Paxlovid’s Mysteries

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Lizzie O’Leary: Yeah. Oh, jeez. Hi, it’s Lizzie. This is a little audio I recorded of myself on Monday, June 27th when I had COVID. At that point, I’d been sick for two weeks, and because I have an autoimmune disease, I went on the antiviral drug Paxlovid. Just after I tested positive. Here’s some more tape. I felt probably significantly better after being on it for probably. Probably three days. Four days.

Lizzie O’Leary: When I took a test. A home test. I was still positive but only had a very faint line. And then that when I went off the Paxlovid the five day course. I started feeling sicker again. And my fever, which has never been high, came back just a little bit. And then I started testing strongly positive.

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Lizzie O’Leary: That is how I sound when I call. I’m going to be fine. But this is. It’s been a bit of a roller coaster. Again, I’m fine, I’m vaccinated, I’m boosted. I have access to great medical care. But I recorded this audio because what happened to me is now something of a hot topic among people who’ve taken Paxlovid.

Speaker 2: So it sounds like you had a pretty standard case of what folks have been calling either COVID rebound or Paxlovid rebound.

Lizzie O’Leary: That’s Rachel Gutmann way. She’s been writing about Paxlovid for The Atlantic.

Speaker 2: Which is when after taking the full five day course of the drug, people start feeling poorly again, testing positive after a certain number of days.

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Lizzie O’Leary: It happened to me and it happened to Anthony Fauci, who took Paxlovid tested negative and then tested positive again.

Speaker 3: And then over the next day or so, I started to feel really poorly, much worse than in the first go around.

Lizzie O’Leary: The rebounds don’t seem to be landing people in the hospital or leading to death, but they’re not fun. And more importantly, they have public health implications because people who thought they weren’t contagious anymore actually might be.

Speaker 2: It was one particular case study of a 67 year old who, during a rebound that I don’t know if he realized she had at the time gave COVID to his grandson.

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Lizzie O’Leary: Yeah, but what we don’t really know yet is what’s driving these rebounds and how common they truly are. Why do you think this feels like such a. Zeitgeisty question right now.

Speaker 2: Oh, gosh. I mean, it’s sort of like a microcosm of wanting to be done with COVID, right? Like we thought we’re done with COVID so many times when there was the first big vaccine rollout in end of 2020, early 2021, we kind of thought we were done or that it was possible that we could be done. The whole world will get vaccinated, herd immunity, yadda yadda, sunshine and roses. And that kind of feels similar to having COVID, getting this drug that’s supposed to make you better, sort of thinking you’re in the clear and then just, you know, it’s all undone and you feel like you’re back to square one. It’s sort of like the hamster wheel of the pandemic in miniature.

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Lizzie O’Leary: Today on the show, Unraveling the mysteries of Paxlovid. Is it really a miracle drug? I’m Lizzie O’Leary and you’re listening to What Next TBD show about technology, power, how the future will be determined. Stick with us. In December of 2021, the Food and Drug Administration granted Pfizer an emergency use authorization for Paxlovid. The U.S. government placed an order for millions of courses of treatment pretty quickly. The drug was met with resounding praise.

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Speaker 2: It was called a monster breakthrough, miraculous, the biggest advance in the pandemic since the vaccines.

Speaker 4: These pills are going to dramatically decrease decrease hospitalizations and deaths from COVID 19. They’re a game changer.

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Lizzie O’Leary: And what garnered the headlines and praise were some pretty amazing numbers from Pfizer’s clinical trial about how well the drug works to keep people out of the hospital and keep them from dying.

Speaker 2: So there were two main sort of sections of the clinical trial. Number one was in unvaccinated people who had some kind of risk factor for severe COVID. That’s the high risk group. So the high risk portion in unvaccinated people found an 89% reduction in risk of hospitalization and death. It was great.

Lizzie O’Leary: That’s stunning.

Speaker 2: It’s fantastic. It’s really, really important that that population can be protected because they’re at the highest risk of going to the hospital, having severe complications, possibly dying from COVID. And, you know, there are still 300 people or so dying a day from COVID. And presumably some of them are not vaccinated and have, you know, these sort of risk factors. So protecting them is super important.

