High prevalence of pfdhfr–pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine–pyrimethamine in combination with artesunate as first-line treatment in Iran

Rouhani, Maryam; Zakeri, Sedigheh; Pirahmadi, Sakineh; Ahmad, Rasheed; Djadid, Navid Dinparast

doi:10.1016/j.meegid.2015.01.020

Cited by 10 publications

(13 citation statements)

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“…Mutant genotype ( I 51 C 59 N 108 I 164 -S 436 G 437 K 540 ), which combined Pfdhfr double mutants ( I 51 , N 108 ) and Pfdhps single mutant ( G 437 ), was highly prevalent among P. falciparum isolates. Lower frequencies of this mutant genotype compared with the present study have been reported from southeastern Iran at 2.7 % during 2008–2005 [ 40 ] and again at 1.8 % during 2008–2010 [ 47 ], as well as in Tanzania at 0.1 % [ 48 ]. Literature review showed that this genotype is not widely distributed and has not been correlated yet with the efficacy of SP either in vitro or in vivo.…”

Section: Discussioncontrasting

confidence: 62%

Frequencies distribution of dihydrofolate reductase and dihydropteroate synthetase mutant alleles associated with sulfadoxine–pyrimethamine resistance in Plasmodium falciparum population from Hadhramout Governorate, Yemen

Bamaga

Mahdy

Lim

2015

Malar J

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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.

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Section: Discussioncontrasting

confidence: 62%

Frequencies distribution of dihydrofolate reductase and dihydropteroate synthetase mutant alleles associated with sulfadoxine–pyrimethamine resistance in Plasmodium falciparum population from Hadhramout Governorate, Yemen

Bamaga

Mahdy

Lim

2015

Malar J

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“…Surveys from Pakistan within the last decade show significant numbers of parasites mutated at DHPS 437G [ 26 – 28 ] as well as 540E and 581G (generally in mixed infections) [ 28 ]. Studies in central India [ 29 , 30 ] and Iran [ 31 , 32 ] also describe increasing mutations at 437G. However, AS + SP treatment of P. falciparum does not yet appear to have been significantly compromised by molecular changes in any of these locations.…”

Section: Discussionmentioning

confidence: 99%

Clinical trials of artesunate plus sulfadoxine-pyrimethamine for Plasmodium falciparum malaria in Afghanistan: maintained efficacy a decade after introduction

Awab

Imwong

Pukrittayakamee

et al. 2016

Malar J

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BackgroundCombination therapy with artesunate plus sulfadoxine-pyrimethamine (SP) was adopted as recommended treatment for Plasmodium falciparum infection in Afghanistan in 2003.MethodsA series of prospective clinical studies examining the efficacy of artesunate plus sulfadoxine-pyrimethamine (AS + SP) against P. falciparum were undertaken in sentinel sites in Afghanistan from 2007 to 2014, accompanied by relevant molecular studies. The first study was a randomized trial of AS + SP versus dihydroartemisinin-piperaquine, while two subsequent studies were standard therapeutic efficacy studies of AS + SP.ResultsThree hundred and three patients were enrolled across four provinces in the north and east of the country. Curative efficacy was high in all the trials, with an adequate clinical and parasitological response (ACPR) of more than 95 % in all groups and trial stages. Genotyping for drug-resistance alleles at dhfr indicated fixation of the S108 N mutation and a prevalence of the C59R mutation of approximately 95 % across all sites. Other mutations in dhfr and dhps remained rare or absent entirely, although five isolates from the first trial carried the dhps triple mutant SGEGA haplotype. In the last study undertaken in 2012–2014 the K13 artemisinin resistance marker was examined; only two of 60 successfully sequenced samples carried a K13-propeller mutation.ConclusionsThese data confirm maintained efficacy 10 years after introduction of artesunate plus SP as combination treatment of P. falciparum in Afghanistan. The molecular data indicate that despite a substantial fall in incidence, resistance has not developed to artemisinins, or intensified to the ACT partner drug components.Trial Registrationhttp://www.clinicaltrials.gov/ct NCT00682578, NCT01115439 and NCT01707199

