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Review 2: "Day 3 Parasitemia and Plasmodium Falciparum Kelch 13 Mutations among Uncomplicated Malaria Patients Treated with Artemether-lumefantrine in Adjumani District, Uganda"

The reviewers overall state that the manuscript is potentially informative, suggesting a need to continuously evaluate the effectiveness of artemether in this context.

Published onMay 28, 2024
Review 2: "Day 3 Parasitemia and Plasmodium Falciparum Kelch 13 Mutations among Uncomplicated Malaria Patients Treated with Artemether-lumefantrine in Adjumani District, Uganda"
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Day 3 parasitemia and Plasmodium falciparum Kelch 13 mutations among uncomplicated malaria patients treated with artemether-lumefantrine in Adjumani district, Uganda
Day 3 parasitemia and Plasmodium falciparum Kelch 13 mutations among uncomplicated malaria patients treated with artemether-lumefantrine in Adjumani district, Uganda
Description

Abstract Artemisinin resistance threatens malaria control and elimination efforts globally. Recent studies have reported the emergence of Plasmodium falciparum parasites tolerant to artemisinin agents in sub-Saharan Africa, including Uganda. The current study assessed the day 3 parasite clearance and its correlation with P. falciparum K13 propeller gene (pfkelch13) mutations in P. falciparum parasites isolated from patients with uncomplicated malaria under artemether-lumefantrine (AL) treatment. This study enrolled 100 P. falciparum-positive patients to whom AL was prescribed between 09/September/2022 and 06/November/2022. Blood samples were collected in EDTA tubes before treatment initiation (day 0) and on day 3. Parasitemia was assessed by microscopy from blood smears and quantitative polymerase chain reaction (qPCR) from the DNA extracted. The day 0 parasite K13 gene was sequenced using Sanger sequencing. Sequence data were analysed using MEGA version 11 software. The data were analysed using STATA version 15, and the Mann‒Whitney U test was used to compare PCR parasite clearance on day 3 using the comparative CT value method and pfkelch13 mutations.The prevalence of day 3 parasitaemia was 24% (24/100) by microscopy and 63% (63/100) by qPCR from the AL-treated patients. P. falciparum K13-propeller gene polymorphism was detected in 18.8% (15/80) of the day 0 DNA samples. The K13 mutations found were C469Y, 12.5% (10/80); A675V, 2.5% (2/80); A569S, 1.25%, (1/80), A578S, 1.25%, (1/80) and; F491S, 1.25%, (1/80) a new allele not reported anywhere. The C469Y mutation, compared to the wild-type, was associated with delayed parasite clearance p=0.0278, Hodges-Lehmann estimation 3.2108 on the log scale, (95%CI 1.7076, 4.4730).There was a high prevalence of day 3 P. falciparum among malaria patients treated using artemether-lumefantrine. We conclude that the K13 mutation associated with artemisinin resistance by P. falciparum is present in Adjumani district, Uganda. This necessitates regular surveillance of the effectiveness and efficacy of artemether-lumefantrine in the country.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.

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Review: In this preprint, Angwe et al. report on a high prevalence of day 3 P. falciparum among malaria patients treated using artemether-lumefantrine in Adjumani district in Uganda and the presence of P. falciparum kelch 13 mutations potentially associated with artemisinin resistance. They correctly conclude that this necessitates regular surveillance of the effectiveness and efficacy of artemether-lumefantrine in the country.

Typically, microscopy is used to determine day 3 parasitemia since the use of PCR can be misleading due to the fact that by day 3, it is not clear if the PCR is picking dead or alive parasites which could lead to an increase in the proportion of positive patients, as observed in this study. The authors utilized both microscopy and PCR but used PCR results to calculate the change in parasite clearance which I think is not appropriate. However, this does not change the fact that they observed above normal day 3 positivity (24%), which is of concern. These results suggest artemisinin partial resistance which is characterized by delayed parasite clearance. Unfortunately, the patients were not followed to day 28 which would have been useful to determine treatment outcome and this important parameter remains unknown. However, if the partner drug is efficacious, artemisinin partial resistance rarely leads to treatment failures.

The reader assumes that the 80 successfully sequenced samples were day 0 samples since this is not clearly stated. The fact that the study reported 10 patients with the validated artemisinin resistance markers, C469Y, and 1 patient with A675V is relevant and requires heightened surveillance and monitoring of AL efficacy.

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