Thursday, March 14, 2019

Japan NIID Reports 3 Xofluza Resistant Flu Viruses In Untreated Patients

Credit NIAID


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 about a year. 
A new type of antiviral is particularly welcome because the two existing neuraminidase inhibitors - zanamivir and oseltamivir (Tamiflu ®) - have been in use for 20 years, and the rise of resistant flu viruses are always a concern.
In 2008 seasonal H1N1 had gone from being almost 100% sensitive to Oseltamivir to nearly 100% resistant (see CIDRAP On the CDC Change Of Advice On Tamiflu).  It was only the arrival of a new, oseltamivir-sensitive H1N1 pandemic virus the following spring that breathed another decade of life into Tamiflu.

While most flu viruses today still respond well to oseltamivir, the effectiveness of antivirals and antibiotics is always perceived to be on a countdown clock. Eventually viruses and bacteria find a way around them.

Since Xofluza's introduction, we've seen some subtle signs of resistance cropping up in Japan - the world's biggest consumer of Baloxavir - 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 the drug is an obvious concern for that patient - as they aren't receiving full benefit from the drug -  but it is relatively rare (see WER: Update On Anti-Viral Resistant Influenza), and these resistant viruses are generally  thought to take `fitness' hit, reducing their transmissibility.
The bigger concern would be finding a biologically fit influenza virus that carries the PA138T baloxavir resistance mutation circulating in the community.  And that, according to the following bulletin published by Japan's National Institute of Infectious Diseases (NIID), has now been documented.

What we have is a Japanese language report machine translated into English, and so the syntax suffers a bit.  Hopefully we'll get an English language version at some point. The gist, however, is pretty clear.
At least 3 H3N2 flu cases (all children) have now been discovered to carry the PA138T resistance mutation, even though none had received the antiviral drug. In some cases, patients were exposed to flu patients who had received the drug, suggesting a possible route of transmission. 
First the full (translated) text of the report (bolding mine, re-paragraphed for readability), then I'll return with a postscript. 

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

A new anti-influenza drug, baroxavir marvoxil (trade name: Zofluza, hereinafter referred to as valoxavir), was approved in Japan in February 2018, and can be used from March. The National Institute of Infectious Diseases and the National Institutes of Health have jointly conducted resistant stock surveillance for valoxavir since the 2017/18 season1,2).

The 38th amino acid I38 of the influenza virus PA protein is highly conserved between A and B viruses, and the PA I 38 T mutation of A (H3N2) virus is 1 in 17,227 PA sequences registered in the gene database Cases not included 3). In addition, even in resistant strain surveillance of epidemic strains carried out in Japan and the United States, no case has been detected with the PA I 38 T mutation 1, 4).
On the other hand, in clinical trials of valoxavir, it has been revealed that the PA I38T mutation is detected by administration of valoxavir and it is involved in the reduction of valoxavir sensitivity of the virus5).
Therefore, PA I 38 T resistant mutation is considered to be a mutation resulting from valoxavir administration3,5). In fact, in December 2018, two strains of valoxavir-resistant mutant A (H3N2) virus were detected in children after administration of valoxavir in Yokohama City with a PA I 38 T-resistant mutation and a drop in susceptibility to valoxavir by approximately 80 to 120 times. 3, 6).
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.
Of the 11 patients with PA I38 T resistant mutation A (H3N2) virus detected in Japan this season by genetic analysis using next-generation sequencer, 8 patients with PA I 38 T resistant mutant virus and mutation in the body of the patient It was found that there was a mixture of susceptible viruses that did not have. On the other hand, from genetic analysis of the virus isolated in humanized MDCK cells (hCK cells) that mimics the virus receptor expression pattern of human upper airway epithelial cells, in 3 of 8 cases, the susceptible virus disappears after virus isolation and PA I 38 T resistant mutation It was confirmed that the virus was completely replaced. Therefore, it was revealed that the growth ability of the PA I38T resistant mutant virus in hCK cells was sufficiently maintained as compared to the sensitive virus. From the experiments using an artificial virus in which I38T mutation has been introduced into PA protein of laboratory strain A / Victoria / 3/75 (H3N2) so far, the proliferation ability of PA I38T resistant mutant virus in cultured cells has no mutation It has been reported to be reduced compared to wild-type virus5) but may not be applied to the current epidemic strains.

Between October 2018 and January 2019, it has been reported that about 5.509 thousand valoxavir have been supplied to medical institutions in Japan, which has jumped from about 400,000 last season. In the case of resistant strain surveillance in Japan, the detection rate of valoxavir resistant mutant virus was 0% last season, but it is increasing this season2).
Valoxavir-resistant mutant viruses reported in Japan have been detected in patients aged 8 months to 14 years, and most are children under 12 years of age. In the phase III clinical trial of valoxavir, the detection rate of resistant mutant virus is as high as 9.7% at age 12 and older and 23.4% for those under 12 years of age. And it has been reported that the duration of morbidity is prolonged compared to the patients in which the susceptible virus has been detected5,7).
In the United States, valoxavir was approved in October 2018 for influenza-infected patients aged 12 years and older, but for children younger than 12 years, Phase III clinical trials are currently in progress and have not been approved. Understanding the developmental trend of the valoxavir-resistant mutant virus is an extremely important public health issue not only domestically but also worldwide, and the National Institute of Infectious Diseases and the National Regional Health Institute will continue to conduct valoxavir resistant strain surveillance. We will provide information promptly.

hCK cells were distributed from Professor Yoshihiro Kawaoka of the Institute of Medical Science, The University of Tokyo.
(Continue . . . )
After the 2008 H1N1 antiviral crisis evaporated with the arrival of a new pandemic H1N1 virus in 2009, we've seen a small number of clusters of oseltamivir resistant viruses around the world, but so far, none have taken hold.
Russia's Late Season Flu Surge Continues - More Resistant H1N1pdm In Moscow
Eurosurveilance: A(H1N1)pdm09 Virus With Cross-Resistance To Oseltamivir & Peramivir - Japan, March 2016
Eurosurveillance: Community Cluster Of Antiviral Resistant pH1N1 in Japan
So while of concern, it is far too soon to determine just how significant these three cases of Baloxavir resistant flu really are. They are a first, however, and merit our attention.   
Meanwhile, three other influenza antivirals - oseltamivir, zanamivir, and peramivir - remain in our armamentarium, and so the cupboard is far from bare. 
There are aggressive surveillance programs in Japan and the United States looking for any signs of baloxavir resistance, and so we should know pretty quickly if there is more to this story. 

Stay tuned.


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