Two mutations in dihydrofolate reductase combined with one in the dihydropteroate synthase gene predict sulphadoxine-pyrimethamine parasitological failure in Ugandan children with uncomplicated falciparum malaria.
The point mutations in the Plasmodium falciparum dihydrofolate reductase (dhfr) and the dihydropteroate synthase (dhps) genes that are linked to sulphadoxine-pyrimethamine (SP) resistance in vitro have been well characterised. To determine whether a few of these mutations could predict SP treatment failure in vivo, two mutations (Asn-108 and Arg-59) in the dhfr gene and one (Glu-540) in the dhps gene were analysed according to the risk of SP parasitological failure (RI-RIII) at day 28 in pre-treatment isolates in 79 Ugandan children aged 6-59 (mean = 18.4, S.D. = 8.8) months with uncomplicated falciparum malaria. Neither the dhfr-108 (P = 0.3) nor the dhps-540 (P = 0.6) or dhfr-108 + dhps-540 (P = 0.04) mutations were significantly associated with SP parasitological failure. However, the dhfr-108 + dhfr-59 (P = 0.04), the dhfr-59 + dhps-540 (P = 0.04) and the dhfr-108 + dhfr-59 + dhps-540 (P = 0.02) mutations significantly increased the risk for SP parasitological failure. Our findings confirm an earlier report that the dhfr-59 and the dhps-540 mutations could be useful genetic markers for rapid screening of populations at high risk of SP resistance.
Talisuna
Ambrose O
AO
Ministry of Health, Epidemiological Surveillance Division, P. O. Box 7272, Kampala, Uganda, Belgium. atalisuna@yahoo.com
Nalunkuma-Kazibwe
Anne
A
Langi
Peter
P
Mutabingwa
Theonest K
TK
Watkins
William W
WW
Van Marck
Eric
E
Egwang
Thomas G
TG
D'Alessandro
Umberto
U
D000818:Animals; D000962:Antimalarials / Q000009:adverse effects* / Q000627:therapeutic use; D002675:Child, Preschool; D004094:Dihydropteroate Synthase / Q000235:genetics*; D004338:Drug Combinations; D004351:Drug Resistance; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000188:drug therapy*; D010963:Plasmodium falciparum / Q000201:enzymology / Q000235:genetics*; D017354:Point Mutation; D011739:Pyrimethamine / Q000009:adverse effects* / Q000627:therapeutic use; D012189:Retrospective Studies; D013413:Sulfadoxine / Q000009:adverse effects* / Q000627:therapeutic use; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics*; D013997:Time Factors; D017211:Treatment Failure; D014454:Uganda / Q000453:epidemiology
D000962:Antimalarials; D004338:Drug Combinations; D013413:Sulfadoxine; D013762:Tetrahydrofolate Dehydrogenase; D004094:Dihydropteroate Synthase; D011739:Pyrimethamine