Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes

Abstract

Background: We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza.

Methods: This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1-11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration.

Results: Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9-62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer).

Conclusions: A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children.

Clinical trials registration: Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417).

Keywords: Japan; antiviral; baloxavir marboxil; children; influenza.

Figure 1.

A, Influenza virus titer (upper panel) and change from baseline in influenza virus titer (lower panel). Data are presented as mean ± SD. The dotted line in upper panel represents lowest level of detection. B, Individual influenza virus titer in patients with PA/I38T/M-substituted viruses (red line) and without PA/I38T/M-substituted viruses (black line). Abbreviations: PA/I38T, isoleucine substituted by threonine at position 38 of virus polymerase acidic protein; PA/I38M, isoleucine substituted by methionine at position 38 of virus polymerase acidic protein; SD, standard deviation; TCID₅₀, 50% tissue culture infective dose.

Figure 2.

Kaplan–Meier analysis of the illness alleviation after treatment with baloxavir marboxil in patients with and without PA/I38T/M-substituted viruses. Influenza illness was composed of cough, nasal discharge/congestion, and body temperature. The median TTIA was 79.6 hours in patients with PA/I38T/M-substituted viruses (n = 18) and was 42.8 hours in patients without PA/I38T/M-substituted viruses (n = 59). Abbreviations: PA/I38T, isoleucine substituted by threonine at position 38 of virus polymerase acidic protein; PA/I38M, isoleucine substituted by methionine at position 38 of virus polymerase acidic protein; TTIA, time to illness alleviation.

Figure 3.

Comparison between proportion (A) of PA/I38T/M-substituted viruses with viral titer (B) and plasma BXA concentration (C). A, Time courses of % proportion of PA/I38 T/M-substituted viruses in the swabs and B, viral titer (log₁₀TCID₅₀/mL) in the swabs were represented. C, BXA concentration in plasma (ng/mL) was plotted by a measured value at 24 hours and simulated value at 48, 72, and 96 hours, which were calculated by Bayesian inference with measured values. The individual patient numbers are shown on top. A threshold frequency of >1% was adopted for calling variant viruses in NGS analysis, and the LLoQ of viral titer was set at 0.7 log₁₀TCID₅₀/mL. Abbreviations: BXA, baloxavir acid; LLoQ, lower limit of quantification; NA, not applicable; ND, below detection limit of 2.05 log₁₀ RNA copies/mL, or no PCR amplification observed, or no variant profiles obtained due to low coverage (<100); NGS, next-generation sequencing; PA/I38T, isoleucine substituted by threonine at position 38 of virus polymerase acidic protein; PA/I38M, isoleucine substituted by methionine at position 38 of virus polymerase acidic protein; WT, wild-type virus.

Figure 4.

Kaplan–Meier analysis of the alleviation of the symptoms of influenza illness after treatment with baloxavir marboxil in patients with and without PA/I38T/M-substituted viruses by HAI virus antibody titer at baseline. Patients with A(H3N2) virus who had paired sequencing data available and with any observed diary data were included in this analysis. The median TTIA was 85.4 hours (antibody <40 with PA/I38T/M-substituted viruses [n = 11]), 29.9 hours (antibody <40 without PA/I38T/M-substituted viruses [n = 15]), 56.0 hours (antibody ≥40 with PA/I38T/M-substituted viruses [n = 6]), and 44.7 hours (antibody ≥40 without PA/I38T/M-substituted viruses [n = 34]). Abbreviations: HAI, hemagglutinin inhibition; PA/I38T, isoleucine substituted by threonine at position 38 of virus polymerase acidic protein; PA/I38M, isoleucine substituted by methionine at position 38 of virus polymerase acidic protein; TTIA, time to illness alleviation.

Figure 5.

Kaplan–Meier analysis of the time to sustained cessation of viral shedding by virus titer after treatment with baloxavir marboxil in patients with and without PA/I38T/M-substituted viruses by HAI antibody titer at baseline. Patients with A(H3N2) virus who had paired-sequencing data available were included in this analysis. The median times to sustained cessation of viral shedding: 216.0 hours (antibody <40 with PA/I38T/M-substituted viruses [n = 11]), 24.0 hours (antibody <40 without PA/I38T/M-substituted viruses [n = 15]), 168.0 hours (antibody ≥40 with PA/I38T/M-substituted viruses [n = 7]), and 24.0 hours (antibody ≥40 without PA/I38T/M-substituted viruses [n = 34]). Abbreviations: HAI, hemagglutinin inhibition; PA/I38T, isoleucine substituted by threonine at position 38 of virus polymerase acidic protein; PA/I38M, isoleucine substituted by methionine at position 38 of virus polymerase acidic protein.