Study finds artemisinin resistance in African children with severe malaria

Mutations in malarial parasites linked to artemisinin-resistance in Southeast Asia have now been found in African children hospitalised for complicated malaria, according to a new study presented at the Annual Meeting of the American Society of Tropical Medicine & Hygiene (ASTMH).

It provides the first evidence that resistance to the lifesaving antimalarial drug may be emerging in the group of patients that account for most of the world’s deaths from malaria: young children in Africa with serious infections.

The study is published in the Journal of the American Medical Association (JAMA) and led by researchers from the Indiana University School of Medicine, Makerere University in Kampala, Uganda the University of Pennsylvania and the London School of Hygiene & Tropical Medicine (LSHTM).

The team found partial resistance to the malaria drug artemisinin in 11 of 100 children, aged 6 months to 12 years, treated in Uganda for a complicated case of infection by the malaria parasite Plasmodium falciparum. The term “complicated” malaria is used to define cases where the disease is at risk of causing potentially life-threatening complications, like severe anaemia or brain-related problems known as cerebral malaria.

The children in the study received what is considered to be the gold standard for treating complicated malaria infections: an intravenous infusion of artesunate, an artemisinin derivative, followed by an oral combination of artemether, another derivative of artemisinin, with a malaria drug called lumefantrine.

The introduction of artemisinin therapies 20 years ago was a major advance in malaria therapy due to their ability to treat cases quickly and came at a time when resistance was already being observed to other available treatments. The first evidence of partial resistance to artemisinin was reported in 2008 in Cambodia and by 2013, studies suggested the antimalarial was failing to treat some cases. Over the last few years, there has been increasing evidence that artemisinin-resistance may have spread into East Africa. 

While all of the children in the study eventually recovered, 10 patients who were thought to have been cured also suffered a repeat malaria attack within 28 days from the same strain of malaria that caused the original infection, suggesting that the initial treatment did not fully kill the infecting parasites. Two children required longer than the standard maximum of three days of therapy because they failed to clear their parasites.

The WHO African region continues to shoulder the highest burden of malaria, with 95% of the total deaths recorded there in 2022.

While studying the outcomes of children who experience episodes of severe malaria, we noticed that some children were slower to respond to treatment, which led us to look into resistance. Given that in Southeast Asia, evidence of partial resistance to artemisinin led to broadly resistant malaria parasites, our major concern is that this pattern will now be repeated in Africa.

Children under the age of five make up the majority of fatal cases of malaria. We can’t afford to let resistance to vital antimalarials continue unchecked, without having effective replacements ready.”

Colin Sutherland, Professor of Parasitology at LSHTM, and co-author of the study

Chandy John, Professor and Director of the Indiana University School of Medicine Ryan White Center for Infectious Diseases and Global Health, and one of the study’s lead authors, said: “This is the first study from Africa showing that children with malaria and clear signs of severe disease are experiencing at least partial resistance to artemisinin.

“It’s also the first study showing a high rate of African children with severe malaria experiencing a subsequent malaria episode with the same strain within 28 days of standard treatment with artesunate, a derivative of artemisinin, and an artemisinin combination therapy (ACT).

“The fact that we started seeing evidence of drug resistance before we even started specifically looking for it is a troubling sign.”

In the study, the team classified patients as suffering from partial resistance based on the World Health Organization’s defined half-life cutoff for parasite clearance, whereby it takes more than five hours to reduce a patient’s parasite burden by 50%.