Recovery and stable persistence of chloroquine sensitivity in Plasmodium falciparum parasites after its discontinued use in Northern Uganda.

Abstract

Background Usage of chloroquine was discontinued from the treatment of Plasmodium falciparum infection in almost all endemic regions because of global spread of resistant parasites. Since the first report in Malawi, numerous epidemiological studies have demonstrated that the discontinuance led to re-emergence of chloroquine-susceptible P. falciparum parasites, suggesting a possible role in future malaria control. However, most studies were cross-sectional, with few studies looking at the persistence of chloroquine recovery in long term. This study fills the gap by providing, for a period of at least 6 years, proof of persistent re-emergence/stable recovery of susceptible parasite populations using both molecular and phenotypic methods Methods Ex vivo drug-susceptibility assays to chloroquine (n = 319) and lumefantrine (n = 335) were performed from 2013 to 2018 in Gulu, Northern Uganda where chloroquine had been removed from the official malaria treatment regimen since 2006. Genotyping of pfcrt and pfmdr1 was also performed. Results Chloroquine resistance (100 nM) was observed in only 3 (1.3%) samples. Average IC 50 values for chloroquine were persistently low throughout the study period (17.4–24.9 nM). Parasites harboring p fcrt K76 alleles showed significantly lower IC 50 s to chloroquine than the parasites harboring K76T alleles (21.4 nM vs 43.1 nM, p-value= 3.9×10 -8 ). Prevalence of K76 alleles gradually increased from 71% in 2013 to 100% in 2018. Conclusion This study found evidence of stable persistence of chloroquine susceptibility with the fixation of pfcrt K76 in Northern Uganda after discontinuation of chloroquine in the region. Accumulation of similar evidence in other endemic areas in Uganda could open channels for possible future re-use of chloroquine as an option for malaria treatment or prevention.

Therapeutic efficacy of artemether-lumefantrine, artesunate-amodiaquine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Sub-Saharan Africa: A systematic review and meta-analysis

“…falciparum revision to chloroquine sensitivity as documented recently in different parts of Sub-Saharan Africa. The revision to parasites with wild type pfmdr1 and pfcrt alleles sensitive to chloroquine and amodiaquine [ 78 – 80 ] is a great advantage to ASAQ.…”

Increase in the proportion of Plasmodium falciparum with kelch13 C580Y mutation and decline in pfcrt and pfmdr1 mutant alleles in Papua New Guinea

“…The significant increase in pfmdr1 N86 wild-type from 59.5% to 91.4% in the three years to 2020 also suggests the potential resurgence of chloroquine sensitivity. Although this phenomenon has been widely observed in African countries [13][14][15], it is very rare in SEA [41].…”

“…In addition to the issue of ART resistance, previous ex vivo drug study also found that most P. falciparum parasites were resistant to chloroquine despite the discontinuation of chloroquine use in the early 2010s [12]. This is contrary to the observations in many African countries where chloroquine susceptibility recovered years after discontinuation [13][14][15].…”

Molecular surveillance of the Plasmodium vivax multidrug resistance 1 gene in Peru between 2006 and 2015

“…In this regard, studies carried out in P. falciparum suggest that CQ-wildtype alleles in pfmdr1 and pfcrt have a selective advantage over resistant genotypes when CQ pressure is not exerted [45][46][47]. In this regard, regions where CQ was discontinued experienced an increase of wildtype pfcrt and pfmdr1 P. falciparum strains [45,46,48]. However, this is unlikely to happen with the P. vivax population in the Peruvian Amazon due to the continued use of CQ as first-line treatment.…”