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A health care worker swabs a person in Shanghai, China, for SARS-CoV-2. Credit: Qilai Shen/Bloomberg via Getty

After the game-changing COVID-19 antiviral Paxlovid began to be used in late 2021, researchers noticed a perplexing trend. In some people taking the drug, symptoms and detectable virus vanish, only to mysteriously return days later.

After months of grasping at straws, scientists are beginning to make some headway in understanding ‘Paxlovid rebound’. Two recent studies suggest that it is surprisingly common for SARS-CoV-2 to return in untreated cases of COVID-191, while hinting that the virus’s comeback is fiercer and more common in people who take Paxlovid2.

“We’re all seeing people who are taking Paxlovid doing really well and then suddenly they’re getting sick again,” says Michael Charness, a physician-scientist at VA Boston Healthcare in Massachusetts, who published an early description of Paxlovid rebound3. “There are so many unanswered questions.”

Paxlovid ― a combination of the oral antiviral drugs nirmatrelvir and ritonavir ― has been a boon in countries where it is widely available. A clinical trial sponsored by the manufacturer Pfizer, headquartered in New York City, showed that it reduced the risk of hospitalization and death in at-risk unvaccinated individuals4. Real-world studies suggest the therapy’s benefits could also extend to vaccinated people5.

The Pfizer trial team noticed cases of rebound both in people who got Paxlovid and in those who took a placebo4. But complete details of these cases are not available, scientists say.

To determine the frequency of rebound in the absence of Paxlovid treatment, Jonathan Li, a physician-scientist at Brigham and Women’s Hospital in Boston, Massachusetts, and his team analysed data from hundreds of people who were randomized to receive a placebo in a large-scale trial of COVID-19 antibody drugs.

More than one-quarter of participants who were infected with SARS-CoV-2 reported a rebound in their symptoms, while 1 in 8 saw the virus return to high levels1. Yet, just 1–2% of people had both features of rebound. The study was posted to the medRxiv preprint server on 2 August and has not yet been peer reviewed.

Li says that this suggests that the rebound of SARS-CoV-2 rarely causes symptoms, and that symptoms’ reappearance could stem instead from factors other than viral resurgence, such as lingering immune responses or another infection altogether. “The main take-home message is that recovery from COVID-19 is not going to be a linear process”, Li says.

Li’s team, as well as many others, are now studying people who take Paxlovid both before and after rebound tends to occur. One such study found signs that Paxlovid rebound is different to the resurgences that occur without treatment2. The study, posted to medRxiv on 4 August, has not yet been peer reviewed.

The study, led by infectious-disease physician and vaccine scientist Kathryn Stephenson at Beth Israel Deaconess Medical Center in Boston, closely followed 11 people who took Paxlovid for COVID-19 and 25 who did not. More than one-quarter of the Paxlovid recipients rebounded, based on levels of SARS-CoV-2, compared with just one of the 25 untreated people. Moreover, people with Paxlovid rebound had high levels of virus for several days, as if they had new acute infections. “The single case of viral rebound without treatment was more like a viral ‘blip’,” Stephenson wrote on Twitter.

Charness says that Paxlovid rebound does seem to be qualitatively different from rebound in untreated people, whose viral levels rarely reached the peaks of their initial infection.

Coronavirus ‘ghosts’ found lingering in the gut

Coronavirus ‘ghosts’ found lingering in the gut

But the cause of Paxlovid rebound remains unclear. Studies have suggested that it’s unlikely to be due to viral drug resistance or feeble immune responses in rebounders. Researchers are testing whether viral replication, having been suppressed by Paxlovid, can bounce back when the drug vanishes from the body, leading to high viral levels and potent immune responses that can cause symptoms to reappear.

Physicians also need a better guide as to how to treat, and ultimately prevent, Paxlovid rebound. Mark Siedner, a clinical epidemiologist at Massachusetts General Hospital in Boston who is studying Paxlovid rebound, says the phenomenon reminds him of what occurs when other diseases are treated for too short a time. “This smells like treatment duration is not long enough for the subgroup of people who have rebound.”

The drug is currently given for five days, but Charness says it’s worth looking at longer treatment periods — as long as this doesn’t promote drug resistance. “There is still a lot to learn.”

doi: https://doi.org/10.1038/d41586-022-02121-z

Clarification 12 August 2022: An earlier version of this story inadvertently referred to Paxlovid ‘resistance’ instead of Paxlovid rebound.

Deo, R., et al. Preprint at medRxiv https://doi.org/10.1101/2022.08.01.22278278 (2022).

Dai, E. Y. et al. Preprint at medRxiv https://doi.org/10.1101/2022.08.04.22278378 (2022).

Charness, M., et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-1588371/v3 (2022).

Soares, H. et al. Preprint at Research Square https://doi.org/10.21203/rs.3.rs-1720472/v2 (2022).

Najjar-Debbiny, R., et al. Clin. Infect. Dis. https://doi.org/10.1093/cid/ciac443 (2022).

Oklahoma Medical Research Foundation (OMRF)

Jülich Research Centre (FZJ)

Alfred Wegener Institute - Helmholtz Centre for Polar and Marine Research (AWI)

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