Abstract
Adequate clinical and parasitologic cure by artemisinin combination therapies relies on the artemisinin component and the partner drug. Polymorphisms in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) and P. falciparum multidrug resistance 1 (pfmdr1) genes are associated with decreased sensitivity to amodiaquine and lumefantrine, but effects of these polymorphisms on therapeutic responses to artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) have not been clearly defined. Individual patient data from 31 clinical trials were harmonized and pooled by using standardized methods from the WorldWide Antimalarial Resistance Network. Data for more than 7,000 patients were analyzed to assess relationships between parasite polymorphisms in pfcrt and pfmdr1 and clinically relevant outcomes after treatment with AL or ASAQ. Presence of the pfmdr1 gene N86 (adjusted hazards ratio = 4.74, 95% confidence interval = 2.29 – 9.78, P < 0.001) and increased pfmdr1 copy number (adjusted hazards ratio = 6.52, 95% confidence interval = 2.36–17.97, P < 0.001) were significant independent risk factors for recrudescence in patients treated with AL. AL and ASAQ exerted opposing selective effects on single-nucleotide polymorphisms in pfcrt and pfmdr1. Monitoring selection and responding to emerging signs of drug resistance are critical tools for preserving efficacy of artemisinin combination therapies; determination of the prevalence of at least pfcrt K76T and pfmdr1 N86Y should now be routine.
Highlights
Recent successes in malaria control have depended on the use of highly efficacious artemisinin combination therapies (ACTs) for first-line treatment of uncomplicated Plasmodium falciparum malaria
Baseline characteristics for patients treated with AL or ASAQ are shown in Supplemental Table 4
The overall clinical efficacy at day 42 was 94.8% (95% confidence interval [CI] = 94–95.5%) in patients treated with AL and 95.1% in patients treated with ASAQ (Table 2)
Summary
Recent successes in malaria control have depended on the use of highly efficacious artemisinin combination therapies (ACTs) for first-line treatment of uncomplicated Plasmodium falciparum malaria. The two most commonly used ACTs worldwide are artemether-lumefantrine (AL) and artesunateamodiaquine (ASAQ).[4] Polymerase chain reaction (PCR)– adjusted efficacy for both combinations remains high in most regions.[5,6,7] there have been some reports of decreasing AL cure rates in Africa[8,9,10,11] and Asia,[12] and reports of high levels of treatment failures of ASAQ.[13,14,15,16,17,18] Resistance to ACT partner drugs has historically manifested before that of artemisinins, whose short half-lives result in the exposure of residual parasites to sub-therapeutic levels of the partner drug alone. Response to the partner drug is a key component of overall ACT efficacy
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