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. 2015 Sep 1;212(5):694-701.
doi: 10.1093/infdis/jiv078. Epub 2015 Feb 11.

Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi

Elena Artimovich  1 , Kristan Schneider  2 , Terrie E Taylor  3 , James G Kublin  4 , Fraction K Dzinjalamala  5 , Ananias A Escalante  6 , Christopher V Plowe  1 , Miriam K Laufer  1 , Shannon Takala-Harrison  1
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Persistence of Sulfadoxine-Pyrimethamine Resistance Despite Reduction of Drug Pressure in Malawi

Elena Artimovich et al. J Infect Dis. .

Abstract

Background: In 2007, Malawi replaced sulfadoxine-pyrimethamine (SP) with an artemisinin-based combination therapy as the first-line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy. Here we estimate the effect of reduced SP pressure on the prevalence of SP-resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci.

Methods: Samples obtained from individuals with clinical malaria during a period of high SP use (1999-2001), a transitional period (2007-2008), and a period of low SP use (2012) were genotyped for resistance markers at pfdhfr-ts codons 51, 59, and 108 and pfdhps codons 437, 540, and 581. Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr-ts and pfdhps.

Results: An increase in the prevalence of the resistance haplotypes DHFR 51I/59R/108N and DHPS 437G/540E occurred under sustained drug pressure, with no change in haplotype prevalence 5 years after reduction in SP pressure. The DHPS 437G/540E/581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure. Changes to the sweep characteristics flanking pfdhfr-ts and pfdhps were minimal.

Conclusions: In contrast to the rapid and complete return of chloroquine-susceptible falciparum malaria after chloroquine was withdrawn from Malawi, a reemergence of SP efficacy is unlikely in the near future.

Keywords: DHFR; DHPS; malaria; pyrosequencing; resistance; selective sweeps; sulfadoxine-pyrimethamine.

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Figures

Figure 1.
Figure 1.
Change in Plasmodium falciparum dihydrofolate reductase (DHFR; A) and dihydropteroate synthase (DHPS; B) haplotype prevalence over 3 periods in the history of sulfadoxine-pyrimethamine (SP) use in Ndirande, Malawi. Prevalence is calculated as the percentage of individuals with a given haplotype. The 3 periods consisted of a period of high SP use (1999–2001), a transitional period (2007–2008), and a period of low SP use (2012). Black bars indicate statistically significant differences. Error bars represent 95% confidence intervals. The asterisks indicate the use of the Yates correction.
Figure 2.
Figure 2.
Expected heterozygosity in microsatellite loci flanking the genes encoding Plasmodium falciparum dihydrofolate reductase (DHFR)–thymidylate synthase pfdhfr-ts (A) and dihydropteroate synthase (DHPS) (pfdhps; B). Samples with missing data were excluded. Error bars represent ±1 SD. Dashed lines represent average genomic level expected heterozygosity, based on unlinked loci. The single asterisks indicate a significant difference between 2 periods. The double asterisk indicates a significant difference between all 3 periods, based on permutation. P values of <.05 were considered statistically significant. Abbreviation: SP, sulfadoxine-pyrimethamine.
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References

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