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

I F Khalil; M Alifrangis; D S Tarimo; T Staalsø; G M H Satti; T G Theander; A M Rønn; I C Bygbjerg

doi:10.1179/136485905X46441

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

I F Khalil, M Alifrangis, D S Tarimo, T Staalsø, G M H Satti, T G Theander, A M Rønn, I C Bygbjerg

28 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Annals of Tropical Medicine and Parasitology
Volume	99
Issue number	5
Pages (from-to)	441-8
Number of pages	7
ISSN	0003-4983
DOIs	https://doi.org/10.1179/136485905X46441
Publication status	Published - 2005

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Khalil, I. F., Alifrangis, M., Tarimo, D. S., Staalsø, T., Satti, G. M. H., Theander, T. G., Rønn, A. M., & Bygbjerg, I. C. (2005). 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. Annals of Tropical Medicine and Parasitology, 99(5), 441-8. https://doi.org/10.1179/136485905X46441

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. / Khalil, I F; Alifrangis, M; Tarimo, D S et al.
In: Annals of Tropical Medicine and Parasitology, Vol. 99, No. 5, 2005, p. 441-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Khalil, IF, Alifrangis, M, Tarimo, DS, Staalsø, T, Satti, GMH, Theander, TG, Rønn, AM & Bygbjerg, IC 2005, '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', Annals of Tropical Medicine and Parasitology, vol. 99, no. 5, pp. 441-8. https://doi.org/10.1179/136485905X46441

Khalil IF, Alifrangis M, Tarimo DS, Staalsø T, Satti GMH, Theander TG et al. 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. Annals of Tropical Medicine and Parasitology. 2005;99(5):441-8. doi: 10.1179/136485905X46441

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title = "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",

abstract = "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.",

author = "Khalil, {I F} and M Alifrangis and Tarimo, {D S} and T Staals{\o} and Satti, {G M H} and Theander, {T G} and R{\o}nn, {A M} and Bygbjerg, {I C}",

note = "Keywords: ATP-Binding Cassette Transporters; Adult; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Resistance; Genes, MDR; Humans; Malaria, Falciparum; Membrane Proteins; Membrane Transport Proteins; Mutation; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Sudan; Tanzania",

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T1 - 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

AU - Khalil, I F

AU - Alifrangis, M

AU - Tarimo, D S

AU - Staalsø, T

AU - Satti, G M H

AU - Theander, T G

AU - Rønn, A M

AU - Bygbjerg, I C

N1 - Keywords: ATP-Binding Cassette Transporters; Adult; Animals; Antimalarials; Child; Child, Preschool; Chloroquine; Drug Resistance; Genes, MDR; Humans; Malaria, Falciparum; Membrane Proteins; Membrane Transport Proteins; Mutation; Parasitemia; Plasmodium falciparum; Protozoan Proteins; Sudan; Tanzania

PY - 2005

Y1 - 2005

N2 - 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.

AB - 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.

U2 - 10.1179/136485905X46441

DO - 10.1179/136485905X46441

M3 - Journal article

C2 - 16004703

SN - 0003-4983

VL - 99

SP - 441

EP - 448

JO - Annals of Tropical Medicine and Parasitology

JF - Annals of Tropical Medicine and Parasitology

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