Yuxin Zhao, Haitian Fan
PA I38T/M substitutions are associated with noteworthy virological rebound and delayed clinical recovery, predominantly in pediatric populations. These findings emphasize the requirement for age-specific resistance monitoring and support the evaluation of combination antiviral therapies to mitigate resistance emergence.
BACKGROUND: Seasonal influenza imposes substantial clinical and economic burdens, with pediatric populations facing escalating risks of severe complications. While baloxavir marboxil (baloxavir) is an efficacious cap-dependent endonuclease inhibitor, the emergence of treatment-induced PA I38T/M substitutions has raised critical public health concerns. This study aimed to quantify the incidence and clinical consequences of these mutations across diverse populations and explore their mechanistic basis through structural modeling.
METHODS: A systematic review and meta-analysis of prospective clinical trials was conducted. Primary outcomes included the pooled incidence of mutations and the time to illness alleviation (TTIA). Leave-one-out sensitivity analyses and structural modeling were integrated to evaluate robustness and potential mechanisms.
RESULTS: Five prospective clinical trials comprising pediatric, uncomplicated, and high-risk adult patients were included. The pooled incidence of PA substitutions was 10.5% (95% CI: 0.0% to 21.1%; I2 = 94.6%). While the overall pooled incidence was robust, the highest mutation rates (up to 23.4%) were disproportionately observed in pediatric cohorts. Overall pooled analysis showed a numerical but statistically non-significant 15.47-hour delay in TTIA (95% CI: -40.96 to 71.91; P = 0.359; I2 = 81.8%). However, subgroup analysis revealed this overall non-significance was an artifact of stark demographic divergence: the mutant-induced TTIA prolongation showed a modest numerical increase of 5.67 hours in adults, whereas this gap widened to 36.8 hours in the pediatric cohort. Furthermore, PA substitutions extended the median duration of infectious viral shedding from 24.0 to 180.0 hours in pediatric patients.
CONCLUSIONS: PA I38T/M substitutions are associated with noteworthy virological rebound and delayed clinical recovery, predominantly in pediatric populations. These findings emphasize the requirement for age-specific resistance monitoring and support the evaluation of combination antiviral therapies to mitigate resistance emergence.