Rebound Symptoms After Paxlovid for COVID-19: Many Cases and Many Unanswered Questions

In early May, the skeptical cardiologist began hearing reports of “Paxlovid rebound”: patients who developed recurrent COVID-19 symptoms 2 to 8 days after completing a treatment course of Paxlovid. Little did I suspect that I would end up with a case of this rebound phenomenon.

The CDC posted a health advisory on “COVID-19 Rebound After Paxlovid Treatment” on May 24 which concluded that these case reports should not alter the typical 5-day treatment course of Paxlovid:

COVID-19 rebound has been reported to occur between 2 and 8 days after initial recovery and is characterized by a recurrence of COVID-19 symptoms or a new positive viral test after having tested negative. A brief return of symptoms may be part of the natural history of SARS-CoV-2 (the virus that causes COVID-19) infection in some persons, independent of treatment with Paxlovid and regardless of vaccination status. Limited information currently available from case reports suggests that persons treated with Paxlovid who experience COVID-19 rebound have had mild illness; there are no reports of severe disease. There is currently no evidence that additional treatment is needed with Paxlovid or other anti-SARS-CoV-2 therapies in cases where COVID-19 rebound is suspected.

A five-day treatment of the antiviral medication, Paxlovid, in non-hospitalized, unvaccinated patients at high risk of progression to severe disease had been shown to reduce the risk of hospitalization or death by 88% in a large randomized clinical trial.

When I wrote about Paxlovid (predominantly covering in detail its interaction with numerous cardiac drugs) in January of this year it was just becoming available but now it is widely available at community pharmacies.

Paxlovid and My Rebound

When I contracted COVID-19 in early May I was able to begin taking the antiviral medication within an hour of a positive home antigen test. I felt like within 12 hours of starting the medication my symptoms improved and during the 5 days of taking it I was progressively better each day.

Two days after stopping the Paxlovid I felt very good in the morning and rode my bike for 40 minutes. However, in the afternoon I began feeling anxious and worried for no apparent reason. These symptoms prompted me to drink a can of Arrogant Bastard Ale, the first alcohol I had consumed since I developed COVID-19 symptoms. (This, in retrospect was a bad idea for it appears I have developed post-COVID alcohol intolerance as one of several “intermediate COVID-19” symptoms.)

The next day (day 10, 3 days after stopping Paxlovid) I noted the new development of a slight runny nose and a worsening of my cough. In the afternoon, I became extremely fatigued. That night, sneezing and runny nose worsened, accompanied by upper airway congestion, frequent, cough and headache. I felt so tired I went to bed at 8 PM and slept for 9 hours.

The symptoms worsened over the next few days. On days 11 and 12 I experienced worsening of the upper respiratory infection symptoms with sneezing and runny nose, upper airway congestion, more frequent coughing, and headache. My temperature remained normal but weakness and fatigue were prominent.

The worsened symptoms post-Paxlovid continued through day 15 and then I began a slow steady improvement.

A Series of Paxlovid Rebound Cases

Eight cases of Paxlovid rebound were reported in a recent preprint case series. These were non-immunocompromised individuals aged 31 to 72 years. The symptoms noted during relapse (typically days 9-12 of the illness) were usually like mine: milder versions of the original COVID-19 symptoms including nasal congestion, sore throat, fatigue and headache.

The authors include this very complicated but informative spreadsheet detailing the time course of positive tests, Paxlovid administration, and symptoms:

Of note, the authors documented that “One symptomatic and one presymptomatic patient transmitted SARS-CoV-2 to family members during relapse.”

The authors concluded that ” The presence of high viral load and the occurrence of two transmission events suggest that patients with relapse should isolate until antigen testing is negative.”

Multiple Family Members with Paxlovid Rebound

An astute reader of my blog who contracted COVID-19 in early May noted multiple cases of Paxlovid rebound (PR)in her family and with her permission, I am sharing her detailed summary of these cases below:

She noted that younger members of her extended family who developed COVID-19 did not take Paxlovid and did not experience any rebound including a 40-year-old son-in-law and grandchildren aged 11 and 13.

