Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment

Verena Carrara, Julien Zwang, Elizabeth Ashley, Ric Price, Kasia Stepniewska, Marion Barends, A Brockman, Tim Anderson, Rose McGready, Lucy Phaiphun, Stephane Proux, M Vanvugt, R Hutagalung, Khin Manug Lwin, Aung Pyae Phyo, P Preechapornkul, Mallika Imwong, S Pukrittayakamee, Pratap Singhasivanon, Nicholas J White & 1 others François Nosten

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3 ), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border.

    Methods and Findings: 3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0-98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2-5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/ 40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend).
    Conclusion: Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage. � 2009 Carrara et al.
    Original languageEnglish
    Article numbere4551
    Pages (from-to)1-11
    Number of pages11
    JournalPLoS One
    Volume4
    Issue number2
    DOIs
    Publication statusPublished - 23 Feb 2009

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    Mefloquine
    Thailand
    malaria
    parasites
    artemisinin
    gametocytes
    antimalarials
    Myanmar
    parasitemia
    Rosa
    testing
    Antimalarials
    Therapeutics
    Parasitic Diseases
    infection
    Parasitemia
    Falciparum Malaria
    Hazards
    Malaria
    Parasites

    Cite this

    Carrara, Verena ; Zwang, Julien ; Ashley, Elizabeth ; Price, Ric ; Stepniewska, Kasia ; Barends, Marion ; Brockman, A ; Anderson, Tim ; McGready, Rose ; Phaiphun, Lucy ; Proux, Stephane ; Vanvugt, M ; Hutagalung, R ; Lwin, Khin Manug ; Phyo, Aung Pyae ; Preechapornkul, P ; Imwong, Mallika ; Pukrittayakamee, S ; Singhasivanon, Pratap ; White, Nicholas J ; Nosten, François. / Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment. In: PLoS One. 2009 ; Vol. 4, No. 2. pp. 1-11.
    @article{189c50440f204f1c9f59426c0a76a886,
    title = "Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment",
    abstract = "Background: Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3 ), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border. Methods and Findings: 3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5{\%} before 2001 to 21.9{\%} since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95{\%} CI, 2.00-2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95{\%} CI, 1.07-1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5{\%} (95{\%} CI, 91.0-98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95{\%} CI, 3.2-5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30{\%} (12/ 40) in 1996 to 53{\%} (24/45) in 2006 (p = 0.012, test for trend). Conclusion: Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage. � 2009 Carrara et al.",
    keywords = "antimalarial agent, artesunate, artesunate plus mefloquin, doxycycline, mefloquine, unclassified drug, clinical trial, dose response, drug bioavailability, drug dose regimen, drug efficacy, drug sensitivity, gametocyte, gene number, human, in vitro study, major clinical study, malaria falciparum, migration, Myanmar, parasitosis, Plasmodium falciparum, recurrent infection, review, single drug dose, Thailand, trend study, Artesunate",
    author = "Verena Carrara and Julien Zwang and Elizabeth Ashley and Ric Price and Kasia Stepniewska and Marion Barends and A Brockman and Tim Anderson and Rose McGready and Lucy Phaiphun and Stephane Proux and M Vanvugt and R Hutagalung and Lwin, {Khin Manug} and Phyo, {Aung Pyae} and P Preechapornkul and Mallika Imwong and S Pukrittayakamee and Pratap Singhasivanon and White, {Nicholas J} and Fran{\~A}§ois Nosten",
    year = "2009",
    month = "2",
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    doi = "10.1371/journal.pone.0004551",
    language = "English",
    volume = "4",
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    publisher = "Public Library of Science (PLoS)",
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    Carrara, V, Zwang, J, Ashley, E, Price, R, Stepniewska, K, Barends, M, Brockman, A, Anderson, T, McGready, R, Phaiphun, L, Proux, S, Vanvugt, M, Hutagalung, R, Lwin, KM, Phyo, AP, Preechapornkul, P, Imwong, M, Pukrittayakamee, S, Singhasivanon, P, White, NJ & Nosten, F 2009, 'Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment', PLoS One, vol. 4, no. 2, e4551 , pp. 1-11. https://doi.org/10.1371/journal.pone.0004551

    Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment. / Carrara, Verena; Zwang, Julien; Ashley, Elizabeth; Price, Ric; Stepniewska, Kasia; Barends, Marion; Brockman, A; Anderson, Tim; McGready, Rose; Phaiphun, Lucy; Proux, Stephane; Vanvugt, M; Hutagalung, R; Lwin, Khin Manug; Phyo, Aung Pyae; Preechapornkul, P; Imwong, Mallika; Pukrittayakamee, S; Singhasivanon, Pratap; White, Nicholas J; Nosten, François.

