Trends of ex vivo sensitivity of Plasmodium falciparum to standard anti-malarials and correlation between sensitivities to different anti-malarials in Eastern Uganda

Abstract

Introduction: Malaria infection in the year 2017 alone killed approximately 435,000 people globally and 14,000 were from Uganda. Currently in sub-Saharan Africa, artemether-lumefantrine (AL) is recommended as first line treatment for uncomplicated malaria infection, unfortunately resistance to AL has been reported in south east Asia though uncommon in Africa. There is a need to monitor the sensitivity of malaria parasites to different recommended anti-malarial drugs used to treat malaria in Uganda. General objective: To determine the trends of ex vivo sensitivity of Plasmodium falciparum parasites to standard anti-malarial drugs, the effect of epidemiological factors and the correlations between the sensitivity of these parasites to anti-malarial drugs in Eastern Uganda. Methods: Ex-vivo sensitivity patterns of 291 P. falciparum isolates from people aged 6 months and older in Busia and Tororo were analyzed against various anti-malarial drug in period of June 2016 to December 2018. The study participants were part of an ongoing REACT project. Trends were explored using scatter plots of IC50s against date of collection and a lowess line fitted, IC50s summarized into geometric means, association with epidemiological factors done using linear regression and correlations using Spearman’s rank correlation with Sidak adjustment. P-values <0.05 considered statistically significant. Results: The trends showed parasites becoming more sensitive to chloroquine with time (β=-0.023, p-value=0.019) while piperaquine (β=0.0031, p-value<0.001) and pyrimethamine (β=19.12, p-value<0.001) showed opposite trend though dihydroartemisinin (β=0.0005, p-value=0.193) remained the same within this period. Epidemiological factors namely: season had association with ex vivo sensitivity with piperaquine (β=-1.08, p-value=0.027) and lumefantrine (β=-2.09, p-value=0.003), location with chloroquine (β=15.31, p-value=0.032) and atovaquone (β=-0.13, p-value=0.01). Aminoquinolines were fairly correlated with each other, amodiaquine verses chloroquine (r=0.54, p-value<0.0001) except for piperaquine, piperaquine verses chloroquine (r=0.15, p-value=0.9967) and piperaquine verses amodiaquine (r=0.22, p-value=0.3103). Conclusions: Increasing sensitivity of Plasmodium falciparum parasites to chloroquine in Eastern Uganda was observed, whereas an opposite but slow trend was observed for lumefantrine, therefore there is a need to continue monitoring its sensitivity in population. Age, and seasonality had effects on the ex vivo sensitivity, though these are small. There were fairly strong correlations between aminoquinolines except for piperaquine.