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Declining trend of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant alleles after the withdrawal of Sulfadoxine-Pyrimethamine in North Western Ethiopia.

Tessema SK, Kassa M, Kebede A, Mohammed H, Leta GT, Woyessa A, Guma GT, Petros B - PLoS ONE (2015)

Bottom Line: Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes.The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63) to 15.9% (10/63) (P<0.001), while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65) to 55.4% (40/65) (P = 0.08).The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Faculty of Science, Addis Ababa University, Addis Ababa, Ethiopia.

ABSTRACT
Antimalarial drug resistance is one of the major challenges in global efforts of malaria control and elimination. In 1998, chloroquine was abandoned and replaced with sulfadoxine/pyrimethamine, which in turn was replaced with artemether/lumefantrine for the treatment of uncomplicated falciparum malaria in 2004. Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes. The prevalence of mutation in Pfdhfr and Pfdhps genes were evaluated and compared for a total of 159 isolates collected in two different time points, 2005 and 2007/08, from Pawe hospital, in North Western Ethiopia. The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63) to 15.9% (10/63) (P<0.001), while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65) to 55.4% (40/65) (P = 0.08). The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001). On the whole, significant decline in mutant alleles and re-emergence of wild type alleles were observed. The change in the frequency is explained by the reduction of residual drug-resistant parasites caused by the strong drug pressure imposed when sulfadoxine/pyrimethamine was the first-line drug, followed by lower fitness of these resistant parasites in the absence of drug pressure. Despite the decrease in the frequency of mutant alleles, higher percentages of mutation remain prevalent in the study area in 2007/08 in both Pfdhfr and Pfdhps genes. Therefore, further multi-centered studies in different parts of the country will be required to assess the re-emergence of sulfadoxine/pyrimethamine sensitive parasites and to monitor and prevent the establishment of multi drug resistant parasites in this region.

No MeSH data available.


Related in: MedlinePlus

Temporal changes in the frequency of Pfdhfr and Pfdhps single nucleotide mutations between 2005 and 2007/08.The asterisk indicates the statistical significance of the difference according to Fisher’s exact test.
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pone.0126943.g002: Temporal changes in the frequency of Pfdhfr and Pfdhps single nucleotide mutations between 2005 and 2007/08.The asterisk indicates the statistical significance of the difference according to Fisher’s exact test.

Mentions: The frequency of the Pfdhfr S108N mutation decreased from 92% (58/63) in 2005 to 74.6% (47/63) (P = 0.002) in 2007/08. The relative frequencies of the Pfdhfr C59R and N51I mutations decreased from 62% (39/63) to 25.4% (16/63) (P<0.0001) and from 82.5% (52/63) to 55.5% (35/63) (P <0.0001) in 2005 and 2007/08, respectively. Pfdhps mutation at position 437 decreased from 75.4% (49/65) to 69.8% (44/65) (P = 0.35) and at position 540 decreased from 80% (52/65) to 63% (41/65) in 2005 and 2007 (P = 0.012), respectively (Fig 2). Change in the allelic frequencies of the Pfdhfr triple (S108N/C59R/N51I), Pfdhps double (A437G/K540E) and quintuple (the three Pfdhfr and two Pfdhps) mutations mirrored the trends observed in the prevalence analyses. The frequency of parasites carrying quintuple mutations decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001) between 2005 and 2007/08. A significant decrease in the frequency of Pfdhfr triple mutation (S108N/C59R/N51I), from 50.8% (32/63) to 15.87% (10/63) (P<0.001), was detected. For Pfdhps double mutation (A437G/K540E), there was only a marginal difference between the two surveys with a frequency 69.2% (45/65) and 55.4% (40/65) (P = 0.08) in 2005 and 2007/08, respectively (Fig 3).


Declining trend of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant alleles after the withdrawal of Sulfadoxine-Pyrimethamine in North Western Ethiopia.

