The flu fighter Tamiflu is one of the most recognizable antiviral medications in the world — but its weaknesses suggest that devising a similarly simple treatment for COVID-19 will be challenging.

After spending some $20 billion to develop vaccines at top speed, the U.S. is turning its attention to treating COVID-19 after a person is infected. Last week, health officials said the Antiviral Program for Pandemics will use $3.2 billion to target drugs for COVID and other viruses with the potential to foment pandemics.

Anthony Fauci, the country’s top infectious-disease official and adviser to President Joe Biden, compared the hoped-for drugs to Tamiflu, which was used in 2009 to counter a milder pandemic of swine flu. But that medication’s history shows the pitfalls of expecting antivirals to contain an explosive infection like COVID.

“Putting that as your first line of defense is a dangerous choice to make,” said Stephanie DeWitte-Orr, who studies antivirals and immunity at Wilfrid Laurier University in Waterloo, Ontario. While antivirals are an important backup in the fight against COVID, she said, in most cases, that’s all they should be — a backup plan.

Tamiflu, otherwise known as oseltamivir, was developed by Roche Holding, approved in the U.S. in 1999, and has been available as a generic since 2016. More than 100 regulators, including the Food and Drug Administration, approved the drug based on a rigorous review of its trials, Roche said in an email. Public health authorities including the World Health Organization and the Centers for Disease Control and Prevention, along with doctors’ groups, recommend it in their guidelines for flu treatment and prevention, Roche said.

Like most antivirals, Tamiflu blocks or slows replication of virus that’s already in the body. If taken quickly, Tamiflu can reduce the duration of infection by one to two days, studies show.

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“The benefits are, in an average healthy person, perhaps not that meaningful,” said William Schaffner, a Vanderbilt University infectious disease expert who advises the U.S. Centers for Disease Control and Prevention. “But for some people with underlying illnesses, that little difference could be the difference between being admitted to an intensive care unit or not.”

Some antivirals work extremely well, such as those that treat the relatively slow-growing, yet persistent HIV virus. Combinations of these drugs are able to keep the potentially lethal pathogen effectively under control for decades, but not eliminate it.

But, like COVID, flu infections mount relatively quickly. Most people don’t start taking Tamiflu within the recommended 48 hours from the start of infection, Schaffner said. The longer the virus stays on offense, the less effective the drug becomes.

“It’s like trying to get in front of a runaway train,” Laurier’s DeWitte-Orr said. “You can hold onto the back and slow it down, but to stop it fully in its tracks would be very difficult.”

Another issue that can quickly arise with antivirals, especially when they’re overused, is resistance. The U.S. spent more a billion dollars to stockpile Tamiflu before the 2009 pandemic caused by swine flu — a far milder pathogen than SARS-CoV-2 — only for the virus to develop resistance, rendering the drug ineffective for millions.

“This is always the issue with antivirals,” said Chris Woods, a professor of medicine and global health at Duke University. “The pathogens are creative, they replicate very quickly, and if you don’t knock them out quickly, they’ll find a way to evade and survive.”

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Numerous drugs have laid siege to COVID and failed, starting with the antimalarial drug hydroxychloroquine that was touted by former President Donald Trump. Even more auspicious-looking entries, like Merck & Co.’s molnupiravir, developed with Ridgeback Biotherapeutics, haven’t shown an impact on hospitalizations and deaths in patients with severe COVID. The drug is still in testing for less-severe cases.

Other medications have met with some success. Like Tamiflu, Gilead Sciences Inc.’s remdesivir, the only COVID antiviral cleared for use in the U.S., aims to slow virus replication. But because it’s administered intravenously in the hospital over days, it’s inaccessible to people in the early stages of disease.

Monoclonal antibodies from Eli Lilly & Co. and Regeneron Pharmaceuticals Inc. target proteins on the viral surface, and appear effective at reducing related hospitalizations among high-risk patients. While these are used to treat patients before they become acutely ill, they must also be given by IV, and are costly.

A cheaper, oral alternative would be particularly attractive.

“If we can get to something fairly cheap, like Tamiflu, that will be a major breakthrough,” Woods said.

Yet drug companies might still shy away from the field. The risks and investment to develop an antiviral that might be taken for just a few weeks — rather than the lifetime of treatment required for HIV, for example — or may succumb to resistant strains may overshadow the potential rewards.

The lack of antivirals might be most important for people whose immune systems are impaired — like those who have received transplants and some cancer patients — who don’t get full protection from COVID vaccines. The drugs should be as effective for immunocompromised patients as for healthy people, since most antiviral drugs don’t depend on the body’s natural protective system to do their job, Schaffner said.

But antivirals will never be a replacement for vaccines, he said. Patients should try to prioritize prevention over treatment, he said, noting that once a person is infected, they may be putting both themselves and those around them at risk.

“Treatments, as good as they might be, are always imperfect,” he said. “Why risk that when you can prevent the disease on the front end?”