U.S. health authorities and researchers are investigating why some people who appeared to recover from Covid-19 after taking Pfizer Inc.’s antiviral pill developed symptoms again soon after.

Paxlovid is supposed to treat the newly infected, keeping them out of the hospital. Within two weeks of appearing to get better, however, some users experienced cold-like symptoms such as sore throat and cough, according to physicians and published case reports.

The rebound cases haven’t resulted in severe disease so far. Doctors and health authorities still encourage Paxlovid’s use among people at high risk of developing severe Covid-19.

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Yet the cases are the latest puzzle confronting health authorities, researchers and physicians trying to stay ahead of the virus.

The health experts said they aren’t sure if the relapsed patients are contagious. Nor are they sure what causes the rebounds, theorizing that patients may be taking Paxlovid too early or not long enough. The experts also don’t know how common the rebounds are, though Pfizer said its real-world data indicates the relapses occur in fewer than 1 in 3,000 patients.

Meantime, doctors said they were wrestling with how to handle the cases, although some doctors are recommending patients restart isolation.

A lab technician visually inspects Paxlovid tablet samples in Freiburg, Germany, late last year.

Photo: thomas hansmann.fotograf/Associated Press

“This is something public health agencies will have to wrap their heads around and figure out what to do,” said Michael Charness, chief of staff at the VA Boston Healthcare System.

He posted one case study on a preprint server online of a 71-year-old man, who was vaccinated and boosted, who developed cold symptoms about a week after he felt better following a course of Paxlovid.

Pfizer Chief Executive Albert Bourla said in an interview that the current label doesn’t prohibit a second course of treatment, if doctors determine it is needed.

Recently, however, the Food and Drug Administration said there wasn’t evidence of a benefit from giving a longer course of treatment or repeating treatment in rebound patients.

The FDA reiterated Paxlovid’s effectiveness and encouraged people at high risk of severe Covid-19 who are newly infected to talk with their doctors about undergoing treatment.

The FDA, which didn’t mention a risk of relapse in its original prescribing instructions for doctors, hasn’t tweaked the directions so far. It declined to say what, if anything, it has told doctors about how to handle the cases.

The FDA is reviewing clinical-trial data. National Institute of Allergy and Infectious Diseases researchers are planning to examine how often the rebound cases occur, why and whether extending treatment is a remedy, a spokeswoman said.

Pfizer said it remains confident in Paxlovid’s effectiveness at preventing hospitalization and death from Covid-19 in high-risk people, a spokesman said.

Pfizer Chief Executive Albert Bourla said the current label for Paxlovid doesn’t prohibit a second course of treatment, if doctors determine it is needed.

Photo: Christopher Goodney/Bloomberg News

The company said a virus developing resistance doesn’t appear to be the cause. Pfizer is reviewing data from its clinical trials and monitoring real-world use of the drug to try to better understand the rebound cases.

Doctors and health authorities consider Paxlovid to be an important Covid-19 treatment. People with new infections at high risk of developing severe disease can take the pills over five days at home to avoid going to the hospital.

The drug, which was found to be 88% effective in its pivotal trial, works by blocking activity of a key enzyme known as protease that the virus needs to replicate.

Since their authorization in late December, the pills have become a go-to Covid-19 treatment. Some 80,000 people in the U.S. have taken Paxlovid, according to Pfizer.

Neither the FDA nor CDC said they had a tally of the number of cases.

In the company’s late-stage clinical trial, about 2% of the 1,120 subjects who took the drug had rebounds around 10 to 14 days after starting treatment, compared with 1.5% of the 1,126 volunteers who received the placebo during the same time period, a Pfizer spokesman said.

Researchers have reported studying at least two people who completed five days of treatment and recovered only to experience a second round of symptoms.

One was a 48-year-old-man with a pre-existing rare inflammatory disease called Behcet’s syndrome who was vaccinated and boosted, according to researchers at University of California, San Francisco.

After his rebound case, the man developed long Covid symptoms such as chest soreness and brain fog, the researchers said.

“There was hope that antiviral therapy would basically make long Covid go away entirely but it seems that it’s still possible to develop long Covid after antiviral therapy, particularly in the setting of these rebound symptoms,”  said Michael Peluso, an assistant professor of medicine at UCSF and an author on the case report.

One theory for the rebound cases, researchers say, is that patients took the drug too early in the course of disease, which prevented their immune systems from mounting a full response to help control the infection.

Another theory is that Paxlovid isn’t in the body long enough to fully stamp out the virus in some people, allowing it to revive once treatment ends.

There may be a small number of lingering infected cells that persist for a long time, especially in the upper respiratory tract where it takes longer to clear the virus, said John Mellors, chief of the infectious diseases division at the University of Pittsburgh Medical Center and the University of Pittsburgh.

“They could be a source to reignite the infection,” he said.

Pfizer decided on a five-day course of treatment after reviewing effective regimens for antivirals for other infectious diseases, and deciding a longer duration was unlikely to help, a company spokesman said.

Given the potential causes, some doctors have explored giving patients a longer course of treatment than the five days currently authorized, or repeating treatment in patients whose symptoms have returned.

Dr. Mellors said he is considering treating patients with weakened immune systems for longer, in consultation with the FDA and Pfizer.

For other patients, however, doctors expressed uncertainty about what to do, in part because they appear to lack a common trait, and include those vaccinated and both young and elderly.

“I don’t think we have a real good grasp on what to do with them yet,” said Dr. Bruce Farber, chief of public health and epidemiology for Northwell Health, a large health system in New York, which he said has had several rebound patients.

Write to Jared S. Hopkins at jared.hopkins@wsj.com