Paxlovid Rebound: What Scientists Know So Far

EASYr. David Ho has spent his entire career researching HIV and other viruses, so he thought he knew what to expect when he was recently infected with SARS-CoV-2. His symptoms were not too severe, but after discussing with his doctor, Ho decided to take Paxlovid, an antiviral COVID-19 therapy administered by Pfizer, over a five-day course. At 69, he fits the description of someone who should. The US Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) introduce Paxlovid for people at high risk for severe COVID-19, including seniors.

Cough carefully monitors his infection. He had access to PCR testing and gene sequencing in his lab at Columbia University, as well as rapid antigen kits to test yourself at home. He started Paxlovid the day after he first experienced cold symptoms and the antigen test came back positive. A PCR test on day 2 confirmed infection and Ho continued on daily therapy with two different pills for five days, as indicated. Every day from day 4 to day 9, his antigen test was negative, and two PCR tests done on day 5 and day 7 were also negative.

But on the 10th day, she had a headache, runny nose and mild cough. Ho decided to test himself at home and to his surprise, he tested positive again, the PCR test result confirmed. His team sequenced the virus to compare it with the genetic sequence from his previous infection and found that it resembled the virus he had been infected with a few days earlier — indicating that the virus withdraw did not mutate to become resistant to Paxlovid, nor did he become infected with another virus. The same infection flared up again after being extinguished for a few days.

“I was surprised to see the recovery,” he said. “I was expecting Paxlovid to sort things out.”

Recovery like Cough is always a potential side effect of medication. In studies, Pfizer reports that 1% to 2% of people taking the drug recover. The company said that recovery rates were similar in the treated group in its study and among those given the placebo, suggesting that “elevated viral RNA in the nose is uncommon and unrelated.” solely concerned with treatment”. But more and more people are reporting a flare-up of the infection again after taking Paxlovid – so many that “it doesn’t happen at 1% or 2%,” said Ho, who also shared the data. and discussed with scientists at Pfizer said. “It happens quite a bit.” Anecdotes about people who test positive, take a course of Paxlovid, test negative, and then test positive again a few days later are rife on social media. It has been scientifically documented; Researchers at the University of California, San Diego recently described a case of recovery on May 18 paper was published on the server prior to printing in Research Square (meaning it has yet to be peer-reviewed). And on May 24, CDC issued health advice instruct the physician caring for the patient on medication how to manage relapses.

Ho decided to delve deeper into this phenomenon when he learned that a colleague, Dr. Michael Charness at the VA Boston Health Care System, had a similar experience. Scientists (both vaccinated and booster) collaborated and conducted perhaps the most comprehensive analysis of the phenomenon to date, because they were able to conduct daily checks and monitor evolution negative to positive and also performed genetic sequencing of the virus to confirm that the infection was caused by the same virus that flared up again, and not a new infection. Of them paperpublished in Research Square, describing their own cases, as well as eight additional cases where people reported a rebound of the virus after taking Paxlovid.

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

Why do people even take Paxlovid if their COVID-19 is recoverable?

Paxlovid is a combination of two drugs: one protease inhibitor used to treat HIV infection, which stops the virus from making important proteins it needs to replicate, and another that prevents the liver from breaking down the drug too much. rapidly in the body.

It is not currently FDA approved, but doctors can prescribe it under an emergency use authorization. Authorization is based on studies conducted by Pfizer showing this drug efficiency up to 88% in protecting unvaccinated people from needing to be hospitalized with COVID-19, or dying from the infection. The company is continuing to study Paxlovid in vaccinated and boosted people to see if their immune response somehow reacts differently to the drug.

“We are continuing to monitor the data, but we have not seen any resistance develop to date in patients treated with Paxlovid,” a Pfizer spokesperson said in a statement to TIME. . We believe that the return of elevated viral RNA detected in the nose is uncommon and is not uniquely related to treatment. We remain very confident in the clinical efficacy of Paxlovid in preventing serious COVID-19 outcomes in high-risk patients. ”

Why did Paxlovid’s recovery happen?

Scientists are still trying to determine why people with COVID-19 are taking Paxlovid, testing negative for a few days, then testing positive again. But they are exploring a number of potential reasons. One theory is that people are simply being re-infected in rapid succession with different variants of SARS-CoV-2, because cases are increasing in the country and because the virus mutates so quickly. Another explanation could be that because the virus mutated so quickly, it developed a way to escape Paxlovid and became resistant to its effects.

