Avoiding Paxlovid Rebound could mean taking a longer course

PAntiviral prescription Paxlovid has fly up since the drug is licensed for emergency use last December. Celebrities who recently tested positive — including President Joe Biden, White House medical adviser Dr. Anthony Fauci and late-night host Stephen Colbert — have also taken the drug.

But some people — including three famous patients — have reported recurrent infections after taking the drug. Paxlovid recovery occurs when a person takes the drug for a few days, tests negative, and then tests positive again a few days later.

A growing number of cases are raising questions about whether people should take Paxlovid for longer to avoid recurrent infections. Here’s what virologists and the latest studies say.

How popular is Paxlovid recovery?

Researchers have determined that people who test positive after finishing a five-day course of Paxlovid will not develop new infections. Genetic studies have shown that the virus that returns soon after a person stops treatment is the same virus that caused the initial infection. But it’s still unclear how often the infection recurs. In initial studies submitted to the U.S. Food and Drug Administration (FDA) for emergency use authorization, Paxlovid drug manufacturer Pfizer found that relapses occurred. in 1-2% of patients – the same rate as in the placebo group.

Dr David Ho, professor of medicine and director of the Aaron Diamond Center for AIDS Research at Columbia University, is studying Paxlovid’s recovery and believes the prevalence is likely higher. He said: “In my own experience, I have counted 15 friends, family members and colleagues who have taken Paxlovid, and more than half have recovered. While it’s not a scientific proof, “doctors with a large COVID-19 practice will tell you it’s not uncommon.”

Figuring out exactly how often recovery occurs may not happen anytime soon. If recovery is infrequent, tens of thousands of people taking the drug will have to be monitored to fully determine how often people test positive again. Dr Mark Siedner, a clinical epidemiologist at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, who has studied recovered Paxlovid patients, said: “I’m afraid it won’t. ever done.

To get at least some idea of ​​frequency, Siedner’s team is recruiting several hundred people for a study that will hopefully shed some light on the question. Volunteers will have their noses picked three times a week and researchers will analyze the samples for any live viruses, and if viruses are present, culture them to see if they continue to be active and contagious. infected or not. His team did a small study showing that people with relapsed Paxlovid are still contagious when they test positive a second time, meaning they need to extend their quarantine period for at least another 5 days. and continue to wear a mask during that time if they come into contact with others.

Siedner said health officials at the FDA will have to weigh the benefits and risks of Paxlovid to see if a doctor can prescribe a longer course of treatment.

The case of longer treatment

Does it justify a longer course of treatment? “In my mind, yes,” said Ho, who, in addition to studying Paxlovid’s recovery, has experienced it himself. In studies, Ho says he has observed Paxlovid do the job of blocking SARS-CoV-2, stopping the virus from further replicating and essentially trapping it in an intermediate form. This version of the virus is not yet fully formed and requires a few more development steps before it becomes active and can infect new cells. Paxlovid blocks the virus at this stage. But in Ho’s studies, the half-life of the virus in this suspension is close to a day – anywhere from 19 to 22 hours – meaning it takes a long time for about half of the viruses to survive. withdraw decomposition. For an infected person, if there is still enough of this intermediate form in the body after the fifth and last day of Paxlovid treatment, the virus can reactivate, end the process, and start again. begin to re-infect the cells — thereby causing the infection to flare up again.

“This virus is quite persistent,” Ho said. “And we believe that five days of treatment isn’t enough to break down that form so it doesn’t last by the end of those five days.”

Based on their lab results, Ho’s team calculated that extending Paxlovid by a few days — three to five days from the current regimen — could reduce the risk of recovery by 10 times. A few more days will eliminate more of the intermediate form of the virus circulating in the body. Ho says more studies are needed to confirm that and to confirm that it is safe to extend the medication by a few days.

