Paxlovid & Virologic Rebound


Paxlovid (nirmatrelvir-ritonavir) is an oral antiviral that inhibits the main protease of SARS-CoV-2. It reduces the incidence of hospitalization and death among patients with mild to moderate COVID-19, and is particularly recommended in patients who are over 65yo, are immunocompromised, have specific comorbidities, and/or are over 50yo and unvaccinated.

Paxlovid is associated with a virologic rebound (VR) phenomenon characterized by recurrence of symptoms and reversion to SARS-CoV-2 test positivity after initial recovery with treatment. 

The frequency and epidemiology of VR is poorly understood, in part because of a lack of consensus around how to define it. Prior studies have estimated the frequency of VR after Paxlovid to be anywhere from 1-2% (similar to rates of VR occurring in patients who did not receive Paxlovid) to 14%

Recent Data

A recent prospective observational cohort study in the Annals of Internal Medicine compared the frequency of VR in patients with and without Paxlovid treatment for acute COVID-19 in the outpatient setting. The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive elevated viral loads (see study for how viral load elevation was defined).

The study found that frequent monitoring by both PCR and viral culture during the acute stages of COVID-19 showed that VR occurred in ~20% of persons taking Paxlovid and 2% of those who were not using therapy. VR was also associated with prolongation of viral shedding (median, 14 vs. 3 days). 

Source: Edelstein et al. Ann Intern Med. 2023

The authors noted that we should consider strategies to prevent or mitigate the potential risk for rebound-associated transmission. Notably, 100% (57 of 57) of people who did not experience VR after Paxlovid use had a negative culture result 5 days after completion of therapy. By contrast, most persons (14 of 15) who experienced VR after Paxlovid use had a positive culture result at or around that same time point. Rapid antigen testing 5 days after completion of therapy might help identify VR and might help determine who would benefit from prolonged isolation after Paxlovid treatment. 

Of note, when the authors restricted their analysis to 3 time points based on viral load, as was done in prior trials, they detected a 2.4% rate of VR. This suggests that the discrepancy between the incidence of VR found in this study and that described in prior studies may result from differences in frequency of sampling and use of culture methods to detect VR. 


Nevertheless, two CDC analyses of multiple studies have found no statistically significant relation between incidence of VR and previous treatment with antiviral drugs:

Overall, these studies yielded no statistically significant evidence that treatment with any of the approved drugs for treating COVID-19 raised the risk for VR. When VR did occur, it generally affected patients who were immunocompromised or who had significant comorbidities, and it was not associated with increased mortality or hospitalization.

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