Charlie Woodrow: Artemisinin Resistance
Artemisinins are very poweful tools in the treatment of malaria, and the emerging loss of their activity has the potential to create a major public health problem. Understanding how this resistance has developed and spread helps better treat patients, treat populations and eliminate malaria, which is the new goal in South East Asia.
Q: Why is artemisinin resistance a problem?
Charlie Woodrow: I think artemisinins are a one-off drug. They are the most effective, most rapidly acting antimalarial that we have. They are very safe and well tolerated, so losing them is a major problem. Artemisinins are used in all antimalarial treatments for the main form of malaria which we see around the world, falciparum malaria. They are used in combination with a partner drug but all treatments should contain an artemisinin. Once we start to lose that activity, which is what we see in resistance, we have major problems both in treating individual patients and in controlling malaria as a public health problem.
Q: How is artemisinin resistance developed?
CW: That is a classic example of evolution: when you treat a patient with malaria and you do not kill all the parasites, the survivors are more likely to be resistant to artemisinin. The reasons why this might happen relate to why treatment might fail. Patients who do not complete their courses, patients who have just taken artemisinin without this partner drug that we need as well, and there is also a problem with fake or sub-standard antimalarials which do not contain enough of the compound.
The other big factor is the immune system. We tend to see artemisinin resistance appearing in areas where patients have low immunity, in what we call low transmission settings, so that is outside Africa. Resistance has generally tended to appear in South East Asia or South America. For artemisinins it has been South East Asia because the drug has been made in China for much of its life span. The local availability of artemisinins has been high so eventually because of evolution we see resistance developing.
Q: How can we counter these resistance strains?
CW: The simple thing is to give treatments correctly: to make sure when we are giving these artemisinin combination therapies, patients are completing the courses and that their infections are being cured. We can choose the partner drug that is used in combination with the artemisinin carefully to make sure that there is still efficacy for the partner drug (that are slower acting antimalarials like mefloquine or lumefantrine). Then in the future we have to think of other alternatives. When we look at infections like HIV and TB, we would also treat those with three drugs and that is a possibility for the future of malaria, although difficult to achieve in reality. Beyond that: new drugs, but there are very few available at the moment.
Q: What are the most important areas of research which have developed over the last 5-10 years?
CW: The main area of research in this field has been the documentation of artemisinin resistance in the field. There was theoretical discussion about this before but it is quite clear that there is artemisinin resistance in the ring-stage of the parasite (that is a certain subset of the life cycle) that has developed across a wide area of South East Asia.
Then more importantly in the last couple of years we have understood this form of resistance and we are beginning to understand in biological detail what the mechanism is, and that is important for several reasons. The first one is to convince everyone that it is major problem. If you can say this mutation in a particular gene happens with artemisinin resistance then it is much easier than the more conceptual idea that some parasites don’t respond so well in people. Then understanding the mechanism, which in simple terms is a mutation in a particular protein which is called Kelch 13 protein, then allows us to study where resistance has spread to, using quite simple techniques.
Q: Why does your line of research matter and why should we fund it?
CW: Understanding artemisinin resistance both in terms of how far it has spread across South East Asia at the moment, and what the mechanism is, is fundamental to understanding how to treat patients, how to treat populations and how to eliminate malaria, which is a new goal that has been promoted by funding bodies and governments across the region. I think the main issue is how do we manage malaria over the next 20-30 years if we don’t understand why parasites respond well or poorly to artemisinins? That is going to be very hard.
Q: How does your research fit into translational medicine within the department?
CW: I think continuing on that idea of elimination, which is the new goal for control of malaria in South East Asia, and having the means to be able to look at how artemisinins are operating in remote areas, is the biggest advance in the last year. We can take some blood that has been stored on a piece of paper and bring it to a central lab, and using a fairly simple forensic technique which is the polymerase chain reaction (PCR), we can actually determine where parasites from rather remote areas - for example in Myanmar, where some areas are very difficult to access with normal clinical studies - are resistant to artemisinins. I think that is having a big effect in terms of control programmes, in choosing how they treat Malaria. We are also seeing lots of effects in terms of how people do science. We work with students and researchers from areas in Myanmar and in other emerging countries in terms of economies, and they are now able to understand what is happening in their country, in a way that was just not possible two or three years ago.
This interview was recorded in June 2015.