What is Paxlovid rebound?

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Scientific American spoke with infectious disease experts about what the phenomenon is, how common it might be, and what people should do if they get it.
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What is Paxlovid rebound?

The CDC defines Paxlovid rebound as when a patient who, after receiving a full five-day course of treatment, either has a reemergence of COVID symptoms or tests positive after a previous, negative test. Under this classification, when you rebound, “you can have virus without symptoms, symptoms without virus, and you can have the two together,” Smith says. He adds that he’s slightly annoyed by the blanket classification of “rebound” because in virology, a “rebound” is when there is a reemergence of measurable amounts of virus.

The Pfizer clinical trial reported between 1 and 2 percent of those who received the drug tested positive for COVID after finishing the Paxlovid course; their illness rebounded. Those rebounds were not statistically different from rebounds experienced by people with COVID who received the placebo, however.

“From a research definition, the reemergence of symptoms with a positive test is ‘symptomatic [Paxlovid] rebound,’” says Amy Barczak, an infectious disease doctor at Massachusetts General Hospital and COVID researcher. “A positive test and the absence of symptoms—which nobody is looking for—that would be ‘asymptomatic Paxlovid rebound.’” The latter is what Biden has, and was detected because he was testing daily.

Adi Shah, an infectious disease specialist at the Mayo Clinic in Minnesota, explains that another complicating factor he considers in patients is differentiating between a true rebound of symptoms and just a very slow improvement in symptoms after starting Paxlovid. Clinically, this is a vital distinction because it can change how people are deciding to isolate. These differences also have ramifications for research; to accurately say how many people experience Paxlovid rebound, it needs to be correctly identified.

It’s important to remember that “if your patient needs it, the drug works, even in the setting of some people [having] rebound,” Smith says. “The clinical trials were very clear that this was a great drug to keep people out of hospital and from dying. So don’t be scared of the rebound.”

Who is experiencing Paxlovid rebound, and how common is it?

“In our [work], being of an elderly age and then having other risk factors—like diabetes, heart disease, kidney disease, or some sort of cancer—does put you at a higher risk of rebound,” says Shah. Many of these are the same as the risk factors for severe COVID.

Unfortunately, as previously noted, it’s difficult to know exactly how frequently Paxlovid rebound occurs because “rebound” needs to be uniformly defined first. Barczak explains that if rebound is sometimes classified as only a reoccurrence of symptoms and other times classified as having multiple negative tests followed by multiple positive tests, this could change the percentage of people thought to be experiencing the phenomenon. Regardless, she still estimates rebound associated with reemergence of the virus to be higher than what was reported in the original Pfizer clinical trials. “What we say is, somewhere between 2 and 10 percent [of people taking Paxlovid experience rebound],” she says. “I think it’s probably somewhere in that range, but I don’t [know] precisely.”

In a recently published retrospective review of Mayo Clinic patients, Shah found that about 1 percent of Paxlovid users rebounded, which is consistent with the Pfizer clinical trial. But based on discussions he has since had with patients and other physicians, “I think the actual rate might be high as high as 5 to 10 percent,” he says.
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What should you do if you have Paxlovid rebound?

“I want to emphasize that the good thing is, even if you have rebound, outcomes are good,” Shah says. In general, “you’re not needing additional COVID therapies, you’re not needing hospitalization, and you’re not experiencing high mortality or morbidity.”

However, it is still important to isolate after a rebound…
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In addition to isolating and masking-up, it is important to tell your doctor that you are, once again, experiencing symptoms of COVID…
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What causes Paxlovid rebound?

Rebound may occur because some patients are not receiving high enough doses of nirmatrelvir, the part of Paxlovid that targets COVID enzymes. That dose already needs to be boosted in the body, which is why ritonavir is part of the treatment regime. Smith’s own research found that rebound was not a result of the virus becoming resistant to the drug. He hypothesizes that people in the “real world” might decide to skip a dose because Paxlovid can make food taste bad. Or those who rebound may be part of the minority of people who don’t experience the right rate of drug release with the combination of nirmatrelvir and ritonavir. Either way, experiencing a lower dose could lead to pockets of virus surviving through the treatment and then reemerging days later. Smith thinks that ongoing research really needs to focus on the idea that some patients may not be exposed to the correct dosage of Paxlovid.

ABOUT THE AUTHOR(S)

Fionna M. D. Samuels was a 2022 AAAS Mass Media Fellow at Scientific American. She’s pursuing a Ph.D. in chemistry at Colorado State University. Follow her on Twitter @Fairy__Hedgehog

Recent Articles by Fionna M. D. Samuels

https://www.scientificamerican.com/article/what-is-paxlovid-rebound-and-how-common-is-it/

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