Increasing Prevalence of a Novel Triple-Mutant Dihydropteroate Synthase Genotype in Plasmodium falciparum in Western Kenya

Abstract

The molecular basis of sulfadoxine-pyrimethamine (SP) resistance lies in a combination of single-nucleotide polymorphisms (SNPs) in two genes coding for Plasmodium falciparum dihydrofolate reductase (Pfdhfr) and P. falciparum dihydropteroate synthase (Pfdhps), targeted by pyrimethamine and sulfadoxine, respectively. The continued use of SP for intermittent preventive treatment in pregnant women in many African countries, despite SP's discontinuation as a first-line antimalarial treatment option due to high levels of drug resistance, may further increase the prevalence of SP-resistant parasites and/or lead to the selection of new mutations. An antimalarial drug resistance surveillance study was conducted in western Kenya between 2010 and 2013. A total of 203 clinical samples from children with uncomplicated malaria were genotyped for SNPs associated with SP resistance. The prevalence of the triple-mutant Pfdhfr C50 I51R59N108: I164 genotype and the double-mutant Pfdhps S436 G437E540: A581A613 genotype was high. Two triple-mutant Pfdhps genotypes, S436 G437E540G581: A613 and H436G437E540: A581A613, were found, with the latter thus far being uniquely found in western Kenya. The prevalence of the S436 G437E540G581: A613 genotype was low. However, a steady increase in the prevalence of the Pfdhps triple-mutant H436G437E540: A581A613 genotype has been observed since its appearance in early 2000. Isolates with these genotypes shared substantial microsatellite haplotypes with the most common double-mutant allele, suggesting that this triple-mutant allele may have evolved locally. Overall, these findings show that the prevalence of the H436G437E540: A581A613 triple mutant may be increasing in this population and could compromise the efficacy of SP for intermittent preventive treatment in pregnant women if it increases the resistance threshold further.

<p>Trends in Molecular Markers Associated with Resistance to Sulfadoxine-Pyrimethamine (SP) Among <em>Plasmodium falciparum</em> Isolates on Bioko Island, Equatorial Guinea: 2011–2017</p>

“…25 Pfdhfr and Pfdhps sequences from 20 other countries (18 for Pfdhps and 18 for Pfdhfr) were downloaded from NCBI or our previous study 26 to analyse global genetic diversity. [27][28][29][30][31][32][33][34][35][36]…”

“…IRNI and NRNI are the two most common Pfdhfr haplotypes worldwide. In the vast majority of Africa, IRNI is prevalent in many endemic regions, including Bioko Island, Gabon, 37 Cameroon, 33 Kenya 36 and Malawi. 32 NRNI also appears frequently, with a high percentage occurring in countries outside of Africa, such as Iran (92.3%), 39 Nepal (90.6%), 40 India (63.3%), 34 Indonesia (62.5%), 31 and Papua New Guinea (95.7%).…”

“…A significant difference in haplotype profiles was found between East African countries and West African countries along the Atlantic Ocean (Figure 2). SGKAA has been reported to be the dominant haplotype in most African countries along the Atlantic Ocean, including Cameroon, 33 Nigeria, 38 Gabon, 37 Angola, 35 Democratic Republic of Congo 41 and Bioko Island, and SGEAA is the major haplotype in East African countries, such as Uganda, 29 Tanzania, 29 Kenya 36 and Malawi. 32 The wild-type haplotype (SAKAA) is rare in almost all African and Asian countries but prevalent in Haiti 42 and Papua New Guinea.…”

Gaps between Knowledge and Malaria Treatment Practices after Intensive Anti-Malaria Campaigns in Western Kenya: 2004–2016

“…In 2004, households with a better educated household head or with more young children (< 5 years) were more likely to see doctors. Conversely, households (24), rain (6), witchcraft (9), or a combination of these factors (63).…”

“…It should be noted that SP drugs are usually cheaper than ACTs in private shops, 11 and P. falciparum parasite is highly resistant to SP drugs. 24,25 The government has no control of the sales by private drug vendors either in licensed or unlicensed shops. 26,27 In addition, previous studies found that distance to health services influences insecticide-treated net (ITN) possession and use.…”