Paxlovid rebound update: Your questions answered
Many patients who take Paxlovid are improving and then getting worse. Here's what we've learned so far about who is at risk and who needs to take the drug anyway.
“Covid-19 rebound” or “Paxlovid rebound” can no longer be assumed to be rare. Both President Biden and First Lady Jill Biden have experienced it recently.
Below are answers to Frequently Asked Questions, reflecting my current understanding of where things stand, based on emerging medical research as of late August, 2022. (Some of these are updates of FAQs that appeared in an earlier Inside Medicine on this topic.) The story is still developing, and so some of this may change.
What are “Covid rebound” and “Paxlovid rebound”? Covid rebound is a phenomenon in which people with Covid-19 improve only to get worse a few days later. Paxlovid rebound is when Covid rebound is caused by taking Paxlovid, a drug that helps some Covid-19 patients stave off severe disease and death. Specifically, Covid rebound patients experience near or complete resolution of their symptoms and begin testing negative on rapid antigen tests, often after a few days of treatment (though a smaller number of patients appear to be experiencing rebound without having taken Paxlovid). However, a few days after that, symptoms re-appear (often as bad if not worse than the initial ones) and repeat antigen testing again yields positive results. That means that the patient has gone from being contagious to not contagious back to being contagious again. From what we can tell, rebound does not increase the risk of hospitalization or other bad outcomes.
What is Paxlovid? Paxlovid is an anti-viral medication shown to drastically reduce the rates of progression to severe Covid-19 among high-risk unvaccinated people, in blockbuster data from last year. It does not seem to help younger recipients (note: we don’t know whether that’s true among immune-compromised people).
Who benefits from Paxlovid? Any Covid-19 patient with a pre-existing medical condition placing them at high risk of severe disease who has not been vaccinated should almost certainly take Paxlovid. Among people with prior immunity (either from infection or vaccination), older people appear to benefit, though a lot less, since the rate of hospitalization and death in these people is already so much lower. Meanwhile, a recent observational study did not detect any association between Paxlovid and better outcomes among people ages 40-64, regardless of vaccination status (and they didn’t bother checking any younger).
Does Paxlovid shorten duration of symptoms? No. There has never been data to suggest that.
Does Paxlovid shorten duration of contagiousness? Possibly, among those who do not have rebound. Viral loads did drop faster among Paxlovid recipients, suggesting a shorter contagious period. But rebound now appears common enough to negate that. I know people who have missed important work events because Paxlovid rebound put them back into isolation after thinking they were done with it.
What causes Covid-19 rebound? It’s not actually known that Paxlovid is the cause of rebound. Obviously, many of us have come to believe it is a cause (if not the major one). Alternative explanations include something about the newer variants, something about our existing immunity (i.e., that in exchange for less severe outcomes, the virus manages to make a second stand), or even that nothing has changed but that since many people now have rapid tests, we are just far more able to discover this phenomenon these days.
Is Covid-19 rebound new? I think so, but we don’t know. The possibility that rebound has always been “a thing” is tantalizing, especially given that it emerged after rapid tests became popular, making detection easier. But in Pfizer’s trial, viral loads dropped through day 14. Conversely, when rebound occurs, viral loads spike again. Given just how many seniors (like President and Mrs. Biden) are having rebound now, and many well earlier than day 14, I believe Pfizer would have seen such a signal in their trial, had it been present.
If Paxlovid causes rebound, why wasn’t it detected during the clinical trial? Many possibilities here. First, the clinical trial only included unvaccinated patients. Perhaps something about the combination of vaccination and Paxlovid makes rebound more likely (though, among high risk older people, it’s likely worth the risk of rebound in exchange for fewer severe cases). Second, it could be that starting Paxlovid too soon might be counterproductive. In the original trial, 66% of the participants began taking Paxlovid (or placebo) within 3 days of symptom onset (meaning they’d been infected even longer). Nowadays, with rapid testing, people know about their illnesses sooner. In one small study, all patients who took Paxlovid started taking the drug within 2 days of their diagnosis—diagnoses which are often coming sooner because of rapid tests. Another possibility is that, as above, the availability of rapid tests is merely uncovering something that was there all along. But given what we know, that seems unlikely. At a minimum, we certainly didn’t hear of so many people having a second bout of symptoms in the pre-Paxlovid era. We can’t know whether some people had asymptomatic rebound in the pre-Paxlovid era (yes, Paxlovid rebound can be asymptomatic), but again that didn’t show up in the Pfizer study.
Who is getting Covid-19 rebound? While data are just coming in, small datasets suggest that patients who took Paxlovid are experiencing rebound far more often than those who didn’t. Indeed, some people are getting Covid rebound without having taken the drug, but overall that appears less common (albeit, it seems to be happening at higher rates than observed in the Pfizer trial). Older people seem to experience Covid rebound more often, though it has been seen in younger adults. The data are not granular enough, but combining data with anecdotes, I’d guess that among seniors taking Paxlovid, the rate of rebound may be 50% or higher. (The rate among those currently residing at the White House is 100%.) Given that, I think the rebound rate among younger adults is probably closer to 25%. The rebound risk probably increases with age.
Is Covid-19 rebound contagious? Almost certainly. There are two reasons to think this. First, people who test positive on rapid antigen tests are likely to still be contagious, regardless of when they are in their illness. People with rebound are learning that via rapid tests. Second, a small study documented presumed in-home transmission during a Paxlovid-associated rebound event that could not be otherwise explained. More compellingly, one study found that swabs taken from a patient with Paxlovid rebound had culturable virus, meaning that they were still likely to be contagious.
When does Covid rebound occur and how long does it last? Rebound seems to occur a couple of days to a week after the first negative test, and appears to last several days.
Would longer courses of Paxlovid help? We have no idea. It seems like it could help. But it could backfire. So before we just start giving longer courses, I want to remind everyone of something important….
Paxlovid is teaching us an old lesson: Just because a treatment is warranted in some patients, that does not mean everyone should take it. Yes, there really are downsides to “indication creep.”
At first, the rationale behind prescribing medications proven to work among a subset of patients to all patients has appeal. The reasoning goes that if a drug is effective and safe in one group (say, unvaccinated people at high risk of developing severe Covid-19), the worst that could happen by giving it to another group would be that it was harmless—that is, ineffective, but still safe. Right? Wrong.
If it’s true that Paxlovid has no benefit among immune-competent patients under age 65 (regardless of vaccination status), then offering the drug to them is at best harmless, and at worst, harmful. That means if young patients take Paxlovid unnecessarily, get rebound, miss work or, worse, spread the virus, we’ve done net harm both to them and the community. By the same token, before we start prescribing Paxlovid for longer than the 5-day course that has been studied (as some have suggested, and as even Dr. Fauci did, without any evidence to support it), we should be humble enough to admit that doing so could either reduce the frequency of Paxlovid rebound, or, it could make it worse.
Did you like this? Share it! Better yet, upgrade to Premium and get exclusive articles, audio versions of articles, interviews with big names in medicine and health, and access to the Inside Inside Medicine community on Facebook, where I answer questions and more.
❓💡🗣️ What are your questions? Comments? Join the conversation below.
Follow me on Twitter, Instagram, and on Facebook and help me share accurate frontline medical information!
📬 Subscribe to Inside Medicine here and get updates from the frontline at least twice per week.