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“…Several studies following these methodologies in genes conferring resistance to antimalarials in P. falciparum have indicated evolutionary potential of these genes both at the global scale and also in India (Awasthi et al, 2011; Brown et al, 2015; Das and Dash, 2007; Kumar et al, 2015; Li et al, 2015; Rouhani et al, 2015). Mutations in the gene encoding a P. falciparum CQ resistance transporter ( Pfcrt ) and resulting change in single amino acid (AA) locus 76 from K to T (K76T) were proven a strong marker for CQ (Fidock et al, 2000; Valderramos et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, mutations in the P. falciparum multi-drug resistance gene ( Pfmdr1 ) conferring single AA change at point 86 from N to Y (N86Y) and/or multi-copy number of Pfmdr1 was further reported to be linked with K76T and CQ resistance conferring synergistic increase in resistance when combined (Babiker et al, 2001; Chauhan et al, 2014; Foote et al, 1990; Mwai et al, 2009; Price et al, 1999). Furthermore, mutations (S436A and A437G) in the P. falciparum dihydrofolate reductase enzyme coding gene singly pose mild resistance to SP drugs, and when linked with mutations A581G and /or K540E and /or A613S/T, confer high resistance (McCollum et al, 2012; Peterson et al, 1988; Rouhani et al, 2015). Moreover, polymorphism in the Pfdhps gene encoding S108N is the core mutation, but this confers comparatively lower resistance when present singly (Brooks et al, 1994; McCollum et al, 2012; Reeder et al, 1996; Triglia et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, accumulation of multiple mutations in Pfdhfr gene resulting in double mutants (C59R/S108N and N51I/S108N) shows moderate levels of resistance, the triple mutants N51I/C59R/S108N show a significant level, and the quadruple mutant parasite (N51I/C59R/ S108N/I164L) is considered to be completely resistant to pyrimethamine (McCollum et al, 2012; Sirawaraporn et al, 1997). Very similarly, co-accumulation of resistance-conferring mutations in both the Pfdhfr and Pfdhps genes synergistically diminishes the success of SP (Rouhani et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

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Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

Kar

Chauhan

Nanda

et al. 2016

Infection, Genetics and Evolution

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Considering malaria as a local and focal disease, epidemiological understanding of different ecotypes of malaria can help in devising novel control measures. One of the major hurdles in malaria control lies on the evolution and dispersal of the drug-resistant malaria parasite, Plasmodium falciparum. We herewith present data on genetic variation at the Single Nucleotide Polymorphism (SNP) level in four different genes of P. falciparum (Pfcrt, Pfmdr1, Pfdhfr, and Pfdhps) that confer resistance to different antimalarials in two different eco-epidemiological settings, i.e. Hilly-Forest (HF) and Riverine-Plain (RP), in a high malaria endemic district of Odisha state, India. Greater frequency of antimalarial resistance conferring SNPs and haplotypes was observed in all four genes in P. falciparum, and Pfdhps was the most variable gene among the four. No significant genetic differentiation could be observed in isolates from HF and RP ecotypes. Twelve novel, hitherto unreported nucleotide mutations could be observed in the Pfmdr1 and Pfdhps genes. While the Pfdhps gene presented highest haplotype diversity, the Pfcrt gene displayed the highest nucleotide diversity. When the data on all the four genes were complied, the isolates from HF ecotype were found to harbour higher average nucleotide diversity than those from RP ecotype. High and positive Tajima’s D values were obtained for the Pfcrt and Pfdhfr genes in isolates from both the HF and RP ecotypes, with statistically significant deviation from neutrality in the RP ecotype. Different pattern of Linkage Disequilibrium (LD) among SNPs located in different drug-resistant genes was found in the isolates collected from HF and RP ecotypes. Whereas in the HF ecotype, SNPs in the Pfmdr1 and Pfdhfr were significantly associated, in the RP ecotype, SNPs located in Pfcrt were associated with Pfmdr1, Pfdhfr and Pfdhps. These findings provide a baseline understanding on how different micro eco-epidemiological settings influence evolution and spread of different drug resistance alleles. Our findings further suggest that drug resistance to chloroquine and sulfadoxine-pyrimethamine is approaching fixation level, which requires urgent attention of malaria control program in India.

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High prevalence of pfdhfr–pfdhps triple mutations associated with anti-malarial drugs resistance in Plasmodium falciparum isolates seven years after the adoption of sulfadoxine–pyrimethamine in combination with artesunate as first-line treatment in Iran

Cited by 10 publications

References 57 publications

Frequencies distribution of dihydrofolate reductase and dihydropteroate synthetase mutant alleles associated with sulfadoxine–pyrimethamine resistance in Plasmodium falciparum population from Hadhramout Governorate, Yemen

Frequencies distribution of dihydrofolate reductase and dihydropteroate synthetase mutant alleles associated with sulfadoxine–pyrimethamine resistance in Plasmodium falciparum population from Hadhramout Governorate, Yemen

Clinical trials of artesunate plus sulfadoxine-pyrimethamine for Plasmodium falciparum malaria in Afghanistan: maintained efficacy a decade after introduction

Comparative assessment on the prevalence of mutations in the Plasmodium falciparum drug-resistant genes in two different ecotypes of Odisha state, India

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