Sunday, March 24, 2019

Eurosurveillance: H3N2 Virus With Reduced Susceptibility to Baloxavir - Japan, Feb 2019

Credit NIAID


Like the cliffhanger serials of old, scientific findings and discoveries tend to present themselves in tantalizing chunks of incomplete data, which often leads us to the next clue, a fork in the road, or sometimes a dead end.
Scientific discovery is a process, which can often be messy, and progress is rarely linear (see When Studies Collide (Revisited))
But most importantly, our current understanding of nearly any scientific topic is simply that, and is almost certain to change. Which is why this blog spends so much time attempting to put new studies into context, presenting past works, and trying to make connections between them.

All of which serves as a caveat of sorts to the following Rapid Communications, published in this week's Eurosurveillance, on discoveries made only a few weeks ago regarding the new influenza anti-viral Baloxavir, that have already been partially overshadowed by even more recent events.  
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 about a year, and roughly 5.5 million doses have been administered there. 
In recent months we've seen some subtle signs of resistance cropping up in Japan among patients already being treated with the new antiviral (see CIDRAP's Experts on watch for resistance to new flu drug).

The development of `spontaneous resistance' in a patient receiving an antiviral is a known - but relatively rare - occurrence.  And the mutated virus is generally believed to take a `fitness' hit, making it unlikely (but not impossible) to be transmitted efficiently to others.
After several cases of `spontaneous resistance' developing in Baloxavir-treated children infected with H3N2 were reported last December (see January Eurosurveillance report), Japan began an enhanced national surveillance campaign.
This week's Eurosurveillance report describes two children in Japan, ages 6 & 7, who were found to have a mutated `resistant' H3N2 virus; one of whom received Baloxavir, and the other (with no epidemiological link to the first) who received oseltamivir (Tamiflu). 
But as anyone who has already read my blog of 10 days ago  (see Japan NIID Reports 3 Xofluza Resistant Flu Viruses In Untreated Patients) already knows, the story continues to unfold. 
First some excerpts from the latest Eurosurveillance report, and then I'll return with a bit more.

Rapid communication Open Access
Influenza A(H3N2) virus exhibiting reduced susceptibility to baloxavir due to a polymerase acidic subunit I38T substitution detected from a hospitalised child without prior baloxavir treatment, Japan, January 2019
Emi Takashita1, Chiharu Kawakami2, Rie Ogawa1, Hiroko Morita1, Seiichiro Fujisaki1, Masayuki Shirakura1, Hideka Miura1, Kazuya Nakamura1, Noriko Kishida1, Tomoko Kuwahara1, Akira Ota3, Hayato Togashi3, Ayako Saito4, Keiko Mitamura5, Takashi Abe6, Masataka Ichikawa7, Masahiko Yamazaki8, Shinji Watanabe1, Takato Odagiri1
The cap-dependent endonuclease inhibitor baloxavir marboxil became available in Japan in March 2018 for the treatment of influenza virus infection in patients aged 12 years and older and children younger than 12 years weighing at least 10 kg. Between October 2018 and January 2019, baloxavir was supplied to medical institutions that together serve ca 5.5 million people. 
In December 2018, we detected influenza A(H3N2) viruses exhibiting reduced susceptibility to baloxavir from baloxavir-treated children aged 6 and 7 years [1]. These viruses possessed an I38T substitution in the polymerase acidic subunit (PA), which confers reduced susceptibility to baloxavir [2]. We subsequently increased nationwide monitoring of the baloxavir susceptibility of circulating influenza viruses, irrespective of antiviral treatment [3]. 
In January 2019, we isolated two influenza A(H3N2) viruses, A/YOKOHAMA/87/2019 and A/YOKOHAMA/88/2019, from two hospitalised children (Table 1). Prior to hospitalisation and virus isolation, both children had received antiviral treatment against influenza. The primary-school child aged 6 years who was infected with A/YOKOHAMA/87/2019 had been treated with a single oral dose of baloxavir on the day of symptom onset and fever resolved within one day of baloxavir administration. Face oedema had developed 2 days after baloxavir administration, although this patient had no underlying diseases. The child was diagnosed with nephritis and hospitalised.

The preschool child aged 5 years who was infected with A/YOKOHAMA/88/2019 had received oseltamivir 3 days after onset of illness, although its clinical benefit is greatest when administered within 48 hours of illness onset. Fever tended to resolve after oseltamivir administration. This child had no underlying diseases but was subsequently hospitalised for pneumothorax and subcutaneous emphysema. No epidemiological link was identified between these patients.