    In: PLoS One, Vol. 4, No. 2, e4551 , 23.02.2009, p. 1-11.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Changes in the Treatment Responses to Artesunate-Mefloquine on the Northwestern Border of Thailand during 13 Years of Continuous Deployment

    AU - Carrara, Verena

    AU - Zwang, Julien

    AU - Ashley, Elizabeth

    AU - Price, Ric

    AU - Stepniewska, Kasia

    AU - Barends, Marion

    AU - Brockman, A

    AU - Anderson, Tim

    AU - McGready, Rose

    AU - Phaiphun, Lucy

    AU - Proux, Stephane

    AU - Vanvugt, M

    AU - Hutagalung, R

    AU - Lwin, Khin Manug

    AU - Phyo, Aung Pyae

    AU - Preechapornkul, P

    AU - Imwong, Mallika

    AU - Pukrittayakamee, S

    AU - Singhasivanon, Pratap

    AU - White, Nicholas J

    AU - Nosten, François

    PY - 2009/2/23

    Y1 - 2009/2/23

    N2 - Background: Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3 ), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border. Methods and Findings: 3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0-98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2-5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/ 40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend). Conclusion: Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage. � 2009 Carrara et al.

    AB - Background: Artemisinin combination treatments (ACT) are recommended as first line treatment for falciparum malaria throughout the malaria affected world. We reviewed the efficacy of a 3-day regimen of mefloquine and artesunate regimen (MAS3 ), over a 13 year period of continuous deployment as first-line treatment in camps for displaced persons and in clinics for migrant population along the Thai-Myanmar border. Methods and Findings: 3,264 patients were enrolled in prospective treatment trials between 1995 and 2007 and treated with MAS3. The proportion of patients with parasitaemia persisting on day-2 increased significantly from 4.5% before 2001 to 21.9% since 2002 (p<0.001). Delayed parasite clearance was associated with increased risk of developing gametocytaemia (AOR = 2.29; 95% CI, 2.00-2.69, p = 0.002). Gametocytaemia on admission and carriage also increased over the years (p = 0.001, test for trend, for both). MAS3 efficacy has declined slightly but significantly (Hazards ratio 1.13; 95% CI, 1.07-1.19, p<0.001), although efficacy in 2007 remained well within acceptable limits: 96.5% (95% CI, 91.0-98.7). The in vitro susceptibility of P. falciparum to artesunate increased significantly until 2002, but thereafter declined to levels close to those of 13 years ago (geometric mean in 2007: 4.2 nM/l; 95% CI, 3.2-5.5). The proportion of infections caused by parasites with increased pfmdr1 copy number rose from 30% (12/ 40) in 1996 to 53% (24/45) in 2006 (p = 0.012, test for trend). Conclusion: Artesunate-mefloquine remains a highly efficacious antimalarial treatment in this area despite 13 years of widespread intense deployment, but there is evidence of a modest increase in resistance. Of particular concern is the slowing of parasitological response to artesunate and the associated increase in gametocyte carriage. � 2009 Carrara et al.

    KW - antimalarial agent

    KW - artesunate

    KW - artesunate plus mefloquin

    KW - doxycycline

    KW - mefloquine

    KW - unclassified drug

    KW - clinical trial

    KW - dose response

    KW - drug bioavailability

    KW - drug dose regimen

    KW - drug efficacy

    KW - drug sensitivity

    KW - gametocyte

    KW - gene number

    KW - human

    KW - in vitro study

    KW - major clinical study

    KW - malaria falciparum

    KW - migration

    KW - Myanmar

    KW - parasitosis

    KW - Plasmodium falciparum

    KW - recurrent infection

    KW - review

    KW - single drug dose

    KW - Thailand

    KW - trend study

    KW - Artesunate

    U2 - 10.1371/journal.pone.0004551

    DO - 10.1371/journal.pone.0004551

    M3 - Article

    VL - 4

    SP - 1

    EP - 11

    JO - PLoS One

    JF - PLoS One

    SN - 1932-6203

    IS - 2

    M1 - e4551

    ER -