Covid-19 rebound is probably more common than data suggests, but Paxlovid is still effective

As the coronavirus evolves, the number of treatment options that remain effective against new variants has dwindled. Pfizer’s antiviral pill Paxlovid is one of the few that remain.

However, some people who take Paxlovid — and some who don’t — experience a rebound case of Covid-19, with a resurgence of symptoms or positive tests just days after completing treatment and testing negative.

And recent high-profile rebound cases, including President Joe Biden, Dr. Anthony Fauci and first lady Jill Biden, are raising questions about just how frequently this happens.

“From the data we have so far, Covid-19 rebound is a relatively infrequent event — this is not happening the majority of the time,” a spokesperson from the US Centers for Disease Control and Prevention told CNN. “A small percentage of people with Covid-19 experience a rebound of symptoms, including those who take antiviral medication, such as Paxlovid.”

Experts say that rebound cases are probably more common than data suggests, but it’s difficult to know by exactly how much.

There’s a wide range of estimates for what that “small percentage” might be — from less than 1% of people who take Paxlovid to more than 10% — and definitions of a rebound case are lacking consistency.

And a “brief return of symptoms may be part of the natural history of SARS-CoV-2 (the virus that causes COVID-19) infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status,” according to a health advisory issued by the CDC.

It’s important to get a better handle on the specifics for both individual patients and the broader community, says Dr. Michael Charness, of the Veterans Administration Medical Center in Boston, who has collaborated with a team of researchers at Columbia University to look into cases of Covid-19 that return after Paxlovid treatment.

People experiencing a rebound case can be contagious, so they should be aware of the possibility that they might need to reisolate in line with CDC guidance, he said. And for others, the return of symptoms or a positive test can “certainly be a source of concern for many people, wondering ‘Why is this happening to me?'”

Tracking Covid-19 rebound

In clinical trial documents submitted to the US Food and Drug Administration last year, Pfizer noted that “several subjects appeared to have a rebound in SARS-CoV-2 RNA levels.” Their data shows that about 2% of people showed present or persistent viral load rebound, a share that was similar among both those treated with Paxlovid and the placebo group that wasn’t.

Pfizer does not have additional data on rebound cases beyond the clinical trials, which were conducted during a time when the Delta variant was dominant and the majority of people were unvaccinated.

A preprint study that tracked rebound cases during the Omicron wave found that 2 to 4% of patients experienced a rebound infection or symptoms within a week after treatment, and 5 to 6% had a rebound within a month.

A separate study published in June by researchers from the Mayo Clinic broadly aligned with Pfizer’s clinical trial data. The researchers found that about 1% of patients treated with Paxlovid experienced a rebound of symptoms, an average of about nine days after treatment. The study was retrospective and could not determine whether the patients tested positive along with the return of symptoms.

But according to Aditya Shah, an infectious disease specialist and an author of the report, the true rate is probably closer to 10%.

“You have to acknowledge the limitations of doing this kind of study. All these patients are home, and not every patient who has rebounded symptoms is going to contact their doctor,” Shah said. “So our study definitely had an under representation of true cases.”

Charness also estimates that the Covid-19 rebound rate for vaccinated people who have taken Paxlovid is in a similar range, but uncertainty remains.

“There has not been a study that gives us a clear answer. It’s probably not 50%, and it’s probably not 2%,” he said. “I wouldn’t be surprised if it’s in that 5 to 10% range for people who are treated in the 1 to 2% range in people who are untreated.”

According to the CDC, preliminary data suggests that people with comorbidities may be more likely to experience a rebound case. However, studies to examine risk factors are “ongoing” and “there is no conclusive evidence at this time and more research is needed” they said.

‘Rebound is going to be an inconvenience’

Despite the potential for a rebound case, experts agree that Paxlovid is still a good treatment option.

If a rebound case of Covid-19 is one cost of taking Paxlovid, but it must be weighed against the costs of what could happen with no treatment, Charness said.

The vast majority of people who have a rebound case of Covid-19 after taking Paxlovid have been found to have mild symptoms. Sometimes they may come back stronger, as in Fauci’s case, but they remain far from the levels of severe disease that Paxlovid is meant to protect from.

“I think that, especially for people who are at significant risk for progression, it’s important to take Paxlovid,” he said. “A percentage of those people — yet to be determined — are going to have rebound. But in almost all of those people, the rebound is going to be an inconvenience. And that inconvenience, really, is not as important as the potential of avoiding hospitalization or death.”

Both President Biden and Fauci received a second course of Paxlovid to treat their rebound cases. And just this week, the FDA requested more data from Pfizer to study patients who may need a second course of treatment.

“While further evaluation is needed, we continue to monitor data from our ongoing clinical studies and post-authorization safety surveillance,” Pfizer said in a statement. “We remain very confident in its clinical effectiveness at preventing severe outcomes from COVID-19 in patients at increased risk.”

Overall, public data on Paxlovid prescriptions is scarce. According to the US Department of Health and Human Services, about 4 million courses of Paxlovid have been administered as of mid-August, but there are no additional details about the demographics or health status of those that have received it.

In terms of rebound cases, Charness says a lot of work has been done, but many questions remain.

“I reflect back to February and March when this was something that really wasn’t known and when people who experienced rebound were calling their providers and being told as a test must be wrong,” he said. “Between then and now, there’s been a huge dissemination of information, which is a good thing, but people aren’t 100% sure how to handle it.”