Some people are experiencing 'Paxlovid rebound' after taking the COVID antiviral pill. Here's what you should know.

Paxlovid pill box with three pills printed with PFE and R9 resting on it.
Paxlovid is Pfizer's antiviral medication to treat COVID-19. (Reuters/Wolfgang Rattay/Illustration)
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When the antiviral medication Paxlovid was approved in 2021 to treat COVID-19, doctors began noticing a perplexing trend among some of the patients who took it: a rebound case of the virus. After treatment, some people would recover and test negative for the virus, only to test positive or have symptoms come back a few days later. “Paxlovid rebound,” as it’s known, received a lot of media attention when President Biden and first lady Jill Biden, as well as Drs. Anthony Fauci and Rochelle Walensky, director of the Centers for Disease Control and Prevention, all experienced it last year after taking the medication.

Scientists are not sure why this rebound effect occurs after taking Paxlovid, but here are a few things we do know.

What is Paxlovid? How does it work?

Paxlovid is an oral antiviral pill that can be prescribed to people who come down with COVID-19 and are at risk for developing severe disease. This can be individuals who are unvaccinated, the elderly or people with other medical conditions, such as cancer or diabetes. The drug, developed by Pfizer, can protect these high-risk patients from needing hospitalization. Those who are vaccinated but are at risk for severe outcomes of COVID-19 can also benefit from taking Paxlovid.

U.S. regulators granted emergency use authorization for Paxlovid in December 2021. Today the drug is available by prescription only, from a physician or pharmacist. Anyone 12 and older who weighs at least 88 pounds and is at high risk for severe disease is eligible for the medication. Patients with severe kidney disease — or who are on dialysis — or people with severe liver disease, however, should not take it. The drug can also interact with other medications such as those that treat high cholesterol, high blood pressure and migraines, so patients taking these drugs should avoid taking Paxlovid.

Like many antivirals, Paxlovid works best when taken early in the course of illness. The CDC recommends that treatment begin within the first five days of experiencing symptoms. Once a person is prescribed the medication, they will take three Paxlovid pills twice a day for five days, for a full course that adds up to 30 pills.

The antiviral therapy consists of a combination of two oral antiviral drugs — nirmatrelvir and ritonavir — which work together to stop the viral replication process. By reducing a person’s viral load, the medication lessens the severity of their symptoms.

In clinical trials, which were conducted when the Delta variant was predominant, Paxlovid was found to reduce the risk of hospitalization or death by 89% in high-risk people. Since its approval, many clinical studies that have been conducted around the world have also confirmed its high level of protection against hospitalization and death.

With Omicron being a highly immune-evasive variant that has rendered many antibody treatments ineffective, vaccine experts worried that Paxlovid would lose its effectiveness too. Fortunately, that doesn’t seem to be the case. According to recent research, the drug continues to offer significant protection against hospitalization and death and can also offer a substantial benefit even to vaccinated patients diagnosed with COVID-19.

Other studies, however, have found no evidence of Paxlovid benefiting people younger than 65.

“I don’t think we need to push Paxlovid in every 20-year-old who comes down with COVID or 35-year-old who’s healthy,” Dr. Bruce Farber, chief of public health and epidemiology at Northwell Health, the largest health care system in New York state, told Yahoo News. “But in those who are at high risk, those who are elderly, who have not been vaccinated, those who have comorbidities, those who are immunosuppressed, [for] those people [it] can make a significant difference.”

In addition to keeping high-risk patients from getting very sick, Paxlovid can reduce the risk of symptoms of long COVID, a November study conducted by the Department of Veterans Affairs found.

What is Paxlovid rebound?

The CDC defines Paxlovid rebound as occurring when, after completing the full five-day course of treatment, a person either experiences a reemergence of symptoms or tests positive after having tested negative for COVID-19. According to the CDC, this rebound effect tends to occur between two and eight days after initial recovery. But experiencing a rebound, the agency said, doesn’t mean a person was resistant to Paxlovid, nor does it mean they were reinfected with the virus. Additionally, the CDC has said Paxlovid rebound cases are typically mild and resolve within a few days, and there’s no evidence that additional treatments are needed for these patients.

Despite Paxlovid’s efficacy even in the setting of Omicron, the medication is being underutilized in the U.S. and other parts of the world. According to a report by the London-based health analytics firm Airfinity, U.S. physicians have prescribed the drug in only about 13% of new COVID-19 cases. Experts have said concern about potential Paxlovid rebound may be one of the reasons this is happening.

Farber said that another reason Paxlovid is being underutilized has to do with the virus itself. “This virus is much less virulent even though it’s more contagious,” he said, adding that the need for Paxlovid “became less.”

Scientists are still studying why the rebound effect occurs when taking Paxlovid, as well as who is more likely to experience it. However, recent research has found that rebound can also happen to people who develop COVID-19 and don’t take Paxlovid. Studies are underway to understand why this happens, Farber said.

“More recent data suggests that rebound also occurs in people who recover from COVID who have not gotten Paxlovid, and it occurs at probably similar rates, whether you take Paxlovid or not,” Farber said, adding that rebound cases after the drug has been taken were initially thought to occur in roughly 5% of cases but that research has shown it may happen more often than initially thought. “More recent articles say it may be as common as 10 or 15% of cases,” he said.

What to do if you experience Paxlovid rebound

If someone’s symptoms return or they test positive after Paxlovid treatment, the CDC advises following its isolation guidance and quarantining again for five days. Isolation can end after this period if a person is fever-free for 24 hours without the use of fever-reducing medications. The agency also recommends wearing a mask for 10 days after rebound symptoms start.

The CDC encourages doctors and patients to report Paxlovid rebound cases to Pfizer’s portal for adverse events associated with the drug.

Finally, Farber said that Paxlovid rebound is still fairly uncommon and that it shouldn’t deter people and their doctors from using the lifesaving medication when needed.

“In theory, it could prolong their isolation. But I think [people] should realize that this can occur even without Paxlovid. So it becomes really not an important distinguisher of whether they get it or not,” he said.