Investigating Artemisinin Resistance in the Era of Malaria Elimination in Bangladesh

Malaria continues to be a significant global health challenge, with efforts to eliminate the disease threatened by the rise of drug resistance. This research focuses on understanding resistance to artemisinin, a critical drug in malaria treatment, in Plasmodium falciparum, the parasite responsible for most malaria cases. While artemisinin resistance has been well-documented in Southeast Asia, this study examines its emergence and implications in Bangladesh, particularly in the Chittagong Hill Tracts (CHT), a region accounting for most of the country's malaria cases. To this end, a clinical study site was established in Bandarban, CHT, where patients were followed for parasite clearance after Artemisinin Combination Therapy (ACT) treatment, and samples were collected between 2018 and 2019 for further in vitro studies. The study uncovered the presence of artemisinin resistance (ART-R) in parasites collected from the CHTs using in vitro methods, demonstrating that resistance is already present despite the absence of commonly associated genetic markers. This finding highlights the potential for resistance to arise through alternative pathways, complicating global efforts to monitor and contain its spread. Additionally, the research revealed that resistance to older drugs, such as chloroquine, persists in this region, posing further challenges to malaria control strategies. The work also explored how specific genetic mutations, through genetic modification of the major molecular marker for ART-R, pfkelch13, impact resistance and the parasite’s ability to grow and spread, identifying mutations that confer high resistance levels with minimal fitness costs. These insights underscore the risk of rapid dissemination if these mutations become established locally. The study provides crucial evidence that Bangladesh’s parasites face no inherent barriers to developing and sustaining drug resistance, particularly given the region’s proximity to resistance hotspots in neighboring countries. The work also uncovered an important discovery: resistance can develop through mechanisms beyond the well-known genetic markers typically associated with artemisinin resistance. Through in vitro evolution and subsequent genetic modification in CHT isolates, PfKIC1 was found to be associated with elevated ART-R in the CHT background, This highlights the complexity of the issue and the need for expanded surveillance strategies that account for diverse resistance pathways. By combining field studies, genetic analysis, and laboratory experiments, this research highlights the urgent need for expanded surveillance strategies, tailored treatment approaches, and cross-border collaboration to mitigate the spread of resistance. These findings are critical to preserving the effectiveness of current drug regimens and safeguarding progress toward malaria elimination in Bangladesh and beyond, and stands as a model for comprehensive drug resistance assessment in malaria endemic areas with inadequate resources.