Scientists have identified a rapidly spreading set of genetic changes in the Plasmodium falciparum parasite, which are linked to reduced sensitivity to several important malaria drugs. The discovery raises concerns about the future effectiveness of first-line therapies in parts of Africa.
A research team including specialists from Brown University analyzed the full genomes of parasites isolated from blood samples of infected people in Uganda. The results show a link between a specific complex of genetic changes and lower sensitivity to dihydroartemisinin, lumefantrine, and mefloquine.
Why the discovery is important
Artemether-lumefantrine is among the most widely used combination therapies against uncomplicated malaria in Africa. It combines two medications with different mechanisms of action to reduce the risk of the parasite surviving and the disease returning.
The new data are important because for the first time they outline a molecular marker associated with both reduced sensitivity to an artemisinin component and to lumefantrine – the partner medication in the combination. Reduced sensitivity does not automatically mean that every treatment will fail, but it is a warning sign that effectiveness may be deteriorating.
What was established in Uganda
Researchers identified three mutations and two deletions, forming the so-called PX1 PIN haplotype. The three key changes in the PX1 gene are L1222P, M1701I, and D1705N. The gene encodes a protein that binds to phosphoinositides – molecules involved in cell signaling and membrane processes.
In laboratory analyses, parasites carrying the PX1 PIN haplotype show reduced sensitivity to dihydroartemisinin and lumefantrine compared to parasites without these genetic variants. Lower sensitivity to mefloquine was also observed.
The variants are not an isolated observation. Data from Uganda indicate that this haplotype was first detected in 2008, and then its prevalence increased rapidly. By 2016, its frequency had exceeded 50% in Northern Uganda, and by 2023 – in Eastern Uganda as well.
Need for better surveillance
Previously, health systems had genetic markers used to track partial resistance to artemisinin, including variants in the kelch13 gene. For lumefantrine, however, there was no validated molecular indicator that would allow for early and systematic monitoring.
"We didn't have a single validated molecular marker for resistance to lumefantrine," says the first author of the study, Karamoko Niare. "Our work allowed for the identification of a molecular marker that can be used in epidemiological studies to track the emergence and spread of reduced sensitivity to first-line malaria treatments in Africa."
The discovery could allow laboratories and health institutions to look for specific PX1 variants in parasite samples. Thus, the potential spread of reduced drug sensitivity could be detected earlier, before it leads to widespread treatment failures.
What are the risks
According to lead author Jeffrey Bailey, the rapid spread of these changes is cause for serious concern. "It is extremely alarming that these new mutations are spreading so quickly – this suggests that they play an important role in the survival of the parasite," he states.
"With the rise of drug resistance, we fear this will undermine malaria control and lead to even more deaths," adds Bailey.
It is not yet clear how far the variants have spread outside of Uganda. Therefore, scientists emphasize the need for monitoring in other countries, especially where artemether-lumefantrine remains a primary treatment.
Change in recommendations in the US
The US Centers for Disease Control and Prevention now recommends an extended five-day course of artemether-lumefantrine for uncomplicated malaria caused by Plasmodium falciparum. The standard three-day regimen has been replaced with a total of 10 doses over five days.
The change is related to documented late treatment failures after three-day courses both in endemic areas and among travelers. The longer course aims to increase the parasite's exposure to both components of the therapy and reduce the likelihood of the infection recurring.
Scientists point out that the next important task is to develop models that can predict when treatment effectiveness might become insufficient. In parallel, it is necessary to accelerate the research and development of new antimalarial drugs.