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",

    }

    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 -