Nick White is fighting criminal drug dealers as well as malaria parasites, says Oliver Tickell.
'I honestly love medicine - it's my hobby and I am really passionate about it', says Nick White, Professor of Tropical Medicine at Oxford, explaining why he chooses to spend his month-long annual holiday working unpaid 60-hour weeks at the John Radcliffe hospital as a consultant in internal medicine. 'If you get sick today, it's me you'll be seeing', he adds with a narrow smile, setting off on a ward round.
In his real job, he works to save the lives not of individual patients, but of humanity in its millions: his main focus is malaria, which kills more than a million people a year in sub-Saharan Africa alone. 'After the Second World War we thought we could eradicate malaria, and we did eradicate it from the temperate regions but we failed in the tropics. It came back during the 1970s, '80s and '90s, fuelled by resistance to drugs like chloroquine which had been both cheap and highly effective when first introduced.'
Professor White lives in Bangkok, Thailand, and works at the Mahidol University Faculty for Tropical Medicine as chairman of the Oxford University-based Wellcome Trust Southeast Asian Units (OUWTSAU), a major multinational research programme into serious tropical diseases. The region suffers from highly drug-resistant strains of malaria, and nowhere more so than on the Thai-Burma border, a region deeply affected by the Burmese government's genocidal war against the Karen and other tribal peoples.
By the late 1960s, the malaria parasite Plasmodium falciparum was already becoming resistant to chloroquine, and Chinese medical researchers embarked on an assessment of hundreds of herbs traditionally used as anti-malarials. By far the best to emerge was the wormwood Artemisia annua, and in 1972 Chinese scientists discovered the active ingredient, artemisinin. Information about artemisinin was only published some ten years later in Chinese medical journals, and even then few details emerged, forcing non-Chinese researchers to start their investigations into A. annua and artemisinin from scratch.
Seminal research carried out by OUWTSAU demonstrated the extraordinary effectiveness of artemisinin and its more powerful derivative, artesunate, across Southeast Asia, including areas where resistance to chloroquine was strongest. They went on the develop 'Artemisinin-based Combination Therapy' (ACT): formulations of artesunate together with other anti-malarial agents with different modes of operation. ACT is now recommended by the World Health Organisation as the preferred treatment for malaria worldwide, and artesunate given by injection is increasingly accepted as the best treatment for the deadly 'cerebral' malaria.
'The artemisinin derivatives are fantastic', says White. 'They are rapidly effective, well tolerated, and they reduce the mortality of severe falciparum malaria by 35 per cent.' But in the late 1990s, reports arrived from Cambodia of patients failing to respond to these drugs - an unexpected and extremely worrying development for such a new and promising drug class. Paul Newton, who heads the OUWTSAU programme in Laos, discovered the cause of the problem: counterfeit drugs. His study, published in The Lancet in 2002, found that 38 per cent of artesunate tablets sampled across Southeast Asia were fake, manufactured and distributed for profit by unscrupulous traders and powerful criminal gangs. The artesunate was an especially attractive target due to its high demand and its relatively high cost - twenty times that of chloroquine, at about two dollars for a course of treatment.
'The fakes are remarkably sophisticated, with blister packaging indistinguishable from the original', says White. 'We have so far tracked ten separate generations of fake holograms, and they are getting so good that you need a microscope to recognise the genuine hologram, and even then it is difficult. Meanwhile, people out there are dying needlessly as there is no active ingredient. It is appalling - the only word for it is murder.'
The source of the counterfeits has so far proved elusive. However, one recent success was the development, by Mike Green of the Centers for Disease Control (CDC) in Atlanta, Georgia, of a simple colorimetric test to recognise the difference between the genuine and the fake drugs. A mix of reagents turns bright yellow on exposure to tiny scrapings from a genuine artesunate tablet. But this has now given rise to a new problem. 'In response to the test - maybe - the fakers have started to put small amounts of artesunate into the fake pills, so they can pass the test even though they do not contain enough to be effective', says White. Moreover, he warns, the low doses of artesunate could select for artesunate resistance among malaria parasites exposed to toxic but non-lethal levels of the drug.
Another problem is the widespread use of 'monotherapy' artesunate tablets, which contain effective doses of artesunate but none of the other anti-malarials present in ACT tablets. ACT is based on the successful approach adopted for AIDS and tuberculosis, designed to increase the short-term effectiveness of the drugs (it reduces treatment time from seven days to three) and in the longer term to limit the development of resistance. Even if some resistance is present to one drug in the mix, the others will still kill the pathogen and so prevent the resistance from developing. Monotherapy gives the pathogens a far better chance of acquiring resistance, as has already happened with chloroquine.
In the case of artesunate, says White, that would be a tragedy. 'Artesunate gives us an opportunity to eradicate malaria worldwide, just as we once had the same opportunity with chloroquine. We must seize it or the danger is that it will be squandered, that resistance to the artesunate will establish and spread, and millions upon millions of people will die needlessly all because the world chose to sit back and let it happen.' He strongly supports the revolutionary 2004 report of the US National Academy of Sciences, 'Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance', based on the findings of an Institute of Medicine (IOM) committee on malaria chaired by Stanford's Kenneth Arrow, Nobel Laureate in Economics, and with himself and Oxford epidemiologist Richard Peto among the members.
'The key finding is that the entire cost of making ACT drugs should be financed by international institutions at a cost of US$300-500 million a year', says White. 'Another $500 million or so would be needed for other measures such as insecticidal mosquito nets, as well as further research and monitoring - so that if resistance to any of the ACT drugs emerges, the therapy can be quickly reformulated in that area. The entire programme to eradicate malaria over ten years or so would cost approximately $1 billion a year - roughly the cost of ten F35 fighters. And it is not just doctors calling for this, but economists too: malaria costs Africa's economy $12 billion a year in lost production so the investment makes excellent economic sense as well as saving lives.'
Key to the programme is that the ACT drugs should be provided free to both public sector and private sector, recognising the essential role of private sector pharmacies in poor countries in penetrating well beyond the reach of state health provision. Another component is stimulating increased Artemisia production, by guaranteeing prices to farmers for some years ahead, since approximately 200 square kilometres of Artemisia will need to be under cultivation to produce the required 500 million treatments a year. The eventual aim is is to bring the retail cost of ACT down to that of chloroquine, at about 10¢ per treatment, reflecting distribution costs. 'One result of this approach is that it would solve the counterfeit drugs problem at a stroke by removing the profit from the criminal trade, and undercut the monotherapy drugs which threaten to create resistance', says White.
However, he is sceptical as to the ability of international development institutions to carry out such a policy. The World Bank, for example, recently funded the distribution of hundreds of millions of chloroquine tablets in Africa and India although the drug is considered clinically obsolete. This provoked accusations in The Lancet in April 2006 that the Bank had 'wasted money and lives on ineffective medicines', falsified statistics to exaggerate the effectiveness of their programmes, and engaged in false accounting to claim an increase in anti-malaria spending, while funding was actually being cut.
'You have international agencies with loads of money who make internal decisions with little scientific or medical expertise and no scrutiny', complains White. 'These awful things can happen because the victims have no voice - you will not see the mothers of children who have died of malaria protesting outside Congress in Washington DC or the Houses of Parliament in London! But fortunately there have been positive developments - the World Health Organisation is finally on board with ACT and that does offer some hope for the future.'
Oliver Tickell is a freelance writer living in Oxford.