Global extent of chloroquine-resistant Plasmodium vivax: a systematic review and meta-analysis

Abstract

Background: Chloroquine is the first-line treatment for Plasmodium vivax malaria in most endemic countries, but resistance is increasing. Monitoring of antimalarial efficacy is essential, but in P. vivax infections the assessment of treatment efficacy is confounded by relapse from the dormant liver stages. We systematically reviewed P. vivax malaria treatment efficacy studies to establish the global extent of chloroquine resistance.

Methods: We searched Medline, Web of Science, Embase, and the Cochrane Database of Systematic Reviews to identify studies published in English between Jan 1, 1960, and April 30, 2014, which investigated antimalarial treatment efficacy in P. vivax malaria. We excluded studies that did not include supervised schizonticidal treatment without primaquine. We determined rates of chloroquine resistance according to P. vivax malaria recurrence rates by day 28 whole-blood chloroquine concentrations at the time of recurrence and study enrolment criteria.

Findings: We identified 129 eligible clinical trials involving 21,694 patients at 179 study sites and 26 case reports describing 54 patients. Chloroquine resistance was present in 58 (53%) of 113 assessable study sites, spread across most countries that are endemic for P. vivax. Clearance of parasitaemia assessed by microscopy in 95% of patients by day 2, or all patients by day 3, was 100% predictive of chloroquine sensitivity.

Interpretation: Heterogeneity of study design and analysis has confounded global surveillance of chloroquine-resistant P. vivax, which is now present across most countries endemic for P. vivax. Improved methods for monitoring of drug resistance are needed to inform antimalarial policy in these regions.

Funding: Wellcome Trust (UK).

Figure 1

Study selection

Figure 2

Forest plot of the risk of recurrence at day 28 in patients treated with chloroquine or chloroquine plus primaquine High dose >6 mg/kg. Low dose 3–5 mg/kg. Very low dose <2 mg/kg. As part of a sensitivity analysis, studies in which no recurrences were recorded before day 28 were assigned a numerator of 1, the derived odds ratio was recalculated as 0·43 (95% CI 0·24–0·79; p=0·006). References for all studies are shown in the appendix.

Figure 3

Location of study sites with documented chloroquine-resistant (A) and chloroquine-sensitive Plasmodium vivax (B)

Figure 4

Proportion of patients with parasitaemia on days 2 and 3