WWith COVID-19 infections becoming more common, experts recently urged Doctors are prescribing the antiviral drug Paxlovid more than they ever have to minimize patients’ symptoms and reduce the chance they will develop serious illness. The drug is licensed for people at higher risk of developing severe COVID-19, including older people and people with underlying health conditions. But many patients taking Paxlovid have reported developing rebound infections soon after: they tested positive for the virus again after they supposedly cleared the infection and tested negative. Studies have documented that repeat positive tests are due to the same virus that caused the original infection to return, rather than a new infection. In 2022, the US Centers for Disease Control and Prevention. advised doctors about the potential for rebound infections; the agency continues to recommend the drug for those at high risk of severe illness from COVID-19, but warned doctors to watch for rebound, as people could be contagious when the infection returns.
The so-called “Paxlovid rebound” has raised questions about how common rebound infections are, with and without Paxlovid. Pfizer, maker of Paxlovid, found in its own study of the drug, rebound occurs in approximately 1.7% of Paxlovid patients, which is slightly lower than what they found in the untreated placebo group. Larger studies have not yet established how often rebound occurs in infected and untreated people. but a new study published in the Annals of Internal Medicine It sheds some light on the question, informing about the probability of rebound infections without taking an antiviral.
“When I heard reports of people telling me that they were improving [on Paxlovid] and then it got worse again, I always wondered if this happens during the natural recovery period from COVID-19 infection,” says Dr. Jonathan Li, associate professor of medicine at Harvard Medical School and Brigham Hospital. and Women’s and author of the study. “Only by understanding what happens in untreated infections can we interpret the data we get from patients receiving Paxlovid.”
In the trial, which was part of a larger network of trials testing various antiviral treatments for people with mild to moderate COVID-19, Li tracked symptoms and viral levels, measured with weekly nasal swabs, of about 560 people who received a placebo during the course of their infection. All samples were taken at the beginning of the study and two, three and four weeks later. They also kept a daily record of symptoms, which included fever, headaches, and cough.
About 26% of these untreated people reported that their symptoms returned about 11 days after their onset, and 31% had higher levels of the virus after initially subsiding. Overall, 3% of people reported a return of symptoms and a higher viral load during the one-month study period. (All scenarios indicate a rebound of the infection.)
“These results tell us that symptom improvement is not a linear process, but in fact waxes and wanes over End-shutdown,” Li says. “It is also very rarely associated with a high-level viral rebound. Even without Paxlovid… patients will have a rebound of symptoms and also a potentially viral rebound. We have to be careful saying that Paxlovid will cause a significant rebound side effect, when we don’t know it yet.”
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Several studies and anecdotal data have found vastly different rebound rates between Paxlovid users and untreated people. Anecdotal reports, for example, suggest a much higher rebound rate among people taking Paxlovid than the Pfizer study. But variations across all of this research, including the viral load threshold the researchers set to record virus levels, could explain the differences. One advantage of the current study, Li says, is that patients were sampled weekly, but the small number of positive rebound samples also means it’s hard to draw definitive conclusions about the incidence of rebound.
So how should the results be interpreted?
Li says the most important thing is to remember why people take Paxlovid. “The reason we recommend Paxlovid is not to prevent rebound [infections] but to prevent hospitalization and death,” he says. “When I advise my patients, I tell them that the clinical trial [that the U.S. Food and Drug Administration reviewed to authorize Paxlovid] showed 90% protection against hospitalization and death despite any viral rebound after treatment. We need to keep our eyes on the prize.” Scientists are also investigating whether Paxlovid can help reduce the risk of long-term COVID, although that research is still early and no conclusions can be drawn yet.
Rebound infections are not unusual with viruses, and researchers are learning more about why this particular virus bounces back after waning and how widespread repeat infections are. One possibility, related to the way Paxlovid works, is that the recommended five days of pills are not enough to adequately suppress the virus, so it returns when the drug is stopped. Another theory is that, in response to the immune system, the virus may be moving to different parts of the body and finding new cells to infect, causing surges in virus levels and a return of symptoms. “We need more intensive data looking at both those taking Paxlovid and those not taking it, to better understand what’s going on,” says Li.
Deciding who might benefit from Paxlovid should come after a detailed discussion between doctor and patient, Li says. “I counsel patients based on their overall risk,” she says. “Risk factors such as age do not lead to dichotomous ‘yes or no’ answers; It’s a continuous spectrum.”
The data from your study should help those discussions to better balance the risks and benefits of treatment for individual patients. Further studies are also needed to clarify the rebound cycle, since people who test positive again after testing negative can still transmit the virus to others.
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