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Ahead of Print -Independent Lineages of Highly Sulfadoxine-Resistant Plasmodium falciparum Haplotypes, Eastern Africa - Volume 20, Number 7—July 2014 - Emerging Infectious Disease journal - CDC

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Ahead of Print -Independent Lineages of Highly Sulfadoxine-Resistant Plasmodium falciparum Haplotypes, Eastern Africa - Volume 20, Number 7—July 2014 - Emerging Infectious Disease journal - CDC

Volume 20, Number 7—July 2014


Independent Lineages of Highly Sulfadoxine-ResistantPlasmodium falciparum Haplotypes, Eastern Africa

Steve M. TaylorComments to Author , Alejandro L. Antonia1, Whitney E. Harrington, Morgan M. Goheen, Victor Mwapasa, Ebbie Chaluluka, Michal Fried, Edward Kabyemela, Mwayi Madanitsa, Carole Khairallah, Linda Kalilani-Phiri, Antoinette K. Tshefu, Stephen J. Rogerson, Feiko O. ter Kuile, Patrick E. Duffy, and Steven R. Meshnick
Author affiliations: Author affiliations: Duke University Medical Center, Durham, North Carolina, USA (S.M. Taylor)University of North Carolina, Chapel Hill, North Carolina, USA (S.M. Taylor, A.L. Antonia, M.M. Goheen, S.R. Meshnick)Seattle Children’s Hospital/University of Washington School of Medicine, Seattle, Washington, USA (W.E. Harrington)College of Medicine, Blantyre, Malawi (V. Mwapasa, E. Chaluluka, M. Madanitsa, L. Kalilani-Phiri);National Institutes of Health, Bethesda, Maryland, USA (M. Fried. P.E. Duffy)Seattle Biomedical Research Institute, Seattle (E. Kabyemela)Liverpool School of Tropical Medicine, Liverpool, UK (C. Khairallah, F.O. ter Kuile); University of Kinshasa, Kinshasha, Democratic Republic of the Congo (A.K. Tshefu)University of Melbourne, Melbourne, Victoria, Australia (S.J. Rogerson);University of Amsterdam, Amsterdam, the Netherlands (F.O. ter Kuile)


