Paxlovid No Panacea for the COVID-Vaccinated

Louise B. Andrew, MD, JD


August 16, 2022

Paxlovid is not the panacea for which we, the amply vaccinated, had hoped.

Everyone I know (or have heard of) who has experienced Paxlovid "rebound" is an older person with or without known comorbidities, a physician or researcher, or some kind of celebrity. All reportedly exquisitely vaccinated and boosted.

I haven't maintained a running list, but you know some of these names well. Biden is just the latest. Very curious to learn in the media that Tony Fauci, MD, took a second course of Paxlovid, which goes against current FDA recommendations. ("Do as I say, not as I do?"). Peter Hotez, too.

Oddly, the only question thus far being raised publicly in the medical community is whether a supposedly "illness-mitigating" drug that seems to accompany a significant incidence of rebound or recurrent illness should be taken for even longer than the recommended 5 days.

Rebound from COVID is reported to occur after symptomatic recovery, and is characterized by a recurrence of symptoms and a new positive viral antigen test after having tested negative.

Rebound isn't mentioned at all in the initial results from the Pfizer EPIC-HR (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients) trial, the basis for Paxlovid's emergency use authorization. Post-study analysis recently done by the authors suggested that 1%-2% of participants in both treatment and placebo groups may have experienced rebound, leading one FDA spokesperson to conclude "it is unclear at this point that this [rebound] is related to drug treatment." This trial was conducted prior to Omicron, and no participants were vaccinated.

EPIC-HR illustrated a 6.32% absolute risk reduction in incidence of COVID-19–related hospitalization or death by day 28 in the Paxlovid vs placebo group. What was reported, however is the "relative risk reduction" of hospitalization/deaths between the groups, which is actually .89 but is reported as 89.1%. (Which sounds a lot more reassuring, right? And don't forget that this risk reduction — be it absolute or relative — still needs to be balanced by other risks, and/or benefits, that may be associated.)

Paxlovid seems relatively safe despite numerous contraindications and is now recommended for older individuals or those with one or more risk factors for severe COVID. A recent retrospective study (still in preprint, not yet peer reviewed) of EHRs of > 13,000 individuals in the US experiencing COVID "rebound" after two of the most popular antivirals (including Paxlovid) concluded that age is not a significant risk factor for post–antiviral therapy–associated COVID rebound. But it doesn't appear that they evaluated the phenomenon sufficiently in older (or much older) individuals, as opposed to just those with preexisting conditions. Granted, there is typically a high correlation between length of existence and existing or preexisting conditions.

But this study is among the first publicly available regarding COVID rebound after antivirals that also looked at vaccination status of participants. Despite finding that patients experiencing rebound had higher EHR-documented vaccination rate than those not experiencing rebound, authors report that the differences did not meet thresholds for statistical significance.

Despite this, they state in their conclusion: "Our study showed that the vaccination rates were higher in patients who developed COVID-19 rebound than in those who did not, suggesting that vaccination was not a major contributor for COVID-19 rebound." Seems an odd conclusion.

A more recently preprinted comparison of Paxlovid (also known as NM/R) with molnupiravir use in Hong Kong, conducted during Omicron, reported a 75% "relative risk reduction" in mortality and a 31% relative risk reduction in hospitalization using NM/R over placebo. If replicable, this suggests a significantly decreased risk reduction associated with use of NM/R for Omicron. Not surprising, given the general reduced level of illness severity being seen with Omicron. But it does suggest that there may be progressively diminishing returns to antiviral use, especially if there are other risk considerations.

A small case series published in preprint May 23 reported on 10 early cases of Paxlovid rebound, one of which (a study coauthor) is a Harvard virologist researcher. Albeit a "convenience sample," all 10 cases occurred within two families, suggesting to the author that rebound following such treatment is not rare.

Hay et al reported in another preprint retrospective study of data collected from NBA personnel (including players, staff, and other vendors) who underwent occupational infection surveillance and became infected with the SARS-CoV-2 delta and Omicron variants who did not receive Paxlovid/NM/R. In this study, rebound (as defined by PCR cycle threshold, PCT measurement) occurred in about 0.7%. An unpublished study from this same cohort experiencing Omicron and not Paxlovid (1000 patients) showed no cases of rebound.

Interestingly, COVID rebounds were more common in boosted individuals in this (highly vaccinated) cohort, occurring in 6.48% of boosted individuals vs 0.923% in vaccinated, and in 1.24% in unvaccinated individuals. Also, whereas boosting did reduce rates of infection in the study cohort, boosted individuals who did experience Omicron BA.1 infections tended to remain infectious (using PCT measures) longer than individuals who had only undergone an initial vaccine course.

As mentioned, Pfizer indicated that only 1%-2% of patients who took Paxlovid in initial clinical trials tested positive for COVID again soon after finishing their dosage. Pfizer has not released figures from later trials using vaccinated participants.

But experts fear that the rebound rate may be higher or even much higher than that optimistic pre-Omicron estimate, and that antivirals might actually contribute, perhaps by suppressing patients' immune systems too early. Also, we don't yet know whether there's increased risk of developing long COVID with longer duration of illness. Some very prominent mainstream physicians are admitting that they are unsure about what to recommend, or even what to do for themselves if infected.

I certainly wasn't sure what to do when I fairly recently had COVID (6 weeks after my fourth full vaccination.)

But despite being older and with risk factors, I did not hesitate to not take Paxlovid for what was an incredibly mild illness.

Because, isn't it conceivable that all of these vaccinated physicians, researchers, celebs, and I represent the (as yet undetermined) unlucky rebounding percentage (seemingly much more than 2)?

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About Dr Louise Andrew
Louise B. Andrew, MD, JD, is a fifth-generation physician/attorney and a past officer in the American College of Emergency Physicians and, recently, in the American Medical Association Senior Physicians Section. She cofounded a number of physician service organizations and has received numerous national and international awards. Throughout her career in emergency medicine and since, she has maintained and, websites supporting physicians. She teaches, counsels, testifies, and mediates for physicians, hospitals, and others on aspects of physician wellness, behavior, litigation and regulatory stress management, medical expert witness issues, disability, and physician suicide prevention.


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