title: Declining trend of Plasmodium falciparum dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) mutant alleles after the withdrawal of Sulfadoxine-Pyrimethamine in North Western 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.
authors.affiliation: Department of Biology, Faculty of Science, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Sofonias K
authors.initials: SK
authors.lastname: Tessema
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Moges
authors.initials: M
authors.lastname: Kassa
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Amha
authors.initials: A
authors.lastname: Kebede
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Hussein
authors.initials: H
authors.lastname: Mohammed
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Gemechu Tadesse
authors.initials: GT
authors.lastname: Leta
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Adugna
authors.initials: A
authors.lastname: Woyessa
authors.affiliation: Ethiopian Public Health Institute, Addis Ababa, Ethiopia.
authors.forename: Geremew Tasew
authors.initials: GT
authors.lastname: Guma
authors.affiliation: Department of Biology, Faculty of Science, Addis Ababa University, Addis Ababa, Ethiopia.
authors.forename: Beyene
authors.initials: B
authors.lastname: Petros
mesh_terms: D000483:Alleles; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D005002:Ethiopia / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000453:epidemiology; D009154:Mutation; D010963:Plasmodium falciparum / Q000201:enzymology* / Q000235:genetics; D011739:Pyrimethamine / Q000627:therapeutic use*; D013413:Sulfadoxine / Q000627:therapeutic use*; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*
chemical_list: D000962:Antimalarials; D004338:Drug Combinations; C001205:fanasil, pyrimethamine drug combination; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine