Improving the radical cure of vivax malaria: A multicentre randomised comparison of short and long course primaquine regimens

间日疟原虫疟疾是亚洲、南美洲和非洲资源贫乏流行地区发病的一个主要原因，也是造成死亡的一个重要因素。间日疟疾的最大负担在南亚和东南亚，那里有28.5亿人面临风险，每年有1亿至3亿例间日疟疾病例。间日疟原虫引起反复发热性疾病，与贫血恶化有关，特别是在幼儿和孕妇中。严重贫血和低出生体重导致直接和间接死亡。尽管间日疟疾影响了大量人口，并造成了社会经济负担，但它一直是并将继续是一种被忽视的疾病；2007-2009年期间，用于防治间日疟的全球疟疾研发支出仅占疟疾总支出的3%。自20世纪50年代以来，氯喹一直是治疗急性间日疟疾的主要药物。然而，对氯喹的耐药性最初是在印度尼西亚的巴布亚报告的，现在有充分的证据表明，它在印度尼西亚群岛普遍存在，并已蔓延到流行间日疟的世界的大部分地区。与恶性疟原虫不同，间日疟原虫除了血液阶段外，还有肝脏阶段的寄生虫（称为催眠虫），能够在初次感染后数周甚至数月重新苏醒。彻底治疗间日疟疾需要使用抗疟疾药物，以根除寄生虫的血液和肝脏阶段。伯氨喹仍然是市场上唯一具有肝期活性的药物。然而，由于间日疟原虫的复发模式不同，需要长时间随访以捕捉晚期复发，因此难以确定对普氨喹耐药的效果。由于对其有效性和安全性的担忧，伯氨喹的广泛使用受到严重限制。伯氨喹可导致G6PD缺乏症患者溶血，G6PD缺乏症是一种遗传性疾病，在流行区5-35%的患者中发生。有一些现成的、负担得起的、可靠的诊断工具可以快速检测GPD缺乏症，因此临床医生通常不愿意开一种有潜在危害、疗效有限的治疗方法。目前推荐的14天治疗方案的依从性很差。该提案旨在提供关于使用伯氨喹的关键证据，这种药物越来越被认为是全球抗击疟疾的关键工具。我们假设，短疗程的高剂量伯氨喹方案将提供一种安全有效的抗复发治疗的实用方法。我们的随机安慰剂对照多中心试验将在5个亚洲国家比较两种不同的伯氨喹单独治疗精神分裂的方案。将在南亚（印度、巴基斯坦和阿富汗）和东南亚（越南和印度尼西亚）建立试验中心，南亚占所有病例的70%，间日疟复发间隔时间相对较长，而东南亚的两个地点（越南和印度尼西亚）的间日疟复发间隔时间较短，复发风险较大。主要目的是比较在7天或14天内给予相同总剂量的两种伯氨喹方案。符合纳入标准的纯间日疟患者将被随机分配接受以下三种治疗中的一种：方案1 -标准血液杀灭分裂疗法+ 14天的伯氨喹（总剂量为7mg/kg）。方案2 -标准血液杀菌治疗+ 7天的伯氨喹（7mg/kg总剂量）。方案3 -标准的杀菌疗法。伯氨喹的治疗将推迟到随访期结束。这是控制方案。治疗后，将对患者进行12个月的随访，以监测间日疟复发次数和贫血水平。间日疟疾的每次复发都将采用相同的分配方案进行治疗。

Plasmodium vivax malaria is a major cause of morbidity and an important contributor to mortality in poorly resourced endemic areas in Asia, South America and Africa. The greatest burden of vivax malaria is in South and Southeast Asia, where 2.85 billion people are at risk and experience 100 to 300 million cases of vivax malaria each year. Plasmodium vivax causes repetitive febrile illness associated with worsening anaemia particularly in young children and in pregnant women. Severe anaemia and low birth weight resulting in direct and indirect mortality. Despite the very large population affected by vivax malaria and its socioeconomic burden, it has been and continues to be a neglected disease; global malaria R&D spending on combating P. vivax amounted to just 3% of total spending on malaria between 2007-2009. Since the 1950s chloroquine has been the mainstay of treatment for acute vivax malaria. However resistance to chloroquine was first reported in Papua, Indonesia and there is now good evidence that it is prevalent across the Indonesian archipelago and has spread throughout much of the vivax endemic world. Unlike Plasmodium falciparum, P. vivax has in addition to the blood stage a liver stage of the parasite (known as hypnozoite) capable of reawakening weeks or even months after the primary infection. The complete treatment of vivax malaria requires administration of antimalarials to eradicate both the blood and liver stages of the parasite. Primaquine remains the only drug on the market for its liver stage activity. However the efficacy of primaquine resistance is difficult to determine due to variable relapsing patterns of P. vivax and the need for prolonged follow up to capture the late relapses. The widespread use of primaquine has been severely limited because of concerns regarding both its efficacy and safety. Primaquine causes haemolysis in patients with G6PD deficiency, an inherited disorder occurring in 5-35% of patients in endemic zones. There a few readily available, affordable and reliable diagnostic tools for the rapid testing of GPD deficiency, and thus clinicians often reluctant to prescribe a therapy that is potentially harmful with limited perceived benefit. When it is prescribed adherence to the currently recommended 14 day treatment regimen is poor. This proposal aims to provide critical evidence on the use of primaquine, a drug which is being increasingly recognised as a crucial tool in the global fight against malaria. We hypothesise that a shorter course high dose primaquine regimens will provide a practical approach to antirelapse therapy that is safe and effective. Our randomized placebo controlled multicentred trial will compare two different regimens of primaquine against schizontocidal treatment alone in 5 Asian countries. Trial centres will be established in South Asia (India, Pakistan and Afghanistan) where 70% of all cases occur and the interval between vivax relapses is relatively long, as well as two sites from South East Asia (Vietnam and Indonesia) where the interval between relapses is shorter and the risk of relapse greater.The primary objective will be to compare two primaquine regimens giving the same total dose primaquine over either 7 or 14 days. Patients presenting with pure vivax malaria, meeting the inclusion criteria will be randomly assigned to receive one of the following three treatments:Option 1 - Standard blood schizontocidal therapy + 14 days of supervised primaquine (7mg/kg total dose).Option 2 - Standard blood schizontocidal therapy + 7 days of supervised primaquine (7mg/kg total dose).Option 3 - Standard schizontocidal therapy. Treatment with primaquine will be deferred until the end of the follow up period. This is the control regimen.Following treatment, patients will be followed for 12 months to monitor the number of vivax recurrences and the level of anaemia. Each recurrence of vivax malaria will be treated with the same allocated regimens.