Baloxavir Resistance Markers in Influenza A and B Viruses in the Americas

Abstract

Erick Acocal-Juárez,1– 3 Luis Márquez-Domínguez,2 Verónica Vallejo-Ruíz,2 Lilia Cedillo,3 Gerardo Santos-López2 1Centro de Investigaciones en Ciencias Microbiológicas, Benemérita Universidad Autónoma de Puebla, Puebla Pue, Mexico; 2Laboratorio de Biología Molecular y Virología, Centro de Investigación Biomédica de Oriente, Instituto Mexicano del Seguro Social, Puebla, Mexico; 3Centro de Detección Biomolecular, Benemérita Universidad Autónoma de Puebla México, Puebla Pue, MexicoCorrespondence: Lilia Cedillo; Gerardo Santos-López, Email [email protected]; [email protected]: Influenza control demands multifaceted strategies, including antiviral drugs. Baloxavir, a recent addition to influenza treatment, acts as an inhibitor of the Polymerase acid (PA) component of the viral polymerase. However, mutations associated with resistance have been identified.Purpose: This study analyzed PA gene sequences of influenza A and B viruses (IAV and IBV, respectively) reported in the Americas, retrieved from databases published until May 2023, to identify primary markers of resistance to baloxavir.Patients and Methods: PA gene sequences were obtained from the GISAID and NCBI databases, focusing on countries in the Americas with 500 or more sequences for IAV, and 50 or more sequences for IBV.Results: Of the 58,816 PA sequences analyzed for IAV, only 55 (0.1%) harbored resistance markers, representing approximately 1 in 1000 occurrence. The most frequent markers were I38V (21 cases) and I38M (7 cases) at position 38 of PA, followed by E199G (9 cases) at position 199. For IBV, 14,684 sequences were analyzed, of which only eight presented a resistance marker (0.05%). Five sequences had the M34I marker, while the remaining three had the I38V marker. While frequency of resistance markers in PA is comparable to other regions, these results highlight the need for enhanced sequencing efforts, particularly in Latin America. Such efforts would serve to intensify influenza surveillance and inform public health interventions.Conclusion: While baloxavir demonstrates efficacy against influenza, resistance markers have been identified, including pre-existing ones. Our study adds eight (IAV: six and IBV: two) new spontaneously occurring substitutions to the existing literature, highlighting the need for continued surveillance. Among these, I38M stands out due to its significant tenfold reduction in drug susceptibility. Therefore, vigilant monitoring of these resistance markers in IAV and IBV remains crucial for maintaining baloxavir’s effectiveness and informing future public health interventions.Keywords: antiviral resistance, substitutions, PA protein, polymerase inhibitor

Keywords

• antiviral resistance
• substitutions
• pa protein
• polymerase inhibitor.