Abstract
BackgroundMalaria in Yemen is mainly caused by Plasmodium falciparum and 25 % of the population is at high risk. Sulfadoxine–pyrimethamine (SP) had been used as monotherapy against P. falciparum. Emergence of chloroquine resistance led to the shift in anti-malarial treatment policy in Yemen to artemisinin-based combination therapy, that is artesunate (AS) plus SP as first-line therapy for uncomplicated malaria and artemether–lumefantrine as second-line treatment. This study aimed to screen mutations in the dihydrofolate reductase (dhfr) and dihydropteroate synthetase (dhps) genes associated with SP resistance among P. falciparum population in Hadhramout governorate, Yemen.MethodsGenomic DNA was extracted from dried blood spots of 137 P. falciparum isolates collected from a community-based study. DNA was amplified using nested polymerase chain reaction (PCR) and subsequently sequenced for Pfdhfr and Pfdhps genes. Sequences were analysed for mutations in Pfdhfr gene codons 51, 59, 108, and 164 and in Pfdhps gene codons 436, 437, and 540.ResultsA total of 128 and 114 P. falciparum isolates were successfully sequenced for Pfdhfr and Pfdhps genes, respectively. Each Pfdhfr mutant allele (I51 and N108) in P. falciparum population had a frequency of 84 %. PfdhfrR59 mutant allele was detected in one isolate. Mutation at codon 437 (G437) in the Pfdhps gene was detected in 44.7 % of falciparum malaria isolates. Frequencies of Pfdhfr double mutant genotype (I51C59N108I164) and Pfdhfr/Pfdhps triple mutant genotype (I51C59N108I164-S436G437K540) were 82.8 and 39.3 %, respectively. One isolate harboured Pfdhfr triple mutant genotype (I51, R59, N108, I164) and Pfdhfr/Pfdhps quadruple mutant genotype (I51R59N108I164-S436G437K540).ConclusionHigh frequencies of Pfdhfr and Pfdhps mutant alleles and genotypes in P. falciparum population in Hadhramout, Yemen, highlight the risk of developing resistance for SP, the partner drug of AS, which subsequently will expose the parasite to AS monotherapy increasing then the potential of the emergence of AS resistance. Study findings necessitate the continuous monitoring of the efficacy of the national anti-malarial drugs policy in Yemen. In addition, monitoring SP efficacy using molecular markers that has shown to be a practical and informative method for monitoring the partner drug of AS.
Highlights
Malaria in Yemen is mainly caused by Plasmodium falciparum and 25 % of the population is at high risk
A total of 137 patients infected with P. falciparum based on microscopic examination of blood smear and nested polymerase chain reaction (PCR) were included in the analysis of Pfdhfr mutations at codons 51, 59, 108, and 164, as well as Pfdhps mutations at codons 436, 437, and 540
Of the 137 P. falciparum isolates, genomic DNAs from 128 and 114 isolates were successfully sequenced for Pfdhfr and Pdhps genes, respectively
Summary
Malaria in Yemen is mainly caused by Plasmodium falciparum and 25 % of the population is at high risk. Emergence of chloroquine resistance led to the shift in anti-malarial treatment policy in Yemen to artemisinin-based combination therapy, that is artesunate (AS) plus SP as first-line therapy for uncomplicated malaria and artemether–lumefantrine as second-line treatment. The national anti-malarial drug policy in Yemen was formulated in 1999, including chloroquine (CQ) as firstline and sulfadoxine–pyrimethamine (SP) as a second line monotherapy for treating uncomplicated falciparum malaria [5]. In 2005, due to the increased CQ resistance, anti-malarial drug policy shifted to a combination of artesunate (AS) and SP as the first-line therapy and artemether–lumefantrine as a second-line treatment for uncomplicated malaria [6]. The efficacity of AS + SP as first-line treatment for uncomplicated falciparum malaria was rated at 97 % ACPR in a recent clinical drug efficacy trail carried out in 2013 [8]. It is noteworthy that currently used routine clinical efficacy trail is the gold standard for the assessment of the efficiency of the combined anti-malarial drugs, it does not differentiate between the efficacy of AS and its partner drug
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