Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand

A Uhlemann, R McGready, Elizabeth Ashley, A Brockman, Pratap Singhasivanon, Sanjeev Krishna, N WHITE, F NOSTEN, Ric Price

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background. Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. Methods. In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. Results. Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P < .001). Conclusions. Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites. � 2006 by the Infectious Diseases Society of America. All rights reserved.
    Original languageEnglish
    Pages (from-to)134-141
    Number of pages8
    JournalJournal of Infectious Diseases
    Volume195
    Issue number1
    Publication statusPublished - 2007

    Fingerprint

    Antimalarials
    Thailand
    Plasmodium falciparum
    Parasites
    Alleles
    Artemisinins
    Confidence Intervals
    Mefloquine
    Quinine
    Multiple Drug Resistance
    Infection
    Treatment Failure
    Single Nucleotide Polymorphism
    Therapeutics
    Costs and Cost Analysis
    Population

    Cite this

    Uhlemann, A ; McGready, R ; Ashley, Elizabeth ; Brockman, A ; Singhasivanon, Pratap ; Krishna, Sanjeev ; WHITE, N ; NOSTEN, F ; Price, Ric. / Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand. In: Journal of Infectious Diseases. 2007 ; Vol. 195, No. 1. pp. 134-141.
    @article{cac59378ace94deaa976f3e8ed230fb1,
    title = "Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand",
    abstract = "Background. Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. Methods. In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. Results. Intrahost changes in pfmdr1 copy number were observed in 20{\%} (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68{\%} (95{\%} confidence interval [CI], 46{\%}-85{\%}), and decreases occurred in 2{\%} (95{\%} CI, 0.4{\%}-11{\%}) of isolates; corresponding proportions after artemether-lumefantrine were 25{\%} (2/8) and 11{\%} (2/19); after quinine, 50{\%} (1/2) and 40{\%} (4/10); and after artemisinins alone, 0{\%} (0/10) and 19{\%} (3/16) of isolates (overall P < .001). Conclusions. Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites. � 2006 by the Infectious Diseases Society of America. All rights reserved.",
    keywords = "artemether, artemether plus benflumetol, artemisinin, artesunate, benflumetol, mefloquine, quinine, allele, article, combination chemotherapy, drug treatment failure, gene, gene amplification, host selection, human, malaria, monotherapy, multidrug resistance, nonhuman, pfmdr1 gene, Plasmodium falciparum, priority journal, recurrent infection, single nucleotide polymorphism, Thailand, Alleles, Animals, Antimalarials, DNA, Protozoan, Drug Resistance, Multiple, Multidrug Resistance-Associated Proteins",
    author = "A Uhlemann and R McGready and Elizabeth Ashley and A Brockman and Pratap Singhasivanon and Sanjeev Krishna and N WHITE and F NOSTEN and Ric Price",
    year = "2007",
    language = "English",
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    pages = "134--141",
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    Uhlemann, A, McGready, R, Ashley, E, Brockman, A, Singhasivanon, P, Krishna, S, WHITE, N, NOSTEN, F & Price, R 2007, 'Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand', Journal of Infectious Diseases, vol. 195, no. 1, pp. 134-141.

    Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand. / Uhlemann, A; McGready, R; Ashley, Elizabeth; Brockman, A; Singhasivanon, Pratap; Krishna, Sanjeev; WHITE, N; NOSTEN, F; Price, Ric.

    In: Journal of Infectious Diseases, Vol. 195, No. 1, 2007, p. 134-141.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Intrahost Selection of Plasmodium falciparum pfmdr1 Alleles after Antimalarial Treatment on the Northwestern Border of Thailand

    AU - Uhlemann, A

    AU - McGready, R

    AU - Ashley, Elizabeth

    AU - Brockman, A

    AU - Singhasivanon, Pratap

    AU - Krishna, Sanjeev

    AU - WHITE, N

    AU - NOSTEN, F

    AU - Price, Ric

    PY - 2007

    Y1 - 2007

    N2 - Background. Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. Methods. In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. Results. Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P < .001). Conclusions. Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites. � 2006 by the Infectious Diseases Society of America. All rights reserved.

    AB - Background. Increased pfmdr1 copy number is associated with reduced susceptibility to structurally unrelated antimalarial drugs. We assessed how administration of different antimalarial drugs altered pfmdr1 polymorphism in parasites from patients who experienced treatment failure. Methods. In studies conducted on the northwestern border of Thailand, amplifications and single-nucleotide polymorphisms in pfmdr1 were compared before and after antimalarial drug treatment. Results. Intrahost changes in pfmdr1 copy number were observed in 20% (26/132) of patients with recurrent infections. Among infections that recrudesced after mefloquine-containing regimens, increases in pfmdr1 copy number occurred in 68% (95% confidence interval [CI], 46%-85%), and decreases occurred in 2% (95% CI, 0.4%-11%) of isolates; corresponding proportions after artemether-lumefantrine were 25% (2/8) and 11% (2/19); after quinine, 50% (1/2) and 40% (4/10); and after artemisinins alone, 0% (0/10) and 19% (3/16) of isolates (overall P < .001). Conclusions. Intrahost selection based on pfmdr1 copy number occurs frequently in parasite populations within individual patients. Amplification confers multidrug resistance but probably imposes a significant fitness cost to the parasites. � 2006 by the Infectious Diseases Society of America. All rights reserved.

    KW - artemether

    KW - artemether plus benflumetol

    KW - artemisinin

    KW - artesunate

    KW - benflumetol

    KW - mefloquine

    KW - quinine

    KW - allele

    KW - article

    KW - combination chemotherapy

    KW - drug treatment failure

    KW - gene

    KW - gene amplification

    KW - host selection

    KW - human

    KW - malaria

    KW - monotherapy

    KW - multidrug resistance

    KW - nonhuman

    KW - pfmdr1 gene

    KW - Plasmodium falciparum

    KW - priority journal

    KW - recurrent infection

    KW - single nucleotide polymorphism

    KW - Thailand

    KW - Alleles

    KW - Animals

    KW - Antimalarials

    KW - DNA, Protozoan

    KW - Drug Resistance, Multiple

    KW - Multidrug Resistance-Associated Proteins

    M3 - Article

    VL - 195

    SP - 134

    EP - 141

    JO - Journal of Infectious Diseases

    JF - Journal of Infectious Diseases

    SN - 0022-1899

    IS - 1

    ER -