Changing Antimalarial Drug Sensitivities in Uganda

Antimicrob Agents Chemother. 2017 Nov 22;61(12):e01516-17. doi: 10.1128/AAC.01516-17. Print 2017 Dec.

Abstract

Dihydroartemisinin-piperaquine (DP) has demonstrated excellent efficacy for the treatment and prevention of malaria in Uganda. However, resistance to both components of this regimen has emerged in Southeast Asia. The efficacy of artemether-lumefantrine, the first-line regimen to treat malaria in Uganda, has also been excellent, but continued pressure may select for parasites with decreased sensitivity to lumefantrine. To gain insight into current drug sensitivity patterns, ex vivo sensitivities were assessed and genotypes previously associated with altered drug sensitivity were characterized for 58 isolates collected in Tororo, Uganda, from subjects presenting in 2016 with malaria from the community or as part of a clinical trial comparing DP chemoprevention regimens. Compared to community isolates, those from trial subjects had lower sensitivities to the aminoquinolines chloroquine, monodesethyl amodiaquine, and piperaquine and greater sensitivities to lumefantrine and mefloquine, an observation consistent with DP selection pressure. Compared to results for isolates from 2010 to 2013, the sensitivities of 2016 community isolates to chloroquine, amodiaquine, and piperaquine improved (geometric mean 50% inhibitory concentrations [IC50] = 248, 76.9, and 19.1 nM in 2010 to 2013 and 33.4, 14.9, and 7.5 nM in 2016, respectively [P < 0.001 for all comparisons]), the sensitivity to lumefantrine decreased (IC50 = 3.0 nM in 2010 to 2013 and 5.4 nM in 2016 [P < 0.001]), and the sensitivity to dihydroartemisinin was unchanged (IC50 = 1.4 nM). These changes were accompanied by decreased prevalence of transporter mutations associated with aminoquinoline resistance and low prevalence of polymorphisms recently associated with resistance to artemisinins or piperaquine. Antimalarial drug sensitivities are changing in Uganda, but novel genotypes associated with DP treatment failure in Asia are not prevalent.

Keywords: Plasmodium falciparum; Uganda; artemether-lumefantrine; dihydroartemisinin-piperaquine; drug resistance; ex vivo; k13; pfcrt; pfmdr1; plasmepsin 2.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Amodiaquine / analogs & derivatives
  • Amodiaquine / therapeutic use
  • Antimalarials / therapeutic use*
  • Artemisinins / therapeutic use
  • Aspartic Acid Endopeptidases / genetics
  • Aspartic Acid Endopeptidases / metabolism
  • Child
  • Child, Preschool
  • Chloroquine / therapeutic use
  • Drug Resistance / genetics*
  • Ethanolamines / therapeutic use
  • Female
  • Fluorenes / therapeutic use
  • Gene Expression
  • Humans
  • Infant
  • Inhibitory Concentration 50
  • Lumefantrine
  • Malaria, Falciparum / drug therapy*
  • Malaria, Falciparum / parasitology
  • Male
  • Mefloquine / therapeutic use
  • Membrane Transport Proteins / genetics*
  • Membrane Transport Proteins / metabolism
  • Multidrug Resistance-Associated Proteins / genetics*
  • Multidrug Resistance-Associated Proteins / metabolism
  • Mutation
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects*
  • Plasmodium falciparum / genetics
  • Plasmodium falciparum / growth & development
  • Plasmodium falciparum / metabolism
  • Protozoan Proteins / genetics*
  • Protozoan Proteins / metabolism
  • Quinolines / therapeutic use
  • Uganda
  • Young Adult

Substances

  • Antimalarials
  • Artemisinins
  • Ethanolamines
  • Fluorenes
  • Mdr1 protein, Plasmodium falciparum
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • PfCRT protein, Plasmodium falciparum
  • Protozoan Proteins
  • Quinolines
  • Amodiaquine
  • dihydroartemisinin
  • desethylamodiaquine
  • Chloroquine
  • piperaquine
  • Aspartic Acid Endopeptidases
  • plasmepsin II
  • Lumefantrine
  • Mefloquine