Tessema SK, Kassa M, Kebede A, Mohammed H, Leta GT, Woyessa A, Guma GT, Petros B - PLoS ONE (2015)

Temporal changes in the frequency of Pfdhfr and Pfdhps single nucleotide mutations between 2005 and 2007/08.The asterisk indicates the statistical significance of the difference according to Fisher’s exact test.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591967&req=5

pone.0126943.g002: Temporal changes in the frequency of Pfdhfr and Pfdhps single nucleotide mutations between 2005 and 2007/08.The asterisk indicates the statistical significance of the difference according to Fisher’s exact test.
Mentions: The frequency of the Pfdhfr S108N mutation decreased from 92% (58/63) in 2005 to 74.6% (47/63) (P = 0.002) in 2007/08. The relative frequencies of the Pfdhfr C59R and N51I mutations decreased from 62% (39/63) to 25.4% (16/63) (P<0.0001) and from 82.5% (52/63) to 55.5% (35/63) (P <0.0001) in 2005 and 2007/08, respectively. Pfdhps mutation at position 437 decreased from 75.4% (49/65) to 69.8% (44/65) (P = 0.35) and at position 540 decreased from 80% (52/65) to 63% (41/65) in 2005 and 2007 (P = 0.012), respectively (Fig 2). Change in the allelic frequencies of the Pfdhfr triple (S108N/C59R/N51I), Pfdhps double (A437G/K540E) and quintuple (the three Pfdhfr and two Pfdhps) mutations mirrored the trends observed in the prevalence analyses. The frequency of parasites carrying quintuple mutations decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001) between 2005 and 2007/08. A significant decrease in the frequency of Pfdhfr triple mutation (S108N/C59R/N51I), from 50.8% (32/63) to 15.87% (10/63) (P<0.001), was detected. For Pfdhps double mutation (A437G/K540E), there was only a marginal difference between the two surveys with a frequency 69.2% (45/65) and 55.4% (40/65) (P = 0.08) in 2005 and 2007/08, respectively (Fig 3).

Bottom Line: Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes.The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63) to 15.9% (10/63) (P<0.001), while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65) to 55.4% (40/65) (P = 0.08).The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001).

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, Faculty of Science, Addis Ababa University, Addis Ababa, Ethiopia.

ABSTRACT
Antimalarial drug resistance is one of the major challenges in global efforts of malaria control and elimination. In 1998, chloroquine was abandoned and replaced with sulfadoxine/pyrimethamine, which in turn was replaced with artemether/lumefantrine for the treatment of uncomplicated falciparum malaria in 2004. Sulfadoxine/pyrimethamine resistance is associated with mutations in dihydrofolate reductase (Pfdhfr) and dihydropteroate synthase (Pfdhps) genes. The prevalence of mutation in Pfdhfr and Pfdhps genes were evaluated and compared for a total of 159 isolates collected in two different time points, 2005 and 2007/08, from Pawe hospital, in North Western Ethiopia. The frequency of triple Pfdhfr mutation decreased significantly from 50.8% (32/63) to 15.9% (10/63) (P<0.001), while Pfdhps double mutation remained high and changed only marginally from 69.2% (45/65) to 55.4% (40/65) (P = 0.08). The combined Pfdhfr/Pfdhps quintuple mutation, which is strongly associated with sulfadoxine/pyrimethamine resistance, was significantly decreased from 40.7% (24/59) to 13.6% (8/59) (P<0.0001). On the whole, significant decline in mutant alleles and re-emergence of wild type alleles were observed. The change in the frequency is explained by the reduction of residual drug-resistant parasites caused by the strong drug pressure imposed when sulfadoxine/pyrimethamine was the first-line drug, followed by lower fitness of these resistant parasites in the absence of drug pressure. Despite the decrease in the frequency of mutant alleles, higher percentages of mutation remain prevalent in the study area in 2007/08 in both Pfdhfr and Pfdhps genes. Therefore, further multi-centered studies in different parts of the country will be required to assess the re-emergence of sulfadoxine/pyrimethamine sensitive parasites and to monitor and prevent the establishment of multi drug resistant parasites in this region.

No MeSH data available.


Related in: MedlinePlus