Paxlovid in COVID-19 Vaccinated patients

Join us as we explore new trial data examing Paxlovid's effectiveness in high-risk, vaccinated patients.
 
The GameChanger
Significantly high risk patients are still at risk from active Covid-19 infection. A new trial looks at Paxlovid use in high-risk, vaccincated patients.
 
Host
Geoff Wall, PharmD, BCPS, FCCP, BCGP
Professor of Pharmacy Practice, Drake University
Internal Medicine/Critical Care, UnityPoint Health
 
Reference
New England Journal of Medicine Article

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CPE Information
 
Learning Objectives
Upon successful completion of this knowledge-based activity, participants should be able to:
1. Discuss EPIC SR study findings.
2. Describe benefits of Paxlovid for specific patient groups based on trial data.

0.05 CEU/0.5 Hr
UAN: 0107-0000-24-172-H01-P
Initial release date: 05/13/2024
Expiration date: 05/13/2025
Additional CPE details can be found here.

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Transcript

Speaker 1: 0:08

Hey CE Plan members from CE Impact. This is Game Changers. I'm Jen Moulton and today I have with me Jeff Wall. Good morning, dr Wall. How are you today.

Speaker 2: 0:17

Good morning, Good you.

Speaker 1: 0:19

Good good. It's rainy here where I am. We live in the same town, so I know it's raining where you are too, yep.

Speaker 2: 0:26

And I'll talk to everything else. April showers bring May flowers, hopefully I hope so with May starting, so should note to everybody. I am nursing a bit of a cold, so if my voice sounds a little bizarre, that's why you know so.

Speaker 2: 0:37

Yeah, jeff and I just had the conversation about allergy season, so that's always a fun time of year and in a way it may well be that too, just because we were talking that, I think a lot of places are seeing really high pollen counts because especially in many parts of the Midwest you know spring I'm happy about it came a little early this year, so yeah, yeah, hopefully we get it over with and move on to summer Exactly.

Speaker 1: 1:01

Well, I am actually surprised that I'm saying I'm excited about this topic for so long I was so tired of talking about COVID, but I think this is interesting today and I'm going to let you get into it. But it's gotten a lot of press in the lay media and, I think, on some of the social media channels and that sort of thing, and so I'll let you get into it. But we are having a COVID topic again today. Yes, we are.

Speaker 2: 1:35

So, yeah, you know I think we had raised this a couple of weeks ago in our monthly meetings that you know this paper just kind of dropped in the last three weeks in the New England Journal of Medicine and, yes, it generated, you know, a ton of heat in both the lay media but definitely in social media. So if you're on X or Twitter or whatever they're calling it this week, you know Med Twitter was talking about this a lot, I know. On Instagram from what friends of mine are on, and Facebook, there was just a lot of information or a lot of discussion about this. So we thought it'd be pretty timely to kind of bring this to the fore. And this paper, again published in the New England Journal of Medicine, is basically PaxLavid for vaccinated or unvaccinated adult patients with COVID-19.

Speaker 2: 2:17

And essentially it's an extension of the first epic paper that came out. So you know, it seems like a million years ago but then it seems like yesterday that you know we were in the midst of the pandemic and I can tell you and I'm sure many of the listeners know I mean it was the worst 18 months of my life, you know, as far as being a clinician is concerned, and we were very pleased to see the results of that study that showed about an 80% decrease in the development of hospitalization or death due to COVID, and so, you know, very, very happy and very pleased, and of course it went right through the EUA process and was available pretty quickly. Again, you know it seems like so long ago, but you know, if I remember that you know there was a very limited supply and you know the state health department's had it and you had to, literally, you know, if I remember that you know there was a very limited supply and you know the state health departments had it and you had to literally, you know, go get the stuff and it seemed like it was almost, almost under armed guard, to get it to to, to hospitals and stuff. Like I mean, it was just it was nuts, you know. But but that was the first part of the study. Now of course there's been. You know, pfizer did a kind of continuation study in this epic series and then this is the study that kind of came from that.

Speaker 2: 3:29

And so you know, you may say to yourself today well, you know who cares about COVID anymore. Well, you know, for immunocompromised patients, patients with long COVID, and I just think you know, patients who don't want to be super sick for a while, covid is not gone. You know, yes, I am very grateful to say that it has been at least six months, probably more than that, since I've had a super sick patient with COVID in my ICU or on my floor. But that does not mean that COVID has disappeared. And again, I think the specter of long COVID is going to be with us for decades to come.

