Artemisinin Resistance?

Oct. 28, 2013, 6:58 p.m.

Is the effectiveness of the artemisinin drug family in fighting malaria waning? Has the malaria parasite started to develop resistance? Clear answers are yet to emerge but there is growing concern that the parasites may have started developing processes that may one day make them fully resistant to artemisinins.
In a live chat session on the network in July the discussion addressed recently observed changes in the effectiveness of malaria drugs in Cambodia and neighbouring countries. The artemisinin drug family, mainstay of current combination treatment worldwide, causes rapid reduction in the number of malaria parasites in a patient's bloodstream, such that within 48 hours of initiation of treatment almost all have a completely clear blood film under the microscope. In Cambodia however, since 2009, researchers have documented increasing number of patients with slow clearing parasites, still visible under the microscope at 72 hours and beyond.
Whereas some have already labelled this phenomenon 'resistance' there is as yet little evidence of a negative effect on public health: the combination drugs, by and large, are still working in the Mekong countries. Nevertheless, there is concern that slow clearance is the first step along the pathway towards malaria parasites becoming fully resistant to artemisinins.
What of Africa, where the vast majority of malaria cases, and deaths from the disease occur? Are the current combination drugs, collectively termed ACT, still protecting African children from malaria fevers and risk of death? The answer is yes: in all recently published clinical studies of ACT in Africa, cure rates of over 90% in children are reported for all the commonly used regimens.
Delving deeper, however, the story may just have become a little more complicated. In a study conducted in Mbita, western Kenya, in 2009, Patrick Sawa, Teun Bousema and colleagues found that two major ACT regimens were both very effective at curing malaria among the 300 children who participated. But when they went further, and used a day seven blood sample from 77 and 80 children, respectively, from the two drug comparison groups for mosquito feeding, they found a significant difference between the two ACT formulations. One (artemether-lumefantrine) was significantly better at preventing treated children passing on malaria to mosquitoes, and therefore to other people. This is important because we know that the first sign of developing resistance, in the 1990s and 2000s, to the older malaria drugs like chloroquine and sulphadoxine-pyrimethamine, was an increase in the frequency of mosquito infection after treatment.
Blood samples from the Mbita study were sent to our laboratory at the London School of Hygiene & Tropical Medicine, where we used a new DNA-detection approach to show that some of the children that were apparently "cured" three days after treatment actually had persisting detectable malaria parasites. These were too scarce to be seen under the microscope – only the more sensitive DNA detection approach picked them up. This unexpected sub-microscopic persistence occurred in about a third of the children, and in both treatment groups. These particular children then went on to be significantly more likely to infect mosquitoes at day seven after treatment, and also more likely to be one of the minority (about 10%) that again had parasite positive blood slides under the microscope 28 or 42 days after treatment, once the malaria drugs have been completely cleared from the body. These new, and somewhat puzzling findings have just been reported.
Do these findings mean we are now seeing resistance to ACT in Africa? I do not think this is the case. The Malactres consortium, funded by the European Union to conduct the studies in Kenya, and companion studies in Burkina Faso, Tanzania and Nigeria, is using DNA sequence analysis to determine whether there is something special about these persisting parasites. They may bear genetic characteristics that represent an early step towards resistance, but the drugs are still working well for children in Africa. What these findings do mean is that we cannot rely on ACT forever.
The effort to accelerate development of the next generation of malaria drugs therefore deserves our complete support. This effort has been spearheaded by the Medicines for Malaria Venture with support from funders including the Bill & Melinda Gates foundation, various national government agencies from Europe and North America, and substantial support from the EU. The drug development pipeline is expensive and time-consuming, but we cannot afford to let this process falter as we seek to control malaria across the globe.
Dr Colin Sutherland is head of immunology and infection at the London School of Hygiene and Tropical Medicine, and reader in parasitology. Follow @LSHTM_malaria on Twitter

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