Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine for the treatment of uncomplicated plasmodium falciparum malaria in South Sudan: a multi-site therapeutic efficacy study, 2024–2025

South Sudan has one of the highest malaria burdens per capita in Africa, and artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) are first- and second-line treatments for uncomplicated Plasmodium falciparum malaria. However, despite the emergence of Artemisinin partial resistance (ART-R) and AL failure at some sites in the region, no therapeutic efficacy study (TES) has been conducted since the introduction of ASAQ and AL two decades ago. Our TES aimed to assess the efficacy of ASAQ and AL across four sites in South Sudan. This study was conducted in Juba, Bor, Wau, and Yambio. Children aged 6 months to 59 months with microscopically confirmed uncomplicated P. falciparum monoinfection were assigned to ASAQ or AL and followed for 28 days to assess treatment response. The primary endpoint was the Kaplan–Meier PCR-corrected adequate clinical and parasitological response (ACPR) on Day 28. Day 3 parasite positivity was used as a measure of early treatment response. We enrolled 390 children across all arms; 10.3% overall were lost to follow-up, ranging from 0% in Bor to 24.1% in Juba-ASAQ, and 350 (89.7%) were included in the per-protocol analysis. Kaplan–Meier uncorrected ACPR was: 96.2% (95% CI: 89.2–99.2) in Juba-AL, 95.6% (95% CI: 87.6–99.1) in Juba-ASAQ, 97.7% (95% CI: 92.6–99.7) in Bor (ASAQ) and 93.3% (95% CI: 86.1–97.5) in Yambio (AL). Kaplan–Meier PCR-corrected ACPR exceeded 90% in all sites except Wau: 98.7% (95% CI: 92.9–100.0) in Juba-AL, 100.0% (95% CI: 94.5–100.0) in Juba-ASAQ, 100.0% (95% CI: 95.8–100.0) in Bor (ASAQ) and 98.8% (95% CI: 93.5–100.0) in Yambio (AL). In Wau, only 34 participants were evaluable at Day 28, and no treatment failures were observed. Day 3 parasite positivity was elevated at Bor (13.8%), exceeding the WHO 10% threshold used as an indicator of suspected ART-R. No adverse events were reported. ASAQ and AL remain highly efficacious against uncomplicated P. falciparum malaria in South Sudan, supporting the continuation of the current treatment policy. The high Day 3 positivity rate at Bor warrants enhanced molecular surveillance and repeat efficacy monitoring. This study establishes a baseline for national TES surveillance.