Implications for Treatment and Isolation

A Stat news article on PR indicates that Pfizer’s CEO, Albert Bourla, has suggested that patients who experience one take another course of the drug. However, the CDC is advising against that:

We are continuing to review data from clinical trials and will provide additional information as it becomes available. However, there is no evidence of benefit at this time for a longer course of treatment (e.g., 10 days rather than the 5 days recommended in the Provider Fact Sheet for Paxlovid) or repeating a treatment course of Paxlovid in patients with rRitaecurrent COVID-19 symptoms following completion of a treatment course.

Rita Rubin has written a nice summary for JAMA on PR which was published June 8. She incorporates some of the speculations on why it is occurring that I have seen on social media:

Scientists have proposed a few other possible explanations for rebounds after nirmatrelvir/ritonavir treatment. “Question number 1 in my mind is the timing. I think maybe we’re giving it too early,” del Rio said. Perhaps, Wachter speculated, “If you get started right away, maybe you suppress the virus [and] the immune system doesn’t rev up in the way it normally would.” He and others have also suggested that 5 days might not be a long enough treatment course. “All these theories are total handwaving,” Wachter acknowledged.

A big question that remains unanswered is whether Paxlovid rebound cases remain infectious for a longer duration than the standard COVID-19 case . Many patients are reporting prolonged positive rapid antigen tests associated with their PR (including yours truly) while some are reporting a return of positive rapid antigen tests after a day or two of negative antigen tests.

Michael Mina, an MD, PhD immunologist, feels a positive rapid antigen test is a good marker for infectivity. He sent this tweet out to his >200K followers in late May:

Mina is the chief medical officer for emed which has the strategy “to combine the most authoritative and inexpensive in-home test kits with the largest real-time network of certified remote proctors.” Clearly, if everyone tests daily until negative there will be a lot of additional tests performed.

The CDC is not recommending testing until negative before ending isolation and neither are health care employers.

Recommendations

We clearly don’t know enough about Paxlovid rebound cases to make informed decisions in many areas including treatment approach and isolation therefore my strongest recommendation is to report your case to Medwatch as I did or to Pfizer.

Pending further information from analyses of a large series of these cases by the CDC/FDA I would advise following the CDC guidance.

As I noted in my article on “Starting and Stopping the Isolation Clock” the CDC advises “You can end isolation after 5 full days if you are fever-free for 24 hours without the use of fever-reducing medication and your other symptoms have improved.”

“You should continue to wear a well-fitting mask around others at home and in public for 5 additional days (day 6 through day 10) after the end of your 5-day isolation period. If you are unable to wear a mask when around others, you should continue to isolate for a full 10 days. Avoid people who have weakened immune systems or are more likely to get very sick from COVID-19, and nursing homes and other high-risk settings, until after at least 10 days.”

The CDC May 24 Health Advisory on COVID-19 rebound cases advises:

Patients should re-isolate for at least 5 days. Per CDC guidance, they can end their re-isolation period after 5 full days if fever has resolved for 24 hours (without the use of fever-reducing medication) and symptoms are improving. The patient should wear a mask for a total of 10 days after rebound symptoms started.

In my case, I pondered whether I should take another course of Paxlovid when I developed the rebound but ultimately decided not to. Subsequently, the CDC has come out with recommendations again additional Paxlovid treatment or other antiviral therapy. Fortunately, for now, there is no evidence that PR results in severe COVID-19 cases that require hospitalization.

Paxlovid was proven effective in unvaccinated COVID-19 patients. We need studies that determine what its efficacy and safety is in people like me-fully vaccinated, over age 65 and without other risk factors. Is it prolonging the illness? How is it affecting the prevalence of long or intermediate COVID-19 symptoms? Does it contribute to the late transmission of the virus?

Tolerantly Yours,

-ACP