Avoiding Paxlovid Rebound May Mean Taking Longer Course

PSince December last year, Paxlovid was given emergency authorization for use. The number of prescriptions has risen dramatically. High-profile people who recently tested positive—including President Joe Biden, White House medical advisor Dr. Anthony Fauci, and late night host Stephen Colbert—have also taken the drug.

But some people—including those three famous patients—have reported rebound infections after taking the pills. Paxlovid rebound happens when the person who has taken the drug is negative for some days then comes back positive for it again.

An increasing number of cases has raised questions over whether Paxlovid should continue to be taken for longer durations in an effort to reduce the risk of recurrence. Here’s what virologists and the latest studies say.

What is the frequency of Paxlovid rebounding?

Scientists have shown that patients who tested positive following a Paxlovid five-day course aren’t infected with a new virus. Research has shown that the same virus is responsible for a return of the original infection within a few days after the person stopped receiving treatment. But it’s not yet clear how frequent rebound infections are. In the original studies submitted to the U.S. Food and Drug Administration (FDA) for emergency use authorization, Paxlovid’s drugmaker Pfizer found that rebounds happened in 1-2% of patients—the same rate as in the placebo group.

Columbia University’s Aaron Diamond AIDS Research Center director, Dr. David Ho studies Paxlovid rebound. “In my own experience, I have now counted 15 friends, family members, and colleagues who have taken Paxlovid, and over half have rebounded,” he says. Though that’s not a scientific tally, “physicians with large COVID-19 practices will tell you that it’s not rare.”

It may take a while to figure out how frequently rebound happens. If rebound doesn’t frequently occur, tens of thousands of people taking the drug would have to be followed in order to adequately determine how often people test positive again. “I’m afraid that will never be done,” says Dr. Mark Siedner, a clinical epidemiologist at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School, who has studied patients with Paxlovid rebound.

To get at least some idea of the frequency, Siedner’s group is enrolling a few hundred people in a study that will hopefully shed some light on the question. Three times weekly, volunteers will have their noses cleaned. Researchers will then analyze and test the samples for live viruses and, if necessary, will grow the virus to check whether they are still active or infectious. The team already did a study that showed that Paxlovid rebound patients are still contagious after they have tested positive for the second time. This means that they will need to prolong their isolation period by at least five more days and wear masks while they contact other people.

Siedner states that without large, conclusive data the FDA health officials would need to consider the risks and benefits of Paxlovid when deciding whether to allow doctors to prescribe longer treatment.

Longer treatment is possible

Do you think there is a reason for the longer treatment time? “In my mind, there is,” says Ho—who, in addition to studying Paxlovid rebound, has experienced it himself. In studies, Ho says he’s observed that Paxlovid does its job of suppressing SARS-CoV-2, halting the virus from continuing to replicate and essentially trapping it in an intermediary form. This version of the virus isn’t fully formed, and needs a few more steps of development before it becomes active and can infect new cells. Paxlovid is used to suppress the virus in this stage. But in Ho’s studies, the half life of the virus in this suspended state is nearly a day—anywhere from 19 to 22 hours—which means it takes that long for about half of the virus to decay. For someone who is infected, if there is still enough of this intermediary form in the body after the fifth and final day of Paxlovid treatment, that virus could reactivate, finish its development, and start infecting cells anew—thus causing a rebound infection.

“The virus is rather persistent,” says Ho. “And we believe that five days of treatment is not enough to have that form decay so that it’s nonexistent at the end of those five days.”

Based on his lab results, Ho’s team calculated that extending Paxlovid for several more days—three to five days beyond the current regimen—could reduce the risk of rebound by 10-fold. These extra days could eliminate the intermediate form of virus that circulates in the body. Ho believes that further studies will be needed to prove that Ho is correct and that prolonging the drug for several additional days does not pose a risk.

