Roll out the radical cure with primaquine for vivax elimination: development grant

在柬埔寨、老挝、越南和孟加拉国推广间日疟的伯氨喹根治方案需要什么？如果不彻底治愈，一半以上的间日疟患者会反复复发一次或多次。复发不仅造成痛苦、收入损失和苦难，而且复发疟疾患者也具有传染性，有助于间日疟的继续传播。间日疟的复发可以通过包括伯氨喹在内的药物疗法来预防。这些药物方案未得到充分利用，因为它们可能会引发酶（G6PD）先天性缺陷的人的溶血（红细胞破裂），这可能严重到需要输血。两项重要的进展使根治间日疟变得更加容易。首先，几家公司已经开发了即时检测的复杂设备（生物传感器）来测量G6PD酶的活性。使用生物传感器，卫生保健提供者可以检测出酶缺乏症的患者，并将他们排除在伯氨喹治疗之外。其次，最近的一项研究表明，7天伯氨喹方案与传统的14天药物方案一样安全，在清除间日疟方面也一样好。我们认为患者更有可能完成7天的疗程而不是14天的疗程。这两个发展，生物传感器和7天伯氨喹方案，应导致广泛采用的根治与伯氨喹。然而，许多卫生保健提供者和政策制定者（他们制定卫生保健提供者遵循的指南）并没有意识到这些最新的发展。此外，现有的证据可能无法说服他们。说服他们的一个方法可能是开始讨论准备工作和大型示范试验的最终结果。我们正在计划一项大型试验，在选定的村庄中，所有间日疟患者都接受伯氨喹治疗。我们将根据现行的国家指导方针，比较在常规使用伯氨喹根治的村庄中间日疟的发病率与在未使用伯氨喹的村庄中间日疟的发病率。我们期望G6PD缺乏症患者能够在护理点被可靠地检测到并排除，伯氨喹方案在G6PD正常患者中耐受良好，并且持续治疗间日疟病例的根治性治疗将减少并最终阻止间日疟的传播。示范试验是一项重大任务，关键取决于选择适当的G6PD测试，正确的伯氨喹方案，拟议的研究社区和政策制定者的协议。为了确保条件有希望，我们在此提议提供发展赠款。我们正计划利用这笔赠款进行一项多学科的预备研究。拟议研究的三个主要组成部分是：1）采访相关政策制定者和利益攸关方，了解他们对推出根治措施的看法，以及哪些证据可以说服他们支持推出。2)我们将比较现有的G6PD生物传感器的性能与传统的标准测试的酶缺乏症的诊断，并选择性能最好的生物传感器，可以可靠和可行的村卫生工作者使用。村卫生工作者已经使用快速诊断测试来诊断间日疟患者。此外，他们将使用生物传感器诊断G6PD缺乏症，以确保生物传感器在现场条件下有帮助。我们将探索在村庄一级，卫生工作者和病人对伯氨喹方案的可接受性。4）我们将找到最合适的试验地点。在研究结束时，我们希望积累足够的知识，在我们的目标国家进行大规模的示范试验。

What does it take to roll-out radical cure with primaquine regimens of vivax malaria in Cambodia, Laos, Vietnam, and Bangladesh? Without radical cure more than half of all patients with vivax malaria suffer one or often many repeated relapses. Not only does relapse cause suffering, loss of income and misery, people with relapsing malaria are also infectious and contribute to the continued transmission of vivax malaria. Vivax malaria relapse can be prevented by the administration of drug regimens which include primaquine. These drug regimens are underused because they can potentially trigger hemolysis (rupturing of red blood cells) in people with an inborn error in an enzyme (G6PD), which can be severe enough to require blood transfusions. Two important developments make it now easier to administer radical cure for vivax malaria. First, several companies have developed point-of-care sophisticated devices (biosensors) to measure G6PD enzyme activity. Using biosensors health care providers can detect patients with an enzyme deficiency and exclude them from treatment with primaquine. Second, a recent study has shown that a 7-day primaquine regimen is as safe and as good at clearing vivax malaria as the traditional 14-day drug regimen. We think that patients are more likely to complete a 7-day course than a 14-day course. These two developments, biosensors and 7-day primaquine regimens, should lead to the widespread uptake of radical cure with primaquine. However, many health care providers and the policymakers (who make the guidelines health care providers follow) are not aware of these recent developments. Furthermore, the currently available evidence may not convince them. One way to convince them may be to start discussions on the preparation and eventual results from large demonstration trials. We are planning a large trial in which all vivax patients in selected villages receive a primaquine regimen. We will compare the incidence of vivax malaria in villages where primaquine radical cure is routinely used with the incidence of vivax malaria in villages where primaquine is not used, according to current national guidelines. We expect that people with G6PD deficiency can be reliably detected at the point of care and excluded, that the primaquine regimens are well tolerated in G6PD-normal patients and that continuous treatment of vivax cases with radical cure will reduce and eventually stop the transmission of vivax malaria. The demonstration trial is a major undertaking and critically depends on the choice of an appropriate G6PD test, the right primaquine regimen, the agreement of the proposed study community and the policy makers. To make sure the conditions are promising we are proposing here the funding of a development grant. We are planning to use the grant for a multidisciplinary preparatory study. The three main component of the proposed study are: 1) To interview relevant policymakers and stakeholders on what they think of the roll-out of the radical cure and what evidence would convince them to support the roll-out. 2) We will compare the performance of the available G6PD biosensors with the traditional standard tests in the diagnosis of the enzyme deficiency and select the best-performing biosensors that can be reliably and feasibly used by village health workers. The village health workers already diagnose patients with vivax malaria using rapid diagnostic test. In addition, they will diagnose G6PD deficiency using the biosensors to make sure that biosensors are helpful in field conditions.3. We will explore which is the acceptability by health workers and patient adherence to the primaquine regimen at the village level.4) We will find out the most appropriate sites for the trial.At the end of the study we expect to have accumulated enough knowledge to undertake a large demonstration trial in our target countries.