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 <i>Plasmodium falciparum</i> 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 <i>pfcrt</i> K76T, by 2017 the prevalence of the wild type was >60% at all sites and >90% at 6 sites. For the <i>pfmdr1</i> N86Y and D1246Y alleles, wild type prevalence ranged from 80 to 100%. We found low prevalence of <i>K13</i> 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 <i>pfmdr1</i> and <i>plasmepsin2</i> genes, associated elsewhere with decreased sensitivity to lumefantrine and piperaquine, respectively, was seen in <1% of samples. For the antifolate targets <i>pfdhfr</i> and <i>pfdhps</i>, 5 mutations previously associated with resistance were very common, and the <i>pfdhfr</i> 164L and <i>pfdhps</i> 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.