What’s Up with Paxlovid COVID Rebound Infection?

When Paxlovid (nirmatrelvir + ritonavir) was given emergency use authorization (EUA) on December 22, 2021, by the FDA, there was a lot of excitement. At long last, there was an oral anti-viral medicine that was supposed to be highly effective against COVID-19. Now, though, there are numerous reports of Paxlovid COVID rebound following the initial 5-day treatment program. What’s up with that? Researchers provide an answer in JAMA Network Open (Oct. 27, 2022). It might help you decide whether to consider a prescription for Paxlovid in the event you catch (or re-catch) COVID-19.

Initial Enthusiasm for Paxlovid:

On November 5, 2021, the maker of Paxlovid (Pfizer) offered the following statement about the drug’s effectiveness:

“The scheduled interim analysis showed an 89% reduction in risk of COVID-19-related hospitalization or death from any cause compared to placebo in patients treated within three days of symptom onset (primary endpoint); 0.8% of patients who received PAXLOVID™ were hospitalized through Day 28 following randomization (3/389 hospitalized with no deaths), compared to 7.0% of patients who received placebo and were hospitalized or died (27/385 hospitalized with 7 subsequent deaths)…In the overall study population through Day 28, no deaths were reported in patients who received PAXLOVID™ as compared to 10 (1.6%) deaths in patients who received placebo.”

We were impressed and wrote about the promise of Paxlovid in this article.

Is the Oral Pill Paxlovid an Answer to COVID-19?
What should you know about PAXLOVID, an oral medicine against COVID-19? How hard is it to get an Rx? What about dangerous interactions?

Puzzling Paxlovid COVID Rebound:

Since that initial enthusiasm there have been reports that some patients experioence Paxlovid COVID rebound. People who were vaccinated against SARS-CoV-2 were coming down with the infection and were promptly started on the antiviral drug Paxlovid. Within a day or two they were getting better. After finishing the five-day course of treatment, they assumed they were “cured.” They tested negative for the virus and were feeling pretty good.

Then something strange happened. Instead of continuing to feel fine and resume normal activities, some of these patients began experiencing Paxlovid COVID rebound within a couple of days. That is to say, they were developing symptoms of the coronavirus all over again. They were also testing positive for COVID-19. They isolated themselves from family and friends and assumed they were infectious once more.

What Did the FDA Say about Paxlovid COVID Rebound?

We asked some key executives at the FDA what the agency’s position is on the Paxlovid rebound phenomenon. First, we were told that

“We are on the case.”

A follow-up message from a different FDA exec added this:

“…based on the data the benefit still outweighs the risk of rebound. ‘The benefit of a 5-day treatment course of Paxlovid was demonstrated in the clinical trial that supported the EUA. This study showed that among non-hospitalized patients at high risk of progression to severe disease, treatment with Paxlovid reduced the risk of hospitalization or death by 88%.’”

New Data About Paxlovid COVID Rebound:

Why would people go from a positive test for COVID-19 to a negative test and then get a positive test again a few days later? The answer may lie with the coronavirus. Researchers at the University of California, San Diego (UCSD) just published the results of their study in JAMA Network Open (Oct. 27, 2022).

These investigators utilized data from people in the placebo arm of a Paxlovid clinical trial. The participants in the trial kept detailed diaries of their symptoms. 30% experienced rebound symptoms after at least two days of feeling better.

The most common recurrent problems were cough, fatigue and headache. The lead author remarked:

“It is clear that COVID-19 has waxing and waning of symptoms, whether they are treated or not.”

The authors of the study go on to describe COVID-19 this way:

“Using daily symptoms data from a prospective trial, we found the natural history of untreated COVID-19 was variable and undulating. Over one-third of participants who experienced symptom resolution for at least 2 consecutive days within the first 4 to 5 weeks of COVID-19 symptoms reported recurrent symptoms.”

Remember, these patients were getting placebo, not Paxlovid!

The CDC Guessed Right:

Here is the official CDC response on Paxlovid COVID rebound:

“Paxlovid treatment helps prevent hospitalization and death due to COVID-19. 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.”

Final Words:

The UCSD Study in JAMA Network Open concludes:

“Consistent with an earlier report, our results in persons with untreated COVID-19 shows that recurring symptoms are common among those who initially improve, but these recrudescent symptoms do not portend progression to severe COVID-19.”

“Recrudescent” is one of those doctorspeak $10 words that means a new outbreak after recovery.

One of the health professionals I trust is Dr. Bob Wachter. He is chair of the Department of Medicine at the University of California, San Francisco. He coined the term “hospitalist” in 1996 and is often considered the “father” of the hospitalist field, the fastest growing medical specialty in U.S. history. He is past president of the Society of Hospital Medicine and past chair of the American Board of Internal Medicine.”

Dr. Bob Wachter Tweeted:

“I was asked by a reporter today if I’d take Paxlovid if I had Covid. Last month, this would have been easy: as a 64-year-old person w/ asthma, the answer was an unequivocal YES.

“Today, it’s a closer call–

“I would still take it, mainly based on my teetering but still fairly high confidence that it would lower my chance of an awful outcome (hospitalization/death), and my confidence that rebound would be inconvenient, but not ultimately super-risky.”

Faced with a similar choice, I would probably take Paxlovid as well. Because Paxlovid interacts with lots of other medications, though, anyone who takes this drug should ask both the prescribing physician and the dispensing pharmacist if there are any interactions to watch out for!