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Gene polymorphisms linked to resistance in artemisinin-based malaria treatment
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The choice of artemisinin-based combination treatments for malaria can influence parasite genetics and drug sensitivity, according to results of a recent study published in The Journal of Infectious Diseases.
In Ugandan children undergoing treatment for malaria with artemether-lumefantrine (Coartem, Novartis) or dihydroartemisinin-piperaquine, parasite polymorphisms related to reduced sensitivity to artemether-lumefantrine constituents appeared to increase over time, according to the researchers.
Additionally, the findings underscored the importance of the artemisinin-based therapy partner drug, which has a longer plasma half-life than the artemisinin drug and functions as monotherapy once the artemisinin drug has been cleared.
The researchers evaluated a cohort of 312 children enrolled in a longitudinal trial conducted in Tororo, Uganda, between 2007 and 2012. The children, aged 6 weeks to 12 months, were followed for all health problems. Children were diagnosed with malaria if they had a fever and a positive thick blood smear. After diagnosis with an initial episode of uncomplicated malaria, children aged at least 4 months and at least 5 kg in weight were randomly assigned to artemether-lumefantrine or dihydroartemisinin-piperaquine. There were 134 children in the artemether-lumefantrine treatment arm and 140 in the dihydroartemisinin group. The researchers randomly extracted DNA samples from 50 participants at baseline and analyzed for polymorphisms of interest.
Additionally, 50 samples from subsequent malaria episodes from each treatment group were randomly selected for each 3-month period between January 2008 and June 2012. In total, 1,882 longitudinal samples were evaluated for polymorphisms in pfmdr1 and pfcrt genes.
The researchers found that outcomes for both treatment arms were excellent, with low rates of recrudescence.
In terms of gene polymorphism, there was an increased prevalence over time for pfmdr1 N86. There were decreases in prevalence over time for pfmdr1 Y184. The rates of these changes were uniformly greater in the artemether-lumefantrine arm vs. the dihydroartemisinin arm, according to the researchers.
In an accompanying editorial, Steve M. Taylor, MD, of Duke University’s division of infectious diseases and international health, said these findings emphasize the importance of evaluating resistance to partner drugs as well as resistance to the artemisinin drug.
“It is clear that, far from being sidekick or understudy to the artemisinin drug, these drugs are true antiparasitic partners: If artemisinin is personified by the quicksilver Sherlock Holmes in its pursuit of malaria parasites, the partner drug is the slower, prosaic Dr. Watson of [artemisinin-based combination treatments], rarely grabbing headlines but critical to the job,” Taylor wrote. “Therefore, it seems prudent to complement surveillance of artemisinin resistance with that for partner drugs.”
For more information:
Conrad MD. J Infect Dis. 2014;doi:10.1093/infdis/jiu141.
Taylor SM. J Infect Dis. 2014;doi:10.1093/infdis/jiu142.
Disclosure: The researchers report no relevant financial disclosures.