The biggest cognitive error in pandemic influenza preparedness.

We think we have an antiviral that works well. We don't.

At the beginning of the Covid-19 pandemic, we had no specific antiviral treatments or vaccines. Not that we had a choice in the matter, but because of this, many experts felt that we actually might have been better off with a pandemic caused by a novel influenza virus than a coronavirus. At least in the case of a flu pandemic, the argument was, we’d have effective antivirals already on hand, and vaccines that (once altered) would likely prevent severe disease.

Well, as the quotation goes, “It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.” —Somebody smart.

Yes, we do have antivirals for influenza. The most widely use one is called oseltamivir (marketed as “Tamiflu”).

Here’s the problem: oseltamivir basically sucks.

Two capsules of Tamiflu (oseltamivir). Photo: Scharvik/Getty Images.

For whatever reason, the gulf between how well policymakers and infectious disease experts tend to think oseltamivir works and reality is wide. I’ve never understood this. We have well-vetted meta-analyses (studies of studies, summarized here and here) that show that, at least for the general population, oseltamivir does two things only:

1. Oseltamivir decreases the time that symptoms last by about 17 hours. That’s not nothing, but even with the medication, the mean symptom duration is 6 days, down from 7.

2. Oseltamivir works as prophylaxis, but only modestly. We would need to treat 33 close contacts of a flu-positive person to prevent one infection.

What about other important outcomes? Does oseltamivir reduce hospitalizations in standard-risk patients? Does it reduce the fraction of patients who develop pneumonia? No and no. Might it be helpful for others with very high risks? Maybe. Maybe not. I’ve not seen high-quality data to support that contention. Studies that I have seen that looked at high-risk populations were always lower quality. Meanwhile, the CDC says there is not evidence that the drug prevents influenza infections among immunocompromised people. Also, oseltamivir can and does cause real problems, ranging from nausea to more serious issues like kidney and neuropsychiatric effects.

In other words, oseltamivir is simply not a drug poised to save the day if a novel influenza pandemic were to occur in humans.

That’s why a scoop (in Fortune) that revealed that the CDC recently found that oseltamivir’s ability to inhibit the H5N1 influenza (“bird flu”) currently spreading in cattle in the US was 16-fold lower than that seen for seasonal influenza strains neither impressed nor worried me. (For its part the CDC said that this decrease was more or less expected and that the clinical implications of this finding were not cause for it to change course. That is, if a human were to contract H5N1, the CDC would recommend “prompt antiviral treatment with oseltamivir for patients with confirmed or suspected H5N1 virus infection.”)

My question for the CDC is why? To what end? How much of a difference does the CDC expect a drug like oseltamivir to make in the face of a human outbreak of a pathogen like H5N1? Hopefully, they don’t think it will do much. If they do, they’re probably overconfident. (More on why this matters below.)

What we should be doing instead of putting our money into stockpiling more oseltamivir is urgently working on finding something better. Something that works.

Might oseltamivir work in higher doses? Might it work as part of a cocktail with another antiviral? Possibly. But right now, there are many experts who are only just starting to worry that oseltamivir does not work as well as billed (that is, as implied by treatment guidelines and public messaging). They should not be worried that oseltamivir doesn’t work well enough to make a large difference in a novel H5N1 outbreak. They instead should immediately acknowledge that it almost certainly will not. They should worry that they didn’t realize this 10 years ago, back when this was all settled. They should be calling up drug companies begging them to test something new.

Complacency is a bad thing. In my view, infectious disease specialists and epidemiology teams have been complacent for far too long on this issue. And we have an advantage, here, and one that we are squandering by doing next to nothing in the antiviral space now. Unlike Covid-19, we have actually detected the spread of the H5N1 influenza, a virus with human pandemic potential, circulating in animals. So, we should have a head start. We should use that opportunity. Remember, it took almost two years to get Paxlovid to the market after Covid-19 erupted. But SARS-CoV-2 was a virus we didn’t expect, and knew nothing about at first. Here, the opposite is true. We know quite a lot about two likely foes that could easily cause the next pandemic: H5N1 or H5N2 influenza.

The time to look for a drug that could dramatically improve influenza outcomes among unvaccinated people—the way Paxlovid once did for Covid—is now.