Efficacy of artesunate-mefloquine for chloroquine-resistant plasmodium vivax malaria in Malaysia

An open-label, randomized, controlled trial

Matthew Grigg, Timothy Williams, Jayaram Menon, Bridget Barber, Christopher Wilkes, Giri Rajahram, M Edstein, Sarah Auburn, Ric Price, Tsin Yeo, Nicholas Anstey

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    Background: Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown.

    Methods: A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis.

    Results: From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8–75.6) after CQ and 0% (95% CI, 0–.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5–9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5–9.3; P = .005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60–.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment.

    Conclusions: High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.
    Original languageEnglish
    Pages (from-to)1403-1411
    Number of pages9
    JournalClinical Infectious Diseases
    Volume62
    Issue number11
    DOIs
    Publication statusPublished - 1 Jun 2016

    Fingerprint

    Vivax Malaria
    Mefloquine
    Malaysia
    Chloroquine
    Randomized Controlled Trials
    Treatment Failure
    Confidence Intervals
    Plasmodium vivax
    Anemia
    Bed Occupancy
    Primaquine
    Therapeutics
    artesunate
    Southeastern Asia
    District Hospitals
    Malaria
    Parasites
    Fever
    Odds Ratio

    Cite this

    @article{90eaa1298f6b4f4ea94dca1bfc5197d6,
    title = "Efficacy of artesunate-mefloquine for chloroquine-resistant plasmodium vivax malaria in Malaysia: An open-label, randomized, controlled trial",
    abstract = "Background: Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown.Methods: A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis.Results: From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1{\%} (95{\%} confidence interval [CI], 46.8–75.6) after CQ and 0{\%} (95{\%} CI, 0–.08) following AS-MQ (P < .001), of which 8.2{\%} (95{\%} CI, 2.5–9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95{\%} CI, 1.5–9.3; P = .005). Gametocytes were present at day 28 in 23.8{\%} (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95{\%} CI, .60–.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment.Conclusions: High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.",
    author = "Matthew Grigg and Timothy Williams and Jayaram Menon and Bridget Barber and Christopher Wilkes and Giri Rajahram and M Edstein and Sarah Auburn and Ric Price and Tsin Yeo and Nicholas Anstey",
    year = "2016",
    month = "6",
    day = "1",
    doi = "10.1093/cid/ciw121",
    language = "English",
    volume = "62",
    pages = "1403--1411",
    journal = "Clinical Infectious Diseases",
    issn = "1058-4838",
    publisher = "Oxford University Press",
    number = "11",

    }

    Efficacy of artesunate-mefloquine for chloroquine-resistant plasmodium vivax malaria in Malaysia : An open-label, randomized, controlled trial. / Grigg, Matthew; Williams, Timothy; Menon, Jayaram; Barber, Bridget; Wilkes, Christopher; Rajahram, Giri; Edstein, M; Auburn, Sarah; Price, Ric; Yeo, Tsin; Anstey, Nicholas.

    In: Clinical Infectious Diseases, Vol. 62, No. 11, 01.06.2016, p. 1403-1411.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Efficacy of artesunate-mefloquine for chloroquine-resistant plasmodium vivax malaria in Malaysia

    T2 - An open-label, randomized, controlled trial

    AU - Grigg, Matthew

    AU - Williams, Timothy

    AU - Menon, Jayaram

    AU - Barber, Bridget

    AU - Wilkes, Christopher

    AU - Rajahram, Giri

    AU - Edstein, M

    AU - Auburn, Sarah

    AU - Price, Ric

    AU - Yeo, Tsin

    AU - Anstey, Nicholas

    PY - 2016/6/1

    Y1 - 2016/6/1

    N2 - Background: Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown.Methods: A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis.Results: From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8–75.6) after CQ and 0% (95% CI, 0–.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5–9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5–9.3; P = .005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60–.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment.Conclusions: High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.

    AB - Background: Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia. The efficacy of CQ and alternative artemisinin combination therapies (ACTs) for vivax malaria in Malaysia is unknown.Methods: A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. Primaquine was administered on day 28. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis.Results: From 2012 to 2014, 103 adults and children were enrolled. Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8–75.6) after CQ and 0% (95% CI, 0–.08) following AS-MQ (P < .001), of which 8.2% (95% CI, 2.5–9.6) were early treatment failures. All patients with treatment failure had therapeutic plasma CQ concentrations at day 7. Compared with CQ, AS-MQ was associated with faster parasite clearance (normalized clearance slope, 0.311 vs 0.127; P < .001) and fever clearance (mean, 19.0 vs 37.7 hours; P = .001) and with lower risk of anemia at day 28 (odds ratio = 3.7; 95% CI, 1.5–9.3; P = .005). Gametocytes were present at day 28 in 23.8% (10/42) of patients following CQ vs none with AS-MQ (P < .001). AS-MQ resulted in lower bed occupancy: 4037 vs 6510 days/1000 patients (incidence rate ratio 0.62; 95% CI, .60–.65; P < .001). One patient developed severe anemia not regarded as related to their AS-MQ treatment.Conclusions: High-grade CQ-resistant P. vivax is prevalent in eastern Malaysia. AS-MQ is an efficacious ACT for all malaria species. Wider CQ-efficacy surveillance is needed in vivax-endemic regions with earlier replacement with ACT when treatment failure is detected.

    UR - http://www.scopus.com/inward/record.url?scp=84971524617&partnerID=8YFLogxK

    U2 - 10.1093/cid/ciw121

    DO - 10.1093/cid/ciw121

    M3 - Article

    VL - 62

    SP - 1403

    EP - 1411

    JO - Clinical Infectious Diseases

    JF - Clinical Infectious Diseases

    SN - 1058-4838

    IS - 11

    ER -