Paxlovid isn’t the only antiviral drug that acts this way. Paxlovid is a protease inhibitor—meaning it interferes with the virus’ ability to form the final proteins it needs—and other medications that belong to this class of drugs cause similar infection rebounds. For example, says Ho, ensitrelvir, a SARS-CoV-2 antiviral that the Japanese pharmaceutical company Shionogi is studying, produced similar intermediaries that hadn’t deteriorated before the drug was stopped and bounced back to cause infection again. “It’s related to the mechanism of action of the drug, not related to a deficit in [Paxlovid],” says Ho.

It’s similar to the way antibiotics work: if people stop taking antibiotics before the prescribed time period is up, the infection can return before the enough of the bacteria is eliminated. “We’ve certainly seen infections where if you give the treatment, you knock down the level of bacteria or virus, but if you don’t completely eradicate it—and then it comes roaring back,” Siedner says. With Paxlovid rebound, “my guess is that it’s happening because people aren’t getting treated long enough.”

Some people infected with SARS-CoV-2 who haven’t taken Paxlovid have even experienced rebound infections, in which they test negative and think they’ve recovered, but then test positive several days later, Siedner says. However, the situation is different. “People with Paxlovid rebound have much higher viral loads, the viral load stays high for a much longer period of time, and the symptoms last longer,” compared to people who rebound and haven’t taken the drug, he says. “Paxlovid rebound is the real deal.”

In a statement, a Pfizer spokesperson said that because the company’s initial studies found similar rebound rates in the treatment and placebo groups, those data “suggest the return of elevated detected nasal viral RNA (also known as viral rebound or COVID-19 rebound) is uncommon and not uniquely associated with any specific treatment.”

Ho points out, however that these studies weren’t specifically intended to measure and detect rebound and more thorough analyses are required.

Experts suggest that instead of extending the course of Paxlovid for longer periods of time, patients may be able to begin a second Paxlovid treatment once their results have been confirmed positive. According to a spokesperson from Pfizer, the FDA is currently conducting a clinical trial.

Arguments in favor of a prolonged course

Like any drug, Paxlovid has side effects—the most common of which is an extremely bad taste in the mouth that temporarily affects some people’s ability to eat. Paxlovid can interact with many other drugs such as cholesterol-lowering statins. “We often ask people to hold off on some of their other medications or decrease doses of their medications for five days while taking Paxlovid,” says Dr. Davey Smith, professor of medicine at University of California, San Diego, who has studied Paxlovid rebound in patients. “Asking them to hold off longer may have more risks and outweigh the benefits of doing that. There are a whole bunch of complications in just asking somebody to take the drug for 7 or 10 days.”

Siedner notes, however that doctors must consider the impact of rebounding on patients when weighing the potential benefits and risks of long-term therapy. In a study from Kaiser Permanente of more than 5,000 people who took Paxlovid, fewer than 1% ended up in the hospital because of their symptoms—including those who rebounded. “By and large, the health record systems are not seeing huge numbers of people needing hospitalization that could be avoided with longer treatment,” he says. “If rebound isn’t happening that often, and people who rebound aren’t at higher risk of hospitalization than people who had not taken Paxlovid, then I think there may not be much benefit to giving everyone a longer course of treatment.”

SARS-CoV-2, another potential resistance to Paxlovid could be a concern if the Paxlovid course is extended. Ho presented the first evidence for this in a paper that was published in pre-print format on August 8 via bioRxiv. His lab research revealed that HIV developed many ways of evading Paxlovid when it was exposed to high doses. It raised concerns over the possibility of future antivirals being created or combined with HIV treatment. Further studies will be needed to determine if the virus becomes resistant to Paxlovid over a short period of time and whether the treatment should be extended by just a few more days.

Are Paxlovid pills still worth it?

People with risk factors for COVID-19 are more likely to get sick. Doctors continue to recommend Paxlovid to prevent rebound. The drug helps people avoid getting too sick to require hospitalization or from succumbing to COVID-19. Most people experiencing rebound report relatively mild symptoms and don’t require more intensive medical care. Even if some people won’t be able to suppress their infection completely after a course of Paxlovid, the treatment may still be helping them to avoid more serious disease. Health officials will likely reevaluate the length of this treatment as more information becomes available.

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