Abstract
BACKGROUND: Ethiopia aims to eliminate local malaria transmission by 2030, but rising malaria cases, due to different factors, present a challenge. Understanding the prevalence and distribution of artemisinin partial resistance (ART-R) and other markers related to partner drugs as well as parasite connectivity in Ethiopia can greatly inform malaria control. METHODS: We analyzed 1199 clinical Plasmodium falciparum infections from 12 sentinel sites across five regions in Ethiopia, collected between 2019 and 2023. Using two molecular inversion probe (MIP) panels targeting key drug resistance genes and genome-wide SNPs, we assessed the prevalence of resistance-associated mutations, complexity of infection (COI), and parasite relatedness through identity-by-descent (IBD) and principal component analysis (PCA). RESULTS: The most prevalent k13 R622I mutation appears in 15.7% of samples, with marked regional variation. Three validated ART-R mutations (P441L, P574L, A675V) are detected in Ethiopia for the first time, as far as we are aware, with A675V found exclusively in a Gambella clinic serving refugees from Sudan and South Sudan. Additionally, polymorphisms associated with resistance to partner drugs, including those in crt, mdr1, dhps, and dhfr genes, are nearly fixed. Most samples (87.2%) consist of monogenomic infections (COI = 1), and mutant parasites show high local genetic relatedness at the health facility level, suggesting clonal transmission. PCA reveals regional clustering, particularly in Gambella, highlighting the influence of local drug pressure, regional transmission dynamics, and importation as drivers of the observed drug resistance patterns. CONCLUSIONS: The increasing prevalence of k13 R622I and the emergence of additional ART-R mutations underscore the urgent need for enhanced ACT efficacy monitoring. Early detection of partner drug resistance and ACT failure will be essential to address malaria resurgence and support Ethiopia's elimination goals.