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| Credit NIAID |
But just as we see with antibiotics and resistant bacteria, antivirals can lose effectiveness over time as viruses find ways around them.
Twenty years ago Amantadine was the preferred influenza antiviral. It was cheap, plentiful, and worked reasonably well as both a treatment, and a preventative. But its over use - reportedly even in chicken feed in China - led to widespread resistance, and by 2006 the CDC no longer recommended its use.
While more expensive, Tamiflu (oseltamivir) - an NAI (neuraminidase inhibitor) - became the new treatment standard. While occasional instances of Oseltamivir resistance were recorded prior to 2007, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’).
Studies suggested that these resistant strains were `less biologically fit’, and were therefore unlikely to spread from human-to-human.
That is, until `biologically fit' resistant H1N1 viruses emerged and began circulating in early 2008. By the end of the year - nearly all H1N1 viruses were resistant, forcing the CDC to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).
This resistance was primarily due to an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)).
It seemed as if antiviral crisis was inevitable, when in a Deus Ex Machina moment a new swine-origin H1N1 virus - that happened retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus.
Since then, we've kept a close watch for antiviral resistance - and while we've seen some worrisome clusters - none have managed to compete against wild type viruses. A few past examples include:
Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan
NEJM: Oseltamivir Resistant H1N1 in Australia
Today, we've a new report in the Eurosurveillance Journal of a recent cluster of H1N1 infections at an elementary school in Japan which carried the H275Y mutation, and which appears to have spread pretty efficiently among students.
Since samples were collected from several patients on the same day they began oseltamivir treatment, and sequencing showed identical viruses across 4 patients, the assumption is these findings indicate the spread of a resistant NA H275Y mutant virus within the school class.
I've only posted some excerpts from the study, so you'll want to follow the link and read it in its entirety. I'll have a postscript after the break.
An outbreak of influenza A(H1N1)pdm09 antigenic variants exhibiting cross-resistance to oseltamivir and peramivir in an elementary school in Japan, September 2024 an outbreak
Emi Takashita1,* , Kohei Shimizu2,* , Shuzo Usuku2 , Ryuichi Senda2 , Ichiro Okubo2 , Hiroko Morita1 , Shiho Nagata1 , Seiichiro Fujisaki1 , Hideka Miura1 , Noriko Kishida1 , Kazuya Nakamura1 , Masayuki Shirakura1 , Masataka Ichikawa3 , Yoko Matsuzaki4 , Shinji Watanabe1 , Yoshimasa Takahashi5 , Hideki Hasegawa1
During nationwide monitoring of antiviral susceptibilities of influenza viruses in Japan, we detected 25 A(H1N1)pdm09 viruses in September 2024. Four of these viruses possessed the H275Y substitution in their neuraminidase (NA) protein, which is associated with cross-resistance to the NA inhibitors oseltamivir and peramivir [1]. These viruses were identified in students from the same class at a school. Here, we report an outbreak of the NA H275Y mutant A(H1N1)pdm09 virus in this school.
An outbreak of influenza A(H1N1)pdm09 virus in a school
In Japan, local outbreaks of influenza have been reported since week 29 (starting on 15 July) of 2024 (FluNet, https://www.who.int/tools/flunet). One such outbreak occurred in a class of 24 students at a school in Yokohama, where 11 students aged between 6 and 7 years were absent from school on a day at the beginning of September 2024 (hereafter referred to as day 3) upon diagnosis with influenza or influenza-like illness. The class was subsequently closed for the next 3 days.
The patients exhibited a fever over 38 °C, headache, and fatigue, but no severe illness was reported. On day 3, nasal discharges and gargle samples were collected from four of the 11 patients, and influenza A(H1N1)pdm09 viruses were isolated (Table 1). Of these four patients, two had developed symptoms 2 days before (day 1), and the other two on the previous day (day 2). One patient began oseltamivir treatment on the day of symptom onset, while the other three received oseltamivir or laninamivir on the day of sample collection (Table 1).
Detection of NA H275Y mutant influenza A(H1N1)pdm09 viruses during the school outbreak
Deep sequencing analysis revealed that all four A(H1N1)pdm09 viruses (A/Yokohama/34/2024, A/Yokohama/35/2024, A/Yokohama/36/2024, and A/Yokohama/37/2024) possessed the H275Y substitution in their NA protein, which is associated with cross-resistance to oseltamivir and peramivir [1] (Table 1).
Oseltamivir binds to the active site of NA in a similar manner to peramivir; therefore, the NA H275Y substitution alters the active site structure and confers resistance to both drugs. This substitution was confirmed in both the virus isolates and the clinical specimens. No amino acid substitutions associated with reduced susceptibility to the cap-dependent endonuclease inhibitor baloxavir were detected in the NA H275Y mutant viruses.
The whole genome sequences of the viruses in the specimens were identical, demonstrating clonal spread of the NA H275Y mutant virus strain. These findings suggest an outbreak of the NA H275Y mutant virus within the school class.
(SNIP)In Japan, anti-influenza drugs are commonly prescribed to outpatients without underlying disease [10]. During the 2013/14 season, a large community cluster of NA H275Y mutant A(H1N1)pdm09 viruses occurred in Hokkaido, Japan [11]. The detection rate of these mutant viruses reached 29% in Hokkaido during that season; however, they were eventually replaced by wild-type virus and disappeared [12]. Our previous findings suggest that the cluster virus retained sufficient viral fitness to spread among humans, resulting in a large number of infections.
However, the mutant NA structure was less stable than that of the wild-type virus, and once the wild-type virus began circulating in the community, the mutant virus could not compete and eventually disappeared [12]. Since then, the frequency of viruses with reduced susceptibility to NA inhibitors has remained low, less than 2an outbreak% [3].
However, the growth capability of the oseltamivir- and peramivir-cross-resistant antigenic variants in this study, which possess the NA H275Y and HA Q210H substitutions, was comparable to that of the wild-type virus, at least at later time points in vitro. Future studies are needed to evaluate the viral fitness of these antigenic variants and to assess the biological significance of these substitutions.
Our study has some limitations. While samples were collected from ill students of the class where the outbreak was first detected, clinical specimens were not obtained from five students who experienced influenza or influenza-like illness 3 days later in another class of the same school; therefore, virus analysis could not be conducted, and the potential for further spread of the viruses implicated in the outbreak could not be assessed.
Conclusion
In this outbreak of influenza A(H1N1)pdm09, which affected a Japanese school in September 2024, analyses of viruses affecting four cases revealed cross-resistance to oseltamivir and peramivir, the presence of NA H275Y and HA Q210H mutations and evidence of clonal spread. The viruses moreover exhibited antigenic differences to the seasonal vaccine strain. With their growth being comparable to that of wild-type A(H1N1)pdm09 virus in vitro, at least at later time points, continued monitoring is crucial to assess the potential for further spread of these variants.
Luckily oseltamivir isn't our only antiviral option (see FDA Approved Xofluza : A New Class Of Influenza Antiviral), but it is the most popular antiviral, and has been stockpiled by many countries.
Switching to Baloxavir (Xofluza) would be more expensive, and there are manufacturing and supply issues. It has also shown some susceptibility to resistance as well (see Eurosurveillance: A community Cluster of Influenza A(H3N2) Virus infection with Reduced Susceptibility to Baloxavir - Japan 2023).