Reduced ex vivo susceptibility of Plasmodium falciparum after oral artemether-lumefantrine treatment in Mali

Malar J. 2017 Feb 2;16(1):59. doi: 10.1186/s12936-017-1700-8.

Abstract

Background: Artemisinin-based combination therapy is the recommended first-line treatment for uncomplicated falciparum malaria worldwide. However, recent studies conducted in Mali showed an increased frequency of recurrent parasitaemia following artemether-lumefantrine (AL) treatment.

Methods: Study samples were collected during a large WANECAM study. Ex-vivo Plasmodium falciparum sensitivity to artemether and lumefantrine was assessed using the tritiated hypoxanthine-based assay. The prevalence of molecular markers of anti-malarial drug resistance (pfcrt K76T, pfmdr1 N86Y and K13-propeller) were measured by PCR and/or sequencing.

Results: Overall 61 samples were successfully analysed in ex vivo studies. Mean IC50s increased significantly between baseline and recurrent parasites for both artemether (1.6 nM vs 3.2 nM, p < 0.001) and lumefantrine (1.4 nM vs 3.4 nM, p = 0.004). Wild type Pfmdr1 N86 allele was selected after treatment (71 vs 91%, 112 of 158 vs 95 of 105, p < 0.001) but not the wild type pfcrt K76 variant (23.5 vs 24.8%, 40 of 170 vs 26 of 105, p = 0.9). Three non-synonymous K13-propeller SNPs (A522C, A578S, and G638R) were found with allele frequencies <2%.

Conclusion: Malian post-AL P. falciparum isolates were less susceptible to artemether and lumefantrine than baseline isolates.

Keywords: Artemether; Ex vivo; In vivo; K13 propeller; Lumefantrine; Plasmodium.

MeSH terms

  • Administration, Oral
  • Antimalarials / pharmacology*
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins / pharmacology*
  • Drug Combinations
  • Drug Resistance*
  • Ethanolamines / pharmacology*
  • Fluorenes / pharmacology*
  • Humans
  • Malaria, Falciparum / parasitology
  • Mali
  • Parasitemia / parasitology
  • Plasmodium falciparum / drug effects*
  • Recurrence

Substances

  • Antimalarials
  • Artemether, Lumefantrine Drug Combination
  • Artemisinins
  • Drug Combinations
  • Ethanolamines
  • Fluorenes