Paxlovid Rebound: Rare But Real

“Paxlovid rebound is real and poorly understood,” tweeted Bob Wachter, M.D., on May 11. “We need urgent study & pt counseling.”

Wachter’s tweet came as word about possible Paxlovid rebound started to ricochet around social media and conventional media outlets. Wachter, a professor and chair of the Department of Medicine at the University of California, San Francisco, has emerged as one of the leading social media voices on the COVID-19 pandemic.

Paxlovid rebound refers to the phenomenon of symptomatic COVID-19 coming back a few days after people have finished taking the prescribed five-day course of Pfizer’s oral antiviral medication and test negative. No one is sure why it occurs.

Study results are beginning to trickle in that show that rebound is quite rare. Mayo Clinic researchers reported research findings today in the journal Clinical Infectious Diseases that showed 4 of 483 (0.8%) of patients at higher risk for experiencing severe COVID-19 who were treated with Paxlovid experienced a recurrence of symptoms at a median of nine days after treatment. All four had been vaccinated. The researchers described the cases as mild and treated successfully with additional COVID-19 therapy

FDA officials have acknowledged the problem. In an interview transcript posted on the FDA website in early May, John Farley, M.D., M.P.H., director of the Office of Infectious Diseases in the agency’s Center for Drug Evaluation and Research,discussed the clinical trial that supported the agency’s decision to issue an emergency use authorization (EUA) for Paxlovid. Between1% and 2% of study participants had one or more positive polymerase chain reaction (PCR) tests for the SARS-CoV-2 virus, which causes COVID-19, after testing negative or a test result showing an increase in the amount of SARS-CoV-2.Farley noted, though, the same was true for those assigned to the placebo group, so the rebound couldn’t necessarily be attributedto Paxlovid.

The CDC chimed in on May 24 with an advisory that acknowledged rebound case reports. The CDC also noted that the cases of rebound illness were mild. The advisory says “possible transmission of infection during COVID-19 rebound has been described ” but also said it is unknown whether the chances of transmission during the rebound illness is the same during the initial infection.

Farley and others have noted the benefits of Paxlovid. The trial that led to the EUA showed the antiviral reduced the risk of hospitalization or death by 88% among nonhospitalized patients at high risk of developing a severe case of COVID-19. However, people enrolled in that trial were not vaccinated. The news of Paxlovid rebound has stirred up questions about whether the antiviral might have a different effect on people who have been vaccinated.

Paxlovid consists of nirmatrelvir, which acts directly on the SARS-CoV-2 virus, and ritonavir, a repurposed HIV drug that boosts the effectiveness of nirmatrelvir. As a convenient oral drug with good efficacy data behind it, the antiviral has been heralded has a key weapon in the fight against COVID-19.

One of the proposed explanations for Paxlovid rebound is that immune response to the virus is incomplete because the antiviral knocks down the viral load, so when the five days of treatment are over, the infection springs back. Paul E. Sax, M.D., clinical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston, has floated the idea that SARS-CoV-2 replication is drawn out in some people and that although Paxlovid reduces it, the replication ramps up again once the five-day course is over.

Paxlovid rebound has raised questions about how long people with COVID-19 who have taken the antiviral should isolate. Also unsettled is whether a second course of Paxlovid might be used to treat the rebound infection. Sax, writing in NEJM Journal Watch, said re-treatment is permitted under the EUA and is justified for high-risk patients, such as those who are severely immunocompromised. However, in the transcript posted on the FDA website, Farley said there was no evidence of benefit from longer or repeated treatment with Paxlovid. The CDC advisory also says there is no evidence of benefit from additional treatment.