Bob Taylor: Primaquine for vivax and falciparum malaria

My name is Bob Taylor and I’m a senior clinical research fellow at Oxford University but based here in Bangkok at the Mahidol Oxford Research Unit, also called MORU.

Primaquine is a useful drug for malaria elimination for two principal reasons. In patients who have vivax malaria, you have the vivax malaria in the blood which causes your illness: your fever your headache your chills, and we treat that with a drug that kills the vivax in the blood. But what’s clever about vivax is that it has a sleeping form that rests in the liver. The sleeping form in the liver is called hypnozoites and primaquine kills the hypnozoites. That’s how we can eliminate vivax malaria: we must eliminate the sleeping forms in the liver.

The other way that we can use primaquine is for falciparum malaria. The current thinking with using primaquine is for what’s called transmission blocking, that is blocking transmission from man or human to the mosquito. In the blood we have the malaria parasites that cause your illness, then as the malaria parasite is dividing in the blood male and female forms are developed and they’re called gametocytes, and the primaquine kills those gametocytes. You can imagine if you’re giving primaquine on a wide scale to people who have gametocytes at a community level, that should reduce the transmission within the community.

Now in terms of where we can use primaquine, the mathematical modellers are telling us that the best scenario for using primaquine to block the transmission for falciparum malaria is in areas like in Southeast Asia, where we’ve brought down the burden of malaria quite considerably and it’s in that scenario that primaquine gives us the maximum benefit.

How can we get around the idea of deploying these drugs on a wide scale? That is quite a challenge because at the moment primaquine is only available in certain tablet strengths, and that limits how you can give the drug easily, for example to children. One of the things that I’m studying is working out different tablet strengths for both vivax radical cure and also the transmission blocking, and ideally if we can come up with an age-based regimen for radical cure that would be quite helpful.

At the moment, taking primaquine requires that you take it for two weeks. The primaquine regimen that we’re developing, which won’t require testing for G6PD (glucose-6-phosphate dehydrogenase) deficiency, is actually 20 days long which is even longer. We know that the longer a treatment course is the less likely it is that patients will take their medicines. One study that I’m coordinating is called the IMPROV study where we give the dose of primaquine for 14 days, but we also give others a dose over 7 days, so double dose over a week; that’s being tested for effectiveness and also how well it’s tolerated. That is a good approach: if you can reduce from 14 to 7 days, and it works well and is tolerated by patients, then that’s good news.

This area is particularly 'plagued' is perhaps quite a strong word, but we have multi-drug resistant malaria in Southeast Asia such that the commonly used first line drugs, which are called artemisinin based combinations, are becoming increasingly ineffective in several countries in our region. The way to overcome that, now the thinking is that we should do two things: one is to develop triple antimalarial drug combinations where we use three drugs lumped together, a bit like treating tuberculosis. The other thing in parallel is to develop age-based dose regimens for transmission blocking in primaquine, because obviously if you dose by age it’s much easier compared to dosing by weight. I’m working on the age-based dose in primaquine for transmission blocking. We have a regimen that we’ve developed, on paper, but we need now to put it into practice in this region.

Why should you fund my research? That’s a very good question. The research that I’m doing in primaquine is very important because at the moment very few people are using primaquine. We want to get to a scenario where primaquine is used en masse in malaria endemic countries. In vivax malaria, although the burden is less compared to falciparum malaria, it causes huge morbidity, economic losses, people don’t go to work, they’re anaemic, they’re tired, kids don’t go to school; the burden of disease is very important. And if we can, for a small amount of money, come up with a dose regimen in primaquine, that doesn’t require testing for G6PD deficiency, that’s safe, that’s effective, it could have a massive impact on the vivax burden in the world.

The term translational medicine means different things to different people. One school of thought is going from the bench into humans, and the other, which is where I’m at the other end of the spectrum, is where you do a research in patients or humans and then you translate it into drug policy. For example if we manage to produce this wonderful regimen of primaquine, that is safe and doesn’t require G6PD testing, our work doesn’t stop there. We’ve now then got to make the enormous step to get it into drug policy in different countries around the world.

If this regimen is good and if we can convince the WHO that it’s good, and they can recommend it in their treatment guidelines, I think that would be an enormous step, because many malaria endemic countries listen to what the WHO says, so that would be an important step.