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Two malaria treatments exert opposite selective pressures on the malaria parasite

9 January 2017

Study suggests deployment or rotation of multiple first-line antimalarial medicines will effectively treat malaria and maintain drug efficacy.

Uganda has one of the highest burdens of malaria in the world. Artemisinin-based combination therapies (ACTs), the current recommended treatment against falciparum malaria, are still highly effective at treating malaria patients in the region. However, the emergence of artemisinin and partner drug resistance in the Mekong region of Southeast Asia is of great concern for countries like Uganda, where the malaria burden is high. If the efficacy of ACTs declines due to drug resistance, it will put the lives of millions at risk.

The latest WWARN supported study published in Open Forum of Infectious Diseases suggests that rotating ACT regimens may be the best way to reduce the risk of emergence of antimalarial drug resistance in Africa.

This study provides further evidence that different drugs select in opposite directions for parasite changes that impact on drug resistance,” says Prof Philip Rosenthal, senior author of the study from the University of California, San Francisco and a WWARN Board member. “While an ACT may select for resistance to that therapy, it can select for decreased resistance to other ACTS. Thus, deploying multiple first-line antimalarial therapies or rotating regimens will likely impede the development of clinically relevant resistance to available ACTs in Africa.

Monitoring the presence of genetic markers of reduced drug sensitivity is now an essential part of malaria surveillance. Although previous studies have investigated trends in individual molecular markers and their association with reduced antimalarial efficacy, there have been few investigations into the interactions of multiple molecular markers. The team used a statistical model to assess trends in frequency of interacting molecular markers, known as haplotypes, that are associated with drug sensitivity on the pfmdr1 gene as drug selection may act on a haplotype rather than an individual mutation.

The team’s findings support previous work that genetic selection in Uganda is dominated by the selective pressure of lumefantrine. This is consistent with the increasing use of the ACT artemether-lumafantrine (AL) as first-line treatment in Uganda over the past 10 years. The team also found that AL and another ACT, dihydroartemisinin piperaquine (DP), exert opposite selection pressure.

The imbalance between AL and DP selective pressures demonstrates the value of considering haplotypes in future analyses of trends,” adds Dr Aimee Taylor, first author from the Harvard School of Public Health and Broad Institute who first developed the model as part of her PhD studies with WWARN.

The model was fitted with data from a trial conducted in Tororo, Uganda. This trial included data from 312 children, 6 weeks to 12 months of age at enrolment, who were randomized to receive either AL or DP for each episode of uncomplicated malaria from 2007-2012.

Previous research from WWARN’s AS-AQ/AL Molecular Marker Study Group showed that patients infected with parasites that carry particular mutations in the pfcrt and pfmdr1 genes are at higher risk of treatment failure after artemether-lumefantrine. This study also suggested the potential for concurrent use of multiple ACTs to minimise the risk of resistance, as they select for parasite sequences with opposite impacts on drug sensitivity.

Take a look at the WWARN pfmdr1 & pfcrt Molecular Surveyor, an interactive mapping tool that provides researchers and policy makers with an overview of the changes in the prevalence of molecular markers associated with malaria drug resistance over time and location. Let us know how we can improve this tool to inform your international, regional and national research and surveillance strategies.

Publication details:

Aimee R. Taylor, et al. ‘Artemether-lumefantrine and dihydroartemisinin-piperaquine exert inverse selective pressure on Plasmodium falciparum drug sensitivity associated haplotypes in Uganda’ Open Forum of Infectious Diseases. Published online October 25, 2016 doi: 10.1093/ofid/ofw229