Opinion | Are the Right People Taking Paxlovid?

In this video, Jeremy Faust, MD, editor-in-chief of MedPage Today, outlines several clinical trials on nirmatrelvir-ritonavir (Paxlovid) that tell us how effective the drug is and who it can help the most.

The following is a transcript of his remarks:

Let’s talk about Paxlovid or nirmatrelvir. This is Pfizer’s blockbuster pill for COVID-19. Back in late 2021, we got data showing that in high-risk, non-hospitalized, unvaccinated patients, that this drug Paxlovid was very effective in reducing hospitalizations or death.

But the story has really changed, and I kind of want to walk through a little bit of a chronology of the evidence as we know it, because the real question is: who needs this drug?

If you have a risk factor for developing severe COVID-19 and you’re vaccinated, are you still considered high-risk? Well, the CDC and the FDA certainly think so, because in their guidance on Paxlovid they say that people with severe COVID-19 risk should take Paxlovid. They don’t modify that by saying, “Well, if they’re vaccinated, that really changes the whole story.”

We did get some data from Israel, and also a study from here in the United States, observational data looking at a large dataset, looking at Paxlovid use and how it went among the vaccinated and the unvaccinated. They showed very convincingly with a very, very large data set, that for people who were 65 years or older Paxlovid did help them even if they were vaccinated.

Now, if you look at the numbers that you would need to treat to prevent one hospitalization in that immune cohort, it’s far, far less favorable for the drug. But at the end of the day, the downsides seem pretty minimal.

So, I think there’s pretty good consensus that people who are 65 and older, and maybe even younger than that, 50 or 60-plus, might be benefiting even if vaccinated.

Interestingly, this study also gave us a readout on outcomes among patients who were 40 to 64 years old to see if Paxlovid was helping those folks with and without immunity. It’s very, very clear that for the younger populations, there simply was not a detectable benefit. So, regardless of whether you’re vaccinated or not, [for those] under 64 years of age, this observational data set really seemed to suggest that Paxlovid was not necessary.

What I think is actually quite interesting in that data set, and I want to highlight this — if you were a person, regardless of age, who actually had existing immunity, so you’d been infected or vaccinated before, if you were going to be hospitalized despite all that, it was because you had a history of hospitalization for any reason in recent times. I think that’s very, very powerful information to say that if a patient is sick enough that they’re getting hospitalized for any old reason in the past few months, whether it’s diabetes or malignancy or heart disease, that that risk pool seems to be where Paxlovid is helping the most in the vaccinated cohort.

So I think overall that paper really showed us that there probably is an age cutoff.

But what about symptoms? There seems to be a lot of leaping towards [thinking], “Oh, well it must help symptoms. It must help symptoms because it lowers viral loads.” Now, of course, that’s not necessarily true. Lowering a viral load does not necessarily equate with symptom control. In fact, a lot of symptoms are related to our own immune system, and so a viral load might not even be related to that.

But I think that the most telling piece of information we have on symptom control with Paxlovid is Pfizer’s data itself. The EPIC-HR study, the blockbuster study that showed Paxlovid’s great effect in preventing hospitalizations and deaths, was tracking symptom relief, but it wasn’t reported in the trial. I just wonder why Pfizer would not have told us about this.

Additionally, Pfizer had another study going called EPIC-SR (standard risk), which was primarily aimed at checking self-reported sustained alleviation of all symptoms based on whether or not patients had Paxlovid or not. That trial was halted. It was ended. They stopped recruiting because they knew they had missed the endpoint. They had not met the endpoint they wanted. They did not detect any self-reported sustained alleviation of COVID symptoms in their patients with standard risks who took Paxlovid.

Now, the question is: what’s the harm? Why not just take Paxlovid if it helps people who are unvaccinated, if it helps high-risk people? Well the downside, I think, would be two things to really think about.

First of all is stewardship, right? Any time we are prescribing an antimicrobial, there could be resistance. We don’t want to cause resistance because of overprescribing. So far there hasn’t been an issue, at least not that we’ve been detecting, but I think it’s an important thing to follow.

The second thing is that there’s this phenomenon called “rebound” — “COVID rebound” or “Paxlovid rebound.” Early in the disease you’re contagious or symptomatic, and then you get better. Your symptoms get better and you’re actually not contagious anymore. Then the viral loads come back and you’re symptomatic and contagious again. That’s a problem.

We don’t know how much of this is caused by Paxlovid or how much of this is happening just without Paxlovid, and there’s a real debate about this. So, let’s talk about that real quickly.

Back in the original EPIC-HR study that Pfizer presented in the New England Journal of Medicine the rate of rebound was quite low — 1% or 2% — and it really wasn’t different whether you got placebo or Paxlovid. So they said, “Look, this is not really a thing that’s happening because of Paxlovid.”

But since that trial, a lot of things have changed. The thing we notice is that rebound is far higher than 2% in all patients with COVID-19. That’s concerning that something has changed.

So if Paxlovid is responsible for that, which I think a lot of people think it might be, then what you’re doing is you’re not improving symptoms early on and then the patients can go back to normal; you’re having a short term-improvement — maybe — that’s then balanced out by this rebound, this period where you get worse again, and even scarier, when you think you’re in the clear and are no longer isolating but are contagious again.

There are data sets, small studies, that have confirmed that that’s absolutely happening. The patients who had rebound clearly spread it during the rebound phase, and that was confirmed with genetics. So, this rebound phenomenon is not benign from a population health perspective.

At the moment, I just don’t think that there’s an indication for Paxlovid for people without severe risks, and especially in an immune cohort. We don’t really see a huge benefit, especially with younger patients. But we don’t know. So we’re going to watch this space.

If you have questions on this drug or if you have experiences with it, please share it.

Thank you for joining us here on MedPage Today.