But Ho believes something else is going on. His small study showed that three of the infections in his report – his, Charness and another’s – were recurrences of the first strains, not new or a Paxlovid-resistant variant. new. Based on genetic sequencing data, “we have shown that the recovered virus is not resistant to protease inhibitors. [drug in Paxlovid], because there is no change in the protease sequence,” he said. “It can’t reinfection with another virus. The sequences are identical. Pfizer said their studies similarly showed the virus did not develop resistance to protease inhibitors.

Instead, Ho believes the virus is just doing what it does in response to antiviral drugs. No antiviral drug — whether against SARS-CoV-2 or HIV — actually kills any virus present in an infected person; they work by blocking certain steps in the virus’s replication cycle, freezing them in time so the virus can’t continue to make more copies of itself. Paxlovid specifically disrupts the step involved in the protease enzyme, which joins the long polypeptide chains that the virus produces after infecting a cell. That long protein needs to be cut into its component proteins, which then play the role of creating a new virus. By inhibiting that step, Paxlovid leaves the virus in suspension — and depending on when the drug is started, an infected person could have thousands of these long polypeptide chains already created and floating. around the body, creating a potential reservoir for viral products. can work again. The drug prevents these intermediates from cutting and infecting cells, but when the drug is stopped after day 5, the enzyme is no longer inhibited and can go back to splicing and making viral proteins. That could lead to a flare-up again, as more and more viruses are created that can re-infect cells.

“We know the drug has a very short half-life, which means it doesn’t stay long in the body,” says Ho. “The virus is not killed by the drug, but only by preventing its replication. There’s still a reservoir of viral material, so as a virologist, that’s the first thing that comes to mind. Once the drug is cleared, that reservoir can be active again.”

Ho is currently conducting experiments in his laboratory to find out how long the SARS-CoV-2 intermediate polypeptide can stay in the body, to determine if a 5-day treatment period is long enough. are not. Perhaps one way to minimize recurrent infections is to extend the number of days on Paxlovid, but Pfizer will have to conduct new studies to determine how many more days are needed and how safe and effective the drug is if that’s the case. Pfizer is considering whether these studies should be performed to better understand whether specific populations may require longer treatment with the drug.

Should you take Paxlovid again if the result is positive after finishing the 5 day course?

According to the recent CDC’s health advice Regarding Paxlovid’s recovery, the agency does not recommend that people who have finished a five-day course start taking the drug again. Instead, the CDC advises people who test positive again to restart the 5-day isolation period and wear a mask for 10 days after symptoms recover.

Ho said the CDC reached out to discuss the best strategies for managing the recovery before issuing new guidance. The CDC doesn’t particularly recommend that people who are testing themselves for Paxlovid more often after finishing treatment, but Ho does recommend that people follow current advice and do a quick home test if they have any symptoms. , however mildly, reappeared, regardless of whether they performed Paxlovid or not.

How sick will I be if I test positive again after taking Paxlovid?

The CDC notes that most people who recover experience mild symptoms a second time, and most will clear up on their own without further treatment.

If I test positive after taking Paxlovid, will I still be contagious?

Right. Anyone who tests positive for the rapid test — even after finishing a full course of drug treatment — can become infected again and can pass the virus on to others. It is important for people taking Paxlovid to guard against the possibility of re-infection and to use rapid at-home antigen tests as often as possible and confirm the diagnosis with PCR testing where possible. so they will know if they have complications. positive again.

Of the 10 cases reported by Ho, two people passed the virus on to other members of their household after they relapsed. “The idea of ​​a person being negative for the virus and then being able to come back positive for the virus – that is very interesting,” he said.

Given the resilience, should Paxlovid be taken?

The emergency use authorization now restricts doctors from prescribing the drug only to people at higher risk of serious illness, including older adults and people with compromised immune systems. . Otherwise, healthy people, especially those who have been vaccinated and boosted, may not benefit from this therapy, especially because people need to start taking it as close to when they experience symptoms. the best proof for it to be effective. Recovery may only prolong their isolation, as they can recover without medication and without recurrent infections in a shorter period of time.

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