Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine

mutations in pvdhfr and pvmdr1

Jutta Marfurt, F Demonbrison, S Brega, L Barbollat, Ivo Muller, Albert Sie, M Goroti, John C Reeder, Hans-Peter Beck, S PICOT, Blaise Genton

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background. Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce. Methods. We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response. Results. The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P = .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P = .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites. Conclusions. The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used. � 2008 by the Infectious Diseases Society of America. All rights reserved.
Original languageEnglish
Pages (from-to)409-417
Number of pages9
JournalJournal of Infectious Diseases
Volume198
Issue number3
Publication statusPublished - 2008

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Amodiaquine
Plasmodium vivax
Treatment Failure
Mutation
Parasites
Odds Ratio
Papua New Guinea
Drug Resistance
Genotype
pyrimethamine drug combination fanasil
Therapeutics
Pharmaceutical Preparations

Cite this

Marfurt, Jutta ; Demonbrison, F ; Brega, S ; Barbollat, L ; Muller, Ivo ; Sie, Albert ; Goroti, M ; Reeder, John C ; Beck, Hans-Peter ; PICOT, S ; Genton, Blaise. / Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine : mutations in pvdhfr and pvmdr1. In: Journal of Infectious Diseases. 2008 ; Vol. 198, No. 3. pp. 409-417.
@article{78d5c7c76c10410cb2d195cdb08724ed,
title = "Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1",
abstract = "Background. Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce. Methods. We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response. Results. The treatment failure (TF) rate reached 13{\%}. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60{\%}, 67{\%}, 20{\%}, 40{\%}, and 39{\%} of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P = .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P = .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites. Conclusions. The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used. � 2008 by the Infectious Diseases Society of America. All rights reserved.",
keywords = "amodiaquine, fansidar, molecular marker, antibiotic resistance, article, female, gene locus, gene mutation, genetic polymorphism, genotype, haplotype, human, major clinical study, male, Papua New Guinea, parasitemia, Plasmodium vivax, preschool child, prevalence, priority journal, treatment failure, treatment response, Amodiaquine, Animals, Antimalarials, Child, Preschool, Drug Combinations, Drug Resistance, Female, Genetic Markers, Humans, Infant, Malaria, Vivax, Male, Mutation, Missense, P-Glycoprotein, Polymorphism, Genetic, Protozoan Proteins, Pyrimethamine, Sulfadoxine, Tetrahydrofolate Dehydrogenase, Treatment Outcome",
author = "Jutta Marfurt and F Demonbrison and S Brega and L Barbollat and Ivo Muller and Albert Sie and M Goroti and Reeder, {John C} and Hans-Peter Beck and S PICOT and Blaise Genton",
year = "2008",
language = "English",
volume = "198",
pages = "409--417",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "3",

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Marfurt, J, Demonbrison, F, Brega, S, Barbollat, L, Muller, I, Sie, A, Goroti, M, Reeder, JC, Beck, H-P, PICOT, S & Genton, B 2008, 'Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine: mutations in pvdhfr and pvmdr1', Journal of Infectious Diseases, vol. 198, no. 3, pp. 409-417.

Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine : mutations in pvdhfr and pvmdr1. / Marfurt, Jutta; Demonbrison, F; Brega, S; Barbollat, L; Muller, Ivo; Sie, Albert; Goroti, M; Reeder, John C; Beck, Hans-Peter; PICOT, S; Genton, Blaise.

In: Journal of Infectious Diseases, Vol. 198, No. 3, 2008, p. 409-417.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Molecular markers of in vivo Plasmodium vivax resistance to amodiaquine plus sulfadoxine-pyrimethamine

T2 - mutations in pvdhfr and pvmdr1

AU - Marfurt, Jutta

AU - Demonbrison, F

AU - Brega, S

AU - Barbollat, L

AU - Muller, Ivo

AU - Sie, Albert

AU - Goroti, M

AU - Reeder, John C

AU - Beck, Hans-Peter

AU - PICOT, S

AU - Genton, Blaise

PY - 2008

Y1 - 2008

N2 - Background. Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce. Methods. We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response. Results. The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P = .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P = .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites. Conclusions. The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used. � 2008 by the Infectious Diseases Society of America. All rights reserved.

AB - Background. Molecular markers for sulfadoxine-pyrimethamine (SP) resistance in Plasmodium vivax have been reported. However, data on the molecular correlates involved in the development of resistance to 4-aminoquinolines and their association with the in vivo treatment response are scarce. Methods. We assessed pvdhfr (F57L/I, S58R, T61M, S117T/N, and I173F/L) and pvmdr1 (Y976F and F1076L) mutations in 94 patients who received amodiaquine (AQ) plus SP in Papua New Guinea (PNG). We then investigated the association between parasite genotype and treatment response. Results. The treatment failure (TF) rate reached 13%. Polymorphisms in pvdhfr F57L, S58R, T61M, and S117T/N and in pvmdr1 Y976F were detected in 60%, 67%, 20%, 40%, and 39% of the samples, respectively. The single mutant pvdhfr 57 showed the strongest association with TF (odds ratio [OR], 9.04; P = .01). The combined presence of the quadruple mutant pvdhfr 57L+58R+61M+117T and pvmdr1 mutation 976F was the best predictor of TF (OR, 8.56; P = .01). The difference in TF rates between sites was reflected in the genetic drug-resistance profile of the respective parasites. Conclusions. The present study identified a new molecular marker in pvmdr1 that is associated with the in vivo response to AQ+SP. We suggest suitable marker sets with which to monitor P. vivax resistance against AQ+SP in countries where these drugs are used. � 2008 by the Infectious Diseases Society of America. All rights reserved.

KW - amodiaquine

KW - fansidar

KW - molecular marker

KW - antibiotic resistance

KW - article

KW - female

KW - gene locus

KW - gene mutation

KW - genetic polymorphism

KW - genotype

KW - haplotype

KW - human

KW - major clinical study

KW - male

KW - Papua New Guinea

KW - parasitemia

KW - Plasmodium vivax

KW - preschool child

KW - prevalence

KW - priority journal

KW - treatment failure

KW - treatment response

KW - Amodiaquine

KW - Animals

KW - Antimalarials

KW - Child, Preschool

KW - Drug Combinations

KW - Drug Resistance

KW - Female

KW - Genetic Markers

KW - Humans

KW - Infant

KW - Malaria, Vivax

KW - Male

KW - Mutation, Missense

KW - P-Glycoprotein

KW - Polymorphism, Genetic

KW - Protozoan Proteins

KW - Pyrimethamine

KW - Sulfadoxine

KW - Tetrahydrofolate Dehydrogenase

KW - Treatment Outcome

M3 - Article

VL - 198

SP - 409

EP - 417

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 3

ER -