Presence of reinfecting parasites that carry molecular markers indicates increased parasite tolerability to treatment

25 October 2016

P. falciparum malaria infection can be successfully treated using a combination of artemisinin derivatives and a partner drug, known together as artemisinin combination therapies (ACTs). However, signs of resistance to both the artemisinin derivative and partner drugs have emerged in many parts of the world, threatening the recent gains made against malaria infection. 

The longer acting properties of the ACT partner drug often act as a double-edged sword. The partner drugs remain in a patient’s system longer than the artemisinin component, often for weeks after treatment, so they offer prolonged protection. However, the longer lived partner drugs also increase the risk of selecting drug resistant parasite populations since in the weeks following treatment, any new parasites that infect the patient are exposed to lower levels of the drug.

A study recently published in Malaria Journal, investigates the potential for the emergence of drug resistance pre and post treatment by identifying the presence of known mutations, or molecular markers, that are associated with reduced efficacy of the ACT partner drugs, lumefantrine (in artemether-lumefantrine, AL) and amodiaquine ( artesunate-amodiaquine, AS-AQ). This study was developed as a partnership between WWARN, Institut de Médecine et d'Epidémiologie Appliquée, Drugs for Neglected Diseases Initiative, Epicentre and the National Malaria Control Programme in Liberia.

Our research highlights the importance of studying drug concentration levels post treatment as there is a concern that parasites with these mutations or molecular markers could re-infect patients with higher lumefantrine levels,” says Prof Sabina Dahlström Otienoburu, lead author,  from the Johnson C. Smith University, Charlotte, North Carolina and former WWARN In vitro Coordinator.

The research team worked in Liberia to investigate the prevalence of molecular markers in two parasite genes, pfmdr1 and pfcrt, before and after treatment with AS-AQ and AL.  Molecular analyses of this kind have been rare in Liberia; this study was the first ever analysis in Liberia of the prevalence of these molecular markers after particular ACT treatments.

The study included children under the age of 5, the age group most susceptible to malaria infection in the region, and followed their clinical responses for 42 days after the initial treatment. The researchers found that both AL and ASAQ are still highly effective against P. falciparum malaria infection with very few treatment failures detected during the trial.

“It is essential that we learn more about these markers of resistance and how they influence the conditions of reinfection,” adds Dr Jean-Rene Kiechel, Senior Project Manager at the Drugs for Neglected Diseases Initiative (DNDi). “The more we know about them, the better we are prepared to develop policies and strategies aimed at tackling the threat of antimalarial drug resistance.”

The molecular markers associated with drug resistance were assessed before and after treatment.

Previous research confirms that patients infected with parasites that carry particular mutations in pfcrt and pfmdr1 are at higher risk of treatment failure after artemether-lumefantrine. This WWARN-led study suggests that further research needs to be done to investigate whether concurrent use of these two ACTs could minimise the risk of resistance as they select for opposing alleles.

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. It helps to inform international, regional and national surveillance strategies.

For further details on this study, or our molecular scientific research, please contact Prof Carol Sibley carol [dot] sibley [at] wwarn [dot] org

Publication details:

Otienoburu SD, et al. Selection of Plasmodium falciparum pfcrt and pfmdr1 polymorphisms after treatment with artesunate-amodiaquine fixed dose combination or artemether-lumefantrine in Liberia. Malaria Journal. 2016 Sep 5;15:452. DOI: 10.1186/s12936-016-1503-3.