The U.S. Centers for Disease Control and Prevention (CDC) has admitted that COVID-19 patients may experience a rebound SARS-CoV-2 infection after taking Pfizer’s antiviral drug, Paxlovid. Evidence has shown that patients, including those who have gotten COVID shots and been boosted, may suffer a reoccurrence of COVID two to eight days after completing a five-day course of Paxlovid.1
According to the CDC’s Advisory Committee on Immunization Practices (ACIP), this rebound infection doesn’t mean the anti-viral medication didn’t work, and ACIP continues to recommend the treatment for early-stage COVID suffers. Some patients have milder COVID symptoms than they originally had and others have the same or worse symptoms, while remaining contagious and able to spread the SARS-CoV-2 virus to others.2
In December, Pfizer was granted an Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) to distribute Paxlovid for patients who are at least 12 years of age, have mild or moderate COVID, and are at high risk of severe infection, such as the elderly, smokers, people with underlying medical conditions, and patients who are pregnant or obese. The government has made Paxlovid available for free to all COVID positive people.3 Administered within five days of a COVID diagnosis, three Paxlovid pills are taken two times a day for five days..4
Pfizer claims that its new antiviral drug is 87-89 percent effective at preventing a 28-day hospitalization stay or death for COVID patients.5 However, in a growing number of patients these effects appear temporary with patients initially feeling better and some even testing negative upon completion of the five-day course only to have a resurgence of symptoms and a positive test about a week later. Some patients only have a positive test without having symptoms while others have the same or worse symptoms as their original bout with COVID.6
Infectious disease doctor Davey Smith, MD warned:
There were a lot of symptoms associated with the rebound, actually, almost as much as there was for the original infection. Headache, fatigue, cough.7
Experts Debate How Best to Address Rebound Infections
Pfizer’s CEO, Albert Bourla, encourages patients experiencing a resurgence of infection to simply take another course of the antiviral. The FDA and the CDC have advised patients not to repeat the course of medication and instead to simply quarantine for a minimum of five days and wear a mask for a minimum of 10 days.8
Some speculate that the virus itself causes rebound infections in sufferers, while others question whether it is the antiviral medication that is causing the relapse. Health and Human Service officials continue to recommend Paxlovid, maintaining that doctors should actually prescribe it more often, especially for the most vulnerable patients. As of May 14, 2022, only 670,000 doses have been used in the U.S. out of two million available doses.9
There are currently no plans to conduct a comprehensive study to further investigate the potential reasons why there are rebounding SARS-CoV-2 infections after Paxlovid use. Andre Kalil, MD, professor at the University of Nebraska Medical Center asked:
There’s no question rebound happens—we’ve seen it since the beginning of the pandemic. Is the rebound related to infection itself? Is the rebound related to the administration of drugs like Paxlovid, or is a rebound related to neither? That’s the question.10
Early on, clinicians ruled out the possibility that COVID formed resistance to Paxlovid by analyzing the genome of the virus and finding that there were no mutations to the part of the virus that the medication acts upon. When submitting their documents for an EUA, Pfizer wrote, “several subjects appeared to have a rebound in SARS-CoV-2 RNA levels around Day 10 or Day 14” but, “currently there are no clear signals” that the virus developed resistance to the antiviral medication.”11
Pfizer elaborated in a statement to the Boston Globe…
We continue to monitor data from our ongoing clinical studies and real-world evidence. We have not seen any resistance to Paxlovid, and remain very confident in its clinical effectiveness.12
Other experts disagree and hypothesize that the virus may have developed resistance to Paxlovid, just as some strains of influenza have become resistant to the antiviral, Tamiflu. The theory is that, as the virus tries to copy its genetic code to replicate, it is creating mutations in the viral protein sequences allowing the virus to evade the antiviral medication and leading to a drug resistant infection. Drug trials may not have been long enough to see this effect.13
Another possibility is that the drug is so effective that it neutralizes the virus immediately before it has the chance to trigger the immune system to send B and T cells. While another theory is that the virus is not completely eradicated during the five-day course of antivirals, allowing the virus to repopulate once the medication is stopped.14
Small Patients Had Rebound Infections in Pfizer’s Clinical Trials
In Pfizer’s clinical trials of Paxlovid, rebound infections occurred in one to two percent of patients in both the treatment and placebo groups. Researchers wonder why that number wasn’t higher based on the prevailing theories as to why rebound infections may be occurring.
