Medical Examiner

Paxlovid Has a Slew of Downsides. It’s Not Here to Stay.

Scientists are experimenting with antivirals to come up with something better.

Packs of Paxlovid
Fabian Sommer/picture alliance via Getty Images

The day after I graduated from college, I got an unwanted present: a positive COVID-19 test. I’d made it nearly 2.5 years without catching it, and yet there I was in my childhood home, with two little lines on my antigen test. Luckily, I figured, I had a newish tool at my disposal, in addition to my triple vaccination: Paxlovid.

Use of the antiviral is on the rise. In May, the White House reported that the number of people filling Paxlovid prescriptions has increased from 27,000 per week to 182,000. Pfizer also recently invested $120 million to boost the pill’s production. Other treatment options also exist, such as the less effective molnupiravir Merck pill, but the National Institutes of Health’s COVID treatment guidelines state that Paxlovid is the best option for nonhospitalized patients, in part because it can be taken at home.

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Yet Paxlovid has a lot of downsides. Not only does it negatively interact with some common medications, but there have also been complaints of an awful aftertaste, diarrhea, and muscle aches. Some users reported COVID-19 rebound after Pavloxid (or, as my dad decided to abbreviate it, CRAP). It also best serves patients who are at high risk for bad outcomes of the virus (in clinical trials among high-risk adults with COVID-19, it reduced the risk of hospitalization or death by about 90 percent). Because of this, I found that some doctors were not gung-ho about prescribing it, instead recommending rest and Tylenol.

I decided to go ahead and take the pill, or rather the three mammoth-sized pills, twice a day. I like to think that the hours I subsequently spent on the toilet were a fair trade for a speedy recovery, but who knows how much the pill helped me specifically? After the whole experience, I wanted to know: Would this be the drug we were all going to be stuck with to treat COVID-19 in the future? It’s clear that COVID-19 is here to stay, and can reinfect people multiple times after immunity from an initial infection wanes. Luckily, there are better antiviral treatments coming our way.

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“Our antivirals aren’t perfect right now,” says Katelyn Jetelina, a professor and author of Your Local Epidemiologist.* “A lot of people can’t take Paxlovid because of whatever medications they’re on.” She added that ”we need to find other antivirals that will work for a broader population as well.” SARS-CoV-2 is also an evolving virus. It can mutate to become resistant to antivirals, so developing multiple types of drugs that can target the virus from a different angle is crucial.

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One strategy for developing “new” drugs is to create a cocktail of existing COVID-19 antivirals; in fact, Paxlovid is a mix of two drugs with antiviral properties (nirmatrelvir and ritonavir). “If you use combinations, it’s less likely for the virus to evolve resistance, and you have more potency,” Sara Cherry, a professor of pathology and laboratory medicine at the University of Pennsylvania, explained. In her lab, Cherry has been experimenting with 122 drugs that show antiviral activity, combining different ones such as brequinar and remdesivir to see how the amalgamation fared against the virus in a Petri dish. “Many people, including myself, think it would be very beneficial if we started combination trials [in people] now so we could potentially start giving people combinations to avoid some of the complications that could arise ultimately.”

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David Martinez, a postdoctoral fellow at the Gillings School of Global Public Health at the University of North Carolina at Chapel Hill, is also following a similar approach of experimenting with antiviral combinations. A nondisclosure agreement prevented him from sharing too many specifics with me. But he could tell me that he is currently involved with the development of one treatment that combines Paxlovid with next-generation oral drugs. Like Cherry, he emphasized that this process of combination is crucial in curbing the virus’s path of infection. “Not only are you lowering the chance that the virus can mutate, but what you could also be doing and what we’re testing is can you increase the efficacy of both compounds to blunt the disease caused by the virus,” he explained.

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While it’s hard to say exactly whether COVID-19 drugs of the future would induce diarrhea, the hope is that this tinkering will land us with a combination of drugs that offers a more pleasant (and more effective) experience overall. “If we look at HIV or hepatitis C virus, the first generation antivirals were transformative but the antivirals that have been developed subsequently are even better. They’re better for a lot of reasons. You don’t have to take them as often, they have better potency, they have less side effects,” Cherry said. “This is the first generation and they’re quite good, but each of those drugs have some flaws. The plan is to create more and more drugs that have less side effects and are more potent.”

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There’s one key thing about Paxlovid that experts hope is true of next-generation COVID drugs: Ideally, they would still be self-administered. “Having the ability to take a course of a drug in pill form in the comfort of your home provides an advantage to help diminish the burden caused by a highly transmissible viral pathogen like the COVID-19 virus,” Martinez said. In other words, COVID-positive patients wouldn’t be receiving infusions next to women in labor or someone receiving cancer treatment.

But whether or not people can actually get their hands on a drug in the first place will ultimately determine its success. “One of the biggest problems and one of the things that has existed for eternity has been inequality in access to care,” Dr. William Fischer, the director of emerging pathogens at the Institute for Global Health and Infectious Diseases at the University of North Carolina at Chapel Hill, said. “One of the things that COVID-19 did was reexpose the disparity in access to care.”

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Fischer has been involved with clinical trials for antivirals such as molnupiravir (aka the Merck pill) and monoclonal antibodies. Throughout this, he’s noticed how many therapies are only measured by safety and efficacy and not access. He emphasized how access is the most important thing when moving forward with antivirals development.

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“When we’re developing antiviral therapeutics, we have to think beyond the healthy young population,” he explained. “We have to really understand who are the high-risk individuals, prioritize therapeutics to them. It’s really important we don’t leave out groups, the immunocompromised, the pregnant women, and the children. It’s difficult to do clinical trials in those groups because there are always concerns, but we have to make sure they’re included in therapeutic trials.” And hopefully, whatever treatments come out of those COVID-19 drug trials of the future won’t have as bad of a metallic taste.

Correction, June 15, 2022: This piece originally misidentified Katelyn Jetelina as Kathryn Jetelina.

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