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September 23, 2021
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Disclosures: Please see the study for relevant financial information from all authors. White does not report any relevant financial disclosure.
The researchers identified Plasmodium falciparum It is resistant to artemisinin – the main component of first-line treatment for malaria in endemic areas – in a small group of patients in northern Uganda.
The result was published on 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 widespread in Southeast Asia and experts fear it may appear in other regions.
“Clinical resistance to artemisinin monotherapy in other parts of the world, including Africa, would be problematic” because there is currently no alternative to artemisinin derivatives, researchers from Japan said and from Uganda in the new study.
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 to 2019. The median age of participants was 2.6 years.
In most of the 240 participants included in the study, the parasites were “quickly cleared”, with a median half-life of 1.9 hours (interquartile range [IQR], 1.5-2.3). However, 14 of 240 patients (5.8%) had evidence of slow parasite clearance – defined as a half-life of more than 5 hours – and were considered to be resistant to artemisinin in vivo.
According to the authors, the prevalence of resistance in vivo increased throughout the years of study – 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 met the criteria for early treatment failure, the authors reported.
The prevalence of parasites with kelch13 mutations – the primary means of assessing artemisinin resistance – also increased significantly, from 3.9% in 2015 to 19.8% in 2019, the researchers reported.
In the related editorial, Nicholas J. White, FRS, professor of tropical medicine at Mahidol University in Thailand and at the University of Oxford, called artemisinins “the cornerstone of current antimalarial treatments”.
White noted that progress against malaria has stagnated over the past 6 years in sub-Saharan Africa, where most of the world’s malaria cases are found. Although this happened despite the effectiveness of artemisinin-based combination therapies, “the loss of these essential resistance drugs would be a disaster,” he wrote.
White also noted that the evidence presented 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 existing antimalarial combinations so that instead of a partner drug, two slowly removed partner drugs are included to provide mutual protection in addition to the artemisinin derivatives,” White wrote.
“Combination treatments with triple artemisinin have been shown to be effective in clinical trials,” he continued. “Alternatively, two different combination therapies can be administered in sequence. Whichever approach you choose, it would be better to act now rather than wait years as the situation deteriorates and higher levels of resistance develop.
The references:
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Philip J. Rosenthal, MD
A new article by a group from Uganda and Japan has shown strong evidence of delayed elimination of malaria parasites after treatment with artemisinin – commonly referred to as artemisinin resistance – in northern Uganda.
This follows a recent report from Rwanda also showing a delay in clearance after treatment with artemisinin. The studies differed in various details, but together they offer the first compelling evidence that clinically relevant artemisinin resistance has gained a foothold in Africa.
The results are not surprising because, if the opportunity arises, microbes will develop means of resistance to antimicrobial drugs, and parasites with potential markers of resistance had already been identified. In both cases, the mutations of the P. falciparum The K13 protein, previously shown to mediate resistance in Southeast Asia and already circulating in Rwanda and Uganda, has been associated with delayed clearance measured clinically and in vitro.
Remarkably, as we have seen previously in Southeast Asia, there have been multiple emergences because three different mutations – one observed in Rwanda and the other two in Uganda – are now all circulating and intervening in clearance. delayed parasite. These results are deeply important.
Artemisinin resistance is a problem in the Greater Mekong subregion of Asia, but its impact is limited by the relatively low incidence of malaria in the region. In Africa, where more than 90% of malaria cases occur and more than 90% of the half a million annual deaths from malaria, the spread of resistance to artemisinin-based therapies, our main treatments for falciparum malaria , is likely to be devastating. .
So far, artemisinin-based treatment for severe malaria and artemisinin-based combinations for uncomplicated malaria are probably still effective, as recent reports show. However, given the new findings, close monitoring of changes in drug sensitivity in the laboratory and changes in drug efficacy in clinical trials, as well as vigorous efforts to develop new artemisinin-free antimalarials, are urgently needed. .
Reference:
Philip J. Rosenthal, MD
Professor of Medicine, University of California, San Francisco
Disclosures: Rosenthal does not report any relevant financial information.
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