Abstract
SummaryBackgroundTreatment and control of malaria depends on artemisinin-based combination therapies (ACTs) and is challenged by drug resistance, but thus far resistance to artemisinins and partner drugs has primarily occurred in southeast Asia. The aim of this study was to characterise antimalarial drug susceptibility of Plasmodium falciparum isolates from Tororo and Busia districts in Uganda.MethodsIn this prospective longitudinal study, P falciparum isolates were collected from patients aged 6 months or older presenting at the Tororo District Hospital (Tororo district, a site with relatively low malaria incidence) or Masafu General Hospital (Busia district, a high-incidence site) in eastern Uganda with clinical symptoms of malaria, a positive Giemsa-stained blood film for P falciparum, and no signs of severe disease. Ex-vivo susceptibilities to ten antimalarial drugs were measured using a 72-h microplate growth inhibition assay with SYBR Green detection. Relevant P falciparum genetic polymorphisms were characterised by molecular methods. We compared results with those from earlier studies in this region and searched for associations between drug susceptibility and parasite genotypes.FindingsFrom June 10, 2016, to July 29, 2019, 361 P falciparum isolates were collected in the Busia district and 79 in the Tororo district from 440 participants. Of 440 total isolates, 392 (89%) successfully grew in culture and showed excellent drug susceptibility for chloroquine (median half-maximal inhibitory concentration [IC50] 20·0 nM [IQR 12·0–26·0]), monodesethylamodiaquine (7·1 nM [4·3–8·9]), pyronaridine (1·1 nM [0·7–2·3]), piperaquine (5·6 nM [3·3–8·6]), ferroquine (1·8 nM [1·5–3·3]), AQ-13 (24·0 nM [17·0–32·0]), lumefantrine (5·1 nM [3·2–7·7]), mefloquine (9·5 nM [6·6–13·0]), dihydroartemisinin (1·5 nM [1·0–2·0]), and atovaquone (0·3 nM [0·2–0·4]). Compared with results from our study in 2010–13, significant improvements in susceptibility were seen for chloroquine (median IC50 288·0 nM [IQR 122·0–607·0]; p<0·0001), monodesethylamodiaquine (76·0 nM [44·0–137]; p<0·0001), and piperaquine (21·0 nM [7·6–43·0]; p<0·0001), a small but significant decrease in susceptibility was seen for lumefantrine (3·0 nM [1·1–7·6]; p<0·0001), and no change in susceptibility was seen with dihydroartemisinin (1·3 nM [0·8–2·5]; p=0·64). Chloroquine resistance (IC50>100 nM) was more common in isolates from the Tororo district (11 [15%] of 71), compared with those from the Busia district (12 [4%] of 320; p=0·0017). We showed significant increases between 2010–12 and 2016–19 in the prevalences of wild-type P falciparum multidrug resistance protein 1 (PfMDR1) Asn86Tyr from 60% (391 of 653) to 99% (418 of 422; p<0·0001), PfMDR1 Asp1246Tyr from 60% (390 of 650) to 90% (371 of 419; p<0·0001), and P falciparum chloroquine resistance transporter (PfCRT) Lys76Thr from 7% (44 of 675) to 87% (364 of 417; p<0·0001).InterpretationOur results show marked changes in P falciparum drug susceptibility phenotypes and genotypes in Uganda during the past decade. These results suggest that additional changes will be seen over time and continued surveillance of susceptibility to key ACT components is warranted.FundingNational Institutes of Health and Medicines for Malaria Venture.
Highlights
Malaria control in Africa has stalled in the past few years, and progress will be threatened by the emergence of resistance to the components of artemisinin-based combi nation therapies (ACTs), the first-line treatments for malaria caused by Plasmodium falciparum.[1,2] ACT activity relies on a rapid-acting artemisinin derivative combined with a more slowly cleared partner drug
We showed significant increases between 2010–12 and 2016–19 in the prevalences of wild-type P falciparum multidrug resistance protein 1 (PfMDR1) Asn86Tyr from 60% (391 of 653) to 99% (418 of 422; p
Added value of this study This study focuses on expanding understanding of genotype– phenotype associations, supported by ex-vivo and genetic characterisations of antimalarial drug susceptibility and resistance
Summary
Malaria control in Africa has stalled in the past few years, and progress will be threatened by the emergence of resistance to the components of artemisinin-based combi nation therapies (ACTs), the first-line treatments for malaria caused by Plasmodium falciparum.[1,2] ACT activity relies on a rapid-acting artemisinin derivative combined with a more slowly cleared partner drug. Resistance to several antimalarials has spread to Africa after establishment in other regions.[2] Clinical efficacies of the leading ACTs have remained excellent in African trials done in the past 5 years,[2,3,4] but the emergence of www.thelancet.com/microbe Vol 2 September 2021
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