Treatments will change the pandemic, but they cant end it alone

The notion that a fearsome infection could soon be treatable with a handful of pills is an exhilarating idea nearly two years into a pandemic that has killed more than 5 million people, at least 770,000 in the United States. But experts - who are thrilled about the prospect of two powerful new medicines - worry that enthusiasm for the idea of treatments may distract from their limitations and the necessity of preventing illness in the first place.

If regulators deem the five-day treatment courses from Pfizer and Merck and its partner Ridgeback Biotherapeutics safe and effective in coming weeks, as most people expect, the drugs could make getting sick far less scary. The United States has already prepurchased millions of treatments. The good news arrives like an echo of last year, when two remarkably effective vaccines were authorized in the middle of the holiday season as a winter surge in new cases loomed.

But these treatments alone aren't likely to close the book on the coronavirus. Instead, they will be a valuable addition to an armamentarium that the world is going to have to keep building and maintaining long term: vaccines, booster shots, more antiviral pills, virus-fighting antibodies engineered to stick around in people's bodies and fast-turnaround testing linked to treatment options.

"It's a huge part of the toolbox; if we can move everything upstream, instead of trying to treat hospitalized patients with late-stage severe disease," said David Boulware, an infectious-disease physician at the University of Minnesota Medical School. "I'm an optimist. Six months from now, I think things are going to be great."

Drugs that can be taken at home to keep mildly sick people from ending up in the hospital will be a turning point. But a major lesson of the pandemic has been that around each corner are more corners.

Remember, the vaccines were better than anyone expected. But more people in the United States, where vaccines are plentiful, have died of covid-19 in 2021, after shots became available, than in the year before.

Antivirals, too, will be powerful but won't be a get-out-of-jail-free card by themselves.

Initially, they will be available to people at increased risk of severe illness due to age or other factors. People will need to recognize their symptoms early, get tested and start treatments right away.

The drugs are good, but not perfect: Merck and Ridgeback's molnupiravir slashed hospitalization and death by half in a clinical trial, but that means some people still ended up in the hospital. Pfizer's Paxlovid reduced hospitalizations and death by an impressive 89%, but must be taken within days of symptoms.

And scientists have learned not to underestimate the virus. As soon as treatments become widespread, scientists will be watching for signs of resistance.

"There's always a sense of optimism with a new strategy that comes along, and I'm optimistic, too, that this is one additional thing that is going to help in our fight against this disease," said Erica Johnson, chair of the Infectious Disease Board of the American Board of Internal Medicine and a physician at the Johns Hopkins Bayview Medical Center. "But I'm also cautious that it is just a single strategy, and it really only works if all the other strategies are healthy and working, too."

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Virus-fighting strategies, not silver bullets

Carl Dieffenbach, director of the Division of AIDS at the National Institutes of Health, has spent decades battling a different virus, overseeing a $1 billion global research portfolio focused on HIV. Although the long quest for a vaccine has been unsuccessful so far, the disease has been transformed by treatments and prevention strategies. Now, he is trying to apply some of that thinking to covid-19.

No one is willing to outline a minimum threshold of treatments needed against a virus that has been so continually surprising, but when pressed, Dieffenbach says that coronavirus treatments that will soon be reviewed by regulators are "a good start" - not the end.

It's important to build an arsenal of drugs that use different techniques to stop the virus. One class of drugs can block the coronavirus from entering cells, as monoclonal antibodies already in use are designed to do. Another class could interfere with proteases, enzymes that the virus uses to process its proteins - like Pfizer's drug. Yet a third could interfere with a different enzyme the virus uses to make copies of itself, like Merck and Ridgeback's molnupiravir.

Dieffenbach thinks all three angles of attack will be needed, as well as backups for each strategy and cocktails that combine them, to avoid allowing the virus to sneak past the protection given by any individual treatment.

"Six [treatments] at a minimum. Nine would be better. Twelve would be even better," Dieffenbach said. "We need the companies to make the drugs at scale, as available as aspirin and Tylenol - metric kilotons."