Speaker 2: 4:02

I was just reading a thing the other day where now they're finding that COVID may actually harbor in megakaryocytes which are kind of the precursors to platelets. So one wonders if people with long COVID were going to be almost approaching like we do with HIV, where HIV is kind of hidden in CD4 cells. Is there a way we're going to be able to attack that in patients? So that's kind of interesting. I think this paper took a look at Paxilidin and again, knowing that Nirmatelavir, of course, is the actual antiviral, and then, of course, to increase levels, we boost it with Ritonavir, which of course is why it has 9 million billion trillion zillion side effect or drug interactions and and and. So you know that. You know it was again being used very, very commonly in patients, but there were still questions, as far as you know. Is this drug beneficial in patients who are vaccinated.

Speaker 2: 4:55

And is this in patients, you know, versus high or low risk, you know? Is it? How beneficial is it? So this was again the the the Epic SR study was a phase two, 3, double-blind randomized placebo-controlled study and patients had to be at least 18 years old in the study and have a positive PCR test or rapid antigen test for SARS-CoV-2 with associated symptoms of COVID-19. Initially their plan was to basically look at high-risk patients and if they were fully vaccinated against COVID-19. I remember at the time of the study, fully vaccinated just meant the primary course, right, so this does not mean boosters or anything along those lines. But after this the drug was approved by the FDA, they significantly amended the protocol because at that point, with the drug approved by the FDA, so I basically we knew that it was beneficial in patients with high risk they kind of altered course in the study and wanted to take a look just in general about PaxLibid patients in both high and low risk patients and whether they were vaccinated or unvaccinated. So I mean a pretty big course change for the study right in the middle of it. And again, you know the reason that they did that is, I mean, why do the study when it's already FDA approved and we know that it. You know, according to the FDA it does work in high risk patients. From the point of the amendment of the protocol, they pretty much stopped enrolling patients at high risk and really only enrolled patients at low risk again, whether they were vaccinated or not, to try and even out the number of patients in the study. And if all that sounds very bizarre, you're right, it does sound very bizarre. They did that, you know. But on the other hand I also say well, you know, even though it was FDA approved, you certainly could have continued the study and got her some more information about that. So, but they did what they did and so the point of the study kind of got altered from high-risk patients who were unvaccinated or vaccinated to basically anybody who you know, low-risk or high-risk patients who are vaccinated or unvaccinated, you know low risk or high risk patients who are vaccinated or unvaccinated, either way.

Speaker 2: 7:07

After a screening period, patients who had a positive PCR, had symptoms, were then randomized in a one-to-one ratio to receive either five days of Paxlovid or placebo. And you know, randomization was kind of done, you know, at a central location. As with most of these other studies, the patient's got an electronic daily diary to record symptoms and the severity of symptoms. And, like most of these studies, the primary objective of the trial was to compare the efficacy as far as time to sustain alleviation of all COVID-19 signs and symptoms through day 28. So the primary outcome was not something gigantic. It was basically, you know, were your symptoms relieved, you know, faster and more completely with Paxilid compared to placebo? Now, an important secondary endpoint was, in fact, covid-19 related hospitalization or death from any cause through day 28. And they also looked at number of medical visits, a number of days in the hospital, et cetera, et cetera.

Speaker 2: 8:04

And they also looked at viral loads in patients who received Paxilid and were viral loads low. Now again, that was a secondary endpoint, and remember that after they enrolled a whole bunch of patients who were at low risk, one wonders whether that study would have had the power to show a difference. The study would have had the power to show a difference Since these were low-risk patients. Many of them never did get hospitalized or were in high risk of hospitalization when they have found that difference.

Speaker 2: 8:30

But in any event for the primary outcome, the alleviation of symptoms. They wanted to enroll 1,140 patients to ensure that 800 patients would finish the study and would provide 90% power to show a 25% difference in the time to sustained alleviation of target symptoms. So basically, you know eight days versus six days of you know of the totals what they were looking for basically.

Speaker 2: 8:55

Primary endpoint then, you know, was not the serious endpoint, but again, not a bad endpoint. And certainly we use Tamiflu for, you know, everybody who has the flu and has a sniffle. That's basically all it's ever really been looked at from an FDA approval standpoint. We give Tamiflu very commonly to patients who are sick enough to be in the hospital. You know there's some retrospective stuff but there's very little prospect of randomized studies looking at Tamiflu in influenza patients who are super sick. So you know, I'm not sure I would really, you know, call Pfizer to task for that.

Speaker 2: 9:31

But the other thing that has garnered a lot of information in social media and a lot, I think, criticism of Pfizer is that it's worth noting that this study was actually completed in 2022. So it actually started in 2021 and was completed in 2022. And here we are in the middle of almost middle of 2024. And this study was just published.

