Part of the Drugs Issue of The Highlight, our home for ambitious stories that explain our world.
In January, New York City launched a program to provide Covid-19 treatments to residents at high risk of being hospitalized or killed by the virus — delivered free, to their door.
It was a potentially revolutionary moment in the pandemic’s trajectory, possible only because, at the close of 2021, the US Food and Drug Administration granted emergency authorization to the first two oral antiviral drugs people can take, at home upon Covid-19 diagnosis, before they get sick enough to be hospitalized.
Paxlovid and molnupiravir, two therapeutic antivirals shown in studies to have varying levels of effectiveness in stunting Covid-19’s dangers for those most at risk, represent a new weapon against a devastating virus that not only spreads with unnerving ease (much more readily than even the 1918 pandemic flu strain) but also has proven so difficult to treat.
Doctors have gotten better at preventing deaths in the severely ill than they were at the beginning of the pandemic, but many people — hundreds every day in the United States alone — are still dying from the disease. There is simply no surefire cure for someone who lands in the hospital.
Although monoclonal antibodies, which help the body fight an infection, have been available for high-risk patients since November 2020, they require IV infusion at a specialized facility, as does the antiviral remdesivir, which demands infusions on three consecutive days, making them much harder for people, especially those who lack reliable transportation or paid time off from work, to access than pills they can take at home.
The new oral antivirals, which arrived with considerably less fanfare than vaccines in late 2020, have the potential to reshape the contours of the pandemic going forward — not just for those at high risk, but also in surprising ways for those who aren’t. Their arrival also marks a potential new era of renewed investment in broadly useful antivirals that could fight not just Covid-19, but also other deadly viruses that have yet to emerge. However, delivering them equitably and in a very short time frame, and the looming threat of resistance, suggest that they face a road pockmarked with challenges.
It wasn’t until the 1960s, 30 years after the first commercially available antibiotics, that the first virus-disarming medications hit the market (the first was a topical drug because it was too toxic to ingest).
Part of the lag was because of the slippery nature of viruses. Unlike bacteria, viruses aren’t, in themselves, alive. Rather, they persist and multiply by taking over a living organism’s cells.
“People think, ‘It’s a germ, why can’t you just eradicate it?’” said Rebecca Wurtz, an infectious disease doctor and population health expert at the University of Minnesota School of Public Health.
Disentangling a virus from the cell it has taken over, however, is extremely tricky: The microscopic needle to thread in developing safe, effective antivirals is to hobble the virus but not damage the host cells it is hijacking. To do it, antivirals can take aim at things like the very specific enzymes the virus uses to make copies of itself, which is how molnupiravir works. “When you’re trying to counteract their activity, it’s a very razor-thin edge,” Wurtz said.
Nevertheless, researchers have continued over the years to develop new antivirals. These drugs can help treat, with varying degrees of efficacy, a multitude of infections, including shingles, herpes, hepatitis, even Ebola.
Timothy Sheahan, a virologist with the department of epidemiology at the University of North Carolina Gillings School of Public Health, had been working on applying remdesivir, which was originally developed to treat Ebola, to coronavirus infections since 2015 and on molnupiravir, which initially targeted influenza, since 2017.
“We never really thought that the stuff we were doing in the lab would lead to the approval of two antiviral drugs by the FDA,” he said. Till the advent of Covid-19, “nobody cared about coronaviruses, or even knew what they were.”
That early foundational research, however, meant that these drugs could come to market as quickly as they did. “Many other antiviral drug candidates didn’t have that body of information just sitting on the shelves,” Sheahan said.
Despite the years of research, molnupiravir (from Merck and Ridgeback Biotherapeutics) and Paxlovid (a combo of nirmatrelvir and ritonavir, which Pfizer started developing at the beginning of the pandemic) still needed to go through clinical trials and testing in the Covid-19 landscape. And then companies needed to start making them. When the emergency authorizations came through for their use in late December, although the federal government had placed orders for millions of courses of the drugs, there were just 300,000 courses of molnupiravir and 65,000 of Paxlovid to go around, just as the omicron variant was poised to sicken tens of millions across the country.
In addition to the initially limited supply, these drugs also have inherent shortcomings. In trials, molnupiravir was only about 30 percent more successful than a placebo in keeping infected study participants from being hospitalized or dying. (Subjects were unvaccinated adults with at least one risk factor for severe Covid-19, and experts expect the drugs to perform better among vaccinated people.) It is also not recommended for people who are pregnant or might become pregnant in the near future.
Paxlovid, for its part, appears to be much more powerful. It is about 89 percent effective in preventing hospitalization or death when high-risk participants took it within three days of having symptoms, according to a report published in the BMJ. But Paxlovid comes with a long laundry list of interactions with common drugs, making it unusable for many of the high-risk people it could otherwise help, such as those on some heart or cancer medications.
