook a randomized controlled trial in Ethiopia.Methods and findingsPatients with normal glucose-6-phosphate dehydrogenase status with symptomatic P. vivax mono-infection were enrolled and randomly assigned to receive either chloroquine (CQ) or artemether-lumefantrine (AL), alone or in combination with 14 d of semi-supervised primaquine (PQ) (3.5 mg/kg total). A total of 398 patients (n = 104 in the CQ arm, n = 100 in the AL arm, n = 102 in the CQ+PQ arm, and n = 92 in the AL+PQ arm) were followed for 1 y, and recurrent episodes were treated with the same treatment allocated at enrolment. The primary endpoints were the risk of P. vivax recurrence at day 28 and at day 42.The risk of recurrent P. vivax infection at day 28 was 4.0% (95% CI 1.5%-10.4%) after CQ treatment and 0% (95% CI 0%-4.0%) after CQ+PQ. The corresponding risks were 12.0% (95% CI 6.8%-20.6%) following AL alone and 2.3% (95% CI 0.6%-9.0%) following AL+PQ. On day 42, the risk was 18.7% (95% CI 12.2%-28.0%) after CQ, 1.2% (95% CI 0.2%-8.0%) after CQ+PQ, 29.9% (95% CI 21.6%-40.5%) after AL, and 5.9% (95% CI 2.4%-13.5%) after AL+PQ (overall p < 0.001). In those not prescribed PQ, the risk of recurrence by day 42 appeared greater following AL treatment than CQ treatment (HR = 1.8 [95% CI 1.0-3.2]; p = 0.059). At the end of follow-up, the incidence rate of P. vivax was 2.2 episodes/person-year for patients treated with CQ compared to 0.4 for patients treated with CQ+PQ (rate ratio: 5.1 [95% CI 2.9-9.1]; p < 0.001) and 2.3 episodes/person-year for AL compared to 0.5 for AL+PQ (rate ratio: 6.4 [95% CI 3.6-11.3]; p < 0.001). There was no difference in the occurrence of adverse events between treatment arms.The main limitations of the study were the early termination of the trial and the omission of haemoglobin measurement after day 42, resulting in an inability to estimate the cumulative risk of anaemia.ConclusionsDespite evidence of CQ-resistant P. vivax, the risk of recurrence in this study was greater following treatment with AL unless it was combined with a supervised course of PQ. PQ combined with either CQ or AL was well tolerated and reduced recurrence of vivax malaria by 5-fold at 1 y.