Credit NIAID
#18,364
During the opening months of any H5N1 pandemic there would likely be only a small supply of (potentially poorly matched) H5 vaccine available, and that would go to high risk/priority individuals.
During that time prevention will rely heavily on NPIs (Non-pharmaceutical Interventions), while pharmaceutical treatment will be limited to antivirals (and potentially mAbs and convalescent serum).
There are currently 3 classes of influenza antivirals available, although the oldest (M2 ion-channel protein blockers) - like Amantadine & Rimantadine - fell out of use nearly 20 years ago after growing resistance led the CDC no longer recommended their use.
Tamiflu (oseltamivir) - an NAI (neuraminidase inhibitor) - became the new treatment standard. While occasional instances of Oseltamivir resistance were recorded prior to 2007, in nearly every case, it had developed after a person was placed on the drug (i.e. `spontaneous mutations’).Abruptly and unexpectedly, by the end of 2008 - nearly all H1N1 viruses had become resistant -forcing the CDC to issue major new guidance for the use of antivirals (see CIDRAP article With H1N1 resistance, CDC changes advice on flu drugs).
An antiviral crisis was averted when in 2009 a new swine-origin H1N1 virus - one that happened retain its sensitivity to Tamiflu - swooped in as a pandemic strain, supplanting the older resistant H1N1 virus.
As added insurance, in 2018 the FDA Approved Xofluza : A New Class Of Influenza Antiviral (aka baloxavir marboxil), but it too has shown occasional signs of resistance (see Eurosurveillance: A community Cluster of Influenza A(H3N2) Virus infection with Reduced Susceptibility to Baloxavir - Japan 2023), particularly in seasonal H3N2.
As a result, while 99% of wild-type seasonal flu viruses remain susceptible to Oseltamivir/Baloxavir, we follow reports of resistant strains with considerable interest:
Eurosurveillance: An outbreak of A(H1N1)pdm09 Exhibiting Cross-resistance to Oseltamivir & Peramivir in an Elementary School in Japan, Sept 2024That interest naturally extends to novel flu viruses, and somewhat reassuringly, in 2023's Antiviral Research: Antiviral susceptibility of clade 2.3.4.4b HPAI H5N1 Viruses Isolated From Birds & Mammals in the United States, 2022 researchers reported only a small number (∼0.8% of 1015 H5N1 viruses) isolated from birds and mammals in the United States in 2022 showed signs of antiviral resistance.
Viruses: Increase of Synergistic Secondary Antiviral Mutations in the Evolution of A(H1N1)pdm09 Influenza Virus Neuraminidases
EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024
The only constant with influenza, however, is change.
Note: The Cambodian clade 2.3.2.1c virus reassorted with a clade 2.3.4.4b virus in 2023 (see Preprint: Emergence of a Novel Reassortant Clade 2.3.2.1c Avian Influenza A/H5N1 Virus Associated with Human Cases in Cambodia) creating a new genotype.
While it leaves out a lot of the nuance of this report, the take-away is that all of the human infections examined in this study still appear to be susceptible to Oseltamivir/Baloxavir, and all but 2 of the (early) Cambodian isolates appeared susceptible to Amantadine.
This study is not without its limitations - and H5Nx continues to reassort and evolve - making anything we say about it's susceptibility to antivirals today subject to change. But for now, it is pretty good news.
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 postscript after the break.
ResearchPhilippe Noriel Q. Pascua1, Anton Chesnokov1, Ha T. Nguyen, Han Di, Juan De La Cruz, Yunho Jang, Andrei A. Ivashchenko, Alexandre V. Ivachtchenko, Erik A. Karlsson, Borann Sar, Chin Savuth, Timothy M. Uyeki, Charles Todd Davis, and Larisa V. GubarevaAbstractDuring 2023–2024, highly pathogenic avian influenza A(H5N1) viruses from clade 2.3.2.1c caused human infections in Cambodia and from clade 2.3.4.4b caused human infections in the Americas. We assessed the susceptibility of those viruses to approved and investigational antiviral drugs.Except for 2 viruses isolated from Cambodia, all viruses were susceptible to M2 ion channel-blockers in cell culture-based assays. In the neuraminidase inhibition assay, all viruses displayed susceptibility to neuraminidase inhibitor antiviral drugs oseltamivir, zanamivir, peramivir, laninamivir, and AV5080.Oseltamivir was ≈4-fold less potent at inhibiting the neuraminidase activity of clade 2.3.4.4b than clade 2.3.2.1c viruses.
All viruses were susceptible to polymerase inhibitors baloxavir and tivoxavir and to polymerase basic 2 inhibitor pimodivir with 50% effective concentrations in low nanomolar ranges.Because drug-resistant viruses can emerge spontaneously or by reassortment, close monitoring of antiviral susceptibility of H5N1 viruses collected from animals and humans by using sequence-based analysis supplemented with phenotypic testing is essential.(SNIP)
DiscussionOur study shows HPAI H5N1 clade 2.3.2.1c and clade 2.3.4.4b viruses isolated from sporadic human cases in Cambodia, Chile, and the United States during 2023–2024 are susceptible to approved NA inhibitors and the PA inhibitor baloxavir.The viruses were also susceptible to M2 blockers, except for the 2 nonreassortant viruses isolated in Cambodia during 2023. Viruses from both clades were susceptible to investigational antivirals AV5080, which targets viral segment NA; tivoxavir, which targets viral segment PA; and pimodivir, which targets viral segment PB2.Nearly all seasonal influenza viruses that have circulated since 2010 were resistant to M2 blockers. In addition, M2 blocker resistance was seen in certain groups of swine and avian influenza A viruses (18,19), which greatly reduced the appeal of this inexpensive class of oral antivirals. However, they may remain useful in certain instances, such as controlling zoonotic outbreaks caused by drug-sensitive viruses, especially when administered in combination with other antivirals (36). Combined therapy may produce a synergistic antiviral effect leading to substantial reduction of viral titers thus lowering the risk for resistance emergence and speeding up recovery (16).(SNIP)In recent years, monitoring systems have sporadically detected oseltamivir- and baloxavir-resistant H5N1 viruses in wild birds, including in clade 2.3.4.4b (22,25,44). Drug-resistant influenza viruses may emerge following treatment, especially in young children and immunocompromised patients (45). Although drug-resistant influenza viruses often show impaired replicative fitness, the concern is their ability to gain a selective advantage because of reassortment and continuous evolution. Hence, new antiviral drugs, including those with novel mechanisms of action, and their combinations, would be a welcome addition to the current antiinfluenza arsenal. Compared with monotherapy, combination treatment potently inhibits H5N1 virus replication and improves survival rates in mice (36,46,47). Data are needed on higher oseltamivir dosing and combination antiviral treatment of patients infected with recent H5N1 viruses to inform treatment recommendations.In conclusion, although the clinical translation of laboratory findings remains to be seen, our data do not change current recommendations to initiate oseltamivir treatment as soon as possible for patients with confirmed or suspected H5N1 (48), and postexposure prophylaxis of close contacts of H5N1 cases (49).
However, higher antiviral dosing and combination antiviral treatment (e.g., oseltamivir and baloxavir) should be considered, in particular for patients with H5N1 who are hospitalized or immunocompromised.
Complicating matters, to be most effective, antivirals need to be given early (< 48 hours) into an infection.
Any way you cut it, our first line of defense will - once again - rely heavily on NPIs (non-pharmaceutical interventions), like face masks, hand washing, ventilation, staying home while sick, and avoiding crowds.
Which is why I'm recommending that people consider now (see A Personal Pre-Pandemic Plan) what they will do if pandemic flu should embark on a new world tour.
