1. In this drug efficacy study, the percentage of patients with malaria following artemisinin-based combination anti-malarial therapy increased steadily between 2016 and 2019.
2. Mutations in the Pkfelch13 gene were highly associated with resistance to artemisinin-based therapy as well as deletions of the hrp2 and hrp3 genes, which current histidine-rich protein 2 (HRP2) rapid diagnostic tests are based on.
Evidence Rating Level: 2 (Good)
Study Rundown: Malaria affects communities worldwide, significantly impacting low- and middle-income regions. Artemisinin-based combination therapies are first-line for uncomplicated P. falciparum infections. However, partial artemisinin resistance has emerged in Asia and Africa, resulting in delayed clearance or persistence of parasites following therapy. The fundamental mechanisms of resistance involve mutations in the Pfkelch13 gene. The current study reported results of efficacy studies from 2016 to 2019 at five sites in Eritrea, Greece, to measure day-three positivity after completing artemisinin-based therapy for uncomplicated P. falciparum malaria. The percentage of patients with positive parasitemia on day three increased steadily during this period. R622I substitution in the Pfkelch13 gene was associated with a greater risk of resistance. Additionally, a proportion of parasites carrying Pfkelch13 R622I mutation also had deletions in hrp2 and hrp3 genes, which could potentially render them undetectable by current HRP-2 rapid tests. Overall, these results indicate that partial artemisinin resistance, underpinned by Pfkelch13 R611I mutation, has emerged in P. falciparum parasites in Eritrea. Furthermore, hrp2 and hrp3 deletions in these lineages could affect their detection with existing rapid tests.
In-Depth [drug efficacy study]: The current study analyzed the results from three open-label, single-group clinical drug efficacy studies to evaluate the partial resistance of P. falciparum to artemisinin in Eritrea. Partial resistance was defined as day-three positivity after artesunate-amodiaquine or artemether-lumefantrine therapy completion. Patients six months or older with uncomplicated P. falciparum, measurable parasitemia, and fever were eligible for inclusion. Exclusion criteria included signs of complicated malaria, infection with another Plasmodium species, severe malnutrition, fever due to another cause, and pregnancy. A total of 852 patients were enrolled. It was found that the percentage of patients with day-three positivity increased from 0.4% in 2016 to 1.95% in 2017 and 4.2% in 2019. A phenotyping study of isolates from patients before treatment found an increase in the prevalence of the Pfkelch13 R622I substitution mutation from 8.6% in 2016 to 21.0% in 2019. Correspondingly, the presence of parasites carrying the Pfkeltch13 R622I mutation increased the odds of day-three positivity by a factor of 6.2 (95% confidence interval, 2.5 to 15.5). Notably, there was evidence of intra-host selection for the Pfkelch13 R622I genotype only after initiating artemisinin-based therapy. Over 5% of patients 15 years or younger with day-three positivity carried parasites with this mutation. Phylogenetic analysis suggested that this genotype was related to parasite populations from Africa. Lastly, deletions in both the hrp2 and hrp3 gene loci were noted in 16.9% of the 65 isolated parasites carrying Pfkelch13 R622I, raising concerns for potentially increasing false negative rates with HRP2-based diagnostic rapid tests. These results demonstrated an emergence of partial resistance to artemisinin-based therapy among P. falciparum in Eritrea driven by the Pfkelch13 R622I mutation.
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