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London School of Hygiene & Tropical Medicine Malaria Centre

Malaria research in drug development, deployment and resistance

Polymorphism in pfmdr1, pfatpase6 and pfubp1 in Plasmodium falciparum infections following treatment with artemether-lumefantrine in eastern Sudan

LSHTM investigators:
Colin Sutherland, David Warhurst & Nahla Gadalla.
External collaborators:
Badria El-Sayed (Tropical Medicine Research Institute, Sudan); Ishag Adam (University of Khartoum, Sudan).
Funding body:
WHO/TDR & IAEA.

Molecular markers for surveillance of Plasmodium falciparum resistance to current artemisinins and their partner drugs are a public health priority.

In Sudan ACTs have been recommended as first-line since 2004. A few reports of the clinical efficacy of artemether/lumefantrine (AL) from Sudan are available, but there is a lack of evaluation of molecular markers for AL in Sudan and elsewhere in Africa.

A 28-day antimalarial drug efficacy trial of artemether-lumefantrine was carried out in eastern Sudan in 2006. In this study 5 (n=100) patients failed treatment with recurrent infections detected by microscopy during the follow-up. In addition 9 further individuals were found to harbour parasite by PCR at day 14. Polymorphisms in pfmdr1, pfatpase6 and pfubp1 were detected by DNA sequencing and pfmdr1 copy number was performed by qPCR. One individual carried parasites with a novel pfmdr1 polymorphism (F1044L). pfmdr1 copy number ranged from  0.73 to 2.33 (95% CI, 1.16 to 1.32) with an average copy number in pretreatment isolates of 1.24. Pfmdr1 copy number estimates above 1.8 in at least two independent experiments were obtained for three pretreatment isolates. Interestingly, pfmdr1-amplified isolates in this study carried the 86Y allele instead of the N86 consistent with other African reports and in contrast to those seen in Southeast Asia. The NFD haplotype of pfmdr1 was found to be selected by AL. There was genetic diversity in both pfatpase6 and pfubp1, but a lack of association of either gene with treatment response.

The appearance of amplified pfmdr1 warrants further investigation into the evolution and spread of this genotype in the study area despite the lack of mefloquine use.