In another twist of the arms race with human medical science Plasmodium falciparum, the malevolently designed parasite that causes malaria and kills hundreds of thousands of children a year, mostly in Africa, has developed resistance to Artemisinin. Scientists were already aware that resistance had arisen in cases of uncomplicated malaria, but this is the first such incidence of resistance in the more severe form of the disease.
Indiana University School of Medicine researchers, in collaboration with colleagues at Makerere University in Uganda have discovered a case of complicated malaria in a child in Uganda.
The team, led by Professor Chandy C. John, MD, of the Indiana University School of Medicine have published their findings in the Journal of the American Medical Association (JAMA) and explain the significance of it in an Indiana University news release:
What information do you have on the growing resistance to Artemisinin by Plasmodium falciparum? The resistance of Plasmodium falciparum to artemisinin-based therapies (ACTs) is an increasing concern, particularly in Southeast Asia and parts of Africa, including Ethiopia and Rwanda. This resistance is marked by mutations in the Pfkelch13 gene, which impair the parasite's susceptibility to artemisinin. The most common mutation identified in East Africa is R622I, alongside others such as A675V and P441L. These mutations have been associated with reduced effectiveness of artemisinin, especially during the early stages of treatment.
While ACTs remain effective in most cases, the rise of resistance has prompted calls for enhanced surveillance and research. Countries like Ethiopia have begun integrating genomic monitoring into routine activities to track resistance patterns. Lessons from Southeast Asia suggest that alternative therapies, like triple-combination treatments, may become necessary to sustain malaria control efforts. However, health agencies advise maintaining current treatments until clinical efficacy shows significant decline.
This growing challenge underscores the importance of continued vigilance and investment in new therapeutic options to mitigate the spread of resistant strains.
Study uncovers first evidence of resistance to standard malaria treatment in African children with severe malaria
INDIANAPOLIS — Indiana University School of Medicine researchers, in collaboration with colleagues at Makerere University in Uganda, have uncovered evidence of partial resistance to artemisinin derivatives — the primary treatment for malaria — in young children with severe, or "complicated," malaria.
Earlier studies have shown partial resistance to artemisinin in children with uncomplicated malaria, but the new study, published in the Journal of the American Medical Association (JAMA), is the first to document such resistance in African children with well-defined signs of severe disease from malaria.
Artemisinin-based therapies have been quintessential in the fight against malaria for the past 20 years. Growing evidence of artemisinin partial resistance in African children with uncomplicated malaria has led to concerns that new therapies, like triple artemisinin combination therapies, may be needed in uncomplicated malaria. The findings of artemisinin partial resistance in children with severe or complicated malaria, as well as the findings of a high rate of recurrent malaria with current standard treatment in these areas raise the question of whether new treatments are needed for severe malaria as well.
Professor Chandy C. John, MD, corresponding author Ryan White Professor of Pediatrics
IU School of Medicine, Indiana USA.
Led by John and co-authors Ruth Namazzi, MBChB, MMEd, and Robert Opoka, MD, MPH, of Makerere University; Ryan Henrici, MD, PhD, of the University of Pennsylvania; and Colin Sutherland, PhD, MPH, of the London School of Tropical Medicine and Hygiene, the study examined 100 Ugandan children aged 6 months to 12 years who were undergoing treatment for severe malaria complications caused by Plasmodium falciparum, the deadly malaria parasite transmitted by mosquitos.
In the study, 10 children had parasites with genetic mutations previously associated with artemisinin partial resistance. The most common mutation, which was seen in eight of these children, was associated with a longer parasite clearance half-life — the time it takes the parasite's burden in the body to reach half of its initial level. The study also showed that 10% of children returned within 28 days of treatment with an infection from the same malaria strain they had during their original admission. These were all children who had received complete intravenous and then oral treatment for severe malaria, and all had cleared the parasite by microscopic examination. John said these findings suggest that the standard intravenous and oral treatment lowers the parasite level to where it cannot be detected by microscopy, but it does not completely eliminate the parasite in some children.
Reports of artemisinin resistance first surfaced in Southeast Asia in 2008 before emerging in East Africa, a trend the IU research team unexpectedly observed through their ongoing work in Uganda. While studying why severe malaria develops in children, the researchers noticed slower responses to artemisinin in some of their Ugandan study participants, prompting the present study.
John presented the study's results at the Annual Meeting of the American Society of Tropical Medicine and Hygiene on Nov. 14 in New Orleans, Louisiana.The study findings point to a need for more data on artemisinin resistance and recurrence of clinical malaria in children with severe malaria. If our study findings are confirmed in other areas, that would suggest that treatment guidelines for severe malaria may require revision.
Professor Chandy C. John, MD.
Abstract
One of the greatest threats to the control of malaria is the emergence of artemisinin partial resistance (ART-R) in Plasmodium falciparum, the most virulent human malaria parasite, in multiple countries in Africa.1 Artemisinins are rapid-acting antimalarial therapeutic agents that are the key components of artemisinin-based combination therapy, which combines an artemisinin derivative with a longer-acting partner drug to treat uncomplicated falciparum malaria. Artemisinin-based combination therapies are the standard of care for this indication. In addition, the artemisinin derivative artesunate, provided intravenously or intramuscularly, is the standard of care to treat severe falciparum malaria, offering significantly improved survival compared with the prior standard, quinine, in African children.2 Artemisinin partial resistance is manifest as delayed parasite clearance after treatment and was first identified in Southeast Asia in 2008.
Henrici RC, Namazzi R, Lima-Cooper G, et al.
Artemisinin Partial Resistance in Ugandan Children With Complicated Malaria.
JAMA. Published online November 14, 2024. doi:10.1001/jama.2024.22343
© 2024 American Medical Association.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.
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