Screenshot: CDC's Interim Guidance on the Use of Antiviral Medications
for Treatment of Human Infections with Novel Influenza A Viruses Associated
with Severe Human Disease - July 2025
#19,349
While newer antivirals have been developed (see FDA Approval Of Xofluza : A New Class Of Influenza Antiviral), oseltamivir (aka `Tamiflu') has remained the `Go to' antiviral for influenza treatment in the United States - and much of the world - for more than 20 years.
Oseltamivir is our most studied antiviral, nations of the world have stockpiled hundreds of millions of doses, and now that can be acquired as a generic drug, its cost has plummeted.
While exact numbers have never been disclosed, our National Strategic Stockpile supposedly has somewhere around 50-60 million courses of oseltamivir on hand; sufficient to treat 15-20% of the nation during a severe flu pandemic (assuming a single, standard dose).
Stockpiles of Baloxavir (aka Xofluza) are similarly unknown, but according to a media report in 2024 (see The U.S. strategic drug stockpile is inadequate for a bird flu outbreak) likely numbers only in the hundreds of thousands of doses.
But oseltamivir's track record against novel flu is far from perfect. To be effective, it must be started early in one's infection (1st 48 hrs, ideally), and even then, a good outcome is far from guaranteed.
The first barrier is getting the drug to the patient in a timely manner, something which we've struggled with, even during normal flu seasons (see Sporadic Tamiflu (Oseltamivir) Shortages Reported In U.S. & Canada).
There is also the problem of resistance, something that can develop spontaneously in 1%-2% of people receiving treatment, or worse - can become `fixed' in circulating strains - such as we saw with H1N1 in 2008.
Last year, in - in Emerg. Microbes & Inf: Oseltamivir Resistant H5N1 (Genotype D1.1) found On 8 Canadian Poultry Farms - we saw a report on a large outbreak of Oseltamivir resistant H5N1 which emerged over several weeks in the fall of 2024.
While we haven't seen that happen on a large scale, 18 months ago concerns over the effectiveness of our current antiviral armamentarium were raised by St. Jude Researchers: Current Antivirals Likely Less Effective Against Severe Infection Caused by Bird Flu in Cows’ Milk.
- Ferrets infected with H5N1 D1.1 and treated with oseltamivir saw little or no clinical or virologic benefit compared to no treatment, with persistent high fevers, weight loss, and systemic viral replication.
- Ferrets treated with Baloxavir saw significantly less fever, weight loss, and viral replication. Some ferrets, however, saw a late rise in fever (after 4 days) and viral shedding, suggesting a viral rebound.
- Ferrets treated with both drugs saw similar clinical protection to baloxavir alone, but did not show signs of rebound.
Note: Ferrets are a good, but not perfect, proxy for humans in influenza research, so these results may not be 100% applicable to humans.
A month later, we looked at a study (Nature Comms: Baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating lethal influenza A(H5N1) HA clade 2.3.4.4b infection in mice) by Webby & Jones et al. which suggests that baloxavir outperforms oseltamivir, favipiravir, and amantadine in treating clade 2.3.4.4b (circa 2022) H5N1 avian viruses (in mice).
And last April, in Emerg Microbes & Inf: Antiviral Activities of Multiple Antivirals Against HPAI H5N1 in Vitro and in Mice, the authors reported the existing 5-day course of oseltamivir appears inadequate to treat severe HPAI H5N1 infection (at least, in mice).
The authors reported Baloxavir as being more potent, but even a 5-day B.I.D course (10 times the current dose) only saved 16.7% of treated mice. Extending treatment to 7 days (14 doses), raised survival to 50%.
The caveat here being that - due to their higher metabolic rate - the half-life of baloxavir is much shorter in mice than in humans. While it remains to be determined, an equivalent dose in humans might be more like 2 or 3 doses spread out over a week's time.
And mice, and ferrets, and other lab animals - while useful - are never a perfect analog for humans. They don't have the same physiology, metabolism, or past virus and/or vaccine exposures that can modify our immune response.
Adding to this long and winding narrative, we have a new report from the EID Journal which provides additional support for the baloxavir-based strategy described above.
As in the previous report, the authors found that baloxavir outperformed both oseltamivir and molnupiravir against clade 2.3.4.4b H5N1 in a mouse model, although it should be noted they began treatment just 6 hours after inoculation.
Combining baloxavir with either oseltamivir or molnupiravir was even more effective in suppressing viral replication and spread beyond the lungs.
The bottom line: both studies suggest oseltamivir monotherapy may be inadequate for severe H5N1, that baloxavir appears more potent, and that combination therapy may prove a more effective regimen - at least in mice.
