IORV: Another Study on The Efficacy of Oseltamivir Against Seasonal Influenza H1N1

Credit NIAID

#18,918

Twenty years ago Amantadine - a cheap, generic drug that had been in use for decades - was the preferred influenza antiviral. But in 2005, after reported overuse in Chinese agriculture, it quickly lost its effectiveness. 

By January of 2006, the CDC had pulled the plug on the use of Amantadine and Rimantadine, and a newer, and far more expensive drug - Oseltamivir (aka `Tamiflu') - became the primary influenza antiviral option. 

While occasional instances of Oseltamivir resistance had been observed, in nearly every case, it developed after a person was placed on the drug (i.e. `spontaneous mutations’). Studies suggested that these resistant strains were `less biologically fit’, and were therefore unlikely to spread from human-to-human.

That is, until a `biologically fit' highly resistant H1N1 viruses emerged in early 2008. By year's end nearly all H1N1 viruses were 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).

This resistance was primarily due to an H275Y mutation - where a single amino acid substitution (histidine (H) to tyrosine (Y)) occurs at the neuraminidase position 275 (Note: some scientists use 'N2 numbering' (H274Y)). 

It seemed as if antiviral crisis was inevitable, but a new swine-origin H1N1 virus - one that happened to retain its sensitivity to Tamiflu - swooped in as a pandemic strain in the spring of 2009, supplanting the older resistant H1N1 virus.

Over the next dozen years - with a few exceptions - oseltamivir remained effective against 99% of seasonal flu viruses, but over the past couple of years we've begun to see some cracks in its veneer.

Eighteen months ago we saw a worrisome report in The Lancet - Global Emergence of Neuraminidase Inhibitor-Resistant Influenza A(H1N1)pdm09 Viruses with I223V and S247N Mutations - which reported a much higher incidence of oseltamivir resistance among samples tested in Hong Kong in 2023.

Unlike the H275Y mutation which caused so much trouble in 2008, these viruses carried dual I223V/S247N mutations.

Since then we've also seen: 

EID Journal: Multicountry Spread of Influenza A(H1N1)pdm09 Viruses with Reduced Oseltamivir Inhibition, May 2023–February 2024

Virus Research: A 15-year Study of Neuraminidase Mutations and the Increasing of S247N Mutation in Spain

And just 3 weeks ago, in Taiwan CDC Statement On Increased Antiviral Resistance in Seasonal H1N1 Cases in 2025, we saw a cryptic report indicating that 6.5% of locally circulating H1N1 viruses in Taiwan were now resistant to Oseltamivir. 

While oseltamivir remains largely effective against seasonal flu, it does appear to be coming under increased pressure. And while there are alternatives to oseltamivir (e.g. Baloxavir) -  oseltamivir remains the most available option. 

All of which brings us to a new study, published this week in Influenza & Other Respiratory Viruses, which - somewhat surprisingly - posits another potential cause of reduced effectiveness of oseltamivir against recent H1N1 viruses. 

Rather than citing previously identified amino acid changes in the NA (e.g. I223V/S247N), Liu et al. propose that an `increase in HA and NA activities' may be responsible for increased resistance in H1N1 viruses.  They state, however:

The reasons for the increased HA and NA activities remain un-clear due to the lack of information on the underlying mechanisms. 

I'll leave it to someone with a substantially higher pay grade to parse this one out.  Suffice to say, they observed higher oseltamivir resistance in 2023 H1N1 viruses, even in H1N1 viruses without previously identified markers. 

The authors then present evidence (in mice) that a baloxavir monotherapy or a baloxavir-molnupiravir combination treatment retained effectiveness against these H1N1 strains, although the combination therapy resulted in better outcomes.  

Note: Baloxavir is far less available here in the U.S., while Molnupiravir (Lagevrio) - a `last resort' COVID antiviral - carries several important warnings; particularly regarding its use during pregnancy, breastfeeding, and in patients under 18.

I've reproduced the abstract below. Those seeking a deeper dive will want to download and read the full PDF.   I'll have a brief postscript after the break.  

Efficacy of Oseltamivir Against Seasonal Influenza H1N1 and the Efficacy of a Novel Combination Treatment In Vitro and In Vivo in Mouse Studies

Danlei Liu, Ka-Yi Leung, Ruiqi Zhang, Hoi-Yan Lam, Yujing Fan, Xiaochun Xie, Wan-Mui Chan, Kelvin Kai-Wang To, Kwok-Hung Chan, Ivan Fan-Ngai Hung
First published: 20 October 2025
https://doi.org/10.1111/irv.70176

PDF
 
ABSTRACT

Background

Influenza surveillance and drug resistance testing have always been central to clinical efforts. Therefore, researching the virus characteristics and antiviral drugs is essential.

Method

The HA and NA activities were assessed in influenza strains, and mutations were identified through gene sequencing. The effects of oseltamivir, molnupiravir, and baloxavir treatments were evaluated in vitro. The effectiveness of molnupiravir monotherapy and its combination with baloxavir was also evaluated in a mouse model. Changes in body weight and lung tissue were examined, including pathological changes, virus replication, and inflammation levels.

Results

Forty-one seasonal influenza H1N1 strains from 2023 were used. The EC50 of oseltamivir was significantly increased compared to the 2009 reference strain.

Correlation analysis showed that the increase in EC50 was related to the HA and NA activities. The antiviral effects of molnupiravir and baloxavir significantly inhibited virus replication; the combination treatment of molnupiravir/baloxavir showed more potent and synergistic inhibitory effects in vitro. 

In the mouse model, molnupiravir treatment effectively inhibited virus replication and lung inflammation, but the treatment did not improve weight loss or reduce mortality. With the molnupiravir/baloxavir treatment, viral replication was significantly inhibited and proved to be more effective than either monotherapy. The combination therapy also showed the lowest inflammatory response along with a higher survival rate.

Conclusions

The increase in HA and NA activities of seasonal influenza reduced the efficacy of oseltamivir treatment, but the effectiveness of molnupiravir and baloxavir was retained. Combination therapy showed a significant antiviral effect, which provides a reference for the clinical treatment.

        (SNIP)

In summary, the HA and NA activities of the 2023 seasonal influenza have increased, thereby diminishing the antiviral effect of oseltamivir. Molnupiravir has shown certain anti-influenza effects, and its combination with baloxavir can more effectively inhibit viral replication and reduce mortality in mouse studies.

       (Continue . . . )

While oseltamivir continues to be effective against the vast majority of seasonal flu viruses currently in circulation - and we don't appear to be anywhere near a repeat of 2008 - we are seeing some early warning signs. 

Which suggests that public health authorities may need to start thinking about stockpiling alternatives (e.g., zanamivir, baloxavir) should these trends continue.

As we are so frequently reminded -  evolution never stops - and while our modern pharmacological victories over bacteria, fungi, and viruses have been nothing short of remarkable - they are often fleeting.