Extending the Duration of Artemether-Lumefantrine Treatment for Uncomplicated Plasmodium falciparum Malaria: Updated US Centers for Disease Control and Prevention Guidance Based on Review of Surveillance, Consultations, and Published Data

BACKGROUND: Artemisinin-based combination therapies (ACTs) are recommended for treatment of uncomplicated Plasmodium falciparum malaria; artemether-lumefantrine (AL) is the only ACT available in the United States. Reports of AL treatment failure among international travelers raise concerns about the continued adequacy of the standard 3-day AL regimen for travelers. METHODS: We reviewed US malaria surveillance data, clinical consultation records, and antimalarial molecular resistance surveillance data at the Centers for Disease Control and Prevention (CDC). We also conducted a literature review and meta-analysis to assess the risk of treatment failure following treatment with AL or atovaquone-proguanil (AP) in travelers treated in nonendemic settings and reviewed the efficacy and safety of AL regimens with durations longer than the standard 3-day (6-dose) course. RESULTS: From November 2022 through October 2025, CDC was consulted on 47 P. falciparum treatment failures, including 40 following AL-based and 7 following AP-based treatments. All reported travel to Africa, and 62% presented with severe malaria. Among AL failures, 85% were late recrudescences occurring 1-8 weeks after initial treatment. In the meta-analysis, the pooled AL treatment failure risk was higher for data collected in 2018 or later (7% [95% CI, 1%-32%]) compared to before 2018 (4% [95% CI, 2%-8%]), although the difference was not statistically significant (P = .3). Extended AL regimens, particularly a 5-day (10-dose) course, were well tolerated and consistently achieved higher lumefantrine exposure. CONCLUSIONS: These findings informed updated CDC guidance recommending an extended 5-day (10-dose) course of AL for treating uncomplicated P. falciparum malaria in the United States.