Artemether-Lumefantrine Versus Chloroquine for the Treatment of Uncomplicated Plasmodium knowlesi Malaria: An Open-Label Randomized Controlled Trial CAN KNOW

Matthew J Grigg, Timothy William, Bridget E Barber, Giri S Rajahram, Jayaram Menon, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price, Tsin W Yeo, Nicholas M Anstey, Matthew J Grigg, Timothy William, Bridget E Barber, Giri S Rajahram, Jayaram Menon, Emma Schimann, Christopher S Wilkes, Kaajal Patel, Arjun Chandna, Ric N Price, Tsin W Yeo, Nicholas M Anstey

Abstract

Background: Plasmodium knowlesi is reported increasingly across Southeast Asia and is the most common cause of malaria in Malaysia. No randomized trials have assessed the comparative efficacy of artemether-lumefantrine (AL) for knowlesi malaria.

Methods: A randomized controlled trial was conducted in 3 district hospitals in Sabah, Malaysia to compare the efficacy of AL against chloroquine (CQ) for uncomplicated knowlesi malaria. Participants were included if they weighed >10 kg, had a parasitemia count <20000/μL, and had a negative rapid diagnostic test result for Plasmodium falciparum histidine-rich protein 2. Diagnosis was confirmed by means of polymerase chain reaction. Patients were block randomized to AL (total target dose, 12 mg/kg for artemether and 60 mg/kg for lumefantrine) or CQ (25 mg/kg). The primary outcome was parasite clearance at 24 hours in a modified intention-to-treat analysis.

Results: From November 2014 to January 2016, a total of 123 patients (including 18 children) were enrolled. At 24 hours after treatment 76% of patients administered AL (95% confidence interval [CI], 63%-86%; 44 of 58) were aparasitemic, compared with 60% administered CQ (47%-72%; 39 of 65; risk ratio, 1.3 [95% CI, 1.0-1.6]; P = .06). Overall parasite clearance was shorter after AL than after CQ (median, 18 vs 24 hours, respectively; P = .02), with all patients aparasitemic by 48 hours. By day 42 there were no treatment failures. The risk of anemia during follow-up was similar between arms. Patients treated with AL would require lower bed occupancy than those treated with CQ (2414 vs 2800 days per 1000 patients; incidence rate ratio, 0.86 [95% CI, .82-.91]; P < .001). There were no serious adverse events.

Conclusions: AL is highly efficacious for treating uncomplicated knowlesi malaria; its excellent tolerability and rapid therapeutic response allow earlier hospital discharge, and support its use as a first-line artemisinin-combination treatment policy for all Plasmodium species in Malaysia.

Clinical trials registration: NCT02001012.

Keywords: Plasmodium knowlesi; artemether-lumefantrine; chloroquine; malaria; randomized controlled trial.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.
Figure 1.
Enrollment flowchart. Abbreviations: AL, artemether-lumefantrine; CQ, chloroquine; P., Plasmodium; PCR, polymerase chain reaction.
Figure 2.
Figure 2.
Meta-analysis of artemisinin-combination therapy (ACT) versus chloroquine (CQ) for treatment of Plasmodium knowlesi malaria, showing difference in proportional parasite clearance at 24 hours. The red and green squares are the relative weight given to each study in the meta-analysis (ie, 65 and 35%, respectively) based on the number of participants in the 2 studies (226 vs 123). The proportional difference in risk of parasite clearance at 24 hours between treatment arms. Abbreviations: ACT, artemisinin-combination therapy; AL, artemether-lumefantrine; ASMQ, artesunate-mefloquine; CI, confidence interval; CQ, chloroquine; RD, risk difference.

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