Paxlovid isn’t the only antiviral drug that works this way. Paxlovid is a protease inhibitor – meaning it interferes with its ability to form the final proteins it needs – and other drugs in this class of drugs cause similar re-infection. For example, Ho said, ensitrelvir, a SARS-CoV-2 antiviral drug that Japanese pharmaceutical company Shionogi is working on, produced similar intermediates without degradation prior to discontinuation of the drug. and bounced back to cause the infection again. “It’s related to the drug’s mechanism of action, not to the deficit [Paxlovid]”Ho said.

It’s similar to how antibiotics work: if people stop taking antibiotics before the allotted time is up, the infection can return before a sufficient number of bacteria have been eliminated. “We’ve certainly seen infections where, if you give treatment, you lower the levels of bacteria or viruses, but if you don’t get rid of it completely,” Siedner said. — and then it flared up again,” Siedner said. With Paxlovid’s recovery, “my guess is it happened because people didn’t get treatment long enough.”

Some people infected with SARS-CoV-2 who do not take Paxlovid even develop recurrent infections, where they test negative and think they have recovered, but then test positive a few days later again. , Siedner said. But the situations are different. “People who recover from Paxlovid have much higher viral loads, viral loads stay high for a longer time, and symptoms last longer,” he said. no drugs, he said. “Paxlovid’s recovery is the real deal.”

In a statement, a Pfizer spokesperson said that because the company’s early studies showed similar recovery rates in the treatment and placebo groups, those data “revealed a return of RNA” Nose-detected virus (also known as viral reconstitution or COVID-19 convalescence) is uncommon and is not uniquely associated with any particular treatment. “

However, Ho noted that those studies were not specifically designed to detect and measure recovery, and more detailed analyzes are needed.

In addition to taking a longer course of Paxlovid, another option to tackle recovery, experts say, is to allow patients to start a second round of Paxlovid when they test positive again, experts say. Gia said. A Pfizer spokesperson confirmed that the company is working with the FDA to set up a trial to study this.

The case against a longer course of treatment

Like any medication, Paxlovid has side effects – the most common of which is an extremely unpleasant taste in the mouth, which temporarily affects some people’s ability to eat. It also interacts with a number of other commonly used medications, including cholesterol-lowering statins. “We often ask people to stop taking certain other medications or reduce their dosage,” said Dr. their medication for five days while taking Paxlovid. in patients. “Asking them to stay longer may have more risks and outweigh the benefits of doing so. There are a lot of complications to just asking someone to take a pill for 7 or 10 days.”

Siedner also notes that when considering the benefits versus risks of longer treatment, doctors need to consider how much of an impact people recover from a second infection. In a study from Kaiser Permanente of 5,000 people who took Paxlovid, less than 1% ended up in the hospital because of their symptoms — including those who recovered. “Overall, the health record system does not show that large numbers of people need to be hospitalized that could be avoided with longer treatment,” he said. “If recovery is not frequent and people who do recover are not at higher risk of hospitalization than people who are not on Paxlovid, then I think there may not be much benefit to giving people a course of treatment. longer.”

Another fear about prolonging Paxlovid’s treatment is that SARS-CoV-2 could become resistant. Ho reported the first evidence of this in a paper published August 8 in preprint on the bioRxiv server. In laboratory studies, he and his team found that when the virus is challenged with a dose of Paxlovid, it develops multiple pathways to evade the drug, raising concerns about the need for it. next-generation antiviral drugs or use them in combination, as doctors do now. What to do to control HIV. More studies are needed to document how quickly the virus develops resistance to Paxlovid and whether extending treatment by a few days increases this risk.

Is it still worth taking Paxlovid?

For people with risk factors that make them more vulnerable to COVID-19, doctors continue to say that the benefits of Paxlovid outweigh the risk of a flare-up again, as the drug protects people from getting sick. sick enough to need to be hospitalized and not die from COVID-19. Most people who do recover report relatively mild symptoms and do not require more intensive medical care. Even if some people won’t be able to completely stop their infection after a course of Paxlovid, treatment can still help them avoid more serious illness. As more data becomes available, health officials can reassess the length of that course of treatment.

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