As more Covid-19 patients are prescribed Paxlovid, confusion over its side effects continues to rise—and some experts to question whether a "Paxlovid-resistant virus" is on the horizon.

The mysteries surrounding Paxlovid

Paxlovid, an oral antiviral Covid-19 treatment, was first authorized for emergency use by FDA in December. According to clinical trial data, the drug was able to reduce the risk of hospitalization or death by almost 90% in unvaccinated patients at high risk of severe Covid-19 outcomes, leading many health experts to call the treatment a "game-changer."

However, a growing number of patients have reported a variety of mysterious side effects, including complaints of a bitter, metallic taste, or one like grapefruit juice mixed with soap, while they were taking the drug. 

In its only published Paxlovid trial results, Pfizer found that 5.6% of Paxlovid-users reported taste disruption, compared with 0.3% of the participants who received the placebo. 

However, Paul Sax, the clinical director of the division of infectious diseases at Brigham and Women's Hospital, said he suspects "way more than half" of the people who have taken the drug have experienced the taste.

In addition, some patients have experienced a "viral rebound" after finishing Paxlovid. In such an event, individuals have reported finishing the five-day treatment, feeling better, and testing negative on an at-home rapid test. But then, their Covid-19 symptoms return, and they test positive again a few days later.

Notably, a Pfizer executive said this month that the company had taken a "preliminary look" at its trial data and determined that viral loads rebounded in roughly 2% of patients. In addition, he said they saw "the same or close to the same percent in the placebo arm."

"Reports from the beginning of the pandemic suggested some participants exhibit fluctuations in nasal viral RNA, and these fluctuations could be a phenomena [sic] of the disease itself," the spokesperson said.

Still, if the measured 2% rate was applied to those who have already taken the drug, there could be thousands of instances of viral rebound after Paxlovid use. 

Last week, CDC released an advisory saying that patients who complete a five-day course of Paxlovid and experience a return of Covid-19 symptoms should isolate for an additional five days. However, the agency also clarified that "Paxlovid continues to be recommended for early stage treatment of mild to moderate COVID-19 among persons at high risk for progression to severe disease."

While no researchers have published studies measuring the prevalence of viral rebounds, many clinicians and Paxlovid patients believe it is much higher than 2%. In fact, anecdotal reports and Twitter surveys have found that as many as 47% of respondents who took Paxlovid say they went through a rebound.

Will there be a Paxlovid-resistant variant?

Initially, some scientists suspected that viral rebound stemmed from viral resistance to Paxlovid.

When Davey Smith, an infectious disease expert at University of California, San Diego, treated a patient who returned with complaints of a cough and headache just 10 days after he started taking Paxlovid, he was concerned. At the time, Smith believed the resurgence of symptoms could only mean one thing.

"I was pretty sure it was resistance," he said. "I'm a virologist, I combat resistance all the time."

However, he was wrong. Researchers have not yet identified any viral mutations that would suggest the coronavirus has developed a resistance to Paxlovid. After analyzing the virus, Smith and his colleagues discovered that the patient was actually an early example of Paxlovid rebound, where the virus comes back without evolving around the drug.

But eventually, in some patients, the coronavirus will evade Paxlovid, just like it has with other Covid-19 drugs, STAT News reports.

"If there is anything we know about viruses and antiviral drugs is that eventually we will see some sort of resistance," said Andrew Pavia, chief of pediatric infectious diseases at University of Utah Health.

Jun Wang, a medicinal chemist at Rutgers University, separately agreed, saying, "Everybody understands this: Resistance is not a question of if, it's a question of when."

Experts fear resistance could be created in various ways. Some fear that prescribing Paxlovid to relatively low-risk patients who may not really need it will create new opportunities for resistance. In addition, resistance could be encouraged by those who start taking the drug but do not complete the full treatment course, therefore not eliminating the virus from their bodies.

Some are also concerned about patients experiencing Paxlovid rebound who decide to take a second course of the drug when the virus comes back because they are providing the virus with more opportunities to find "escape strategies,'' according to STAT News.

Immunocompromised patients have also created immune-resistant variants throughout the pandemic, where there's enough of an immune response to train the virus but not enough to clear it entirely.

However, it is not clear whether there will be widespread resistant variants. In particular, the coronavirus could have a harder time evading Paxlovid than other drugs since patients only take it for five days and because it attacks a protein the virus is not able to change easily. Ultimately, any mutation or modification the virus makes could weaken its ability to replicate or survive.

"At some point, there will be Paxlovid-resistant virus," said Adam Lauring, who studies RNA virus evolution at the University of Michigan. "Whether that clinically becomes a problem or not, it's hard to say." (Gutman, The Atlantic, 5/26; Mast, STAT News, 5/27)