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When President Joe Biden was diagnosed with COVID, he started taking an oral treatment of the antiviral Paxlovid almost immediately. Four days after finishing the Paxlovid regime and testing negative, however, Biden once again tested positive for COVID—but without any symptoms of the disease. This is perhaps the highest-profile example of what people are calling “Paxlovid rebound.” Anthony Fauci, the president’s chief medical advisor, also experienced it. This condition has been reported in a minority of people who have received the antiviral and remains an active area of research.

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.

What is Paxlovid?

Paxlovid is an oral, three-pill antiviral regimen taken daily for five days. The drug, made by Pfizer, is prescribed to people who catch COVID and are at risk of severe disease. This can include those who are unvaccinated, elderly or have other medical conditions ranging from diabetes to cancer. Two of the three pills are nirmatrelvir, a drug that targets enzymes specific to the COVID-causing virus and suppresses replication. The third pill is ritonavir, a drug first developed to help treat HIV/AIDS, which boosts the level of the first medication by slowing its breakdown in the body.

“Everything that we’ve done for COVID came out of the HIV playbook, just flat out,” says Davey Smith, the head of infectious diseases and global public health at the University of California, San Diego. That includes “the development of vaccines, the development of treatments, how we did the testing, how we did epidemiology,” he says.

Clinical trials showed Paxlovid was extremely successful at reducing severe disease. In the group that received the drug, it cut COVID hospitalizations and deaths by 89 percent compared to those who received a placebo sugar pill.

To help people gain access to the lifesaving drug, the Biden-Harris administration rolled out a Test to Treat program so that anyone can be tested for COVID and receive Paxlovid in one trip to a pharmacy or treatment center.

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.

Shah says that, right now, it is difficult to nail down exactly how many people may be experiencing a rebound because “you need real documentation of three tests—a positive, a negative, a positive—and clear documentation of symptoms—all symptoms gone, symptoms come back.” This is challenging to do retrospectively because clinics need to have already collected all that information, and it is challenging to do prospectively because patients may not know they have rebounded so are not testing themselves for COVID, or they may not tell anyone they have rebounded.

Barzcak points out that it’s only recently that doctors and researchers have started enrolling Paxlovid users in studies of rebound. “It takes a while to actually enroll people in these prospective studies,” she explains. Once the results of those studies are published, scientists will likely have a better idea of how many people actually experience the phenomenon.

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. “I think it’s very likely that a subset of individuals—probably not everybody, but a subset of individuals with rebound symptoms after Paxlovid—are newly infectious during that time of rebound,” Barczak says. She and her team took nasal samples from seven individuals experiencing rebound symptoms and were able to culture virus from three people, suggesting those individuals could infect others. Despite this study’s tiny sample size, “people need to be aware that they may be infectious,” she says. “If your symptoms come back, think about protecting the people around you, and isolate, mask and test.”

In addition to isolating and masking-up, it is important to tell your doctor that you are, once again, experiencing symptoms of COVID. “People who are in certain types of chemotherapy and [those with] certain immunosuppressed conditions,” Smith says, “really need to talk to the doctor about that,” because they are at the highest risk for severe disease. These are the people Smith usually treats for rebound with a second course of Paxlovid—just as Fauci was. For others, he tells them to stay home and isolate because “there’s no reason to go around and spread it.” Some experts disagree that a second course of Paxlovid is warranted for rebound cases.

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.

As scientists continue to learn more about Paxlovid rebound, all the doctors Scientific American spoke with emphasized that they will continue to prescribe Paxlovid to their patients who need it. “We can still use Paxlovid effectively,” Barczak says. “And we can protect one another by masking and testing and isolating when rebound happens.”

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