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用伯氨喹根治间日疟疾需要做些什么？如果没有根治，一半以上的间日疟疾患者会出现一次或多次反复复发。疟疾复发不仅会造成痛苦、失去收入和痛苦，而且复发的疟疾患者也具有传染性，并助长间日疟疾的持续传播。间日疟疾的复发可以通过使用包括伯氨喹在内的药物方案来预防。这些药物治疗方案没有得到充分利用，因为它们可能会引发先天性酶缺陷（G6PD）患者的溶血（红细胞破裂），这种情况可能严重到需要输血。两项重要进展使现在更容易对间日疟疾进行根治。首先，几家公司已经开发出即时精密设备（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患者，并将其排除在伯氨喹治疗之外。其次，最近的一项研究表明，7天的伯氨喹治疗方案与传统的14天药物治疗方案在清除间日疟疾方面一样安全有效。我们认为患者完成7天疗程的可能性大于完成14天疗程的可能性。这两项进展，生物传感器和7天伯氨喹方案，应该会导致广泛采用伯氨喹根治。然而，许多卫生保健提供者和政策制定者（制定卫生保健提供者遵循的指导方针）没有意识到这些最近的发展。此外，现有的证据可能无法说服他们。说服他们的一种方法可能是开始讨论大规模示范试验的准备工作和最终结果。我们正在计划进行一项大型试验，让选定村庄的所有间日疟患者接受伯氨喹治疗方案。根据目前的国家指南，我们将比较常规使用伯氨喹根治的村庄的间日疟疾发病率与不使用伯氨喹的村庄的间日疟疾发病率。我们期望G6PD缺乏症患者能够在护理点被可靠地检测出来并被排除在外，期望G6PD正常患者能够很好地耐受普氨喹治疗方案，期望通过根治性治疗持续治疗间日疟病例将减少并最终停止间日疟的传播。示范试验是一项重大任务，关键取决于选择合适的G6PD测试、正确的伯氨喹方案、拟议研究团体和决策者的同意。为了确保条件是有希望的，我们在这里提议提供一笔发展赠款。我们计划将拨款用作多学科的预备研究。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相关者，了解他们对推出根治性治疗的看法，以及哪些证据能说服他们支持推出。2)我们将现有的G6PD生物传感器与传统的标准检测方法在酶缺乏症诊断中的性能进行比较，选择性能最好的、可被村卫生员可靠、可行地使用的生物传感器。村里的卫生工作者已经使用快速诊断测试来诊断间日疟疾患者。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野外条件下有用。我们将探讨卫生工作者和患者在村一级对伯氨喹治疗方案的接受程度。4)我们将寻找最合适的试验地点。在研究结束时，我们希望积累足够的知识，以便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.