Comparison of the Cumulative Efficacy and Safety of Chloroquine, Artesunate, and Chloroquine-Primaquine in Plasmodium vivax Malaria

Cindy S Chu, Aung Pyae Phyo, Khin Maung Lwin, Htun Htun Win, Thida San, Aye Aye Aung, Rattanaporn Raksapraidee, Verena I Carrara, Germana Bancone, James Watson, Kerryn A Moore, Jacher Wiladphaingern, Stéphane Proux, Kanlaya Sriprawat, Markus Winterberg, Phaik Yeong Cheah, Amy L Chue, Joel Tarning, Mallika Imwong, François Nosten, Nicholas J White, Cindy S Chu, Aung Pyae Phyo, Khin Maung Lwin, Htun Htun Win, Thida San, Aye Aye Aung, Rattanaporn Raksapraidee, Verena I Carrara, Germana Bancone, James Watson, Kerryn A Moore, Jacher Wiladphaingern, Stéphane Proux, Kanlaya Sriprawat, Markus Winterberg, Phaik Yeong Cheah, Amy L Chue, Joel Tarning, Mallika Imwong, François Nosten, Nicholas J White

Abstract

Background: Chloroquine has been recommended for Plasmodium vivax infections for >60 years, but resistance is increasing. To guide future therapies, the cumulative benefits of using slowly eliminated (chloroquine) vs rapidly eliminated (artesunate) antimalarials, and the risks and benefits of adding radical cure (primaquine) were assessed in a 3-way randomized comparison conducted on the Thailand-Myanmar border.

Methods: Patients with uncomplicated P. vivax malaria were given artesunate (2 mg/kg/day for 5 days), chloroquine (25 mg base/kg over 3 days), or chloroquine-primaquine (0.5 mg/kg/day for 14 days) and were followed for 1 year. Recurrence rates and their effects on anemia were compared.

Results: Between May 2010 and October 2012, 644 patients were enrolled. Artesunate cleared parasitemia significantly faster than chloroquine. Day 28 recurrence rates were 50% with artesunate (112/224), 8% with chloroquine (18/222; P < .001), and 0.5% with chloroquine-primaquine (1/198; P < .001). Median times to first recurrence were 28 days (interquartile range [IQR], 21-42) with artesunate, 49 days (IQR, 35-74) with chloroquine, and 195 days (IQR, 82-281) with chloroquine-primaquine. Recurrence by day 28, was associated with a mean absolute reduction in hematocrit of 1% (95% confidence interval [CI], .3%-2.0%; P = .009). Primaquine radical cure reduced the total recurrences by 92.4%. One-year recurrence rates were 4.51 (95% CI, 4.19-4.85) per person-year with artesunate, 3.45 (95% CI, 3.18-3.75) with chloroquine (P = .002), and 0.26 (95% CI, .19-.36) with chloroquine-primaquine (P < .001).

Conclusions: Vivax malaria relapses are predominantly delayed by chloroquine but prevented by primaquine.

Clinical trials registration: NCT01074905.

Figures

Figure 1.
Figure 1.
Cumulative proportions of first recurrences after treatment of the initial Plasmodium vivax infection in the current study (A) compared with historical data from US soldiers returning from the Pacific [14] (B), Indonesian soldiers returning from Papua, Indonesia [15, 16] (C), and children aged 1–5 years living in East Sepik Province, Papua New Guinea [17] (D). Note that the cumulative recurrence curve of more slowly eliminated schizonticides (ie, chloroquine, dihydroartemisinin-piperaquine) is shifted to the right, compared with rapidly eliminated schizonticides (ie, artesunate). Permission to use (C) was obtained from the last author and the figure is also under Creative Commons CC-BY license. Permission to use (D) was obtained by Oxford University Press, licence number 4241781058637. Abbreviations: AS, artesunate; AS-PYR, artesunate-pyronaridine; DHA-PP, dihydroartemisinin-piperaquine; PMQ, primaquine.
Figure 2.
Figure 2.
Modeling the proportion of relapses occurring after monotherapy with chloroquine (CQ). If the background rate of new Plasmodium vivax infection is taken into account (estimated from the CQ + primaquine group), an estimated 90% of all relapses in the CQ group occur within 9 weeks.
Figure 3.
Figure 3.
Median absolute hematocrit changes in glucose-6-phosphate dehydrogenase (G6PD)–heterozygous female patients from enrollment to week 8 of the acute P. vivax infection. Patients who had recurrences during the first 8 weeks are included. G6PD-homozygous females are not included. Wild-type (G6PD genotype normal) females in the chloroquine (CQ) + primaquine (PMQ) group are shown as a reference. The dots represent outlier values. The number of heterozygotes in each group are as follows: artesunate (AS), n = 8; CQ, n = 16; and CQ + PMQ, n = 10.

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