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. 2013 Jun 10:12:195.
doi: 10.1186/1475-2875-12-195.

High rates of parasite recrudescence following intermittent preventive treatment with sulphadoxine-pyrimethamine during pregnancy in Benin

Azizath Moussiliou, Yolande Sissinto-Savi De Tove, Justin Doritchamou, Adrian J F Luty, Achille Massougbodji, Michael Alifrangis, Philippe Deloron, Nicaise Tuikue Ndam

High rates of parasite recrudescence following intermittent preventive treatment with sulphadoxine-pyrimethamine during pregnancy in Benin

Azizath Moussiliou et al. Malar J. .

Abstract

Background: Despite widespread parasite resistance to sulphadoxine-pyrimethamine (SP) its use for intermittent preventative treatment during pregnancy remains the policy in Benin and throughout most of sub-Saharan Africa.

Methods: In a prospective study, 982 pregnant women were recruited in Benin and followed until delivery. The prevalence of point mutations in the pfdhfr and pfdhps genes associated with Plasmodium falciparum resistance to SP during consecutive antenatal visits was determined. Parasites clearance among women infected at SP intake was assessed by microscopy and PCR. Association between the persistence of parasites and malaria consequences, were investigated. Recurrent parasites were genotyped to identify recrudescences from re-infections.

Results: The prevalence of pfdhfr/pfdhps quadruple mutants (triple pfdhfr + single pfdhps) was consistently above 80% while quintuple and sextuple mutants remained low. Importantly the higly mutated parasites apparently never included the two key mutations, pfdhfr 164 L or pfdhps 540E. Based on PCR results, SP failed to clear existing parasitaemia in half (48%) of the women who were infected at IPTp schedule. The frequency of recrudescence reached 76% after the second dose. Women with persistent parasitaemia had an increased prevalence of anaemia (P = 0.03).

Conclusion: The data presented here, highlight the inability of SP to ensure optimal antiplasmodial protection in late pregnancy, and invite urgent consideration of an alternative drug or strategy.

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Figures

Figure 1
Figure 1
Flowchart diagram of the study.
Figure 2
Figure 2
Proportions of SNPs associated with SP resistance. DNA from laboratory strains with known pfdhfr and pfdhps haplotypes (3D7, FRC3, K1, HB3, DD2, 7G8) were used as positive controls. Panel A: Proportion of SNPs associated with SP resistance on pfdhps gene: codons S436A, A437G, K540E, K613S/T and A581G. SGKAA, AGKAA are single mutant haplotypes while AGKGS represents double mutant. Mixed infections were excluded in the derivation of allelic haplotypes. Panel B: Proportions of SNPs associated with SP resistance on pfdhfr gene: codons N51I, C59R, S108N and I164L. Proportions are shown for isolates collected at different time-points. CICNI, CNRNI and CNRTI are double mutant haplotypes while CIRNI represents triple mutant. Panel C: Proportions of combined pfdhfr and pfdhps allelic haplotypes. The combined analysis of both loci revealed that more than 80% of the parasite isolates had quadruple pfdhfr/pfdhps allelic haplotypes.
Figure 3
Figure 3
Prevalence rates of recurrent infections. Plasmodium parasites were counted against 200 leukocytes with a 100 × objective lens under oil immersion. Each qPCR reaction mixture contained 5 μL DNA template in a final volume of 20 μL, 10 μL of Master Mix (Applied Biosystem), both the genus-specific and P. falciparum specific primers and probes detection system (Plasmo/Pf) as described [24]. Panel A: Prevalence rates of recurrent infections assessed by microscopy (BS) and PCR. Data are shown as pooled (covering the two months following treatment) or split into first and second month (days 7–30 or 31–60). Panel B: Prevalence rates of recurrent infections assessed by PCR according to the IPTp dose received. Data are shown as pooled (covering the two months following treatment) or split into first and second month (days seven-30 or 31–60).
Figure 4
Figure 4
Proportions of recrudescent and new infections following SP treatment according to the sequence of IPTp uptake.
Figure 5
Figure 5
Prevalence of pfdhfr/pfdhps haplotypes in consecutive parasite samples at baseline and after IPTp uptake.
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