Speaker 2: 9:48

So there's been a lot of commentaries and pundits in the area who have accused Pfizer of, you know, withholding the publication of this study. You know not submitting it for publication primarily because you know because once the drug was FDA approved, patients were not getting Paxilid for free and, as any community pharmacist will tell you, paxilid has now become incredibly expensive, on the order of about $1,000 for a treatment course, and while a lot of insurances will pay for it, they end up giving co-insurances to their patients, which may be 10% or 20%, which then may be $100 or $200, and a lot of patients just simply can't afford that. So you know some pundits have argued. You know that this was kind of a cash grab, that Pfizer knew for a long, long time that it was. You know the results of the study and decided to basically withhold a submission for publication.

Speaker 2: 10:44

You know I'm not going to lie to you. You know I understand that feeling and certainly the track record of several pharmaceutical companies for doing. You know, having shenanigans going on that basically allowed them to continue. You know to make a significant profit off a drug, particularly before a drug drops off the patent cliff, and you know every pharmacist will tell you kind of the joke is you can always tell when a drug's about ready to go off patent, because they come up with an extended release version of it, or they get a new indication and a new name for it, or they combine it with some other medication, right? Those are all kind of tricks that are done that often are of dubious clinical utility.

Speaker 1: 11:24

So you know, I get that feeling.

Speaker 2: 11:26

I get the feeling that drug companies have not always had the best reputation when it comes to that.

Speaker 2: 11:32

I honestly am not sure about that with Pfizer, though you know I don't, I don't, I'm not ready to accuse Pfizer of what would be a pretty, you know, serious, I think, ethical breach by not getting this data out. I wonder, you know, if there was some sort of delay in getting and collecting all the data or things along those lines. So you know, again, I understand the controversy surrounding it, perhaps after COVID and you know I'm a little bit less likely to put my tinfoil hat on and kind of accuse everybody of conspiracy theories, because I spent about 18 months trying to debunk every other conspiracy theory about COVID but at this point in time I'm certainly willing to give Pfizer kind of the benefit of the doubt to say you know, look, there probably was some stuff going on behind the scenes that delayed publication of this trial. So but you know, certainly if you're going to be on social media you're going to hear a lot of that and read a lot about it.

Speaker 2: 12:29

So in the end the study had 1,298 participants who underwent randomization and were the full analysis with 654 patients receiving Paxavit and 634 receiving placebo, and the subgroup analyses were fairly similar.

Speaker 2: 12:46

Taking a look at the baseline characteristics, it was a pretty even split between males and females and the median age was 41. Again, keeping in mind that after a protocol amendment they started enrolling low risk patients, many of whom were younger, the majority were white, the majority were in the United States and Europe. Bmi in the study was only 25. So again, we know that obesity increases the risk of severe COVID, especially super morbid obesity. About half of the patients in the study was only 25. So again, you know, we know that obesity increases the risk of severe COVID, especially super morbid obesity. About half of the patients in the study did receive a full primary series of vaccinations, so about 370 patients in the Paxivic group compared to about 364 in the placebo group. So we had at least half of those patients you know who were vaccinated. To kind of take a look at that data. Most patients had mild to moderate severity because, remember, most of these patients were non-hospitalized, most of them did not require oxygen, et cetera et cetera.

Speaker 2: 13:40

And when they were all done with the study, about half and half were considered regular risk versus high risk, because again, remember that that's what they were trying to do when it was all said and done. It is worth noting that in the high risk patients almost nobody, very, very few patients were considered immunosuppressed. So transplant patients, cancer patients, you know other immunosuppressed states, and a very small percent of patients were very elderly. So keep that in mind as we take a look at the results, because the results basically showed no difference in the primary endpoint. So there was actually no statistically significant difference in the primary endpoint between patients who received Paxlovid and placebo. So no real difference in alleviation of symptoms, no difference in severity of symptoms at day 28. And that was true whether patients were vaccinated or unvaccinated. So whether you're vaccinated or unvaccinated didn't seem to have much of a role in alleviating symptoms.

Speaker 2: 14:35

Then they looked at the secondary endpoint again COVID-related 19 hospitalizations or death from any cause, and again they found again very similar data that in fact there was no statistically significant difference in patients who were low or high risk and whether they were vaccinated or unvaccinated. So it didn't seem like risk or vaccine status in patients who received Paxavit in the study was associated with the risk of COVID-19 hospitalization or death. Adrs were primarily bad taste which anyone who's taken Paxavit will complain about. They did try to exclude patients in the study who are at high risk of drug interactions but I don't think they didn't really comment on that and my guess is, knowing that the multitude of drug interactions with Paxlovid, they probably weren't able to completely do that in studies. But bottom line is that when the study was all said and done there was no significant difference in patients who had standard risk or high risk for severe COVID-19 and vaccine or unvaccinated status.