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Lizzie O’Leary: But there was another part of the trial, what’s called the standard risk trial that was made up of people who were either vaccinated and had a risk factor or were unvaccinated but had a standard risk.

Speaker 2: It was sort of a different story in the standard risk trial. So that’s people who are vaccinated, but it excluded anybody who had received a vaccine in the last 12 months. Which is interesting because a lot of vaccinated people got their vaccines in the last 12 months, and this particular requirement was updated around April, which would have been about 12 months after most people were getting their first and second doses. And if you had a booster between now and then, you’re also excluded. So it’s still only a portion of vaccinated people and also those people who are unvaccinated but don’t have risk factors.

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Speaker 2: They didn’t really find any significant effects of the drug on preventing hospitalization, ICU admissions or death. They found trends pointing in the right way, but they weren’t statistically significant. They also didn’t find any benefit in terms of having symptoms for a shorter amount of time of elevation, any of that. So it’s not as clear from the standard risk data what exactly Paxlovid has to offer for vaccinated people.

Lizzie O’Leary: How much data exists on a vaccinated person or a vaccinated and boosted person taking Paxlovid and what kind of efficacy the drug has for them.

Speaker 2: It was an Israeli study about a month and a half ago that looked at both vaccinated and unvaccinated people, and it was crucially done during the criteria. So another important thing about the high risk trial is that it was conducted pretty much completely in the Delta era. Hmm. So some of the difference, you know, the daylight between the amazing results in the high risk trial and the not as great results of the standard risk trial could also have something to do with the variance. But this Israeli study basically found that people over 65, whether they’re vaccinated or not, got a ton of benefit from Paxlovid and people under 65 got virtually none, regardless of their vaccination status.

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Lizzie O’Leary: Now that we are in this scenario where people can get it and get it for free because the U.S. government has purchased a lot. Who is supposed to be prescribed Paxlovid right now? I think that is a little bit confusing to people.

Speaker 2: Yeah, and it’s confusing to doctors, too. There was an announcement that pharmacists can prescribe it too, so that there are even more people who can prescribe it and still not have clarity about who exactly it’s supposed to be going to. And the emergency use authorization from the FDA is fairly broad. It’s basically if you’re over 12 and you have COVID and it’s been five days or fewer since your symptoms started. And you have a risk factor. Then you can have it. And I mean the risk factor. Worse language has been pretty broad since the beginning of COVID for lots of good reasons. In order to get people vaccines when they needed it, in order to get them all sorts of other resources. But at the same time, you could have a perfectly healthy 15 year old with mild asthma. Be eligible for Paxlovid.

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Lizzie O’Leary: How widespread is its use?

Speaker 2: Since it was authorized in December. And as of June 26, which is the most recent HHS data that’s available, more than 1.8 million Americans have taken it. So it’s a lot.

Lizzie O’Leary: Well, Paxlovid clearly has benefits. There are still a lot of unknowns about it, including why it can cause a weird side effect known as Paxlovid mouth.

Speaker 2: People have described it as bitter, sour, metallic. One person described it to me, like if you mixed grape juice and soap together, that it tastes like grapefruit. It doesn’t sound good. Pfizer said that that was happening in five or 6% of people. But almost everybody I spoke to for the article about Paxlovid said, no way. It’s happening to way, way, way more people. And I spoke to a couple of dozen people just in my reporting on Paxlovid, and every single one had Paxlovid. Now.

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Lizzie O’Leary: Then there is the issue of rebound. I think it might be helpful to define what we’re talking about when we say rebound. How would you describe it?

Speaker 2: I would say that rebound is if you have taken Paxlovid, you’ve finished your course, your symptoms have abated. You test negative. And then within a few days you get a reversal. So you test positive again, your symptoms come back.

Lizzie O’Leary: That feels pretty similar to what happened to me. Although I never tested negative, I only had, like, a tiny little faint line.

Speaker 2: Right.

