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Q&A Tropical medicine and artemisinin resistance in Thailand

last modified Apr 23, 2012 05:09 PM
Professor Nick Day is the Director of the Wellcome Trust major overseas programme in Thailand and Laos/The Mahidol Oxford Tropical Medical Research Unit. The unit has over 500 members of staff, and is largely geared towards clinical research. Nick is also a member of the Cambridge Infectious Diseases steering committee.

Q&AWhat led you to become interested in your area of research?

My parents were teachers who moved from tropical country to tropical country teaching, dragging my siblings and I with them; so I was always exposed to the tropics and, because I was interested in medicine, to tropical medicine. We learnt about malaria in school, which I probably wouldn’t have done in England. So from the age of about 12, I wanted to become a doctor, and to study tropical medicine.Nick Day, Director of the Wellcome Trust Major Overseas Programme in Thailand and Laos

The only way to work on tropical medicine for someone with a traditional UK medical background is to do research, or to join a missionary group and work in a mission hospital. So after my training in the UK, first at Cambridge and then in Oxford for my postgraduate biomedical training, I was lucky to be where there were already established research groups working in the tropics, and I talked to people who were involved, Professors. David Warrell and Nick White, and so moved to the major overseas programme based in Vietnam.

The best place to do research into severe malaria is a place with an enormous amount of severe malaria, very good facilities, and good trained staff, both doctors and nurses. Usually you have one without the other- a lot of malaria, but no capacity to study it, or wonderful facilities but no disease, but in Vietnam, there were both. We wanted to study this new Chinese herbal antimalarial ‘qinghaosu' or artemether and compare it to the standard treatment, quinine, in severe malaria to see whether it would save lives. We also did lots of other studies of other diseases, such as diphtheria, tetanus, typhoid. That was incredible experience: my boss (Prof. Nick White) who was based in Bangkok came over regularly to teach me, and the Vietnamese doctors, particularly Professor Tran Tinh Hien and Dr. Nguyen Hoan Phu who had an enormous wealth of clinical experience treating these tropical infections, worked with us and were able to teach me about tropical infections: how to diagnose and treat them. That convinced me that I wanted to make a full career in tropical medicine research. So in 1996 I went back to Oxford to complete my clinical training and at the same time did a Wellcome Trust fellowship in Staphylococcus aureus infection.

A slight change?

It was a change from malaria but we worked with other bacterial infections in Vietnam, and S. aureus is an important pathogen in the tropics. Although it’s not recognised as a tropical disease because it doesn’t only occur in the tropics, it is in fact more of a problem, since hygiene is not necessarily as good, and there is a lot of drug resistance. It’s also very difficult to treat in resource poor settings, because you don’t have expensive antibiotics such as vancomycin. In the beginning of 2003 I moved to Thailand, this time to take over the directorship of the Thailand Unit from Professor Nick White.

What’s the most exciting thing about your research at the moment?

The most exciting research we are doing at the moment is also the most worrying, and that again is around the artemisinin drugs. These drugs have over the last 20 years proved themselves to be the fastest acting and most valuable anti-malarials we have ever had: so much so that they are now recommend by the WHO to be first line treatment of malaria-both uncomplicated and severe malaria, around the world.

However, in the last 2-3 years in Cambodia/Thai border we have identified strains of P.falciparum which appear to be at least partially resistant to the artemisinins: parasite clearance rates are much slower than usual. If these resistant strains spread, particularly to Africa, then it will lead to a major public health disaster. There is historical precedent for this. For a number of reasons, South East Asia is the home to the most resistant malaria parasites in the world. Anti-malarial drug resistance generally starts in that region-somewhere along the Thai-Cambodian border. This occurred with chloroquine and with sulfadoxine and pyrimethamine, the two major anti-malarial drugs used over the past 50 years. When resistance to these drugs spread from South East Asia across to Africa, it led to literally millions of deaths. The same thing could happen again.

The main bit of research we’re doing at the moment is setting up a network of clinical studies to test the efficacy of artesunate (one of the artemisinins) in 13 sites across SE Asia and 2 in Africa as an early warning system. Unfortunately there is no test for artemisinin resistance- we don’t know yet know its molecular basis. Even if you isolate the parasite there is no in vitro test that can differentiate a resistant parasite from a sensitive one. The only way to tell whether malaria is resistant is to take patients with malaria, give them the drug, and then carefully follow the parasite counts and see whether the counts fall rapidly, as they should, or slowly, if resistant. There are some drugs in the pipeline but it is unclear whether any of them will be able to take centre stage. Some of the new drugs have the same mechanism of action as the artemisinins but are synthetic. If the resistance mechanism is active site specific then these types of drugs won’t work, but if it’s a pump that for example pumps the drug out of the cells, which is the mechanism of action of chloroquine resistance, then it may be very sensitive to the overall shape of the molecule. In that case a molecule with a different backbone but the same active site may be effective.

