Temporal Changes in Prevalence of Molecular Markers Mediating Antimalarial Drug Resistance in a High Malaria Transmission Setting in Uganda

Abstract

Abstract. Standard therapy for malaria in Uganda changed from chloroquine to chloroquine + sulfadoxine-pyrimethamine in 2000, and artemether-lumefantrine in 2004, although implementation of each change was slow. Plasmodium falciparum genetic polymorphisms are associated with alterations in drug sensitivity. We followed the prevalence of drug resistancemediating P. falciparum polymorphisms in 982 samples from Tororo, a region of high transmission intensity, collected from three successive treatment trials conducted during 2003-2012, excluding samples with known recent prior treatment. Considering transporter mutations, prevalence of the mutant pfcrt 76T, pfmdr1 86Y, and pfmdr1 1246Y alleles decreased over time. Considering antifolate mutations, the prevalence of pfdhfr 51I, 59R, and 108N, and pfdhps 437G and 540E were consistently high; pfdhfr 164L and pfdhps 581G were uncommon, but most prevalent during 2008-2010. Our data suggest sequential selective pressures as different treatments were implemented, and they highlight the importance of genetic surveillance as treatment policies change over time.

Efficacy of Artemether-Lumefantrine and Dihydroartemisinin-Piperaquine for Treatment of Uncomplicated Malaria in Children in Zaire and Uíge Provinces, Angola

“…We found high rates of two pfmdr1 haplotypes containing mutations previously associated with lumefantrine resistance, NFD and NYD, in isolates from reinfections and recrudescences from the AL arms in both provinces. Our results are consistent with data from Uganda showing selection of the 86N, 184F, and 1246D mutations following treatment with AL (33,34). Malmberg et al recently reported that parasites with the pfmdr1 NFD and NYD haplotypes could tolerate 15-and 7-foldhigher lumefantrine blood concentrations, respectively, than parasites with the YYY haplotype (35).…”

Intermittent Preventive Treatment with Dihydroartemisinin-Piperaquine in Ugandan Schoolchildren Selects for Plasmodium falciparum Transporter Polymorphisms That Modify Drug Sensitivity

“…The prevalence of the 4 studied polymorphisms was similar to that in contemporaneous samples from Tororo that were reported previously (43). For two polymorphisms, pfcrt K76T and pfmdr1 N86Y, the prevalence of mutant genotypes was significantly higher in samples from children who had received DP within 30 days than in those from children who had not received DP within 60 days (Table 2).…”

Incomplete reversal of genotypic resistance of Plasmodium falciparum to chloroquine after a decade of change in malaria treatment policy in Uganda

“…Although artemetherlumefantrine is still very effective in malaria treatment in Uganda, 32 analysis of data from different clinical trials showed that high prevalence of wild type Pfmdr-86N parasite genotype is associated with decreased parasite sensitivity to artemisinin-lumefantrine. 29 Furthermore, we found higher prevalence (41.8%) of wild type 76K P. falciparum genotype than a previous study by Mbogo et al 33 that reported 17% in Tororo, Uganda. The variation in the findings could be due to the difference in the study periods.…”

“…In the study by Mbogo et al, 33 samples of previous clinical trials collected between 2002 and 2012 were used in the analysis, which included samples collected when CQ was still a recommended drug in the CQ sulfadoxinepyrimethamine combination, unlike samples collected in 2013 to 2014 used in the current study. The findings of this study in addition to that of Mbogo et al, 33 are however indicative of a steady decline in the prevalence of mutant 76T alleles of the Pfcrt-76 gene in Uganda which had previously peaked at 100% in the population. Studies have shown that it took approximately 8 years (1993 to 2001) since the change in malaria treatment policy for CQ sensitivity to re-emerge in Malawi.…”