title: Polymorphism in dhfr/dhps genes, parasite density and ex vivo response to pyrimethamine in Plasmodium falciparum malaria parasites in Thies, Senegal.
abstract: Resistance to sulfadoxine-pyrimethamine (SP) in Plasmodium falciparum malaria parasites is associated with mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes, and these mutations have spread resistance worldwide. SP, used for several years in Senegal, has been recommended for intermittent preventive treatment for malaria in pregnancy (IPTp) and has been widely implemented since 2003 in this country. There is currently limited data on SP resistance from molecular marker genotyping, and no data on pyrimethamine ex vivo sensitivity in Senegal. Molecular markers of SP resistance and pyrimethamine ex vivo sensitivity were investigated in 416 parasite samples collected from the general population, from the Thies region between 2003 and 2011. The prevalence of the N51I/C59R/S108N triple mutation in dhfr increased from 40% in 2003 to 93% in 2011. Furthermore, the prevalence of the dhfr N51I/C59R/S108N and dhps A437G quadruple mutation increased, from 20% to 66% over the same time frame, then down to 44% by 2011. There was a significant increase in the prevalence of the dhfr triple mutation, as well as an association between dhfr genotypes and pyrimethamine response. Conversely, dhps mutations in codons 436 and 437 did not show consistent variation between 2003 and 2011. These findings suggest that regular screening for molecular markers of antifolate resistance and ex vivo drug response monitoring should be incorporated with ongoing in vivo efficacy monitoring in areas where IPTp-SP is implemented and where pyrimethamine and sulfa drugs are still widely administered in the general population.
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Daouda
authors.initials: D
authors.lastname: Ndiaye
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Baba
authors.initials: B
authors.lastname: Dieye
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Yaye D
authors.initials: YD
authors.lastname: Ndiaye
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Daria
authors.initials: D
authors.lastname: Van Tyne
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Daniels
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Bei
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Aminata
authors.initials: A
authors.lastname: Mbaye
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Clarissa
authors.initials: C
authors.lastname: Valim
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Lukens
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Souleymane
authors.initials: S
authors.lastname: Mboup
authors.affiliation: Faculty of Medicine and Pharmacy, University Cheikh Anta Diop, Dakar, PO Box 5005, Dakar, Senegal.
authors.forename: Omar
authors.initials: O
authors.lastname: Ndir
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Dyann F
authors.initials: DF
authors.lastname: Wirth
authors.affiliation: Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Volkman
keywords: Plasmodium falciparum; Pyrimethamine; Resistance; dhfr/dhps