Artemether-Lumefantrine Treatment Selects Plasmodium falciparum Multidrug Resistance 1 ( pfmdr1 ) Increased Copy Number Among African Malaria Infections

Journal Article · 25 March 2025 · Journal of Infectious Diseases

DOI: https://doi.org/10.1093/infdis/jiaf155 · OSTI ID:2554045

Fançony, Claudia ; Fortes-Gabriel, Elsa ; Zage, Félix; Alexiou, Evangelia; Broumou, Ioanna ; Pernaute-Lau, Leyre; Panzo, Jorge; António, Esperança J.; Cristovão, Mario S.; Domingos, José M.; Sassoma, Estevão; Kuatoko, Fernando; Rosario, Edite V. N. ; Martins, António; Färnert, Anna; Bernardino, Luis; de Sousa, Tais N. ; Gil, José Pedro

Abstract Background Decreased efficacy of artemether-lumefantrine, the globally most used antimalarial, has recently emerged in Africa. Methods An efficacy trial was carried out based on directly observed artemether-lumefantrine therapy at Bengo, Northern Angola. One-hundred Plasmodium falciparum uncomplicated malaria patients (2–10 years old) were enrolled, hospitalized for the treatment period, and followed up for 42 days. Polymerase chain reaction (PCR) correction was performed with pfmsp1/2 plus glurp, with analysis considering 2 or 3 coincident markers. Infections were tested by quantitative PCR (qPCR) for pfmdr1 copy number (pfmdr1×N), a potential P. falciparum marker of lumefantrine resistance previously identified in the region. In vitro clone mixtures were built and used to determine the relation between qPCR copy number scores and actual intrainfection quantitative fractions of pfmdr1×N. Results We observed a significant posttreatment selection of gene amplification, suggesting a role in the parasite in vivo response to this drug. pfmdr1×2 qPCR scores of 1.3, 1.4, and 1.5 were determined to correspond to 15%, 25%, and 35% intrainfection rates. Patients carrying infections with a score ≥1.4 at baseline were linked to decreased artemether-lumefantrine day 42 efficacy (79% vs 97% single-copy pfmdr1). All infections were pfmdr1 N86 carriers and no pfk13 mutations were found. Conclusions Our study suggests pfmdr1×N as a marker of P. falciparum in vivo response to lumefantrine in Africa, while indicating patients carrying infections with a pretreatment pfmdr1×N score ≥1.4 before treatment are a group experiencing decreased artemether-lumefantrine performance.

• Sponsoring Organization: USDOE Office of Nuclear Energy (NE), Nuclear Fuel Cycle and Supply Chain
• OSTI ID: 2554045
• Journal Information: Journal of Infectious Diseases, Journal Name: Journal of Infectious Diseases; ISSN 0022-1899
• Publisher: Oxford University PressCopyright Statement
• Country of Publication: United States
• Language: English