Both Pfizer and Merck have begun scaling up their pills before they have received a regulatory green light. Pfizer plans to make 50 million treatment courses in 2022. Merck projects having 10 million treatment courses ready by the end of this year, and more in 2022. The United States has prepurchased about 3.1 million treatment courses from Merck and 10 million from Pfizer.

The question now on many scientists' mind is how the virus will respond as those drugs go into widespread use. Akiko Iwasaki, an immunologist at Yale University School of Medicine, sees combinations of drugs as the future - particularly for people with compromised immune systems who can have covid-19 infections that simmer for weeks or months, allowing the virus to mutate.

"If we have a combination, an antiviral cocktail, it might protect against the emergence of these mutations," Iwasaki said.

Iwasaki and colleagues recently reported a preprint case study of a woman in her 70s whose cancer had weakened her immune system. The patient was sick for six months with a persistent covid-19 infection, and during her treatment received a course of remdesivir, an intravenous antiviral medication. At first, her fever resolved and levels of the virus dropped - until a mutation that gave the virus resistance to remdesivir allowed it to surge back.

In this case, the resistant virus that was able to thrive in the presence of remdesivir wasn't going to take over the world - it was less adept at multiplying than the original strain. But the case illustrates the risk of new variants arising after treatment.

To protect immunocompromised people, other companies - including AstraZeneca and Adagio Therapeutics - are trying another angle of attack: laboratory-brewed monoclonal antibodies that have been engineered to stick around in the blood for a long time, on the idea that they could provide a shot of long-term protection, similar to a vaccine. Regeneron recently released data showing that its monoclonal antibody cocktail, currently authorized as a treatment for people infected or recently exposed, remains about 80% effective against symptomatic infections eight months later, bolstering the case for its drug as a preventive for people who don't respond well to vaccines.

"For us, vaccination has been the jailbreaker, it has allowed us to live life normally," said Hugh Montgomery, a professor of intensive care medicine at University College London leading a trial of the AstraZeneca drug, which has been submitted to U.S. regulators for emergency authorization. "My sister, who has breast cancer and has just got 18 weeks of chemotherapy and can't mount an antibody response to the vaccine - as we've lifted our lockdown, she's become a prisoner in her house."

Instead of one drug or one solution, there will probably be treatment niches - and the market opportunity isn't a one-time flare; it's what pharmaceutical executives call "durable."

On a recent earnings call, Pfizer chief executive Albert Bourla said that he saw a years-long market for antiviral pills. As long as the world needs vaccines, it will also need treatments.

"As long as you have covid around, you will have a need to vaccinate and protect and then you will have a need to treat and save lives," Bourla said.

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A revolution outside the medicine cabinet

For covid-19 treatments to change the world, the world may also have to change.

Alongside medical tools, Dieffenbach is calling for a societal shift - a new normal in which people with respiratory symptoms test as soon as symptoms appear and start drugs within three to five days.

"What I'm advocating for is a fundamental change in approach," Dieffenbach said. "In the future, we don't require people to go to the doctor if they're feeling sick to get tested. There's a rapid test you do at home. People are motivated to get a prescription, or already have a prescription so they can start taking it right away. That's where we're going to have to get to."

Even as experts anticipate the arrival of lifesaving drugs, they worry. Will people use the existence of medicines as an excuse to avoid vaccination or boosters? Will people who could clearly benefit - those who have avoided the vaccines - seek out testing at the first sign of a sore throat and get access to drugs quickly enough?

Doctors are hopeful that people will realize that avoiding sickness altogether is the best option. Boulware said one colleague puts it this way: syphilis is treatable with penicillin. But it is far better to not get it in the first place.

"It's almost like applying the correct tool for the task at hand. Treatments are going to play a back up role to vaccines," said Rajesh Gandhi, an infectious diseases physician at Massachusetts General Hospital.

The existence of treatments could also trigger the start of a philosophical discussion on how to deal with sickness itself. Pre-covid, people hopped on flights and went to school and work with runny noses and coughs. If people go back to old habits, it may be hard to identify and treat people early enough in their illness.

"I don't think we're going back to just ignoring people who are sick," said Larry Corey, a virologist and past president of the Fred Hutchinson Cancer Research Center in Seattle. "Coming to school or coming to work and just assuming that no matter what, it's not going to hurt you."