Abstract
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. 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. 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. 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.Clinical Trials Registration NCT01708876.
Highlights
Chloroquine (CQ)-resistant Plasmodium vivax is increasingly reported throughout southeast Asia
Treatment failure by day 28 was 61.1% (95% confidence interval [CI], 46.8–75.6) after CQ and 0% following AS-MQ (P < .001), of which 8.2% were early treatment failures
Compared with CQ, AS-MQ was associated with faster parasite clearance and fever clearance and with lower risk of anemia at day 28
Summary
A randomized, controlled trial of CQ vs artesunate-mefloquine (AS-MQ) for uncomplicated vivax malaria was conducted in 3 district hospitals in Sabah, Malaysia. The primary outcome was the cumulative risk of treatment failure by day 28 by Kaplan–Meier analysis. This 2-arm, randomized, open-label trial was conducted at 3 hospitals in Sabah: Kudat, Kota Marudu, and Pitas District. CQ diphosphate (Kotra Pharma Sdn Bhd, Malaysia), consisting of 155 mg base tablets, was administered at enrollment and 6, 24, and 48 hours after (target total dose 25 mg/ kg). Primary analysis was intention-totreat, with incidence risk of treatment failure at days 28 and 42 calculated using the Kaplan–Meier method and compared using the Mantel-Haenszel log-rank test. Best-fit linear or tobit polynomial regression models were used to estimate the curve of loge parasite counts vs time per the parasite clearance methodology of the World Wide Antimalarial Resistance Network [24].
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