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

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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",
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doi = "10.1093/cid/ciw121",
language = "English",
volume = "62",
pages = "1403--1411",
journal = "Clinical Infectious Diseases",
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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 -