In this study, we detected two PA I38T mutant A(H3N2) viruses respectively from two hospitalised children. In addition, during our nationwide monitoring, we detected nine PA I38T or I38M mutant A(H3N2) viruses from baloxavir-treated patients (Table 3).
All of these viruses were isolated in humanised MDCK cells, hCK cells, which express high levels of α2, 6-sialoglycans and very low levels of α2, 3-sialoglycans [6]. Deep sequencing analysis revealed that eight of these viruses possessed mixed PA I38T/I or I38T/M/I substitutions in the clinical specimens and six of these eight possessed increased proportion of the PA I38T or I38M substitution after virus isolation.
A previous study reported that influenza A/Victoria/3/75(H3N2) viruses with the PA I38T, I38M, or I38F substitutions showed less growth capability than the wild-type virus in cell culture [2]. In contrast, our results indicate that recently circulating A(H3N2) viruses with the PA I38T or I38M substitution grow well, at least in cell culture.
(Continue . . . )

As mentioned earlier, 10 days ago Japan's National Institute of Infectious Diseases (NIID) published a bulletin which described two additional non-baloxavir-treated cases discovered to carry the H3N2 PA138T resistance mutation.

A slightly syntax-challenged translated excerpt from a much longer report follows:

Detection of Valoxavir-Resistant Mutant Virus from Patients Untreated with the Novel Anti-Influenza Drug Valoxavir
(The bulletin publication date 2019/3/12)

In this paper, we report that 3 strains of valoxavir resistant mutant virus were detected from 3 patients who did not receive valoxavir by analysis of A (H3N2) virus collected from November 2018 to February 2019.

The PA I 38 T resistant mutant virus (A / triple / 41/2018) was detected in a 12-year-old child at the Mie Prefectural Institute of Public Health and Environment in November 2018. In a sporadic case, the patient consulted a medical institution the day after the onset of illness and was diagnosed with influenza. The patient had not received anti-influenza medication prior to collection of the sample, and had not received valoxavir.

PA I38T resistant mutant virus (A / Yokohama / 88/2019 and A / Yokohama / 87/2019) are from the children aged 5 and 6 who are hospitalized with influenza at Yokohama City Inst. Of Health in January 2019 was detected.
A 5-year-old child who A / Yokohama / 88/2019 was detected visited a medical institution on the 4th day of onset, and administration of oseltamivir was started and she became apt to have fever, but on the 7th day of onset respiratory symptoms I was admitted and hospitalized.
Before the onset of the disease, there was a flu outbreak in a kindergarten that attended a school. She was sampled at the time of admission but received oseltamivir and had not been treated with valoxavir. On the other hand, a 6-year-old child whose A / Yokohama / 87/2019 was detected received valoxavir administration on the day of onset and healed on the next day. I was admitted to the hospital because of an abnormality.
Specimen collection was on day 6 of valoxavir administration and was considered to be a resistant mutant virus resulting from valoxavir administration. A / Yokohama / 87/2019 and A / Yokohama / 88/2019 have different gene sequences and it was judged that there was no direct transmission of infection between the two patients, but from the onset of the 5-year-old patient The mother developed influenza on the 4th day, the father on the 5th day, and the sister on the 6th day, and the sister developed influenza on the second day after the onset of the 6-year-old patient. There is.

The PA I 38 T resistant mutant virus (A / Kanagawa / IC18141 / 2019) was detected from the 8-month-old baby at the National Institute of Infectious Diseases in February 2019. The patient consulted a medical institution the day after the onset of illness and administration of oseltamivir was started. The patient had a fever of 38.9 ° C at the time of medical examination, but it dropped to below 37 ° C the day after the administration of oseltamivir in the upper half of the 37 ° C the next day. The patient did not receive anti-influenza medication prior to collection of the sample and had not received valoxavir, but on the day before onset, the brother developed influenza and received valoxavir, and transmission of infection among brothers is possible. There is sex.

Since the PA I38T resistant mutation is considered to be a mutation caused by valoxavir administration, the three strains of PA I38T resistant mutant viruses (A / triple / 41/2018, A detected from the above three patients who did not receive valoxavir) / Yokohama / 87/2018 and A / Kanagawa / IC18141 / 2019) suggest the possibility of transmission from valoxavir-treated patients.

(Continue . . . )

In 2008 seasonal H1N1 went 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 - replacing the resistant virus - that averted a crisis.
While three cases does not a crisis make, the discovery of additional resistant viruses in children who had not received Baloxavir - combined with the finding that `recently circulating A(H3N2) viruses with the PA I38T or I38M substitution grow well, at least in cell culture' - means that researchers in Japan, the United States, and elsewhere are going to have to maintain a sharp lookout for additional cases.  

Stay tuned.


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