As the federal government distributed the limited supply of these medications across the nation earlier this year, many also worried that more vulnerable populations, such as high-risk individuals in under-served communities, would lack equal access to the lifesaving drugs. A fraction of the courses — about 15 percent — was distributed to federally funded health centers that serve these groups. That left the bulk of the first shipments to be distributed through private pharmacies, to be doled out to those who were able to access them first, a sort of non-system that by default favors the well-resourced.
Even for those who have not had to try to avail themselves of these new drugs, they have already had another side effect: pandemic stress reduction. For those who, due to previous illnesses, age, a compromised immune system, or other factors, are less protected by vaccination, these pills offer an added level of security.
“It is reassuring,” said Raymund Razonable, vice chair of infectious diseases at the Mayo Clinic. The clinic is still collecting data, but anecdotally, among the high-risk patients he and his colleagues have prescribed these new drugs to so far, they’ve tended to have a good outcome: silence. “They’re not going to call you again,” he said, “because they’re better.”
On a population level, dramatically reducing the number of people who get sick enough to need hospitalization could help preserve the entire health care system during future waves of the virus. This would keep hospitals from being overwhelmed, preserving care for more people, including those who have health needs other than Covid-19.
Whether these drugs will be deployed more widely, directly to people at lower risk, remains to be seen.
If future Covid-19 variants cause relatively “mild” breakthrough infections, like omicron has, antiviral drugs might not become standard for everyone who tests positive. A rougher illness outlook could send more people looking for prescriptions. Yet, because the new antivirals were studied in high-risk, unvaccinated individuals, we don’t know much about how effective they will be at improving symptoms for people who are at low risk for severe disease.
If they can help someone at low risk feel much better, much faster, however, “I would take the drug,” said John Swartzberg, an infectious disease specialist at the University of California Berkeley School of Public Health.
There’s a chance these sorts of easy-to-take antivirals could play another important role in the pandemic: keeping more people from getting sick in the first place.
Yet it’s still unclear whether the new oral antiviral drugs would make sense as a prophylactic for the more general low-risk population, experts told cafemadrid. And it is unlikely to be prescribed as an ongoing regime, as PrEP is to prevent HIV.
“HIV PrEP is very effective, but you have to remember to take a pill every day, and it has some side effects,” Wurtz said. “So the ideal prophylactic medication would be something that would be long-acting, inexpensive, highly effective, and non-toxic. None of the options that we have available to use meet those criteria yet.”
It’s also possible that these sorts of medications will decrease the odds that a patient will spread the infection to others, making it “so they’re not just another node in transmission,” Wurtz said.
Wurtz finds this a compelling line of questioning as we look at these drugs’ effect on the future of the pandemic. “We hope and expect that if someone is diagnosed with Covid, and we quickly put them on these antivirals, they’ll be less contagious to other people,” she said. She sees that as an important benefit, particularly for nursing homes and other places with lower community immunity to the virus.
Vaccines, experts say, remain the first and best line of defense. “The vaccine is the best tool because it clearly prevents severe illness, hospitalization, and death,” said Amesh Adalja, an infectious disease, emergency medicine, and critical care doctor at the Johns Hopkins Bloomberg School of Public Health. “Prevention is always better than treatment.”
For those who haven’t mounted as high of an immune response, even after vaccination, or haven’t been able or have chosen not to be vaccinated, the pills could someday be prescribed after a known exposure, even before a positive diagnosis.
The antiviral Tamiflu is already prescribed this way to prevent those at high risk from catching a potentially fatal case of influenza. For example, if an outbreak of flu occurs in an assisted living facility, often everyone is given a course of Tamiflu to prevent additional infections. For Covid-19, monoclonal antibodies have been authorized for this sort of post-exposure prevention in high-risk people since July 2021.
Having courses of oral antivirals on hand for US nursing homes could potentially save thousands of lives during future Covid-19 waves. But the rest of the globe could see an even more dramatic benefit as we look ahead to many more years of living with the virus.
Easy-to-take antivirals could drastically reduce hospitalization and death among the billions of people who remain vulnerable to the disease, including those who have been unable to be vaccinated and those living with conditions that put them at higher risk, such as HIV.
“If we could get the drugs to them, we could prevent an awful lot of hospitalizations and deaths just with the oral medication,” Swartzberg noted. “But it’s a real steep climb to work out all the logistics.” The pills would need, for example, to be substantially cheaper than they are currently in the US: $530 for a course of Paxlovid and $700 for molnupiravir (costs that the US government is currently covering for its residents).
The drugs would still need to surmount many of the same distribution hurdles as other lifesaving medications that frequently fail to become universally accessible.
Whenever we deploy a new weapon against a virus on a broad scale, on the faces of the very scientists and medical workers we would expect to be most jubilant, there might pass a barely perceptible shadow of worry. The specter of resistance always looms.
