Revealing molecular strategies to preserve drug efficacy

Genetic changes in Plasmodium falciparum, the deadliest malaria parasite, are linked to reduced efficacy of the two partner components of the most widely used antimalarial medicine treatments, artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL).

Although previous studies had shown that particular mutations in the pfcrt and pfmdr1 genes affect the susceptibility of these two drugs differently, a clear connection to the treatment efficacy of the artemsinin combination therapies (ACTs) had not been established.  The very intensive use of either ACT is likely to exert substantial selection pressure on the partner drugs, compromising their overall effectiveness and facilitating the emergence of new foci of resistance to artemsinins, as well.

In the latest study from the WWARN Molecular Module and the AS-AQ/AL Molecular Marker Study Group, the teams have confirmed that patients infected with parasites that carry particular mutations in pfcrt and pfmdr1 are at higher risk of treatment failure after artemether-lumefantrine. This direct connection between the molecular markers and clinical treatment outcome provides solid evidence that the molecular markers can be used to identify sites with early risk of declining efficacy of the ACT.

“This study is an important step in helping us to monitor the emerging signs of drug resistance and preserve the efficacy of our valuable artemisinin combination therapies,” says Dr Carol Sibley, senior author of the study and Scientific Director of WWARN. “By detecting changes in the presence of these mutations we could provide evidence of the evolution of drug resistance in the malaria parasite much sooner than before. The earlier we see signs of drug resistance, the faster decision makers can devise appropriate interventions to assure the continued efficacy of ACTs in patients, especially in Africa where the threat of resistance spreading could affect millions of lives.”

The research team analysed pooled data from more than 7,000 patients derived from 31 drug efficacy trials. Although both AL and AS-AQ interact with the proteins that pfcrt and pfmdr1 encode, each partner drug targets different versions of the two genes. Because they exert opposing selective pressures on the same parasite proteins, the researchers speculate that the concurrent use of these two ACTs could act as a counterbalance to maintain the effectiveness of each drug.

“Identifying these early clues of declining drug efficacy is a high priority so that changes in drug use or management might be put in place to mitigate the risk of increasing resistance,” says  Andreas Mårtensson, Associate Professor in the Department of Microbiology, Tumor and Cell Biology (MTC), at the Karolinska Institutet in Sweden.

Future clinical trial studies and population studies could apply these methods to monitor early changes in these parameters within regions of Asia and Africa where AL or ASAQ are both heavily used. The simple approaches and results could provide governments and policy-makers with a valuable early-warning signal   to help manage the threat of resistance before  widespread treatment failures occur, and preserve the useful therapeutic life of these life-saving antimalarials for as long as possible.

Publication details

Meera Venkatesan et al. Polymorphisms in Plasmodium falciparum Chloroquine Resistance Transporter and Multidrug Resistance 1 Genes: Parasite Risk Factors that Affect Treatment Outcomes for P. falciparum Malaria after Artemether-Lumefantrine and Artesunate-Amodiaquine Advanced online publication in American Journal of Tropical Medicine doi:10.4269/ajtmh.14-0031