Temporal Trends in Artemisinin Partial Resistance and Other Antimalarial Drug Mutations in Plasmodium falciparum from Kagera Region, Northwestern Tanzania, 2021-2023.
| Title: | Temporal Trends in Artemisinin Partial Resistance and Other Antimalarial Drug Mutations in Plasmodium falciparum from Kagera Region, Northwestern Tanzania, 2021-2023. |
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| Authors: | Simkin A; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.; Mandai S; Ifakara Health Institute, Dar es Salaam, Tanzania.; Fola AA; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.; Center for Computational Molecular Biology, Brown University, Providence, RI, USA.; Young NW; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.; Center for Computational Molecular Biology, Brown University, Providence, RI, USA.; Pereus D; Ifakara Health Institute, Dar es Salaam, Tanzania.; Bakari C; Ifakara Health Institute, Dar es Salaam, Tanzania.; Madebe RA; National Institute for Medical Research, Dar es Salaam, Tanzania.; Seth MD; National Institute for Medical Research, Dar es Salaam, Tanzania.; Mrengela RB; Ifakara Health Institute, Dar es Salaam, Tanzania.; Kisambale AJ; Ifakara Health Institute, Dar es Salaam, Tanzania.; Chacha GA; National Institute for Medical Research, Dar es Salaam, Tanzania.; Mandara CI; National Institute for Medical Research, Dar es Salaam, Tanzania.; Francis F; National Institute for Medical Research, Dar es Salaam, Tanzania.; Mbwambo D; National Malaria Control Programme, Dodoma, Tanzania.; Garimo I; National Malaria Control Programme, Dodoma, Tanzania.; Chacky F; National Institute for Medical Research, Dar es Salaam, Tanzania.; Aaron S; National Malaria Control Programme, Dodoma, Tanzania.; Lusasi A; National Malaria Control Programme, Dodoma, Tanzania.; Molteni F; Swiss Tropical Public Health Institute, Dar es Salaam, Tanzania.; Njau RJA; Department of Parasitology and Medical Entomology, Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.; Kajange S; President's Office, Regional Administration and Local Government, Dodoma, Tanzania.; Nhiga SL; National Malaria Control Programme, Dodoma, Tanzania.; Mohamed A; President's Office, Regional Administration and Local Government, Dodoma, Tanzania.; Juliano JJ; Division of Infectious Diseases, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Curriculum of Genetics and Molecular Biology, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Institute for Global Health and Infectious Diseases, University of North Carolina School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Ishengoma DS; Ifakara Health Institute, Dar es Salaam, Tanzania.; National Institute for Medical Research, Dar es Salaam, Tanzania.; Bailey JA; Department of Pathology and Laboratory Medicine, Brown University, Providence, RI, USA.; Center for Computational Molecular Biology, Brown University, Providence, RI, USA. |
| Source: | MedRxiv : the preprint server for health sciences [medRxiv] 2025 Nov 28. Date of Electronic Publication: 2025 Nov 28. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101767986 Publication Model: Electronic Cited Medium: Internet NLM ISO Abbreviation: medRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment, yet the emergence of artemisinin partial resistance (ART-R) in Africa threatens their efficacy. ART-R is primarily associated with mutations in the Plasmodium falciparum kelch13 (K13) gene, notably R561H, which has been linked to delayed parasite clearance in East Africa. We conducted longitudinal molecular surveillance in Tanzania's Kagera region from 2021 to 2023 to characterize temporal and spatial trends in ART-R and other antimalarial resistance markers. Using molecular inversion probes targeting key antimalarial resistance genes, we genotyped 2,826 isolates from seven districts. The WHO-validated K13 mutation R561H persisted in border districts of Karagwe and Kyerwa, with prevalence ranging from 14-26%, and appeared for the first time in Muleba (5.0%) and Bukoba rural district (0.7%) in 2023, indicating eastward spread toward Lake Victoria. Regional average prevalence of R561H rose from 5.5% in 2021 to 11.3% in 2022, then stabilized at 6.9% in 2023. Additional validated (A675V) and candidate (V568G, P441L) mutations were detected at low frequencies, suggesting ongoing diversification of the parasite population under local selection pressures. Partner-drug resistance markers showed minimal change: MDR1 N86Y remained near fixation, while CRT K76T declined from 5.9% (2021) to 2.4% (2023). Antifolate resistance was entrenched, with early DHFR and DHPS mutations near fixation and high-level resistance markers (DHFR I164L and DHPS A581G) exhibiting marked spatial heterogeneity, peaking at 38.1% and 48.1%, respectively, in eastern districts. These findings reveal micro-geographic heterogeneity in resistance and ongoing spread, emphasizing the need for district-level surveillance to detect emerging hotspots and guide interventions. Sustained molecular monitoring is critical to inform treatment policy, preserve ACT efficacy, and mitigate the risk of widespread resistance in East Africa. Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment, yet the emergence of artemisinin partial resistance (ART-R) in Africa threatens their efficacy. ART-R is primarily associated with mutations in the Plasmodium falciparum kelch13 (K13) gene, notably R561H, which has been linked to delayed parasite clearance in East Africa. We conducted longitudinal molecular surveillance in Tanzania's Kagera region from 2021 to 2023 to characterize temporal and spatial trends in ART-R and other antimalarial resistance markers. Using molecular inversion probes targeting key antimalarial resistance genes, we genotyped 2,826 isolates from seven districts. The WHO-validated K13 mutation R561H persisted in border districts of Karagwe and Kyerwa, with prevalence ranging from 14-26%, and appeared for the first time in Muleba (5.0%) and Bukoba rural district (0.7%) in 2023, indicating eastward spread toward Lake Victoria. Regional average prevalence of R561H rose from 5.5% in 2021 to 11.3% in 2022, then stabilized at 6.9% in 2023. Additional validated (A675V) and candidate (V568G, P441L) mutations were detected at low frequencies, suggesting ongoing diversification of the parasite population under local selection pressures. Partner-drug resistance markers showed minimal change: MDR1 N86Y remained near fixation, while CRT K76T declined from 5.9% (2021) to 2.4% (2023). Antifolate resistance was entrenched, with early DHFR and DHPS mutations near fixation and high-level resistance markers (DHFR I164L and DHPS A581G) exhibiting marked spatial heterogeneity, peaking at 38.1% and 48.1%, respectively, in eastern districts. These findings reveal micro-geographic heterogeneity in resistance and ongoing spread, emphasizing the need for district-level surveillance to detect emerging hotspots and guide interventions. Sustained molecular monitoring is critical to inform treatment policy, preserve ACT efficacy, and mitigate the risk of widespread resistance in East Africa. |
| Competing Interests: | Competing Interests: No authors declare a competing interest. Generative AI was used in the drafting of this manuscript. The authors take full responsibility for the contents of the manuscript. |
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| Grant Information: | K24 AI134990 United States AI NIAID NIH HHS; R01 AI156267 United States AI NIAID NIH HHS; R01 AI189911 United States AI NIAID NIH HHS; R01 AI190302 United States AI NIAID NIH HHS |
| Contributed Indexing: | Keywords: Plasmodium falciparum; Tanzania; artemisinin; genomics; kelch; malaria; resistance; surveillance |
| Entry Date(s): | Date Created: 20251208 Date Completed: 20251222 Latest Revision: 20251222 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12676548 |
| DOI: | 10.1101/2025.11.26.25341086 |
| PMID: | 41358296 |
| Database: | MEDLINE |
Journal Article; Preprint