Uncovering why malaria drugs fail
Scientists focus on a Cambodian region where treatments lose their effect, reports Robin McKie
Pailin is a small settlement nestling in tropical rainforest near Cambodia’s border with Thailand. It is an unassuming town that lies at the centre of one of the country’s main logging areas. Pailin harbours secrets, however. It was in this town, in the late 1970s, that the Khmer Rouge set up one of its main strongholds and ruled Cambodia with a ferocity that caused at least 2 million deaths. It is a grim legacy, by any standards.
But Pailin has another unwanted claim to fame, one that is also associated with widespread death. The town, it transpires, lies at the heart of a region that has seen successive waves of resistance to malaria drugs arise in local people and then spread across the globe. The resulting death tolls can be measured in millions of lives, say scientists.
Just why malarial drug resistance has arisen here is not clear. Nevertheless, scientists are emphatic: the region has seen the creation of several mutations in malaria parasites that have allowed them to shrug off medicines that once protected humans. Even worse, they have discovered that a new wave of malarial drug resistance has recently appeared in this tiny area and has already spread into Thailand, Laos and Vietnam, and begun to move into Myanmar and travel towards India and Bangladesh.
“The problem is that we are pussyfooting around,” said Prof Sir Nicholas White, of the Mahidol Oxford Tropical Medicine Research Unit. “The World Health Organization (WHO) has not provided the necessary leadership. We need very firm direct action and at present we are not getting that.”
Resistance to major malaria drugs first appeared in the late 1950s when chloroquine – then a highly effective successful treatment for the disease – began to lose its efficacy. Crucially, this resistance first appeared in Pailin on the Cambodian-Thai border and then spread to Africa by the early 1980s. Several million deaths were added to the already grim toll of lives lost to the disease as a result.
Scientists have recently discovered once more that resistance to key malarial drugs – in this case, the artemisinins – has evolved – and in exactly the same place as before: the farms and village that surround Pailin. Just why this tiny region of southeast Asia has proved to be such a fertile zone for the emergence of deadly resistance to malarial medicine is not clear, a point stressed by Dominic Kwiatkowski, director of the centre for genomics and global health at Oxford University.
“We would love to know the answer, but it is not obvious,” Kwiatkowski said.
“One idea is that resistance keeps arising here for historical reasons. Maybe it has something to do with the way that malarial medicines are administered here. But how exactly?” In fact, this theory is just one of a great many other suggestions that have been put forward to explain why this resistance is appearing here first.
The local strain of malaria parasites may have some special properties, or the ecology of the region may have features that boost the rise of resistance. “The crucial point is that we need to do something about it and once we have, we need to monitor the situation very, very carefully,” said Kwiatkowski.
One factor that has recently become clear is that malarial drug resistance appeared very quickly in the region. Writing in Lancet Infectious Diseases in February, researchers from the Wellcome Sanger Institute and collaborators reported that resistance to combination therapies that included artemisinins arose almost as soon as the treatment was introduced as a first-line malarial drug. However, that this loss of efficacy was not spotted, for a variety of reasons, until several years had passed.
The implications of this failure were stressed by Ben Rolfe, head of the Asia Pacific Leaders Malaria Alliance. “On our watch, drug resistant strains have spread almost unnoticed,” he told the British journal BMJ recently. “As a result, we now risk a global resurgence of the disease.”
The question facing scientists – and heads of state and health leaders – is straightforward: what can be done? White is emphatic. “We have a window of opportunity but it is closing rapidly,” he said.
What is needed is a campaign, run with military efficiency, to use current drugs – while they still have some efficacy – not only on people who
already have malaria but on those individuals who have been infected but who have not succumbed or shown symptoms of the disease.
“These individuals carry small numbers of parasites and although they don’t get ill they are sources of new infections,” said White. “Mosquitos bite them, take their blood and spread it to others. They are the source of new infections.”
The plan, proposed by White and other scientists, is that everyone in a village in a malaria hotspot should be treated with anti-malarial drugs – regardless of their symptoms. “It is called mass drug administration. It is very controversial but it works – if it is done as part of a concerted strategy. If you do it badly you will only make the problem of resistance worse, so this has to be done right. But if we don’t do it we won’t be able to eliminate malaria quickly enough, and if resistance worsens it may become untreatable,” says White.
WHO officials say that the dangers posed by the new malaria superbug are exaggerated and that better prevention, monitoring and treatments will limit its spread from the Mekong region. Others are not so sure, however.
White said: “We are running out of time and unless we act rapidly, people will suffer and the people who will suffer most will be the children of Africa.”
Precaution ... Pailin province residents sleep under protective nets