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In this video, Michael Mina, MD, PhD, formerly an epidemiologist at Harvard and now chief science officer of eMed, discusses the cause of viral rebound with ritonavir/nirmatrelvir (Paxlovid), what it could mean for the evolution of COVID, and how to advise patients.

The following is a transcript of his remarks:

So there's been a major concern around Paxlovid rebound.

What is happening when people have a rebound of virus after they take Paxlovid is we're seeing as people will get infected, they'll get on treatment, which is very good that we have these effective treatments available today. But then what we're seeing is after people come off the treatment – after their 5 day course is over – they might become negative on tests, but clearly the virus hasn't completely diminished. And after a couple of days, they rebound. They get detectable virus on both PCR and oftentimes antigen tests. And many people are actually now getting symptomatic with disease that looks a lot like an initial COVID infection.

So what we're seeing is that, while the treatment is clearly serving to protect the individual while they're on the treatment, it might need to be extended to actually ensure that the body has cleared all of the virus before coming off of the treatment.

Should we be concerned about resistance occurring from rebound? Absolutely. I think that it is a major concern. Paxlovid is one of the most important tools that we've had in this pandemic since the beginning of the pandemic. We want to do everything we can to not encourage, from an evolutionary perspective, resistance to occur.

But we know, from basic evolutionary principles and what we know of drug resistance in the past, is that whenever you let up on a drug before the pathogen is totally cleared, that sort of creates this sweet spot where now the virus is growing up and there's still a little bit of the drug left and they get to interact. That just helps facilitate the potential advantage of a random mutation that does allow escape and resistance from this treatment to sort of flourish in that short amount of time when the drug is coming off and the virus is growing back up.

So that does create a sort of breeding ground for resistance or to improve the probability that a resistance mutation will occur. That's the last thing we want here. We absolutely do not want resistance to occur against Paxlovid.

This is why I think there is a massively urgent need to understand what's the rate of this. Is this all social media buzz, or is this really occurring? And I think it is. I feel very confident that it's really occurring at a higher rate. We don't know if it's certain populations. We don't know if there's a way to predict it after somebody comes off Paxlovid.

Should we be testing people with a rapid test at home on the last day of Paxlovid? And if they're still positive, should we keep them on a further course? But we also know that people become negative, fully negative, and then rebound back to positive. So they go below the threshold of detection on the test.

All of these questions are absolutely critical for us to start to understand today and to really start focusing on. We need to run the clinical trials. It's something that we are starting to do here at eMed with our test-to-treat program at home. We're actually able to take the individuals who are on Paxlovid and send them additional tests so that they can test themselves when they come off of Paxlovid, and we can start monitoring that incidence.

So we have to be studying this. It should be a priority of the CDC and the FDA right now, as well as the NIH, to really get to the bottom of how often is it [occurring] and what is the frequency in certain demographics, in different populations.

What I would like people to recognize is that this is not a failure of Paxlovid. It might be that we need to just change the duration, but we know that Paxlovid is saving lives today. We know it is a highly, highly effective treatment. So people shouldn't look at this as a negative of Paxlovid, they should recognize that this is a fast-moving pandemic. When new treatments come along, we have to tighten up what the appropriate regimen and duration of treatment is.

So I think that we should really be able to take this information and say, "Look, it's a good thing that we have testing out in people's homes so that we can actually recognize that this is occurring." And we should use all of these tools to be able to monitor this process, to start giving physicians the appropriate recommendations.

Right now, what I would recommend for the average person or the average patient is to say, if you're putting your patient on Paxlovid, encourage them to test again once they come off. Encourage them to look to see if they have rebound so that they can act appropriately afterwards, if it does occur.

Ideally, it's not the majority, not even close to the majority. But we don't want people to get off Paxlovid, have sky high viral loads, and just assume that they are totally cured and can go hug grandma.

We really want to encourage people to continue being safe in this pandemic. And part of that is to test yourself after you're done with your course of treatment. And you know, unfortunately, if you're still positive, then talk to your physician or talk to your patient if they come to you and try to work out with them what the best course of action is for them.

If they're not symptomatic, maybe they continue isolating. If they are symptomatic, maybe you put them on another course or monoclonals. But at the moment, it's going to be kind of a patient-by-patient decision making process.

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