Detection of Variants With Reduced Baloxavir Marboxil and Oseltamivir Susceptibility in Children With Influenza A During the 2019–2020 Influenza Season

Abstract

Background We aimed to detect influenza variants with reduced susceptibility to baloxavir marboxil (baloxavir) and oseltamivir and identify differences in the clinical course between children with and without these variants after anti-viral treatment. Methods During the 2019–2020 influenza season, we enrolled children with confirmed influenza A (20 treated with baloxavir and 16 with oseltamivir). We analyzed patients’ sequential viral RNA loads and infectious virus titers, the drug susceptibilities of clinical isolates, and amino acid substitutions in the viral polymerase acidic protein subunits or neuraminidase. We assessed patients’ clinical information using questionnaires. Results All viral RNA loads and virus titers were significantly decreased after treatment, but we detected baloxavir-resistant and the oseltamivir-resistant variants in 5 of 20 and 3 of 16 patients, respectively. The duration of fever was similar between patients with and without the variants, but infectious viral shedding lasted 3 days longer in patients with baloxavir-resistant variants. In addition, the duration to improvement of clinical symptoms was longer in these patients (75.0 h vs. 29.5 h; p = 0.106). Conclusions After anti-viral treatment, the emergence of baloxavir-resistant variants may affect the patients’ clinical course, but oseltamivir-resistant variants had no clinical impact.

Clinical and Virologic Impacts of Respiratory Viral Co-infections in Children With Influenza

“…Study participants were recruited from among children laboratory-confirmed as having influenza A during the 2018–2019 16 and 2019–2020 17 influenza seasons. Among these children, we enrolled 38 and 35 who were treated with baloxavir and oseltamivir at the recommended dosage as indicated in the package insert, respectively, to investigate the clinical efficacy of baloxavir and oseltamivir.…”

“…The identity of the influenza A virus subtype and viral RNA loads were determined in previous studies. 16,17…”

“…The identity of the influenza A virus subtype and viral RNA loads were determined in previous studies. 16,17 The primer pair used at the Department of Pediatrics, Fukushima Medical University to amplify hRnV also amplifies some EnVs. Therefore, when hRnV and/or EnV were detected, the responsible virus was determined by referring to the PCR results for hRnV and EnV and the gene sequencing results for hRnV, 27 which was performed at the Research Center for Influenza and Respiratory Viruses, National Institute of Infectious Diseases (Text, Supplemental Digital Content 1, http://links.lww.com/INF/F17 and Table, Supplemental Digital Content 2, http://links.lww.com/INF/ F18).…”

“…16,17 Parents or guardians were interviewed to obtain information on the patients' background and they were also tasked to record the patients' body temperature and clinical symptom scores from 0 (best) to 5 (worst) for cough, rhinorrhea/nasal obstruction and appetite thrice daily. 16,17 These 3 clinical symptom scores were combined to form a 15-point scale, and the time required for the scale to decrease to ≤5 points (ie, score for each clinical symptom was ≤2) and remain there for more than 24 hours was determined. 16,17 We defined the time of fever decline as the time elapsed from when a patient had a body temperature of >37.5°C to that of <37.5°C for >24 hours.…”

“…14 Similarly, the cap-dependent endonuclease inhibitor [oral baloxavir marboxil (baloxavir)] is effective in treating children with mild influenza. [15][16][17] In Japan, all neuraminidase inhibitors (oral oseltamivir, inhaled zanamivir and laninamivir and intravenous peramivir) and baloxavir have been approved for treatment in children. However, because there are no antivirals available for respiratory viruses other than the influenza virus, patients with these respiratory virus infections are generally treated with symptomatic drugs, such as expectorants and antipyretics.…”