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Background  The emergence of resistance against artemisinin combination treatment is a major concern for malaria control. ACTs are recommended as the rescue treatment, however, there is limited evidence as to whether treatment and re-treatment with ACTs select for drug-resistant  P .  falciparum  parasites. Thus, the purpose of the present study is to investigate the impact of (re-)treatment using artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) on the selection of  P .  falciparum multidrug resistance-1  ( Pfmdr1 ) alleles in clinical settings.    Methods   P .  falciparum  positive samples were collected from children aged 12–59 months in a clinical trial in DR Congo and Uganda.  Pfmdr1  single nucleotide polymorphisms (SNPs) analysis at codons N86Y, Y184F, and D1246Y were performed at baseline and post-treatment with either AL or ASAQ as a rescue treatment using nested PCR followed by restriction fragment length polymorphism (RFLP) assays.    Results  The pre-treatment prevalence of  Pfmdr1  N86 and D1246Y varied significantly between the sites, (p>0.001) and (p = 0.013), respectively. There was borderline significant directional selection for  Pfmdr1  184F in recurrent malaria infections after treatment with AL in Uganda site (p = 0.05).  Pfmdr1 NFD  haplotype did not significantly change in post-treatment infections after re-treatment with either AL or ASAQ. Comparison between pre-treatment and post-treatment recurrences did not indicate directional selection of  Pfmdr1  N86, D1246 alleles in the pre-RCT, RCT and post-RCT phases in both AL and ASAQ treatment arms.  Pfmdr1  86Y was significantly associated with reduced risk of AL treatment failure (RR = 0.34, 95% CI:0.11–1.05, p = 0.04) while no evidence for D1246 allele (RR = 1.02; 95% CI: 0.42–2.47, p = 1.0). Survival estimates showed that the  Pfmdr1  alleles had comparable mean-time to PCR-corrected recrudescence and new infections in both AL and ASAQ treatment arms.    Conclusion  We found limited impact of (re-)treatment with AL or ASAQ on selection for  Pfmdr1  variants and haplotypes associated with resistance to partner drugs. These findings further supplement the evidence use of same or alternative ACTs as a rescue therapy for recurrent  P . falciparum  infections. Continued monitoring of genetic signatures of resistance is warranted to timely inform malaria (re-)treatment policies and guidelines.

plos one

Impact of treatment and re-treatment with artemether-lumefantrine and artesunate-amodiaquine on selection of Plasmodium falciparum multidrug resistance gene-1 polymorphisms in the Democratic Republic of Congo and Uganda