Paxlovid Rebound: What Scientists Know So Far

DDavid Ho spent most of his career researching HIV and other viruses. He thought that he had a good idea about what to expect when he contracted SARS-CoV-2. His symptoms weren’t very severe, but after discussing it with his doctor, Ho decided to take Paxlovid, the antiviral COVID-19 therapy made by Pfizer, for the five-day course. Ho was at least 69 years old and fit the criteria of someone who should. Paxlovid has been recommended by both the U.S. Food and Drug Administration and Centers for Disease Control and Prevention for patients at high risk for severe COVID-19.

Ho kept track of his infection. At Columbia University’s lab, he had access to PCR tests and genetic sequencing. There were also rapid antigen kits available for home testing. After he had first developed symptoms of a cold, he began taking Paxlovid. An antigen test came back positive. Ho took two daily pills of Paxlovid for the five-day period as prescribed. A PCR test confirmed that the infection had been confirmed on day 2. His antigen testing were positive every day, except for day 9 when he was negative. The PCR test on Day 5 and 7, however, were both negative.

On day 10, Ho experienced a mild headache, runny nose and mild cough. Ho tried to check himself at home and, to his delight, he tested positive again. A PCR test also confirmed the results. His team sequenced the virus to compare it to the genetic sequence from his earlier infection and found that it was identical to the virus that he had been infected with days before—suggesting that the virus hadn’t mutated to become resistant to Paxlovid, nor had he become infected again with a different virus. After being treated for just a few days, another infection erupted.

“I was surprised to see the rebound,” he says. “I was expecting Paxlovid to take care of things.”

A rebound like Ho’s was always a known potential side effect of the drug. Pfizer reports that the rebound rate for people who have taken the medication was between 1% and 2% in studies. The company says the rates of rebound in the treated group in its study and among those receiving placebo were similar, indicating that “elevated nasal viral RNA is uncommon and not uniquely associated with treatment.” But a growing number of people are reporting infection rebounds after taking Paxlovid—so many that “there’s no way it’s occurring at 1% or 2%,” says Ho, who has also shared his data and discussed it with scientists at Pfizer. “It’s happening quite a bit.” Anecdotes from people who test positive, take a course of Paxlovid, test negative, and then days later test positive again abound on social media. It’s been scientifically documented; researchers at the University of California, San Diego recently described one case of rebound in a May 18 paper published on the pre-print server Research Square (which means it has not yet been peer reviewed). On May 24, the CDC published a health advisory that instructed doctors treating patients who have taken the drug to address rebound cases.

Ho was inspired to research the phenomena further by Dr. Michael Charness from the VA Boston Healthcare System. Both scientists were both booster-vaccinated. They collaborated to create what may be the largest analysis of this phenomenon. The paper was published by Research Square and describes both their cases as well as those of eight other people who reported a rebounding virus following taking Paxlovid.

Here’s what we know about Paxlovid rebound so far.

What’s the point of taking Paxlovid when their COVID-19 might rebound?

Paxlovid combines two drugs. The first is a protease inhibitor that’s used to combat HIV infection. It stops the virus making the critical proteins that it requires to reproduce. And the second prevents liver cells from burning the drug too fast.

It’s not currently FDA approved, but doctors can prescribe it under an emergency use authorization. Pfizer studies showed that it was 88% effective at protecting people who have not been vaccinated from COVID-19 and dying. To see how Paxlovid reacts to vaccine recipients, the company continues to monitor them.

In a statement to TIME, a Pfizer spokesperson said “We are continuing to monitor the data, but we have not seen any resistance emerge to date in patients treated with Paxlovid. It is unlikely that nasal virus RNA can be detected again after treatment. We remain very confident in Paxlovid’s clinical effectiveness at preventing severe outcomes from COVID-19 in high-risk patients.”

What makes Paxlovid’s rebound possible?

Scientists still try to figure out why COVID-19 patients are using Paxlovid. They test negative for many days and then come back positive. They are still exploring many possible reasons. Another possibility is that the virus is rapidly mutating and people are getting infected more often with new variants of SARS. One possibility is that the virus has found a way out of Paxlovid to become immune to its symptoms and mutates quickly.