Similar to bacteria becoming resistant to antibiotic treatments, such as in dreaded MRSA infections, viruses can rapidly evolve to shrug off once-deadly attacks by antiviral medications. In some ways, they’re even better at it. “They’re far less sophisticated than bacteria, therefore they need even less to carry on and survive,” Wurtz explained. “They’re literally just packages of patterns; they’re not even really alive. So they can test and cope with mutations, including mutations that make them resistant to antivirals.”
The Covid-19 virus replicates so quickly in a single person — and across so many people — it has almost countless chances to try out new mutations that will make it better at infecting people, evading vaccines, and surviving attempts to quash it with treatments. “So resistance is inevitable,” Wurtz said.
We’ve already seen the genetic gymnastics Covid-19 has performed to frequently get around vaccine-induced immunity (if with greatly reduced severity). The virus has done this by changing aspects of its external spike protein, which is what the vaccines had primed our immune systems to look out for. Fortunately, the new antiviral drugs work on a more intimate and integral part of the virus, its replication machinery, that it is more hard-pressed to alter.
Still, cautioned Mayo Clinic’s Razonable, “We’ve learned from before that there is always going to be some sort of fight between the virus and whatever drugs we have. So there’s always going to be the anticipation of resistance coming.” Some past strains of the flu, for example, have proven resistant to Tamiflu treatment.
One way to try to stave off resistance is to help people take the medication exactly as instructed. (The new antiviral courses require multiple pills to be taken twice a day for five consecutive days.)
The other essential tactic we have for combating resistance is to be ready with new and different pharmaceutical weapons. “If we know resistance is going to come, we should get ourselves ready and develop some other drugs, with different mechanisms of action, so that when the time comes, we’ll be ready,” Razonable said.
The lineup of potential new drugs to help prevent more Covid-19 deaths, experts say, is fair. But it could be better. Before 2020, much of the recent research had been in highly targeted antivirals that were less likely to work on a new virus.
The pandemic renewed interest in broad-spectrum antivirals of the sort Sheahan has worked on, which could be effective against a wide swath of viruses, including new mutations of the coronavirus and as-yet-unknown viruses. (They worked on assessing remdesivir and molnupiravir for such a broad band of coronaviruses by testing them not just against ones that had infected humans, such as SARS and MERS, but also on those circulating in a range of animals, such as mice, bats, and pigs, which could sow future pandemics.) As Sheahan noted, “it’s a process that takes time.”
For now, for the two oral antivirals to wield the greatest force in reshaping the hospitalization and death curves of the pandemic, people who can benefit from them most must get them — and quickly. That hasn’t been easy so far.
Both molnupiravir and Paxlovid need to be taken within five days of first symptoms. Why? “When you think about disease caused by Covid-19 and the severity, it’s an interaction of two things: the virus and your immune system,” Adalja explained. “Right after about five days or so, the virus is probably less of a player, and it’s your immune reaction to the virus,” he said. “If you let the virus rip for five days in someone, they may already be at the cusp of being hospitalized anyways. So the faster, the better.”
It’s easy to see how that process wouldn’t always go so smoothly. Testing is one weak link in the chain.
Swartzberg described a scenario where someone develops symptoms but first needs to acquire a rapid test. Once they do, if their first test is negative, they might wait a couple of days and test again. If their test is negative again but they still think they might be infected, they might seek out an appointment for a PCR test — and then have to wait 48 hours for results. “You can see where it’s beyond five days right there,” he said. And the person in this scenario hadn’t even gotten as far as contacting their doctor or nurse, let alone having their prescription in hand to start trying to track down the pills.
Adalja noted that the prescribing process itself will need to be quick and low-friction. “Doctors have to be comfortable saying a home test is a threshold to prescribe,” he said, and not insisting on confirmation from an official PCR test.
New York City’s home-delivery program addressed another logistical issue, which is simply getting the medication to Covid-infected people, whom no one wants turning up in the local pharmacy line in person.
And there’s been a telling surprise: In early February, there was actually an oversupply of these potentially lifesaving medications at some US pharmacies. This suggests that the many hurdles in obtaining these drugs, as well as their not-insignificant limitations, mean we’re not yet ready to extinguish the pandemic’s deadly blaze with billions of blister packs and some water.
Once these challenges are addressed, though, could these types of drugs meaningfully change the future of the pandemic for all of us?
“Cases are going to ebb and flow every year,” Adalja said. “As this transitions to endemic, there will likely be a role for this drug in keeping people out of the hospital.”
Yet, as much as these sorts of oral antivirals might mercifully lop off the spikes of hospitalization and death we have seen in the pandemic so far, they will not end it. “Oral antivirals will always have a role in people who are elderly and immunocompromised, but not as a pandemic-stopper,” Wurtz said. “Vaccination is the pandemic-stopper.”
Katherine Harmon Courage is a science writer and frequent contributor to cafemadrid.