Lizzie O’Leary: Rebound feels like a significant thing to talk about, though, because it makes me wonder whether there’s any data on if the treatment is extending the course of the infectious period or if you had this moment where you tested negative and you started socializing or you felt, I’m in the clear and then you go out and and infect people. It feels like a very thorny question, not just for individuals, but for public health.

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Speaker 2: Absolutely. And that’s what you were talking about, the scenario in which people think they’re in the clear and then go out and infect other people is one of the reasons why it’s really important to find out exactly how widespread Paxlovid rebound is. I mean, if it’s really only happening in a few percent of people, then maybe it is okay to tell people, you know what, if you finish your course, it’s been ten days since the start of your symptoms. You’re free. But, you know, if ten or 20% of people are getting rebound, we might want to issue different guidance.

Lizzie O’Leary: Pfizer has said that it’s seen a rebound rate of about 2% of patients who take Paxlovid. But as the drug is more widely adopted, patient experiences seem like they might tell a different story.

Speaker 2: I mean, part of the problem with the Pfizer data is that all we have is a number. All we have is 2%. And we don’t really know where they got that number from. They haven’t released the data behind it, at least not that I have seen. And the Mayo Clinic study that found that it was closer to 1% was in 483 people, which was a lot of people, but maybe not enough to really suss out the incidence when this is being given to close to 2 million people at this point. People I spoke to said that this would be the kind of thing that it would be good to study within a hospital system. So to just track everybody that a particular system prescribes Paxlovid to and then see what happens. And there are certainly people who are doing that, but there just haven’t been results yet.

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Lizzie O’Leary: When we come back, what are the stakes for society if Paxlovid isn’t as good as we thought?

Lizzie O’Leary: There was something in your story that really stuck out to me, and I feel like it highlighted why this is so important. Because you wrote that an individual patient would never know really if Paxlovid worked for them, because you can’t know how sick you would have gotten if you didn’t take it. But there’s this idea that if the drug doesn’t do that much for vaccinated people. They’re giving it out and spending, you know, the country’s money on it might be a waste of our dwindling resources. And it makes me wonder, how do we know? If we’re spending our money and energy well as a country in kind of the arsenal of our tools to fight COVID.

Speaker 2: This is a question that goes way beyond Paxlovid. It’s something that we’ve been struggling with, basically the whole pandemic, America’s tendency to sort of focus on one thing and run with it. And so we could say that we’re in an era of, you know, Paxlovid is a thing now. We’ve tried vaccines. We’ve given up on masks. We’ve given up on vaccine mandates. We vaccinated some people. Let’s just relax a little bit and everybody put all their eggs in that basket. And as far as exactly how much money we should be spending on it or whether it’s a waste, I think that’s more of a public health slash political judgment call.

Speaker 2: You know, if we had unlimited funding, then giving people Paxlovid when it’s not necessarily doing a ton for them might not be that much of an issue. But when it’s taking up half of the funding that Congress has been able to agree on, then that’s a stickier issue. And it’s really an open question whether that funding could be better spent doing further vaccine outreach, which has still been shown to connect with some holdouts and get them vaccination, or whether that could be better spent upgrading ventilation in schools and public buildings. There are lots of other things that money could be spent on and Paxlovid isn’t necessarily an inherently bad investment for the country to make.

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Lizzie O’Leary: What else don’t we know about Paxlovid and what do you want to know? I mean, when I went on it, I was struck by the fact that there’s basically no data on breastfeeding. And I’m at the end of breastfeeding my child and, you know, my doctor saying, well, you probably should and but there’s no real data. Check with your pediatrician and pediatricians like I don’t know. I was shocked by how little information there is.

Speaker 2: I would say that’s a huge, outstanding question. One of the biggest ones for me is whether Paxlovid has any effect on long COVID. Hmm. So there are some folks who have one COVID who have been pushing for research about whether Paxlovid can actually alleviate long COVID if you already have it. And then the other question is, does taking Paxlovid while you have COVID prevents you from getting long COVID afterward? That’s a really important question. I think especially as a lot of the country has sort of adopted this posture of, you know, everyone’s going to get it. Consequences are what they are. The consequences are a little bit different if, you know, a significant portion of the country is going to have these long term effects that impact their life.

