Resistant malaria ‘has gained a foothold in Africa’

ByKen Downey Jr.

Researchers identified Plasmodium falciparum that is resistant to artemisinin — the main component of first-line treatments for malaria in endemic areas — among a small group of patients in northern Uganda.

Perspective from Philip J. Rosenthal, MD

The finding was published Wednesday in The New England Journal of Medicine, months after a similar report confirmed evidence of artemisinin resistance in neighboring Rwanda. Artemisinin resistance is already prevalent in Southeast Asia, and experts have expressed concern that it will emerge in other regions.

Most cases of malaria occur in Africa, where the *Anopheles gambiae* mosquito is an important vector. Source: CDC/James Gathany.

“Clinical resistance to artemisinin monotherapy in other global regions, including Africa, would be problematic” because there are no currently available alternatives to artemisinin derivatives, researchers from Japan and Uganda said in the new study.

The researchers conducted a longitudinal study from 2015 to 2019 in northern Uganda among patients with P. falciparum infection who were treated with intravenous artesunate from 2017 through 2019. The median age of the participants was 2.6 years.

In most of the 240 participants included in the study, parasites were “rapidly cleared,” with a median half-life of 1.9 hours (interquartile range [IQR], 1.5-2.3). However, 14 of the 240 patients (5.8%) had evidence of slow parasite clearance — defined as a half-life of more than 5 hours — and were considered to have in vivo artemisinin resistance.

According to the authors, the prevalence of in vivo resistance increased throughout the study years — from 4.6% in 2017 to 6.7% in 2018 and 6.5% in 2019 — but the difference was not significant. None of the cases fulfilled the criteria for early treatment failure, the authors reported.

The prevalence of parasites with kelch13 mutations — the primary way artemisinin resistance is assessed — also increased significantly, from 3.9% in 2015 to 19.8% in 2019, the researchers reported.

In related editorial, Nicholas J. White, FRS, professor of tropical medicine at Mahidol University in Thailand and the University of Oxford, called artemisinins “the cornerstone of current antimalarial treatments.”

White noted that progress against malaria has stalled over the last 6 years in sub-Saharan Africa, where most of the world’s cases of malaria are. Although this has occurred despite the efficacy of artemisinin combination therapies, “the loss of these essential medicines to resistance would be a disaster,” he wrote.

White also noted that evidence outlined in the study suggests that artemisinin resistance to P. falciparum emerged locally in Uganda, rather than being imported. He said new antimalarial drugs are on the horizon, but still years away.

“One approach is to extend the combinations of existing antimalarials so that instead of one partner drug, two slowly eliminated partner drugs are included to provide mutual protection in addition to the artemisinin derivatives,” White wrote.

“Triple artemisinin combination treatments have proved to be effective in clinical trials,” he continued. “Alternatively, two different combination therapies can be given in sequence. Whichever approach is chosen, it would be much better to act now rather than wait for years while the situation deteriorates and higher levels of resistance develop.”

References:

Perspective

Philip J. Rosenthal, MD

A new paper from a group from Uganda and Japan has shown strong evidence for delayed clearance of malaria parasites after artemisinin therapy — commonly referred to as artemisinin resistance — in northern Uganda.

This follows a recent report from Rwanda also showing delayed clearance after artemisinin therapy. The studies differed in various details, but together they offer the first convincing evidence that clinically relevant artemisinin resistance has gained a foothold in Africa.

The results are not surprising because, given the opportunity, microbes will evolve means of resistance to antimicrobial drugs, and parasites with potential markers of resistance had already been identified. In both cases, mutations in the P. falciparum K13 protein, shown previously to mediate resistance in Southeast Asia and already shown to be circulating in Rwanda and Uganda, have been associated with delayed clearance measured clinically and in vitro.

Remarkably, as seen previously in Southeast Asia, there have been multiple emergences because three different mutations — one seen in Rwanda and the other two in Uganda — are now all circulating and mediating delayed parasite clearance. These results are profoundly important.

Artemisinin resistance is a problem in the Greater Mekong Subregion of Asia, but its impact is limited by the quite low incidence of malaria in the region. In Africa, where more than 90% of cases of malaria and more than 90% of the roughly half million annual deaths from malaria occur, the spread of resistance to artemisinin-based therapies, our main treatments for falciparum malaria, is likely to be devastating.

So far, artemisinin-based treatment of severe malaria and artemisinin-based combinations for uncomplicated malaria are likely still efficacious, as seen in recent reports. However, considering the new findings, close surveillance for changes in drug susceptibility in the lab and changes in drug efficacy in clinical trials, along with aggressive efforts to develop new non-artemisinin antimalarials, are urgently needed.

Reference: