A health worker takes SARS-CoV-2 samples from a person in Shanghai, China.Credit: Qilai Shen/Bloomberg via Getty
After Paxlovid, the game-changing antiviral against COVID-19, began to be used in late 2021, researchers noticed a disconcerting trend. In some people who take the drug, symptoms and detectable virus go away, only to mysteriously return days later.
After months of hanging on to straws, scientists are starting to make some headway in understanding ‘Paxlovid bounce’. Two recent studies suggest that it is surprisingly common for SARS-CoV-2 to come back in untreated cases of COVID-191, while hinting that the return of the virus is fiercer and more common in people taking Paxlovid2.
“We all see people who take Paxlovid very well and then all of a sudden they get sick again,” says Michael Charness, a physician-scientist at VA Boston Healthcare in Massachusetts, who published an early description of Paxlovid3 rebound. “There are so many unanswered questions.”
viral resurgence
Paxlovid, a combination of the oral antiviral drugs nirmatrelvir and ritonavir, has been of great help in countries where it is widely available. A clinical trial sponsored by the New York City-based manufacturer Pfizer showed that it reduced the risk of hospitalization and death in unvaccinated people at risk4. Real-world studies suggest that the benefits of the therapy could also extend to vaccinated people5.
The Pfizer trial team noted cases of rebound in both people who received Paxlovid and those who took a placebo4. But full details of these cases are not available, scientists say.
To determine the rate 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 analyzed data from hundreds of people who were randomized to receive a placebo in a large group. COVID-19 antibody drug scale testing.
More than a quarter of participants infected with SARS-CoV-2 reported a rebound in their symptoms, while 1 in 8 saw the virus return to high levels1. However, only 1% to 2% of people had both rebound characteristics. The study was published on the medRxiv preprint server on August 2 and has not yet been peer-reviewed.
Source: Ref. 1.
Li says this suggests that SARS-CoV-2 rebound rarely causes symptoms, and re-emergence of symptoms could be due to factors other than viral resurgence, such as persistent immune responses or another infection altogether. “The main take-home message is that recovery from COVID-19 will not be a linear process,” says Li.
Li’s team, like many others, is now studying people taking Paxlovid both before and after the rebound. One such study found signs that Paxlovid rebound is different from flares that occur without treatment2. The study, published on medRxiv on August 4, has not yet been peer-reviewed.
The study, led by infectious disease physician and vaccine scientist Kathryn Stephenson of Beth Israel Deaconess Medical Center in Boston, closely followed 11 people who took Paxlovid for COVID-19 and 25 who did not. More than a quarter of Paxlovid recipients recovered, based on SARS-CoV-2 levels, compared to just one of 25 untreated people. Also, people with Paxlovid rebound had high levels of virus for several days, as if they had new acute infections. “The one case of untreated viral rebound was more like a viral ‘blink’,” Stephenson wrote on Twitter.
Charness says that Paxlovid rebound appears to be qualitatively different from rebound in untreated people, whose viral levels rarely reached the peaks of their initial infection.
But the cause of the Paxlovid rebound remains unclear. Studies have suggested that it is unlikely to be due to viral drug resistance or weak immune responses in rebounds. The researchers are testing whether viral replication, after being suppressed by Paxlovid, can recover when the drug is cleared from the body, leading to high viral levels and powerful immune responses that can cause symptoms to return.
Clinicians also need better guidance on 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 happens when other diseases are treated for too short a time. “This smacks of treatment duration not being long enough for the subgroup of people who rebound.”
Currently, the drug is given for five days, but Charness says longer treatment periods are worth considering, as long as this doesn’t promote drug resistance. “There is still a lot to learn.”
Source: www.nature.com