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Background  Development and spread of  Plasmodium falciparum  resistance to artemisinin-based combination therapy (ACT) constitutes a major threat to recent global malaria control achievements. Surveillance of molecular markers could act as an early warning system of ACT-resistance before clinical treatment failures are apparent. The aim of this study was to analyse temporal trends of established genotypes associated with artemether-lumefantrine tolerance/resistance before and after its deployment as first-line treatment for uncomplicated malaria in Tanzania 2006.    Methods  Single nucleotide polymorphisms in the  P. falciparum multidrug resistance gene 1  ( pfmdr1 ) N86Y, Y184F, D1246Y and  P. falciparum chloroquine transporter gene  ( pfcrt ) K76T were analysed from dried blood spots collected during six consecutive studies from children with uncomplicated  P. falciparum  malaria in Fukayosi village, Bagamoyo District, Tanzania, between 2004–2011.    Results  There was a statistically significant yearly increase of  pfmdr1  N86, 184F, D1246 and  pfcrt  K76 between 2006–2011 from 14% to 61% (yearly OR = 1.38 [95% CI 1.25-1.52] p < 0.0001), 14% to 35% (OR = 1.17 [95% CI 1.07-1.30] p = 0.001), 54% to 85% (OR = 1.21 [95% CI 1.03-1.42] p = 0.016) and 49% to 85% (OR = 1.33 [95% CI 1.17-1.51] p < 0.0001), respectively. Unlike for the  pfmdr1  SNP, a significant increase of  pfcrt  K76 was observed already between 2004–2006, from 26% to 49% (OR = 1.68 [95% CI 1.17-2.40] p = 0.005). From 2006 to 2011 the  pfmdr1  NFD haplotype increased from 10% to 37% (OR = 1.25 [95% CI 1.12-1.39] p < 0.0001), whereas the YYY haplotype decreased from 31% to 6% (OR = 0.73 [95% CI 0.56-0.98] p = 0.018). All 390 successfully analysed samples had one copy of the  pfmdr1  gene.    Conclusion  The temporal selection of molecular markers associated with artemether-lumefantrine tolerance/resistance may represent an early warning sign of impaired future drug efficacy. This calls for stringent surveillance of artemether-lumefantrine efficacy in Tanzania and emphasizes the importance of molecular surveillance as a complement to standard  in vivo  trials.

Temporal trends of molecular markers associated with artemether-lumefantrine tolerance/resistance in Bagamoyo district, Tanzania