Ho suspects that there’s more. His small study showed that three of the infections in his report—his, Charness’, and that of one other person—were rebounds of the first, not new strains or a new Paxlovid-resistant variant. Based on the genetic sequencing data, “we showed the rebounding virus is not resistant to the protease inhibitor [drug in Paxlovid], because there is no change in protease sequence,” he says. “It’s not reinfection with another virus. The sequences are identical.” Pfizer says its studies similarly showed that the virus is not developing resistance to the protease inhibitor drug.

Ho thinks that the virus does what viruses do to respond to antiviral medication. No antiviral drugs—whether against SARS-CoV-2 or HIV—actually kill any virus present in an infected person; they work by blocking certain steps in the virus’ replication cycle, freezing them in time so the virus cannot continue to churn out more copies of itself. Paxlovid interrupts the process involving the protease enzyme. This is responsible for splicing the string of polypeptides made by the virus once it has infected a cell. This long protein must be broken down into its components proteins. These component proteins then help in creating a new virus. By inhibiting that step, Paxlovid leaves the virus in a suspended state—and depending on when the drug was started, an infected person could have thousands of these long polypeptide strings already made and floating around in the body, creating a latent reservoir of viral product that could become active again. This drug keeps these intermediate forms from being cut and infecting the cells. But once the drug has stopped after five days, the enzyme no longer needs to be inhibited. It can then go back at splicing the viral proteins. There could be a rebound because there is more virus being created that can infect the cells.

“We know the drug has a very short half life, which means it doesn’t linger for long in the body,” says Ho. “The virus hasn’t been killed by the drug, but only blocks its replication. There is still a reservoir of viral material, so for a virologist, that’s the first thing we think of. Once the drug is washed out, that reservoir can become active again.”

Ho has been conducting experiments at his lab in an attempt to discover how long SARS CoV-2’s intermediary protein can stay in the body. It’s possible that one way to minimize rebound infections is to extend the number of days people take Paxlovid, but Pfizer would have to conduct new studies to determine how many additional days would be needed, and how safe and effective the drug would be if that were the case. Pfizer may conduct such studies to determine if certain populations need to be treated with longer periods of the drug.

Do you need to take Paxlovid again after you’ve completed the 5-day course?

According to the CDC’s recent health advisory on Paxlovid rebound, the agency does not recommend that people who have finished the five-day course restart taking the pills. The CDC recommends that people who have tested positive for rebound symptoms should be kept isolated for five days and wear masks 10 days following the onset of symptoms.

Ho said that before the publication of the updated guidance, the CDC had reached out to Ho to find the most effective strategies to managing rebound. Although the CDC doesn’t recommend people who have been prescribed Paxlovid to test more frequently after treatment is over, Ho suggests that they follow current guidance and perform an at-home rapid test if symptoms reappear.

Do I risk getting sick if my Paxlovid test is positive?

According to the CDC, most people who recover from a rebound will experience mild symptoms again and many of them will be able to heal themselves without additional care.

Do I get contagious even if my Paxlovid test is positive?

Yes. Anyone who tests positive on a rapid test—even after finishing a full course of the drug treatment—is again contagious and can pass the virus on to others. It’s important for people taking Paxlovid to be on the lookout for the possibility of a rebound infection and use rapid at-home antigen tests as often as they can, and confirm the diagnosis with a PCR test if possible, so they will know if they turn positive again.

In the 10 cases in Ho’s report, two people transmitted the virus to others in their household after they had relapsed. “The idea of somebody who goes virus-negative and then could become virus-positive again—that’s of great concern,” he says.

Is Paxlovid worth it?

Doctors are currently restricted by the emergency use authorization from prescribing this drug to patients at greater risk for serious illness. This includes people over 65 and people with compromised immune systems. People who are otherwise healthy, particularly those with boosters and vaccines, might not be able to benefit from this therapy. This is because the drug must begin as soon as they feel symptoms. Because they may recover faster without the drug, rebound could prolong their quarantine period.

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