Some Covid-19 patients are reporting a recurrence of symptoms after taking Pfizer's antiviral medication Paxlovid—and while health experts say that this "viral rebound" does not mean the treatment is ineffective, they are calling for health agencies to investigate the issue.

Some patients report 'viral rebound' after Paxlovid treatment

Paxlovid, an oral antiviral Covid-19 treatment, was first authorized for emergency use by FDA in December. According to clinical trial data, the drug was able to reduce the risk of hospitalization or death by almost 90% in unvaccinated patients at high risk of severe Covid-19 outcomes, leading many health experts to call the treatment a "game-changer."

How to improve access to Covid-19 treatments

However, a growing number of patients are now reporting cases of "viral rebound" after finishing Paxlovid. In such an event, individuals have reported finishing the five-day treatment, feeling better, and testing negative on an at-home rapid test. But then, their Covid-19 symptoms return, and they test positive again a few days later.

A preprint case study reported that a 71-year-old man, who was fully vaccinated and boosted, saw his virus rebound after taking Paxlovid. The patient initially took Paxlovid the day his symptoms began and was symptom-free two days later. However, after a week, he was sick once again, with his symptoms lasting for roughly four days the second time.

Genetic sequences of the virus showed that it was the same throughout the patient's two symptomatic periods, indicating that it was not a reinfection from a different virus. Tests for 21 other respiratory viruses also came up negative, so the coronavirus was the only pathogen making the patient sick. In addition, researchers did not identify any mutations that would suggest it had developed a resistance to Paxlovid.

According to Michael Charness, the chief of staff of the VA Boston Healthcare System who posted the preprint study, these cases of viral rebound may be due to Paxlovid suppressing the coronavirus too soon, which then compromises the immune system's response to the infection.

Separately, Timothy Brewer, a professor of medicine and epidemiology at the University of California, Los Angeles, said viral rebound may occur if remnants of the coronavirus remain in parts of the body that Paxlovid cannot access, such as beyond the blood-brain barrier.

Brewer suggested that some patients may not absorb Paxlovid as effectively as others, and a longer course of treatment may be needed to sufficiently eliminate the coronavirus.

Previously, Pfizer had reported a small percentage of clinical trial patients saw their symptoms rebound roughly 10 to 14 days after starting Paxlovid. However, the company noted that viral rebound had also occurred in similar rates among patients who received a placebo during the trial. There was also no association between patients' viral loads and subsequent severe disease.

"We remain confident in its clinical effectiveness at preventing severe outcomes from Covid-19 in high-risk patients," Pfizer said in a statement.

What should you do if you have a viral rebound?

Currently, it is not clear whether patients experiencing a viral rebound of Covid-19 symptoms should continue isolating or seek another course of treatment.

"Should recurrent cases isolate again? Does the EUA allow for repeat treatment and how does the NIH treatment guidelines committee consider use in those at high risk for recurrence like those immune compromised?" asked Jeffrey Klausner, an infectious disease specialist at the University of Southern California.

Paul Sax, clinical director of the division of infectious disease at Brigham and Women's Hospital, said while there is still very little scientific data to guide a recommended response, "At the very least, people who take Paxlovid and clinically recover should not ignore their symptoms if they come back … They should think this is a recurrence of COVID, and then [test] themselves again."

Because Paxlovid is presently only authorized for emergency use, health care providers cannot prescribe it for longer periods. However, some providers believe the authorization allows them to prescribe a second treatment course for patients experiencing a viral rebound.

"That's what I would recommend to someone who had it," Sax said.

In addition, Ghady Haidar, a transplant infectious disease specialist at the University of Pittsburgh Medical Center, said that a longer treatment course may be needed to prevent rebound cases in the first place, particularly among vulnerable patients. "I really don't think that five days of Paxlovid is going to be enough for certain subgroups of immunocompromised people," he said.

Health agencies to investigate cases of viral rebound

According to infectious disease experts, these reported cases of viral rebound are not cause for alarm, but health agencies should investigate these cases and provide guidance for both patients and health care providers on how to respond when they do occur.

"If someone has a case of post-Paxlovid SARS-CoV-2 relapse versus reinfection, it's important that this be flagged to public health authorities,” said Céline Gounder, infectious disease specialist and an editor at large for public health at Kaiser Health News. "The virus should be sequenced so we can learn if it's mutated and developed resistance to Paxlovid."

H. Clifford Lane, director for clinical research and special projects at the National Institute for Allergy and Infectious Diseases (NIAID), said these reported cases of viral rebound give health agencies "reason to re-examine duration of therapy, approaches to therapy, other laboratory tests we might use to predict who could benefit from longer courses of treatment."

Investigating these cases of viral rebound "is a priority," Lane said, calling the issue "a pretty urgent thing for us to get a handle on."

Currently, Lane said NIAID is discussing potential epidemiological and clinical studies to evaluate the occurrence of viral rebound. Similarly, FDA spokesperson Chanapa Tantibanchachai said the agency is "is evaluating the reports of viral load rebound after completing Paxlovid treatment and will share recommendations if appropriate."

On Pfizer's end, spokesperson Kit Longley said the company will continue "to monitor data from our ongoing clinical studies of Paxlovid, as well as real-world evidence" related to cases of viral rebound after Paxlovid treatment. (Ryan, NBC News, 4/27; Johnson, Washington Post, 4/27; Goodman, CNN, 4/27; Lazar, Boston Globe, 4/21; Langreth/Muller, Bloomberg, 4/30)