Counting Malaria Out: resistance is not futile (updated)
The trouble with drugs is they don’t last forever. Drug resistance is, to put it mildly, a problematic business for the malaria community. Once the drugs stop working effectively the mortality rates rise, along with recovery times and healthcare costs.
The first wave of antimalarial drug resistance was stemmed by the development of artemisinin-based combination therapies (ACT), now the first-line treatment for malaria. Artemisinins are the ‘Terminator’ of malaria drugs, killing a range of malaria parasite strains rapidly and without prejudice. Like the Terminator, they are adaptable, with a variety of delivery methods: as an ordinary pill, injection or a suppository. By taking them in combination with another medication they take less time to work (often in three days rather than the seven needed by artemisinin alone).
Combination therapies also help ward against drug resistance but, as you may have already learnt, artemisinin resistance is increasing. It started along the Thai-Cambodia border – the same place from which resistance to chloroquine, the previous frontline anti-malarial drug, emerged and spread back in the 1960s.
As Dr Shunmay Yeung from the London School of Hygiene and Tropical Medicine (LSHTM) explained at the Counting Out Malaria conference, the reasons why are partly to do with Western Cambodia itself. From a clinical standpoint, people from this region take longer to clear malaria from their systems. The biological reasons for that are still not entirely clear, but research has shown that this is a heritable trait.
From an environmental point of view, the area is perfect for the spread of malaria – and the development of resistance. Western Cambodia has suffered plenty of political turmoil in recent decades, leading to mass population movement and a weakened public health system. Like many other Asian countries, artemisinin has a long historical use as a traditional medicine, and the derivative artesunate is widely available. So it’s no surprise that the malaria parasite has had time and opportunity to develop a defence against the active ingredient.
On the other side of the border, Thailand has a relatively strong pubic health system, and cases of resistance consequently concentrate along the border with Cambodia. Both countries are trying to deal with this issue using a variety of solutions. In 2009, they launched a containment programme aiming to eliminate malaria through early detection and treatment and targeting mobile populations such as migrant workers. They are also employing a combination of ‘carrot and stick’ tactics, from banning the use of oral artemisinin monotherapies to piloting affordable medical facilities.
Political tensions between the two countries continue to pose a problem, but tackling drug resistance is vital if we are to avoid the pattern of 40 years ago – with chloroquine resistance spreading eventually to East Africa, then across the continent. Yeung warned that a lack of evidence for resistance does not mean there is not resistance.
However, she also pointed out there was a difference between tolerance and full-blown resistance, which offered some hope that all is not lost. ACT is still an extremely effective treatment. What we need are better diagnostic tools to help define and measure resistance and continued efforts to understand the development of drug tolerance and resistance, as well as new drugs to overcome them.
Substandard and fake
One of the factors contributing to drug resistance is the problem of substandard and counterfeit malaria drugs. Dr Paul Newton, a leading researcher in the field from the Wellcome Trust-Mahosot Hospital-Oxford Tropical Medicine Research Collaboration in Laos, called it “an under-appreciated Asian public health disaster”.
In his talk at the conference, Newton highlighted the importance of distinguishing between counterfeit goods (which are a deliberate attempt to mislead the consumer) and substandard goods (which are a problem with poor manufacturing). The results of both are equally terrible, but the tactics needed to deal with these are different, one involving the police and the other regulatory authorities.
At the top of the list of terrible consequences is death because the drugs don’t work against malaria or contain something toxic. Counterfeit artesunate has been found to contain a range of wrong ingredients, including metamizole (which causes bone marrow damage and is a banned drug in much of the EU), safrole (whose only use is in manufacturing of the illegal drug MDMA or ecstasy) and sildenafil (commonly known as Viagra) – most likely because the factories produce a variety of fake drugs leading to mixing of the ingredients.
There is also the risk of resistance building up, with many counterfeits found to contain traces of anti-malarials such as artesunate and chloroquine. But crucially, fake or substandard drugs cause people to lose faith in the medicine. Newton told the story of a village in East Burma who lost a young farmer to malaria in 2005 after he took, what turned out to be counterfeit artesunate. The villagers were so upset they gathered the artesunate in the village – real and fake – and burned it all.
According to Newton, recent reports of poor quality drugs have almost all been about anti-malarial drugs. Studies have estimated that 33–53 per cent of shop bought artesunate in South East Asia is counterfeit – one NGO reportedly bought 100,000 tablets in one shop that all turned out to be fake.
But things are looking up. Collaborative efforts between the Chinese government, INTERPOL, public health workers and researchers including Newton have helped to track down and arrest fake drug producers in Southern China.
These initiatives continue. An international task force, IMPACT, has been established to deal with the problem, and the researchers have established the Counterfeit Drug Forensic Investigation Network (CODFIN), a free forensic service using techniques to help analyse fake drugs and identify where they come from.
Perhaps more importantly, they are working on better ways to distinguish between genuine drugs and the fakes. The odd typo and fake hologram aside, you’d be hard pressed to tell the difference with the naked eye. A favourite game of Newton’s is to play a game of ‘Russian Roulette’ with European professors at conferences. He says 5 out of 6 pick the wrong drug – and if a drug expert can’t tell the difference, what chance a patient will?
It’s a constant arms race between the drug manufacturers and regulatory authorities and the counterfeiters. Some governments have taken to publically naming and shaming retailers that sell fake drugs, as Ghana did recently when fake Coartem (an ACT) was found. Yet the World Health Organization also estimates that 30 per cent of governments have substandard drug regulation or none at all.
Like drug resistance, it’s not an easy problem to solve, enmeshed in problems of drug accessibility, cost, drug prescription, patient adherence to the dosage regimen, poverty and regulation. But the co-ordinated international efforts currently underway provide hope of defeating both drug resistance and the problem of substandard and counterfeit drugs.
You can access audio recordings and slides from the conference talks at the LSHTM malaria website.