Sulfadoxine-resistant Plasmodium falciparum undermines malaria prevention with sulfadoxine/pyrimethamine. Parasites with a highly resistant mutant dihydropteroate synthase (dhps) haplotype have recently emerged in eastern Africa; they negated preventive benefits of sulfadoxine/pyrimethamine, and might exacerbate placental malaria. We explored emerging lineages of dhps mutant haplotypes in Malawi, the Democratic Republic of the Congo, and Tanzania by using analyses of genetic microsatellites flanking the dhps locus. In Malawi, a triple-mutant dhps SGEG (mutant amino acids are underlined) haplotype emerged in 2010 that was closely related to pre-existing double-mutant SGEA haplotypes, suggesting local origination in Malawi. When we compared mutant strains with parasites from the Democratic Republic of the Congo and Tanzania by multiple independent analyses, we found that SGEG parasites were partitioned into separate lineages by country. These findings support a model of local origination of SGEG dhps haplotypes, rather than geographic diffusion, and have implications for investigations of emergence and effects of parasite drug resistance.
Antimalarial drug resistance threatens to undermine efforts to control Plasmodium falciparummalaria. In sub-Saharan Africa, Pfalciparum resistance to sulfadoxine/pyrimethamine (SP) is widespread, as shown by clinical treatment failures and the prevalence of molecular markers of drug resistance (1). Despite these findings, SP remains a major tool for malaria control when administered as a partner drug with artemisinins and as intermittent preventive therapy in infants (IPTi), children, and pregnant women (IPTp). Of these SP-based interventions, IPTi with SP is safe and effective (2), IPTi in children receiving SP and amodiaquine has shown promise in western Africa (3,4), and IPTp-SP is used widely across sub-Saharan Africa. All 3 policies are recommended by the World Health Organization for many settings in Africa (57). Spread of sulfadoxine-resistant parasites will compromise the effectiveness of these programs.
IPTp-SP has been adopted most broadly; however, its efficacy appears to be decreasing in areas with increasing parasite resistance to SP (8,9). Reduced susceptibility to sulfadoxine is conferred mainly by nonsynonymous substitutions at codons 436, 437, 540, and 581 of the P. falciparum dihydropteroate synthase (dhps) gene that encodes the enzymatic target of sulfadoxine (10). Parasites with mutant dhps haplotypes are restricted to sub-Saharan Africa, and parasites with the A437G, K540E, and A581G mutations (mutant amino acids are underlined), which are known as dhps triple mutants (haplotype SGEG across codons 436, 437, 540, and 581), have been limited to eastern Africa. In sites in Tanzania in which the SGEGhaplotype is prevalent, IPTp-SP does not appear to improve birth outcomes (9), and IPTi with SP is not effective (11).
In addition, recent evidence suggests that IPTp-SP might exacerbate placental malaria when women are infected with parasites that have the A581G mutation in dhps (12), which suggests that these parasites manifest increased pathogenicity under drug pressure. In contrast, there was no evidence of pathogenicity caused by A581G-bearing parasites in Malawi, and SP retained some efficacy in preventing illness caused by malaria during pregnancy (J. Gutman et al., unpub. data). These contrasting effects of this resistant parasite haplotype suggest that effects of the A581G mutation might vary among populations. However, if parasites from northern Tanzania dessiminate, parasites bearing the dhps A581G mutation could broadly undermine malaria control efforts in infants and pregnant women in Africa.
Because of these findings, molecular surveillance for this mutation is critical to assess the durability of SP for malaria prevention. Genetic studies have shown that mutations conferring resistance to chloroquine (13) and pyrimethamine (14) have arisen only a few times and then diffused across regions and continents. In contrast, resistance to sulfadoxine appears to have arisen independently in multiple locations (15,16), after originating only in Southeast Asia, followed by export to Africa (supported by global survey findings) (17). Efforts to prevent dissemination of the A581G mutation hinge on understanding whether the mutation arises de novo or is spread among locations.
To better understand the emergence of sulfadoxine-resistant Pfalciparum in eastern Africa, we first used microsatellite genotyping to study the emergence of parasites harboring dhpshaplotypes with the A581G mutation in a longitudinal study in Malawi during 1997–2010 (8). We then compared the genetic background of these triple-mutant SGEG parasites in Malawi in a cross-sectional analysis with mutant parasite haplotypes from Tanzania and the Democratic Republic of the Congo (DRC). In these 2 investigations, we hypothesized that extant SGEA haplotypes in Malawi would share a genetic lineage with recently emerged SGEG haplotypes, and that these SGEG haplotypes from Malawi would represent a distinct lineage compared with SGEG haplotypes from other settings in eastern Africa.

Dr Taylor is an infectious disease specialist at Duke University Medical Center, Durham, North Carolina. His research interests are malaria drug resistance and pathogenesis.


We thank Jaymin Patel, Jon Juliano, Christian Parobek, Venkatachalam Udhayakumar, and Mohammed Tauqeer Alam for providing laboratory assistance and helpful discussions, and the persons who participated in the clinical studies.
M.F. and P.E.D. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.


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Technical Appendix

Suggested citation for this article: Taylor SM, Antonia AL, Harrington WE, Goheen MM, Mwapasa V, Chaluluka E, et al. Independent lineages of highly sulfadoxine-resistant Plasmodium falciparumhaplotypes, eastern Africa. Emerg Infect Dis [Internet]. 2014 Jul [date cited].http://dx.doi.org/10.3201/eid2007.131720External Web Site Icon
DOI: 10.3201/eid2007.131720
1Current affiliation: Duke University School of Medicine, Durham, North Carolina, USA.

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