Perspective

Transmission of Xofluza-resistant flu virus reported in Japanese siblings

A recent report published in Emerging Infectious Diseases detailed a case of likely human-to-human transmission of an influenza A virus with reduced susceptibility to Xofluza between two siblings in Japan.

“[Xofluza (baloxavir marboxil, Genentech)] susceptibility of influenza viruses, especially among infected children [younger than] 12 years of age, should be closely monitored for public health planning purposes and for making clinical recommendations for antiviral drug use,” Emi Takashita, PhD, a virologist at the National Institute of Infectious Diseases in Tokyo, Japan, and colleagues wrote.

Takashita and colleagues reported detecting 32 mutant influenza A viruses that carried amino acid substitutions indicating reduced susceptibility to baloxavir marboxil during Japan’s 2018-2019 influenza season.

In February 2019, they detected two influenza A (H3N2) viruses in two siblings. The first child was aged 10 years, experienced symptom onset on Feb. 5 and was treated with baloxavir marboxil 12 hours later. The child’s fever resolved within 12 hours, according to the report. The second child was aged 8 months and experienced symptom onset a day later.

Image of H3N2 virons 
H3N2 is a subtype of the influenza A virus.
Source: CDC

Deep sequencing analysis of nasal samples from each child revealed that the whole-genome sequences of their viruses were identical. Takashita and colleagues determined that while the viruses had reduced susceptibly to baloxavir marboxil, they were susceptible to the four neuraminidase inhibitors approved for use in Japan.

“The median incubation period of influenza A virus is 1.4 days, and virus shedding can be detected 1 day before the onset of symptoms. Considering that the infant did not have much contact with the outside family, the infant acquiring the mutant virus from the sibling is the most likely option,” they wrote. – by Joe Gramigna

Disclosures: Infectious Diseases in Children could not confirm relevant financial disclosures at the time of publication.

A recent report published in Emerging Infectious Diseases detailed a case of likely human-to-human transmission of an influenza A virus with reduced susceptibility to Xofluza between two siblings in Japan.

“[Xofluza (baloxavir marboxil, Genentech)] susceptibility of influenza viruses, especially among infected children [younger than] 12 years of age, should be closely monitored for public health planning purposes and for making clinical recommendations for antiviral drug use,” Emi Takashita, PhD, a virologist at the National Institute of Infectious Diseases in Tokyo, Japan, and colleagues wrote.

Takashita and colleagues reported detecting 32 mutant influenza A viruses that carried amino acid substitutions indicating reduced susceptibility to baloxavir marboxil during Japan’s 2018-2019 influenza season.

In February 2019, they detected two influenza A (H3N2) viruses in two siblings. The first child was aged 10 years, experienced symptom onset on Feb. 5 and was treated with baloxavir marboxil 12 hours later. The child’s fever resolved within 12 hours, according to the report. The second child was aged 8 months and experienced symptom onset a day later.

Image of H3N2 virons 
H3N2 is a subtype of the influenza A virus.
Source: CDC

Deep sequencing analysis of nasal samples from each child revealed that the whole-genome sequences of their viruses were identical. Takashita and colleagues determined that while the viruses had reduced susceptibly to baloxavir marboxil, they were susceptible to the four neuraminidase inhibitors approved for use in Japan.

“The median incubation period of influenza A virus is 1.4 days, and virus shedding can be detected 1 day before the onset of symptoms. Considering that the infant did not have much contact with the outside family, the infant acquiring the mutant virus from the sibling is the most likely option,” they wrote. – by Joe Gramigna

Disclosures: Infectious Diseases in Children could not confirm relevant financial disclosures at the time of publication.

    Perspective
    Edward A. Bell

    Edward A. Bell

    This study by Takashita and colleagues raises important concerns about the human-to-human transmissibility of influenza viruses with reduced susceptibility to baloxavir, the antiviral agent newly labeled in the United States to treat influenza. Influenza A(H3N2) viruses containing an I38T substitution in the polymerase acidic gene were found. These mutant viruses contain substituted amino acids at position 38 of the gene encoding for polymerase acid. Baloxavir inhibits viral endonuclease, thus inhibiting viral replication. This mechanism differs from the antiviral neuraminidase inhibitors, such as oseltamivir. Additionally, baloxavir is unique because it is labeled as a one-dose treatment regimen. In the U.S., baloxavir is labeled for use in children aged 12 years or older, but in Japan, it is used for children aged younger than 12 years who weigh at least 10 kg. In the phase 3 study supporting baloxavir’s labeling, baloxavir was compared with placebo in subjects aged 12 to 19 years, unlike subjects aged older than 19 years, with additional randomization to placebo or oseltamivir. Phase 2 and 3 studies have demonstrated baloxavir efficacy in treating influenza symptoms and have additionally shown shorter durations of infectious virus detection in treated subjects. However, these studies have also demonstrated relatively high rates of reduced viral drug susceptibility (9.7%) to baloxavir. Additional studies have demonstrated higher rates of reduced susceptibility (up to nearly 20%). Thus, transmissibility of influenza viruses with reduced baloxavir susceptibility remains a concern. 

    The Takashita study sheds additional light on this concern and raises additional concerns of human-to-human transmissibility of influenza viruses with reduced susceptibility to baloxavir (including isolation from children not treated with baloxavir). Additional data on influenza viral susceptibility are needed. Although baloxavir may offer potential advantages for treatment of influenza (eg, one-dose regimen), its use should be tempered until more data are known. As with all antiviral drugs used in the treatment of influenza, recommendations describing appropriate use should be followed, when possible. 

    • Edward A. Bell, PharmD, BCPS
    • Infectious Diseases in Children Editorial Board member
      Professor of pharmacy practice
      Drake University College of Pharmacy and Health Sciences
      Blank Children’s Hospital and Clinic

    Disclosures: Bell reports no relevant financial disclosures.