Speaker 2: 15:38

There was no difference in Paxlovid helping at all. So there was no difference in alleviating symptoms or there was no difference in patients who were hospitalized or died from COVID. Now it is worth noting that there's been several concerns with the study. The first is remember that COVID is and was kind of a rapidly changing infectious disease and this was done during 2021 and 2022. So again, these were mostly early variants, right, and they note in the paper that this was kind of the tail end of the alpha variant and then moving into the delta variant, and so you know currently the spread.

Speaker 2: 16:16

The variants that are currently spreading, at least in the United States, don't seem to be very virulent, and I think it's one of the reasons why we haven't seen a big spike in hospitalizations or death in the last six months to a year, but it's worth noting that that also may have something to do with the fact that we now a significant part of the population who has been vaccinated, who has had boosters and or may have had COVID already.

Speaker 2: 16:39

Right, and so is it possible, now that we've reached a point where where most patients have enough antibodies on board that they're unlikely to get severe disease? Also, will the next variant of COVID and again, covid isn't going to disappear right? Will the next variant of COVID be more severe and will Paxlovid be beneficial in those patients? Also, the other piece that a lot of experts have commented on is again the fact that very, very few patients were very elderly and almost nobody was immunocompromised, whether they were vaccinated or not, and so I think many experts are saying I would not apply this data to those patients, especially severely immunocompromised patients, who are probably at the highest risk of going on to develop a severe COVID-19, regardless of previous vaccination or infection status. So you know, if you're taking care of patients and especially if they're on immunosuppressive drugs, have cancer that may have suppressed the immune system, have some other disease state that may significantly suppress the immune system, I'm not sure I would use this data to withhold Paxlovid in those patients elderly, especially the very elderly with multiple other comorbidities, particularly severe obesity or lung disease. I would probably not. I'm not sure I would really apply this data to them, but in patients you know who have standard risk or even maybe slightly high risk patients if they've been vaccinated, in particular for this current variant, right so, just because they got vaccinated three years ago. I'm not sure you can change that to this data. But if someone is COVID positive and or they've received, you know, because we're probably going to go with yearly boosters at this point, especially if they've received their yearly booster, I think I would kind of approach this now how I kind of approach the flu, which is, if you received your flu vaccine and you have kind of mild to moderate systems symptoms and are not at high risk, you probably don't need a thousand dollars worth of Paxlovid, you know. But if you're at high risk, I think that it becomes more of a risk benefit assessment.

Speaker 2: 18:46

Taking a look at their drug interactions and stuff, and I'm sure most pharmacists are well aware of this. But even now, years after the fact, I still keep the Liverpool COVID-19 drug interaction website bookmarked on my computer. It is kind of the one-stop shop when you're assessing interactions and at one time I think I was using it almost every day, multiple times a day. Now today it's a little bit less than that obviously, but it is something that you can still use. So I guess, again, this is a lot of heat generated by this paper and I think it, you know, again this is a lot of heat generated by this paper and I think it does give us some good information that I think we may be heading in toward a similar situation to Tamiflu and influenza, that in most patients at standard risk, especially if they've been vaccinated, they probably don't need Tamiflu. But at high risk patients, especially, you know, compromised patients, I think, I think Paxlovid is still probably a reasonable intervention.

Speaker 2: 19:41

So that's where we're at Jen.

Speaker 1: 19:43

Yeah, it's. You know, again can't believe we're still talking about this, but you know, I think, as I was listening to you talk, I you know I think this was such a good, this was a good topic to address, because I have seen it a lot, and I think there's two themes you touched on both of them One, that COVID is still constantly changing, so we know that, with influenza changes every year, and so that vaccine has to change every year, and I think that's starting to happen with COVID. And the other thing, though, is mistrust and I think that we saw so much of that, as things were constantly changing and people's mistrust of public health and what people were saying. And now there's this article that you bring up, and, right or wrong, it's out two years later than when the data was available. So I think those are two things that, as, as pharmacists, we hear a lot, and you know what's the response to that.

