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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 nearly a year ago (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral, but has been in approved for use in Japan since early 2018.
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.
A month ago, in EID Journal: H-2-H Transmission Of A(H3N2) with Reduced Susceptibility to Baloxavir, Japan, we looked at a study that reported:
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.The researchers concluded: `These 4 children were probably infected with mutant viruses acquired from hosts previously treated with baloxavir.'
The spontaneous development of resistant viruses in a patient who is already receiving antiviral drugs is a known - but relatively rare (roughly 1%) - complication. Usually, these mutated viruses suffer a fitness penalty' - making them less likely to be transmitted on to others.
Usually, but not always.In 2008 we saw the old seasonal H1N1 flu virus go from being nearly 100% sensitive to Oseltamivir to almost 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 in the spring of 2099 - one which supplanted the newly resistant strain - that salvaged Tamiflu's usefulness against H1N1.Since the emergence of pdmH1N1, 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.
The concern is that we might someday see another resistant and easily transmitted virus emerge; one that is `biologically fit' enough to spread efficiently in the community.While we don't appear to be anywhere near that dreaded scenario right now, scientists continue to monitor the incidence of Baloxavir resistance, and are testing these mutated viruses to determine their `fitness' and transmissibility relative to the wild-type/seasonal viruses in circulation.
All of which brings us to a new open-access study, published this weekend in the Journal of Infectious Diseases, that looks at the biological fitness of baloxavir resistant viruses collected last winter and finds them to be only mildly impaired.The full study is available in a provisional PDF, so follow the link to read it in its entirety. I'll have a brief postscript when you return.
Replicative fitness of seasonal influenza A viruses with decreased susceptibility to baloxavir
Anton Chesnokov, Mira C Patel, Vasiliy P Mishin, Juan A De La Cruz, Lori Lollis, Ha T Nguyen, Vivien Dugan, David E Wentworth, Larisa V Gubareva
The Journal of Infectious Diseases, jiz472, https://doi.org/10.1093/infdis/jiz472
Published: 21 September 2019
Abstract
Susceptibility of influenza A viruses to baloxavir can be affected by changes at amino acid residue 38 in polymerase acidic (PA) protein. Information on replicative fitness of PA-I38-substituted viruses remains sparse. We demonstrated that substitutions I38L/M/S/T not only had a differential effect on baloxavir susceptibility (9- to 116-fold), but also on in vitro replicative fitness.
While I38L conferred undiminished growth, other substitutions led to mild attenuation. In a ferret model, control viruses out competed those carrying I38M or I38T substitutions, although their advantage was limited. These findings offer insights into the attributes of baloxavir resistant viruses needed for informed risk assessment.(SNIP)
Summary
Recently circulating seasonal influenza A viruses carrying PA-I38L/M/S/T substitutions showed differential effect on baloxavir susceptibility and in vitro replicative fitness. In ferret infection model, replication of A(H3N2) viruses carrying I38M or I38T was mildly impaired compared to control/wildtype viruses.
(SNIP)
In this study, we provided data on replicative fitness of baloxavir-resistant viruses that are needed to inform public health risk assessment. Replication of the PA-I38-substituted viruses was only mildly impaired, yet it may reduce their airborne transmission. This assumption needs to be investigated.
Moreover, PA-I38-substituted viruses may rapidly restore full replicative capacity by acquiring compensatory changes. They can also gain evolutionary advantage via antigenic drift or shift.
Therefore, it is essential to closely monitor the emergence of PA-I38-substituted viruses and their spread in communities.
(Continue . . . )
Over the summer, the J.I.D. also published the following on-topic editorial commentary:
Baloxavir and Treatment-Emergent Resistance: Public Health Insights and Next Steps
Larisa V Gubareva, Alicia M Fry
The Journal of Infectious Diseases, jiz245, https://doi.org/10.1093/infdis/jiz245
Published: 16 July 2019
Baloxavir represents the first new class (cap-dependent endonuclease inhibitor) of influenza antiviral to be approved in two decades, and it shows promise as a versatile tool against a wide variety of Influenza viruses.
A recent EID Journal Dispatch elucidates:
Volume 25, Number 10—October 2019
Dispatch
Susceptibility of Influenza A, B, C, and D Viruses to Baloxavir
Vasiliy P. Mishin, Mira C. Patel, Anton Chesnokov, Juan De La Cruz, Ha T. Nguyen, Lori Lollis, Erin Hodges, Yunho Jang, John Barnes, Timothy Uyeki, Charles T. Davis, David E. Wentworth, and Larisa V. Gubareva
Abstract
Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2–98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors.
These early reports of baloxavir resistance - while of concern - remain highly scattered. We should get a much better idea of its scope and significance this winter, as enhanced surveillance is planned in both Japan and the United States.
Stay tuned.
