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. 2021 Mar 29;223(6):985-994.
doi: 10.1093/infdis/jiaa687.

Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

Victor Asua  1 , Melissa D Conrad  2 , Ozkan Aydemir  3 , Marvin Duvalsaint  2 , Jennifer Legac  2 , Elias Duarte  2 , Patrick Tumwebaze  1 , Deborah M Chin  3 , Roland A Cooper  4 , Adoke Yeka  1 , Moses R Kamya  1 , Grant Dorsey  2 , Sam L Nsobya  1 , Jeffrey Bailey  3 , Philip J Rosenthal  2
Affiliations

Changing Prevalence of Potential Mediators of Aminoquinoline, Antifolate, and Artemisinin Resistance Across Uganda

Victor Asua et al. J Infect Dis. .

Abstract

Background: In Uganda, artemether-lumefantrine is recommended for malaria treatment and sulfadoxine-pyrimethamine for chemoprevention during pregnancy, but drug resistance may limit efficacies.

Methods: Genetic polymorphisms associated with sensitivities to key drugs were characterized in samples collected from 16 sites across Uganda in 2018 and 2019 by ligase detection reaction fluorescent microsphere, molecular inversion probe, dideoxy sequencing, and quantitative polymerase chain reaction assays.

Results: Considering transporter polymorphisms associated with resistance to aminoquinolines, the prevalence of Plasmodium falciparum chloroquine resistance transporter (PfCRT) 76T decreased, but varied markedly between sites (0-46% in 2018; 0-23% in 2019); additional PfCRT polymorphisms and plasmepsin-2/3 amplifications associated elsewhere with resistance to piperaquine were not seen. For P. falciparum multidrug resistance protein 1, in 2019 the 86Y mutation was absent at all sites, the 1246Y mutation had prevalence ≤20% at 14 of 16 sites, and gene amplification was not seen. Considering mutations associated with high-level sulfadoxine-pyrimethamine resistance, prevalences of P. falciparum dihydrofolate reductase 164L (up to 80%) and dihydropteroate synthase 581G (up to 67%) were high at multiple sites. Considering P. falciparum kelch protein propeller domain mutations associated with artemisinin delayed clearance, prevalence of the 469Y and 675V mutations has increased at multiple sites in northern Uganda (up to 23% and 41%, respectively).

Conclusions: We demonstrate concerning spread of mutations that may limit efficacies of key antimalarial drugs.

Keywords: Plasmodium falciparum; PfCRT; PfDHFR; PfDHPS; PfK13; PfMDR1; Uganda; drug resistance.

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Figures

Figure 1.
Figure 1.
Map of Uganda. The districts where samples were collected are shown.
Figure 2.
Figure 2.
Prevalence of mutations associated with aminoquinoline resistance. Gray, no samples obtained. Abbreviations: PfCRT, Plasmodium falciparum chloroquine resistance transporter; PfMDR1, Plasmodium falciparum multidrug resistance protein 1.
Figure 3.
Figure 3.
Prevalence of Plasmodium falciparum dihydrofolate reductase (PfDHFR) 164L and Plasmodium falciparum dihydropteroate synthase (PfDHPS) 581G mutations. Gray, no samples obtained.
Figure 4.
Figure 4.
Prevalence of Plasmodium falciparum kelch protein (PfK13) 469Y and 675V mutations. Gray, no samples obtained.
See this image and copyright information in PMC

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