What are your thoughts on a malaria vaccine?

Vast amounts of money have been poured into malaria vaccine research over the past 50 years, and given how much money has been invested, the progress has been woeful. There is at least one vaccine under development which does work a little bit, but more work has to be done before it is deployable, and I think that it is unlikely we will have a vaccine in the next 10 years which will be deployable on a wide scale.

What do you see as the greatest challenges facing infectious disease researchers over the next 20 years?

I think that anti-malarial drug resistance is going to continue to be a problem and negating the impact of that is going to take an enormous amount of investment in research, new drugs, and other ways of controlling malaria. A great deal of news footage has been written in the last few years about the prospects of not just malaria control, but eradication: artemisinin resistance is a major threat to this. With the increased resources available from governments, and large funding organisations, we may well be able to get on top of P. falciparum malaria in many parts of the world. But then we have a new challenge, which is to get rid of P.vivax. Very little research has been done on P. vivax and it looks like it will more difficult to eliminate because unlike P.falciparum, P.vivax hides in the liver in the form of the hypnozoite, so that years later you can get relapses of vivax mArtemisia vulgaris L.alaria, and standard anti-malarial drugs don’t touch it.

There is also the risk of an emerging pandemic of an infectious disease, most likely viral infection, along the lines of a highly virulent form of influenza virus, or SARS. The risk of a pandemic which will kill hundreds of millions of people is high over the next couple of hundred years. But it is interesting that the factors that make us more vulnerable than we ever have been before to a pandemic of this type; plane travel, high density living, and constant interaction with other communities; for some infections, and this is probably true for influenza, may actually be protective. This is because you are unlikely to have areas of the world which have not been exposed to an evolving virus, whereas in the past there were areas in the world where the population had not seen certain strains. This may not work for something completely new, like SARS. Fortunately SARS, although it caused a lot of problems, wasn’t as good at spreading. Dealing with a problem like that is obviously going to be a challenge-we’re going to have to be prepared. I think with influenza there is always going to be resistance to investment in preparedness and there are already accusations against WHO and the vaccine producers after the 2009 H1N1 outbreak, that the whole thing was over blown- which I completely disagree with. They were in a no-win situation.

Anti microbial drug resistance will also always be a major theme. It is clearly going to continue to be a problem, and the development of new antibacterial/microbial drugs to keep up with resistance is going to be a huge challenge, because the business model in the pharmaceutical industry is such that it’s not an attractive option for pharmaceutical companies to be in that market. A lot of the solutions may well be innovative economic solutions/incentives to pharmaceutical companies. I think there is as big role academics could play. Clinical pharmacology for example is an incredibly important field, and something which has been neglected over the past 20 years or so in the UK. Clinical pharmacological studies have been left to pharmaceutical companies, while academic pharmacology departments tend have to have gone down the pharmacogenomics path, investing in molecular biology. There is very little we can do for patients with infectious diseases other than trying to prevent infection, give a vaccine if it’s available (it usually isn’t), and give an anti-infective drug if there is one available. Very often the dosing of the drug for example has been worked out by the pharmaceutical company, and for groups such as children and pregnant women, extrapolated from adults for one particular background, e.g. previously healthy Caucasian 25 year old men. Consequently it’s very easy to under-dose, and that has a knock on effect on drug resistance.

Maintaining levels of vaccination against the previously common childhood infections that we now no longer see as a problem is also a challenge. Very few doctors in the UK will ever have seen a case of diphtheria, but it’s a horrible disease, and our cultural memory of diseases like polio, tetanus, diphtheria is somewhat nostalgic, something associated with Edwardian/Victorian times. These diseases kill in a horrible way. Parents who decide not to vaccinate their children because vaccination is part of some medical conspiracy- the number of books about vaccination being a medical conspiracy is in itself a fascinating phenomenon-is of great importance to overcome. People are unable to weigh the risk properly- unafraid of diphtheria or measles because they don’t really know they can do, and don’t get seen frequently. In the 1990s there was a big outbreak of diphtheria in Russia, which because of low vaccination rates. I’ve seen a hundred or so cases and it’s a fascinating but horrible disease.

Who has influenced you most in your career?

Definitely the person who has influenced me the most is Prof. Nick White, my boss while I was working in Vietnam, and a close friend and mentor. He taught me the importance of clinical research, grounding your studies in clinical science. He also taught me that it’s okay to feel unfocussed when it comes to tropical medicine. There is so little research done in many tropical diseases, that in areas where there is very little research investment but a huge disease burden, it is better to study lots of diseases, and lots of aspects of disease particular to that population. We are always told by our funders that we should be more focused, and we always argue that as long as we assess the situation properly, we usually find that it’s best to have a broader programme of research.