The roles of the pfcrt 76T and pfmdr1 86Y mutations, immunity and the initial level of parasitaemia, in predicting the outcome of chloroquine treatment in two areas with different transmission intensities.
The resistance of Plasmodium falciparum to chloroquine (CQ) is probably mediated by point mutations in two genes: pfcrt and pfmdr1. The aim of the present study was to investigate, in patients treated with CQ, the association between host factors, such as immunity and initial level of parasitaemia, and the ability to clear P. falciparum parasites carrying the key chloroquine-resistance (CQR) mutations, pfcrt 76T and pfmdr1 86Y. Identical CQ-efficacy trials were performed in 51 young children (aged <5 years) from Kibaha, in north-western Tanzania, and 44 patients (aged 3-57 years) from Darawish, in eastern Sudan. In both areas, all the CQ-treatment failures had infections with the 76T and 86Y alleles before treatment. Although the presence of these two alleles was significantly associated with treatment failure in Sudan (P=0.001), the corresponding association in Tanzania did not reach statistical significance (P=0.1). Of the 39 patients from Darawish and 44 from Kibaha who harboured parasites with the CQR mutations, 12 and 19, respectively, managed to clear their parasitaemias. The ability to clear CQR parasites was significantly associated with the initial level of parasitaemia (with P-values of 0.05 in Tanzania and 0.01 in Sudan) and with age-- the best surrogate for protective immunity in endemic areas (with P-values of 0.02 in Tanzania and 0.001 in Sudan). These results confirm previous observations that indicated that the 76T and 86Y alleles play a role in the mechanism of CQR, although other factors, such as level of parasitaemia when treated and age, are also important. The 76T and 86Y alleles could still be used as predictive markers for CQR, in non-immune individuals and low-transmission areas.
Khalil
I F
IF
Department of International Health, Institute for Medical Microbiology and Immunology and Center for Medical Parasitology (CMP), Copenhagen, Denmark. insafk@immi.ku.dk
Alifrangis
M
M
Tarimo
D S
DS
Staalsø
T
T
Satti
G M H
GM
Theander
T G
TG
Rønn
A M
AM
Bygbjerg
I C
IC
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000328:Adult; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D019450:Genes, MDR / Q000235:genetics / Q000276:immunology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009154:Mutation; D018512:Parasitemia / Q000235:genetics* / Q000276:immunology; D010963:Plasmodium falciparum / Q000235:genetics; D015800:Protozoan Proteins / Q000235:genetics*; D013397:Sudan; D013636:Tanzania
D018528:ATP-Binding Cassette Transporters; D000962:Antimalarials; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; C416369:PfCRT protein, Plasmodium falciparum; D015800:Protozoan Proteins; C059987:mdr gene protein, Plasmodium; D002738:Chloroquine