Changing Molecular Markers of Antimalarial Drug Sensitivity across Uganda

Abstract

The potential spread of antimalarial drug resistance to Africa, in particular for artemisinins and key partner drugs, is a major concern. We surveyed Plasmodium falciparum genetic markers associated with drug sensitivity on 3 occasions at ∼6-month intervals in 2016 and 2017 at 10 sites representing a range of epidemiological settings in Uganda. For putative drug transporters, we found continued evolution toward wild-type sequences associated with increased sensitivity to chloroquine. For pfcrt K76T, by 2017 the prevalence of the wild type was >60% at all sites and >90% at 6 sites. For the pfmdr1 N86Y and D1246Y alleles, wild type prevalence ranged from 80 to 100%. We found low prevalence of K13 propeller domain mutations, which are associated with artemisinin resistance in Asia, but one mutation previously identified in northern Uganda, 675V, was seen in 2.0% of samples, including 5.5% of those from the 3 northernmost sites. Amplification of the pfmdr1 and plasmepsin2 genes, associated elsewhere with decreased sensitivity to lumefantrine and piperaquine, respectively, was seen in <1% of samples. For the antifolate targets pfdhfr and pfdhps, 5 mutations previously associated with resistance were very common, and the pfdhfr 164L and pfdhps 581G mutations associated with higher-level resistance were seen at multiple sites, although prevalence did not clearly increase over time. Overall, changes were consistent with the selective pressure of the national treatment regimen, artemether-lumefantrine, with increased sensitivity to chloroquine, and with poor efficacy of antifolates. Strong evidence for resistance to artemisinins was not seen. Continued surveillance of markers that predict antimalarial drug sensitivity is warranted.

Keywords: Uganda; antimalarial drug sensitivity; molecular markers.

FIG 1

Surveillance sites in Uganda. The map shows study sites and estimated parasite prevalence for children 2 to 10 years of age. Estimates are based on community surveys between 1985 and 2010 under the Malaria Atlas Project. White locations have indeterminate prevalence based on insufficient data; these are primarily high-elevation areas with known low malaria transmission intensity.

FIG 2

Prevalence of wild-type, mixed, and mutant alleles at the named sites over the indicated survey periods. The numbers above the site names represent survey periods (1, April 2016 to June 2016; 2, November 2016 to January 2017; 3, May 2017 to June 2017).