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| Credit NIAID |
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The new, one-dose influenza antiviral Baloxavir marboxil (trade name Xofluza®) was approved in the United States last October (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral, but has been in use in Japan for over a year.
This new class of antiviral is particularly welcome as the two existing neuraminidase inhibitors - zanamivir and oseltamivir (Tamiflu ®) - have been in use now for 20 years, and there are always concerns over creeping resistance.In early March of this year, however, we saw several reports - and a Eurosurveillance Rapid Communications - on the detection of a small number of Baloxavir resistant flu viruses among patients in Japan - including three that had not received the antiviral drug.
The spontaneous development of resistance in a patient while being treated with an antiviral is a known - but relatively rare - complication. While a concern for the patient being treated, these mutated viruses generally suffer a `fitness penalty', making them less likely to be transmitted on to others.
The concern is that a person receiving an antiviral might someday produce a resistant and easily transmitted strain. One that is `biologically fit' enough to spread efficiently in the community.Prior to 2008, this scenario was thought unlikely, but 11 years ago we saw the old seasonal H1N1 flu virus go from being almost 100% sensitive to Oseltamivir to nearly 100% resistant (see CIDRAP On the CDC Change Of Advice On Tamiflu) in a matter of months.
It was only the unexpected arrival of a new, oseltamivir-sensitive H1N1 pandemic virus the following spring - one which supplanted the newly resistant strain - that salvaged Tamiflu's usefulness against H1N1.Since then, we've seen a few pockets of suspected community transmission of resistant flu viruses (see Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan & NEJM: Oseltamivir Resistant H1N1 in Australia), but no sustained transmission.
Today we've a Dispatch published in the CDC's EID Journal that focuses on a family cluster of Baloxivir-resistant H3N2 from last winter.I've only posted some excerpts from a much longer report, so follow the link to read it in its entirety. I'll have a brief postscript when you return.
Volume 25, Number 11—November 2019
Dispatch
Human-to-Human Transmission of Influenza A(H3N2) Virus with Reduced Susceptibility to Baloxavir, Japan, February 2019
Emi Takashita, Masataka Ichikawa, Hiroko Morita, Rie Ogawa, Seiichiro Fujisaki, Masayuki Shirakura, Hideka Miura, Kazuya Nakamura, Noriko Kishida, Tomoko Kuwahara, Hiromi Sugawara, Aya Sato, Miki Akimoto, Keiko Mitamura, Takashi Abe, Masahiko Yamazaki, Shinji Watanabe, Hideki Hasegawa, and Takato Odagiri
Abstract
In 2019, influenza A(H3N2) viruses carrying an I38T substitution in the polymerase acidic gene, which confers reduced susceptibility to baloxavir, were detected in Japan in an infant without baloxavir exposure and a baloxavir-treated sibling. These viruses’ whole-genome sequences were identical, indicating human-to-human transmission. Influenza virus isolates should be monitored for baloxavir susceptibility.
(SNIP)
Conclusions
During the 2018–19 influenza season in Japan, we detected 32 mutant influenza A(H3N2) viruses carrying various types of PA I38 substitutions, 4 of which were isolated from children < 12 years of age without prior baloxavir exposure.
Almost all mutant viruses isolated from baloxavir-treated patients possessed mixed PA I38T/I, I38M/I, I38R/I, I38T/M/I, I38T/K/I, or I38T/M/R substitutions (5), indicating these mutant viruses emerged under the selective pressure of baloxavir.
In contrast, the 4 mutant viruses recovered from children without prior baloxavir treatment, including the virus described in this study, contained the PA I38T substitution and not a mixture including wild-type 38I. These 4 children were probably infected with mutant viruses acquired from hosts previously treated with baloxavir.
Previous studies reported that oseltamivir-resistant viruses were detected in oseltamivir-treated 1–12-year-old children on day >4 after oseltamivir administration (8,9). During our monitoring for baloxavir-induced mutant influenza viruses, we found that, among baloxavir-treated patients, all but 1 of the mutant viruses were detected 3–6 days after baloxavir administration.
One mutant virus was detected the day after baloxavir administration in a 2-year-old child from a family cluster, and this virus possessed a mixture of I38T/I substitutions (50% T and 50% I). This child might have been infected with a mixed population containing mutant and wild-type viruses; this incident suggested possible human-to-human transmission of the mutant influenza A(H3N2) virus encoding the PA I38T substitution.
The 8-month-old infant infected with A/Kanagawa/IC18141/2019 in this study had no exposure to baloxavir before specimen collection. The sibling of this infant, infected with A/Kanagawa/IC18144/2019, was treated with baloxavir for a half day before the infant’s symptoms began. A/Kanagawa/IC18141/2019 and A/Kanagawa/IC18144/2019 viruses possessed the same genomic sequences.
In Kanagawa, Japan, H3N2 virus activity was highest in February 2019, and an influenza outbreak occurred in the primary school attended by the sibling. Furthermore, during October 2018–February 2019, baloxavir was supplied to medical institutions that together served ≈5.6 million persons in Japan.
These observations suggest 2 possibilities: the infant was infected by the sibling who was infected by another host harboring the virus with the PA I38T substitution, or both children were infected by another host harboring the virus with the PA I38T substitution. The median incubation period of influenza A virus is 1.4 days (10), and virus shedding can be detected 1 day before the onset of symptoms (11). 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.
During our monitoring, 4 of 5 pH1N1 viruses and 26 of 32 H3N2 viruses with the PA I38 substitution were isolated from children < 12 years of age. Our results confirm that the frequency of viruses with this mutation is higher in patients < 12 years of age than those 12–64 years of age, as previously reported (5).
Therefore, baloxavir susceptibility of influenza viruses, especially among infected children < 12 years of age, should be closely monitored for public health planning purposes and for making clinical recommendations for antiviral drug use.(Continue . . . )
It is not exactly news that viruses and bacteria can evolve and adapt very quickly, and that pharmacological victories over them are often fleeting. We see this with both antibiotics and antivirals, and for now, there seems to be no way around it.
Four cases of acquired resistant H3N2 virus infection in Japan - while concerning - does not constitute an imminent crisis.But given the limits of testing and surveillance, it is also likely that some cases have gone undetected, and so ongoing surveillance in both Japan and the United States this winter will be important.
In any event, we still three other influenza effective antivirals in our armamentarium - oseltamivir, zanamivir, and peramivir - and so the cupboard is far from bare.
Stay tuned.
