Impact of polymerase acidic subunit (PA) substitutions on fever and symptoms in pediatric influenza A patients treated with baloxavir: A pooled four-season analysis

Abstract

Background: Baloxavir marboxil is used for influenza treatment in Japan. However, the clinical and virologic significance of baloxavir-associated PA variants in children remains unclear.

Methods: We conducted a four-season, multicenter study from 2018-2019 to 2023-2024 in pediatric patients under 19 years old with influenza A who were treated with baloxavir. Clinical data were collected at the first visit; diary cards were maintained for up to 8 days. Clinical specimens were collected twice, with a median interval of 4 days. PA substitutions were screened by real-time RT-PCR and confirmed by next-generation sequencing and Sanger methods.

Results: Among 247 patients, 24 (9.7%) harbored PA variants, one pre-treatment and 23 post-treatment. PA/I38T was the most common substitution. A(H3N2) patients had a higher frequency of PA variants than A(H1N1)pdm09 (13.8% vs. 5.1%). Although PA variants were associated with slower viral RNA decline, no significant differences were observed in fever duration (median 22.6 vs. 15.6 h) or symptom duration (median 105.0 vs. 113.3 h) compared to wild-type virus infections.

Conclusion: PA variants, especially PA/I38T, emerged more frequently in A(H3N2) infections but had minimal clinical impact. The rarity of pre-treatment variants supports limited community transmission. Continued surveillance is warranted, particularly in younger children.

Keywords: Antiviral resistance; Baloxavir; Children; Clinical effectiveness; Influenza.