Speaker 2: 20:40

I mean, I think certainly social media has allowed I mean for lack of a better term, you know, anti-vaxxers to basically crawl out of the woodwork and really amplify their voices. I mean I'm seeing people not wanting to get tetanus shots when they come in because they were, you know they. They got cut or hurt themselves, you know, and it's like you know, well, I don't really need this. When was the last time you ever saw, you know, tetanus? And you know I'm like you know you've got to be kidding me here. You know, and so I mean I think I think we certainly when it comes to a lot of this stuff, it's like, you know we're talking, we're talking about vaccines that have been proven safe and effective for 50 plus years. Now is probably not the time to start questioning those.

Speaker 2: 21:26

You know, and you know, admittedly, you know, I think, I think that you know public health professionals probably fumbled the ball somewhat on, you know, saying people on point with communications and information, with, with, uh, with, uh, with the pandemic, but you know, I think they did the best they could with what they had and you know this. You know it was the first major, you know, pandemic in over a century and you know it. I think I think there was a lot of unknown information. I think you know the last major, if you don't count the, the pandemic, the flu pandemic of 1958. You know, if you talk, if you're going to kind of go back to the pandemic of, of the so-called spanish flu or influenza, right at the tail end of world war one, you know there was still a lot of misinformation. The difference was that information was published in a local newspaper, not, you know, on on a platform where the whole world could see it.

Speaker 2: 22:15

You know, and I think that that's one of the differences, one of the things that I think public health experts and infectious disease experts are really worried about is you know what happens, you know when the next pandemic comes around. And I don't know if you've been doing any reading, but there's a lot of concern about the H1N1 flu variant that you know for the first time looks like it's, it's, it's. We've actually, for the first time, had reports of human to human transmission which we had not seen previously, and that there's been deaths reported because of it. And you know, you know, some estimates suggest that there would be somewhere.

Speaker 2: 22:50

If this were to be a major pandemic, there'd be somewhere between a 10 and 20% mortality rate associated with it. And you know for reference, the mortality rate for COVID and what the disruption was to our health system was only about two to 3%. And so you know, I mean you know, yeah, one could only imagine what would happen if that were to become a major pandemic. Now, the good news about that is that we already have vaccines, right, we already have vaccines against H1N1. It would theoretically be pretty simple to tweak those vaccines and get them to people. But again, as you point out now in 2024, what a lot of people say nah, you're gonna do that. You know, and I don't know what's gonna happen there, so yeah, you know there's definitely some concern there.

Speaker 1: 23:38

Yeah Well, and we'll have to address that topic.

Speaker 2: 23:42

On all honesty, I hope we never have to address that. Yeah right, Right. Well, but preparedness.

Speaker 1: 23:48

I mean I think that was one of the things with COVID. You know, we weren't prepared. I mean it really kind of came out of nowhere and we you say like not in our lifetime. So I think we weren't prepared. And now we are a little more prepared. So hopefully with a vaccine and knowing what to expect, that's better. But again that mistrust is frightening a little bit and I think we're seeing it play out with measles.

Speaker 1: 24:10

I mean we have a resurgence of that and I know we've talked about that on the podcast. Actually, right before we got on I got an email that Caitlin Gedalina, who is your local epidemiologist.

Speaker 2: 24:27

Oh yeah.

Speaker 1: 24:27

Great. She's one of the top times 100 most influential people in health.

Speaker 1: 24:33

And I was actually going to mention her anyway, as I was prepping for this, so it was ironic that that she wants that. That came out today. But you know she is one that if you want to stay ahead on public health, you know she's super reputable, she's looking at the evidence, she's putting it into terms that we can all understand, which I think was a mistake that public health made. You know they weren't forward-facing for the public and so she served that role during COVID. She actually kind of like started doing this during COVID and now she's talking about lots of public health issues. But I would highly recommend people follow her, if you know, if you really want to stay up to date on some of these public health concerns. And you know she addresses things like this COVID study and you know, just really looking at the data and why maybe it came out, you know, two years later and all that.

Speaker 1: 25:24

So anyway, I just put a plug in for her because she's a really reputable source. We actually had her on the podcast one time during COVID, but your local epidemiologist YLE, and you can look at her on Substack or Google or whatever, so she's great.

Speaker 2: 25:40

Cool. Yep, I agree.

Speaker 1: 25:41

Yeah, I have to stay on top of it. Okay Well, thank you so much Again. Can't believe we're talking about COVID, but I think it was a really good topic and it's a lot that's out there, and so we need to really understand the data, and you always go through that so well, so I appreciate it.

Speaker 1: 25:59

That's it for this week. So if you are a CE plan member, be sure to claim your CE credit for this episode by logging in at CEimpactcom and, as always, have a great week and keep learning. We will talk to you next week.