One clue could be that the patients in the clinical trial were quite different than the population for which Paxlovid is generally prescribed now. Study participants were unvaccinated, had to meet specific high-risk criteria, and were infected with the Delta variant. The majority of the real-world population taking Paxlovid are vaccinated and boosted, do not meet the specific high-risk criteria, and are infected with the Omicron variant.15
Some researchers speculate that the issue is that the immune system responds differently to Omicron than it does to other COVID variants. Or that Omicron infections trend to be upper respiratory tract infections and the medication isn’t staying in that area of the body long enough to completely disable the virus.16 Pfizer’s trials took place when Delta was the dominant strain of COVID and now the dominant strain is Omicron.17
According to Monica Gandhi, MD, an infectious disease doctor, rebound infections…
could be simply because we’re simply not using it in the populations in which it’s been studied. We’re not even, to be fair, using them in the population for which the FDA gave it an emergency use authorization.18
Patients Tell Their Story
A case report tells the story of a of a 71-year-old man who was fully vaccinated and boosted, but tested positive for the Omicron variant of COVID and began a course of Paxlovid. After two days of taking the antiviral medication, his symptoms went away. However, four days after he completed the five-day course, he tested positive for Omicron again. All of his symptoms including a runny nose, sore throat and breathing difficulty returned.19 There were no mutations to the virus found that could have developed resistance to the medication.20
Patients and doctors have been reporting their experiences with rebound infections on social media including Twitter and Reddit. Patients have told Paul Sax, MD, Clinical Director of the Division of Infectious Disease at Brigham and Women’s Hospital, about their rebounding infections. Concerned, he said:
At the very least, people who take Paxlovid and clinically recover should not ignore their symptoms if they come back. They should think this is a recurrence of COVID, and then [test] themselves again.21
Pfizer has yet to release the full data from the clinical trials which may help researchers and doctors determine why so many patients are experiencing rebound infections. Meanwhile, Pfizer issued the following statement:
We remain confident in its clinical effectiveness at preventing severe outcomes from Covid-19 in high-risk patients.22
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Click here to view References:
1 Thompson D. COVID Can ‘Rebound’ After Treatment With Paxlovid, CDC Says. U.S. News & World Report May 24, 2022.
3 Shaheen M. CDC warns that Covid patients treated with Biden-touted antiviral Paxlovid may have symptoms rebound after they finish treatment – saying its part of virus’s ‘natural history’. Daily Mail May 24, 2022.
4 Health Fre Bendix A. CDC warns of ‘Covid-19 rebound’ after taking Paxlovid antiviral pills. NBC News May 24, 2022.
5 Auwaerter P. Paxlovid Rebound: What Is Happening? Medscape May 13, 2022.
6 Mast J. As reports of ‘Paxlovid rebound’ increase, Covid researchers scramble for answers. STAT May 24, 2022.
11 Lazer K. A puzzling phenomenon: Patients report a rebound of COVID-19 symptoms after taking the antiviral Paxlovid. Boston Globe Apr. 21, 2022.
13 Mast J. As reports of ‘Paxlovid rebound’ increase, Covid researchers scramble for answers. STAT May 24, 2022.
17 Lee BY. Paxlovid Rebound: FDA Investigating Reports Of Covid-19 Relapses After Taking Pfizer Antiviral. Forbes May, 19, 2022.
18 Mast J. As reports of ‘Paxlovid rebound’ increase, Covid researchers scramble for answers. STAT May 24, 2022.
19 Lee BY. Paxlovid Rebound: FDA Investigating Reports Of Covid-19 Relapses After Taking Pfizer Antiviral. Forbes May, 19, 2022.
20 Goodman B. Covid-19 cases that return after antiviral treatment puzzle doctors. CNN Apr. 27, 2022.
21 Lazer K. A puzzling phenomenon: Patients report a rebound of COVID-19 symptoms after taking the antiviral Paxlovid. Boston Globe Apr. 21, 2022.
22 Goodman B. Covid-19 cases that return after antiviral treatment puzzle doctors. CNN Apr. 27, 2022.