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Paxlovid Rebound: When COVID Symptoms Return After Pills Are Gone

Health experts are puzzled why some people get well, then feel sick again, after antiviral treatment ends

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Robert Kneschke / EyeEm

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Some COVID-19 patients who take Paxlovid to dodge the dangers of a severe infection are finding themselves in a puzzling situation: Days after they finish the drug and feel better, their symptoms return — and sometimes so does the double line indicating a positive result on an at-home coronavirus test. 

Experts stress that this phenomenon, known as “Paxlovid rebound,” is not an indication that the antiviral pills are ineffective. “Paxlovid is still working to keep you out of the hospital, and that’s what it was designed to do,” says William Schaffner, M.D., a professor of preventive medicine and infectious diseases at Vanderbilt University School of Medicine. Clinical trials found that the prescription medication lowers the risk of hospitalization and death from COVID-19 by nearly 90 percent.

Still, with thousands of Americans prescribed Paxlovid each day, there are a few things to know about the drug’s rebound effect.   

Returning symptoms tend to be mild

It’s unclear why some people who take Paxlovid get better, only to have COVID-19 symptoms (and sometimes a positive test) recur a few days later. Most of the data are anecdotal, but Ashish Jha, M.D., COVID-19 response coordinator for the White House, says that post-Paxlovid relapse is something health officials are “looking at very carefully.”​​

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The good news: Patients who report a return of symptoms “are not getting particularly sick and are not ending up in the hospital,” Jha said during a recent briefing.

What’s more, symptoms tend to clear in an average of three days without additional treatment, the Centers for Disease Control and Prevention (CDC) said in a May 24 advisory.

“It tends to be a relatively mild and short-lived phenomenon,” Schaffner confirms.

Reinfection or the development of resistance to the drug doesn’t appear to be the cause. One theory is that a five-day course of Paxlovid successfully lowers the amount of virus in the body, like it’s designed to do, but may not remove it all. Meanwhile, the immune system takes a back seat while the antiviral treatment leads the charge, and when the Paxlovid stops, “the virus has a chance to kind of resurrect itself,” explains Robert Wachter, M.D., professor and chair of the department of medicine at the University of California, San Francisco (UCSF).

Researchers are looking into whether extending the course of the drug — say, to 10 days, instead of five — might solve the issue. But right now, there’s no evidence that doing so will be beneficial, according to John Farley, M.D., director of the Office of Infectious Diseases at the U.S. Food and Drug Administration (FDA).

A brief return of COVID-19 symptoms could also “be part of the natural history” of a coronavirus infection in some people, “independent of treatment with Paxlovid and regardless of vaccination status,” the CDC said in its advisory. Rebound turned up in about 1 to 2 percent of participants in Paxlovid’s clinical trials, both in people who received the placebo and those who took the treatment.

Experts are hoping to get a better grasp on how often this phenomenon occurs and who may be at greatest risk for relapse, especially now that Paxlovid is more widely available.

Jha estimates that about 20,000 Americans are prescribed the at-home treatment every day. If just 2 percent of that population experiences a return of symptoms, consistent with the trial, “that would mean 400 people are having rebound every day,” Jha pointed out. Wachter, who chronicled his wife’s journey with Paxlovid rebound on Twitter, predicts that the share is even higher among real-world patients.

Officials are exploring whether variants play a role in the newly reported rebound cases, since Paxlovid was tested when the delta strain was dominant. “And so the question is: Is this more common with omicron?” Jha said, referencing the highly contagious variant that’s currently circulating. “We’re actually doing a lot of work right now to try to sort that out. We’re talking to health systems, getting real-world-experience data.”   

Returning symptoms call for isolation, masks

Rebound not only has the potential to “prolong the period of, to some extent, feeling crummy” for those who get hit with symptoms a second time, Wachter points out, but it also extends the duration that they need to take precautions around others. The reason being, if you test positive on a rapid at-home test, you’re capable of transmitting the virus to others.

“Unfortunately, [you have to] restart the clock,” Wachter says. The CDC advises that people with returning COVID-19 symptoms or a new positive test after having tested negative isolate again for at least five days.

And don’t forget your mask when you need to be around others. “We’ve always said in our CDC recommendations that if you have symptoms, you should put your mask on,” CDC Director Rochelle Walensky, M.D., said in a recent briefing. The agency advises individuals to wear a mask for 10 days from the start of their rebound symptoms.

It’s also possible to experience rebound without symptoms — or with symptoms minor enough to overlook — which is why Wachter says “the safest strategy” after finishing a course of Paxlovid, especially if you live or work with vulnerable people, is to continue at-home testing for about another week after you first turn negative. You don’t need to stay in isolation that whole time, he says, “but if you turn positive, you are infectious and you should go back into isolation.”

And it’s a good idea to check in with your doctor if you relapse, Schaffner suggests, especially if you are immunocompromised or have multiple underlying conditions that put you at higher risk for complications from COVID-19. There is currently no evidence that additional treatment with Paxlovid or other anti-SARS-CoV-2 therapies is needed in cases where COVID-19 rebound is suspected, the CDC says, but your health care provider might want to keep checking in to make sure the infection clears.

While we wait for answers to this latest pandemic head-scratcher, Wachter says the “biggest risk” is that people are going to “sour” on Paxlovid and opt not to take it. “But I’d say from where I am today … getting on an antiviral quickly that lowers the chances of a bad outcome is an important part of our armamentarium [medical arsenal], and I’d hate to lose it.”  

The FDA says the reports of post-Paxlovid relapse do not change the conclusions from the drug’s clinical trial, which showed a “marked reduction in hospitalization and death.” Since the start of the pandemic, the vast majority of COVID-19 hospitalizations and deaths, of which there have been more than 1 million, have been among adults 50 and older.

Similarly, the CDC continues to recommend Paxlovid for early-stage treatment of mild to moderate COVID-19 among people at high risk for progression to severe disease. 

Rachel Nania writes about health care and health policy for AARP. Previously, she was a reporter and editor for WTOP Radio in Washington, D.C. A recipient of a Gracie Award and a regional Edward R. Murrow Award, she also participated in a dementia fellowship with the National Press Foundation.​​