Lizzie O’Leary: But of course, all of this takes a long time to study, especially when it comes to tracking long COVID and what kind of treatments might be helpful.

Speaker 2: These are effects that last months and apparently years. And so you would really want to follow up with people over months and years. So we’re not going to have answers on that for a while. And if you get COVID today and you’re somebody who has maybe a risk factor, but you’re young, you’re not super worried. Like nobody can tell you whether Paxlovid would decrease your chances of getting long COVID, which, I mean, for me, I am not immunocompromised. I am young. COVID does not scare me that much. Personally, I’m vaccinated. Like I know that I’m very unlikely to end up in the hospital or die from COVID.

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Speaker 2: But the thing that scares me most personally right now is, well, we don’t really know who’s getting COVID, and it could be me. And so if I. We’re faced with, you know, oh, well, we don’t know if Paxlovid could possibly maybe prevent this outcome that possibly maybe could happen to you. I don’t know what I would do about that.

Lizzie O’Leary: Zooming out a little bit. I wonder a lot about kind of. If this is just how it has to be with drugs and treatments that are developed in the middle of a public health emergency. And I want to be careful not to say that there are safety risks here or anything like that. But but just that we are in this real time data collection event in which we are all data points.

Speaker 2: We’ve all been guinea pigs since the beginning of the pandemic. There are a lot of ways that we’re being guinea pigs right now. There are sort of particularities of. The FDA’s authorization process and drug development in the U.S. that make it different from other countries. And it could be different. In the details. But sort of the balance between certainty and speed in drug development. I don’t really know that there is a way around that. I think that’s sort of a law of nature.

Lizzie O’Leary: What do you think happens now? Is there going to be a souped up Paxlovid? Will there be some other wonder drug? I mean, I keep wondering what our toolbox is going to look like from a national and international perspective. Or whether, as you mentioned before, we’re too focused on individual tools and have lost the ability to zoom out and think this doesn’t need to be an either or but an and kind of question.

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Speaker 2: As far as the future of Paxlovid itself, one of the interesting things that we’ll want to see is that Pfizer and the NIH are collaborating on a study of whether extending the dose time would help prevent some of those rebounds. So one of the theories behind why people might be rebounding, if it is in fact related to Paxlovid, is that they’re just not taking the drug for long enough. And so, you know, if it turns out that an eight day course means that virtually nobody is rebounding, then that changes the calculus again. And that, you know, in this hypothetical future, then maybe prescribing Paxlovid becomes an easier decision for doctors and pharmacists to make. That’s one possible future.

Speaker 2: Another possible future is nothing changes about the drugs, doctors and patients continuing or continue having these conversations. And some doctors decide to do it. Some doctors decide not to, depending on various risk factors, and it becomes a tool that is available to individuals, some of whom use it and some of them don’t.

Speaker 2: As far as broader implications. Paxlovid is something you give to people after they have already gotten COVID. And there’s a whole world of things that we as a country, we as a global community could be doing to prevent that very first step, which is preventing people from getting COVID.

Speaker 2: So things like. Smarter approaches to masking smarter and perhaps more enforced approaches to ventilation upgrades. Testing requirements, improved access to testing, improved speed of testing, improved accuracy of testing. All these things could help stop chains of transmission and prevent people from even needing Paxlovid, and it would still be great to have it available if somebody did in fact get infected. But certainly it seems like it could do more good as part of a wider ecosystem of care.

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Lizzie O’Leary: Rachel Gutman Way, thank you so much for your reporting and for coming on the show.

Speaker 2: Thank you so much for having me, Lizzie.

Lizzie O’Leary: Rachel Gutman Wei is a senior associate editor at The Atlantic. All right. That is it for the show today. What next? TBD is produced by Evan Campbell. Our show is edited by Tory Bosh. Joanne Levine is the executive producer for What next? Alicia montgomery is vice president of Audio for Slate. TBD is part of the larger what next family, and it’s also part of Future Tense, a partnership of Slate, Arizona State University and New America. We will be back next week with more episodes. I’m Lizzie O’Leary. Thanks for listening.