#17,580
Since it would take months to create, manufacture, and deploy significant quantities of any novel flu vaccine, our first line of defense against any emerging avian or swine flu pandemic threat would be our existing armamentarium of influenza antivirals.
Our oldest class of flu antivirals - M2 ion channel blockers (e.g. Amantadine, Rimantadine) - were developed in the 1950s. But by late 2005 Amantadine began to lose its effectiveness against the H3N2 seasonal flu virus and some strains of the H5N1 bird flu.But antivirals - like antibiotics - are constantly being challenged by ever-evolving viruses and bacteria, that continue to find ways to evade them.
Tamiflu (Oseltamivir) which had been approved in 1999, while far more expensive, became the new treatment standard. Within a couple of years, however, seasonal H1N1 began to show growing resistance to Tamiflu as well (although H3N2 remained sensitive).In January of 2006 the CDC issued a warning to doctors not to rely on Amantadine or Rimantadine to treat influenza.
This resistance was due to a mutation, known as H274Y, where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 274.
By the winter of 2008 - in the space of just about a year – seasonal H1N1 had gone from almost 100% sensitive to the drug to nearly 100% resistant (see CIDRAP On the CDC Change Of Advice On Tamiflu).
It seemed as if antiviral crisis was unavoidable, when in a Deus Ex Machina moment - a new swine-origin H1N1 virus - one that happened to be sensitive to Tamiflu, emerged as a pandemic strain in the spring of 2009.
In a matter of months pdmH1N1 supplanted the old H1N1 virus, and the crisis was averted. Or at least postponed.
Since then, resistance to Tamiflu has been low (roughly 2%), but a few small cracks in its veneer have appeared. As added insurance, in 2018 the FDA Approved Xofluza : A New Class Of Influenza Antiviral (aka baloxavir marboxil).
But viral evolution continues, and with the rapid spread and spillover into mammals of numerous genotypes of HPAI H5N1, researchers are are warily watching for any signs of antiviral resistance.
We've a detailed report from researchers at the CDC's Influenza Division, the National Veterinary Services Laboratories at Ames, Iowa, and a couple of research laboratories, which finds that small number of H5N1 viruses isolated from birds and mammals in the United States in 2022 showed signs of antiviral resistance.
While the vast majority of the viruses sampled remained susceptible to oseltamivir (aka Tamiflu (tm)) and baloxavir, these few exceptions are worthy of our attention.
First the link, and abstract, from the report. Follow the link to read it in its entirety. After which I'll return with more.
Antiviral susceptibility of clade 2.3.4.4b highly pathogenic avian influenza A(H5N1) viruses isolated from birds and mammals in the United States, 2022
Highlights
• Sporadic drug resistance was detected in clade 2.3.4.4 b HPAI A (H5N1) viruses isolated from birds in the US, 2022.• Investigational oral neuraminidase inhibitor AV5080 was most effective at reducing virus enzyme activity.• Dual mutation N295S + T438N in the neuraminidase conferred reduced inhibition by all neuraminidase inhibitors tested.• Cap-dependent endonuclease inhibitors baloxavir and AV5116 showed similar antiviral activity in cell culture.• First report of A (H5N1) virus with PA-I38T and a cluster of PA-A37T viruses displaying reduced baloxavir susceptibility.
Abstract
Clade 2.3.4.4 b highly pathogenic avian influenza (HPAI) A (H5N1) viruses that are responsible for devastating outbreaks in birds and mammals pose a potential threat to public health. Here, we evaluated their susceptibility to influenza antivirals.
Of 1015 sequences of HPAI A (H5N1) viruses collected in the United States during 2022, eight viruses (∼0.8%) had a molecular marker of drug resistance to an FDA-approved antiviral: three adamantane-resistant (M2-V27A), four oseltamivir-resistant (NA-H275Y), and one baloxavir-resistant (PA-I38T).
Additionally, 31 viruses contained mutations that may reduce susceptibility to inhibitors of neuraminidase (NA) (n = 20) or cap-dependent endonuclease (CEN) (n = 11). A panel of 22 representative viruses was tested phenotypically.
Overall, clade 2.3.4.4 b A (H5N1) viruses lacking recognized resistance mutations were susceptible to FDA-approved antivirals. Oseltamivir was least potent at inhibiting NA activity, while the investigational NA inhibitor AV5080 was most potent, including against NA mutants.
A novel NA substitution T438N conferred 12-fold reduced inhibition by zanamivir, and in combination with the known marker N295S, synergistically affected susceptibility to all five NA inhibitors.
In cell culture-based assays HINT and IRINA, the PA-I38T virus displayed 75- to 108-fold and 37- to 78-fold reduced susceptibility to CEN inhibitors baloxavir and investigational AV5116, respectively. Viruses with PA-I38M or PA-A37T showed 5- to 10-fold reduced susceptibilities.
As HPAI A (H5N1) viruses continue to circulate and evolve, close monitoring of drug susceptibility is needed for risk assessment and to inform decisions regarding antiviral stockpiling.
While it is true that many of the amino-acid changes linked to reduced antiviral susceptibility are also thought to reduce the `biological fitness' of the influenza A virus, that did little to inhibit the pre-2009 H1N1 virus.
Over the years we've looked at surveillance for antiviral resistant flu viruses, and ways that our own behavior might exacerbate the threat.
- Two summer ago, in EID Journal: Cluster of Oseltamivir-Resistant & Antigenically Drifted Influenza A(H1N1)pdm09 Viruses, Texas, USA, January 2020, we looked at a cluster of resistant seasonal flu viruses which emerged just before COVID shut down influenza around the globe.
- In 2016, in Eurosurveilance: A(H1N1)pdm09 Virus With Cross-Resistance To Oseltamivir & Peramivir - Japan, March 2016 we looked at an elevated number of NAI resistant viruses with `permissive mutations' circulating in Japan.
- More than 16 years, and overt 17,000 blogs ago, in The Law of Unintended Consequences (Jan ‘07), I wrote about growing concerns over what effects the large-scale use of Oseltamivir (Tamiflu ®) might have on the environment and the evolution of avian flu viruses (see study Potential Risks Associated with the Proposed Widespread Use of Tamiflu).
- A couple of years later, in Pandemics & The Law Of Unintended Consequences, we looked at not only the potential effects of antivirals in our sewage system, but also how the consumption (and excretion) of antibiotics during a pandemic might affect wastewater treatment plants (WWTPs).
- And last September, in Preprint: Spillover of Human Antivirals May Promote Resistant Pathogens in Animal Reservoirs, we returned once more to this topic.
