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Paxlovid Rebound: When COVID Symptoms Return After Pills Are Gone

Health experts say the benefits of the drug far outweigh the risk of recurring mild symptoms

Man with allergy or an infection sneezing
Robert Kneschke / EyeEm / Getty Images

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.

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

Returning COVID 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, though it’s important to note that this can also happen to people with COVID-19 who don’t get treated with Paxlovid, says Steven Lawrence, M.D., a professor of medicine in the Division of Infectious Diseases at Washington University School of Medicine in St. Louis, Missouri. In fact, 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. ​​

It’s also unclear how often rebound occurs after treatment for COVID-19. Some research suggests it happens in about 3 to 5 percent of people who take Paxlovid or molnupiravir, another oral antiviral treatment for COVID.

The good news: When rebound does happen, it tends to be “very mild,” Lawrence says. 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, 2022, advisory.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.

And given that Paxlovid can significantly slash one’s odds of severe illness, Lawrence says the short-lived rebound phenomena “doesn't in any way take away anything at all about the importance and the effectiveness of the drug.” 

Why does Paxlovid rebound happen?

If you experience rebound after taking Paxlovid, it does not mean the treatment has failed, says William Garneau, M.D., assistant professor of medicine at Johns Hopkins Medicine. There’s also no evidence to suggest that recurring symptoms means the virus has grown resistant to the medication.   

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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. 

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 & Drug Administration (FDA). 

Returning COVID symptoms call for isolation, masks

If you experience COVID rebound, whether it’s due to Paxlovid or not, you’ll need to take precautions. 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 about isolation guidelines. 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. The CDC advises individuals to wear a mask for 10 days from the start of their rebound symptoms.

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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.” (Need more tests? Households in the U.S. can order four free at-home tests from the federal government at COVID.gov/tests.) 

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 may want to do rechecks 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 will “sour” on Paxlovid and opt not to take 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.

Rebound is “an interesting phenomenon that may occur,” Lawrence says. “But it [doesn’t] take away from the potential lifesaving impact of the drugs.”  

Editor's Note: This article, originally published May 25, 2022, has been updated to reflect new information.