How all of this might translate to humans, who would be unlikely to receive antiviral treatment in such short order - remains to be seen.
I've only posted the abstract and some extended excerpts from the EID dispatch. Follow the link to read it in its entirety. I'll have a postscript after you return.
Comparison of Baloxavir-Based Combinations and Monotherapies for Treating Influenza A(H5N1) Clade 2.3.4.4b Virus Infection in Mice
Seong Cheol Min, Ju Ryeong Lee, Beom Kyu Kim, Ji-Hyun Park, Dong Gyu Lee, Gi Chan Lee, Se Hee An, Santosh Chokkakula, Aman Jain, Young Ki Choi, Yun Hee Baek, and Min-Suk Song
Abstract
Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause animal outbreaks and sporadic zoonotic infections. In a mouse model of lethal influenza disease, we compared oseltamivir, baloxavir, and molnupiravir monotherapies with 2-drug combinations.
Baloxavir-based combinations improved survival, reduced lung viral loads, and prevented extrapulmonary dissemination, supporting H5N1 preparedness strategies.
Highly pathogenic avian influenza A(H5N1) clade 2.3.4.4b virus continues to cause widespread outbreaks and sporadic zoonotic infections, underscoring the need to optimize antiviral strategies (1–3). Licensed influenza antiviral drugs can reduce disease severity but might be compromised in severe infections by high viral burdens, treatment delays, and treatment-emergent resistance, motivating evaluation of combination regimens (4–7).Recent H5N1 treatment studies using mouse models suggest antiviral performance can vary by exposure route and disease progression (8–11). To inform preparedness-oriented selection, we compared direct-acting antiviral drugs from distinct classes in a lethal mouse model. We tested monotherapies and 2-drug combinations of 2 licensed influenza antiviral agents, oseltamivir phosphate (OSP; neuraminidase inhibitor) and baloxavir acid (BXA; cap-dependent endonuclease inhibitor), and molnupiravir (MPV; nucleoside analog) to assess whether combinations provided synergistic benefit.
(SNIP)
Conclusions
In a lethal clade 2.3.4.4b H5N1 mouse model, monotherapies with OSP, MPV, or BXA improved outcomes in a dose-dependent manner but did not consistently prevent death or extrapulmonary spread. In contrast, 2-drug combinations, particularly those containing BXA, achieved complete survival at both dosing regimens and suppressed pulmonary replication to near LOD while preventing neuroinvasion and cardiac dissemination.Those findings are consistent with recent clade 2.3.4.4b A(H5N1) studies showing strong in vivo activity of BXA and BXA-containing regimens and extend those observations by directly comparing BXA/OSP and BXA/MPV with OSP/MPV in a lethal mouse model (8,10,11,14). Our findings extend recent antiviral-combination studies in less virulent influenza models by showing that BXA-containing combinations provided the strongest protection in a lethal clade 2.3.4.4b H5N1 model (14,15).Together, our findings provide an experimentally grounded rationale to prioritize BXA-based 2-drug regimens as a preparedness-oriented option for emergent H5N1 infections when antiviral treatment is initiated early after infection, particularly where severe disease or resistance risk can compromise single-agent performance.
Currently, the CDC's guidance is for prompt oseltamivir treatment of suspected or confirmed novel influenza A infections, while allowing clinicians to consider adding baloxavir in selected severe or high-risk cases.
- Combination antiviral treatment (e.g., oseltamivir and baloxavir) can be considered for hospitalized patients with novel influenza A virus infection because it is possible that some novel influenza A viruses might become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents 36789
- Oseltamivir resistance has been reported in hospitalized patients with HPAI A(H5N1) virus infection, resulting in fatal outcome 3. If a hospitalized patient treated with oseltamivir or peramivir manifests progressive lower respiratory disease, the presence of a resistant virus should be considered. After consultation with CDC's Influenza Division, investigation for antiviral resistance should be performed.
- Combination treatment with a neuraminidase inhibitor and baloxavir did not have clinical benefit compared with neuraminidase inhibitor and placebo in a randomized clinical trial in hospitalized patients with seasonal influenza, but the addition of baloxavir reduced duration of infectious viral shedding 10
The reality is, even oseltamivir may be hard to get - at least during the first critical 24-48 hrs of infection - during any global influenza pandemic. It seems likely that `extended' baloxavir or combination therapy will be limited to hospitalized patients with severe disease.
While I would certainly avail myself of whatever antivirals are available in an influenza pandemic, my primary strategy is always one of prevention. I've already got my supply of masks, hand sanitizer, and OTC meds in the hall closet, and have stayed current with all of my vaccines.
