by WWith COVID-19 infections becoming more common, experts have recently urged doctors to prescribe the antiviral drug Paxlovid more than they should in order to minimize patients’ symptoms and reduce their chances of developing serious disease. The drug is authorized for people at higher risk of developing severe COVID-19, including those who are older and people with underlying health conditions. But many patients taking Paxlovid have reported rebound infections shortly afterward: testing positive again for the virus after the infection initially cleared and testing negative. Studies have documented that the repeat positive tests were 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 physicians about the possibility of rebound infections; The agency continues to recommend the drug for those who are at high risk of the disease of COVID-19, but warned doctors to be aware of the rebound because people could be contagious when their infection returned.
The so-called “Paxlovid rebound” has raised questions about how common rebound infections are, with and without Paxlovid. Pfizer, the manufacturer of Paxlovid, found in its own study of the drug that rebound occurs in about 1.7% of Paxlovid patients, which is slightly lower than what they found in the placebo group without treatment. Larger studies have not yet established how often rebound occurs in people who are infected and untreated. But a new study published in the Annals of Internal Medicine sheds some light on the issue, reporting how likely infections are to rebound without taking an antiviral.
“When I heard reports of people telling me they were getting better (on Paxlovid) and then getting worse again, I always wondered if this happens during the natural recovery period of a COVID infection -19,” says Dr. Jonathan. Li, associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital and author of the study. “Only by understanding what happens in untreated infections can we interpret the data we’re getting from patients receiving Paxlovid.”
In the trial — which was part of a larger network of trials testing different antiviral treatments for people with mild-to-moderate COVID-19 — Li tracked the symptoms and viral levels, measured by weekly nasal swabs, of about 560 people died. placebo during their infection. Everyone was swabbed at the beginning of the study and at two, three, and four weeks later. They also kept a daily log of symptoms, including fever, headache, and cough.
About 26% of these untreated people reported that symptoms returned about 11 days after they started, and 31% had higher virus levels after their initial drop. Overall, 3% of people reported a return of symptoms and a higher viral load during the month-long study period. (All cases indicate re-infection.)
“These results tell us that symptom improvement is not a linear process but, in fact, occurs over time,” says Li. “It’s also very rare to have a high-level viral rebound. Even without Paxlovid…patients will have symptomatic rebound, and may have viral rebound as well. We have to be careful when we say that Paxlovid will cause a significant recurrent side effect, when we don’t know yet.”
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Various studies and anecdotal data have found that relapse rates are significantly different between Paxlovid users and untreated individuals. Anecdotal reports, for example, suggest a much higher rate of rebound among people taking Paxlovid than the Pfizer study. But differences between all of this research, including the viral load threshold the researchers set to record virus levels, could account for the differences. One advantage of the current study, says Li, is that the patients were swabbed every week – but the small number of positive rebound samples also means that it is difficult to draw any definitive conclusions about the frequency of rebound.
So how should the results be interpreted?
Li says it’s important to remember why people take Paxlovid. “The reason we recommend Paxlovid is not to prevent recurrence (of infections) but to prevent hospitalization and death,” he says. “When I counsel my patients, I tell them that the clinical trial (reviewed by the US Food and Drug Administration to authorize Paxlovid) showed 90% protection from hospitalization and death despite any viral rebound after treatment. We have to keep our eyes on the prize.” Scientists are also looking at whether Paxlovid can help reduce Long’s risk of COVID, although that research is still early and no conclusions can be reached yet.
Rebound infections are not unusual with viruses, and researchers are learning more about why this particular virus bounces back after shedding and how widespread reinfections are. One possibility, related to how Paxlovid works, is that the recommended five days of pills may not be enough to prevent the virus properly, so it comes back when the medication stops. Another theory is that as an immune system response, the virus may be moving to different parts of the body and finding new cells to infect, causing virus levels to rise and symptoms to return. “We need more rigorous data looking at those who take Paxlovid and those who don’t, to better understand what’s going on,” says Li.
Deciding who might benefit from Paxlovid should come after a thorough discussion between the doctor and the patient, says Li. “I advise patients based on their overall risk,” he says. “Risk factors such as age do not give dichotomous ‘yes-no’ answers; it’s a continuous spectrum.”
Data from their study should help inform these discussions, to better balance the risks and benefits of treatment for individual patients. More studies are also needed to clarify the recurrence cycle, since people who test positive again after testing negative can spread the virus to others.
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