By Robert Langreth & Madison Muller

U.S. government researchers are planning studies of how often and why coronavirus levels rebound in some Covid patients who have completed a five-day course of treatment with Pfizer Inc.’s Paxlovid.

“It is a priority,” said Clifford Lane, deputy director for clinical research at the National Institute of Allergy and Infectious Diseases, calling the issue “a pretty urgent thing for us to get a handle on.” The agency is discussing a variety of possible epidemiological and clinical studies to examine post-Paxlovid rebound with scientists at the Centers for Disease Control and Prevention, he said.

The demand for answers is rising as Paxlovid has become a key element of the Biden administration’s pandemic approach, with the drug being made available at pharmacies nationwide. Among other questions the NIH hopes to get a better handle on is how often viral rebounds occur after five days of Paxlovid treatment, who’s at risk for relapse, and whether it could be avoided with a longer regimen.

Little is known about the rebound cases, including how frequently they occur and whether the highly transmissible omicron variant plays a role. While there’s no proof it’s caused by the drug, doctors say they need more information about what action to take when the virus surges in someone who’s just been treated.

The only case reported in the medical literature is a preprint posted Tuesday on researchsquare.com by researchers at the VA Boston Healthcare System. It recounts the history of a 71-year-old man who recovered rapidly on Paxlovid before experiencing a temporary rebound in symptoms and a spike in viral levels on the ninth day after his first positive test that resolved a few days later.

A number of similar cases have been described on Twitter and medical blogs, and several doctors reported hearing of such cases in recent weeks.

“Providers who are going to be prescribing this should be aware that this phenomenon occurs, and if people have symptoms worsening after Paxlovid, it’s probably still Covid,” said Paul Sax, a Harvard Medical School professor and Clinical Director of the Division of Infectious Diseases at Brigham and Women’s Hospital. Sax personally saw post-Paxlovid rebound occur a few weeks ago in one of his HIV patients, according to an April 25 blog post.

Buried Data

“The big problem is that when this drug was released, this information wasn’t included,” in the label, he said in an interview. Instead, it was briefly cited on the 23rd page of a Food and Drug Administration document that few doctors read, he said.

The FDA said it’s “evaluating the reports of viral load rebound after completing Paxlovid treatment and will share recommendations if appropriate.” Eligible patients should continue discussing Paxlovid treatment with their health-care providers, the agency said in an email. The CDC didn’t have an immediate comment when reached by email.

Among the people who have experienced post-Paxlovid rebound is David Ho, a veteran virologist who leads the Aaron Diamond AIDS Research Center at Columbia University. Ho said he came down with Covid on April 6, a day after flying back from a medical conference in Paris. His doctor prescribed Paxlovid, and within days of taking it, his symptoms dissipated and tests turned negative.

But 10 days after first getting sick, the symptoms returned and his tests turned positive for another two days. Ho said he sequenced his own virus and found that both infections were from the same strain, confirming that the virus had not mutated and become resistant to Paxlovid. A second family member who also got sick around the same time also had post-Paxlovid rebound in symptoms and virus, Ho says.

“It surprised the heck out of me,” he said. “Up until that point I had not heard of such cases elsewhere.”

While the reasons for the rebound are still unclear, Ho theorizes that it may occur when a small proportion of virus-infected cells may remain viable and resume pumping out viral progeny once treatment stops.

Longer Dosing

Pfizer’s own final-stage study showed that “a small number” of patients experienced a rebound after being treated with either the drug or a placebo, the company said in a statement. The rate of rebound was no higher among those who received Paxlovid than placebo recipients, the company said.

“This suggests the observed increase in viral load is unlikely to be related to Paxlovid,” Jerica Pitts, a Pfizer spokeswoman, said in an email. Pfizer has seen no evidence of resistance to the medication, she said.

If viral rebound is shown to occur at a significant rate, one implication is that some people may need longer dosing of Pfizer’s drug than the standard five days, said Lane, the NIAID deputy director.

“There’s two things that suppress the virus: the drug and the host immune response,” he said. “If you stop the drug before the host immune response has had a chance to kick in, you may see the virus come back.”

There are important public health implications in understanding how often viral rebound occurs, said Michael Charness, chief of staff for the VA Boston Healthcare System and part of the team that reported viral rebound in the 71-year-old patient. Doctors and patients need to know about the possibility it could come back and whether it is infectious. That’s true even if the rebound turns out not to be related to the Pfizer drug.

When Paxlovid was developed and studied, the variants circulating were quite different from the subvariants of highly transmissible omicron that are infecting people now, said Greg Poland, director of the Mayo Clinic’s vaccine research group. It’s possible these newer variants could warrant longer or repeated courses of Paxlovid, but further studies are needed to determine the best way forward, he said.