Therapeutic Efficacy of Artemether-Lumefantrine for Uncomplicated Falciparum Malaria in Northern Zambia

Abstract

Artemether-lumefantrine (AL) is a first-line agent for uncomplicated malaria caused by Plasmodium falciparum. The WHO recommends periodic therapeutic efficacy studies of antimalarial drugs for the detection of malaria parasite drug resistance and to inform national malaria treatment policies. We conducted a therapeutic efficacy study of AL in a high malaria transmission region of northern Zambia from December 2014 to July 2015. One hundred children of ages 6 to 59 months presenting to a rural health clinic with uncomplicated falciparum malaria were admitted for treatment with AL (standard 6-dose regimen) and followed weekly for 5 weeks. Parasite counts were taken every 6 hours during treatment to assess parasite clearance. Recurrent episodes during follow-up (n = 14) were genotyped to distinguish recrudescence from reinfection and to identify drug resistance single nucleotide polymorphisms (SNPs) and multidrug resistance protein 1 (mdr1) copy number variation. Day 7 lumefantrine concentrations were measured for correspondence with posttreatment reinfection. All children who completed the parasite clearance portion of the study (n = 94) were microscopy-negative by 72 hours. The median parasite elimination half-life was 2.7 hours (interquartile range: 2.1-3.3). Genotype-corrected therapeutic efficacy was 98.8% (95% CI: 97.6-100). Purported artemisinin and lumefantrine drug resistance SNPs in atp6, 3D7_1451200, and mdr1 were detected but did not correlate with parasite recurrence, nor did day 7 lumefantrine concentrations. In summary, AL was highly effective for the treatment of uncomplicated falciparum malaria in northern Zambia during the study period. The high incidence of recurrent parasitemia was consistent with reinfection due to high, perennial malaria transmission.

Figure 1.

Study flow diagram.

Figure 2.

Parasite concentration–time profiles of children with uncomplicated malaria during treatment with artemether–lumefantrine. (A) Scatter plot of parasite count against time for all participants (nil values not shown). (B) Parasite clearance comparison in children with (dash) and without (solid) fever on presentation. (C) Parasite clearance in children who went on to have reinfection (dash) or no reinfection (solid). (D) Parasite clearance in participants with high (solid) or low (dash) lumefantrine exposure, defined as day 7 concentrations in the upper or lower quartile. Points and error bars are means and standard errors.

Figure 3.

Parasite concentration–time profiles aligned by time of peak parasitemia (T_peak). (A) Parasite clearance of participants with T_peak of 0 hour (n = 61). (B and C) Parasite clearance of participants with T_peak of 6 hours (n = 23) and 12 hours (n = 11), respectively. All participants received an initial dose of artemether–lumefantrine at 0 hour and doses two through five at times indicated by the arrows. Curves (B and C) peak after initial treatment, and curves (A and B) rebound 30 hours after T_peak, a possible indication of recent schizont rupture and emancipation of a new generation of ring-stage trophozoites. Data are means and standard errors.

Figure 4.

Prevalence of drug resistance single nucleotide polymorphisms in parasites among the 14 participants with recurrent parasitemia, comparing baseline with recurrent parasites. Bar graphs show wild-type (light gray), mixed wild-type and mutant (dark gray), and mutant (black) parasites. There were higher frequencies of N71, 431K, and 184F mutations in recurrent than in initial parasite infections, but the differences were not statistically significant. The N71 mutation in 3D7_1451200 and 431K mutation in atp6 possibly reduce susceptibility to artemisinins. The 184F mutation in mdr1 is associated with reduced lumefantrine susceptibility but likely requires the N86 mutation.^– There were no chloroquine resistance transporter (crt) or cytochrome b mutations found. There was a high prevalence of a dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) drug resistance polymorphisms.