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

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.

We propose to accellerate the roll-out the radical cure for vivax malaria by demonstrating to the decision makers that radical cure with 7-day primaquine regimen not only benefits the individual patients but also makes an impact on vivax malaria transmission. We intend to demonstrate such an impact in a large cluster randomised trial in Cambodia, Laos, Vietnam, and Bangladesh. Intervention villages will be randomised to receive radical cure with the acute management of vivax malaria while the control villages receive only acute management, consistent with current national treatment guidelines. The development grant used to prepare for this demonstration project has three components: policymaker interviews, evaluation of the available G6PD tests, an assessment of acceptability and adherence of patients to radical cure using primaquine at the village level. We will ask policymakers regarding their views on the radical cure. To reach maximum effectiveness these regimens have to be rolled-out at village level. What evidence would policymakers need to support the roll-out of the radical cure at village level? Second, diagnostic test options to assess G6PD activity have rapidly expanded over the last years. We expect that at least one accurate biosensor will be available for field testing by the middle of 2019. We will compare the use of a biosensor in a field setting with a fluorescent spot test and the gold standard, spectrophotometry. Third, we will assess the acceptability by the village health workers and patient adherence to the primaquine regimen in the management of vivax patients. We will assess the feasibility and adherence to the primaquine regimen in 80 patients with uncomplicated vivax malaria with normal G6PD activity. Village health workers will administer the schizontocidal therapy and the primaquine regimens. Adherence will be assessed by self-reporting/interviews, drug counts and day 7 drug concentrations (primaquine and carboxyprimaquine).

The immediate result will be an application for funding for a large cluster-randomised trial to assess the effectiveness and impact of transmission of the radical cure with a primaquine regimen.
The proposed studies will inform key aspect of the future demonstration project including the acceptability and adherence to the primaquine regimen for radical cure of vivax malaria and the most appropriate point-of-care G6PD test for use at the village level. By including policymakers in the early stages of the planning and design of the trial we expect a meaningful exchange with policymakers throughout the trial and ultimately to provide the evidence needed to include the radical cure in national treatment guidelines. Furthermore, the proposed roll-out will create a platform for the future replacement of primaquine with tafenoquine which requires only a single dose. Tafenoquine has recently been approved by the US-FDA and licensed in Australia. Yet, more experience will be needed to roll-out tafenoquine at the village levels, specifically in children who have been excluded from earlier trials and women in whom G6PD deficiency can be difficult to diagnose.