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Paxlovid Rebound COVID-19 – What You Need to Know

September 2, 2022

Written by Davin Brar

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Some patients treated with nirmatrelvir-ritonavir (Paxlovid) may develop rebound symptoms or convert to a positive antigen test after completion of treatment and initial clinical improvement. Unfortunately, such patients may continue to shed virus and remain infectious while experiencing rebound symptoms.

Why does this matter?
There are numerous new therapies being developed to combat COVID-19. In the ED, we will not only be prescribing these therapies, but will also have to manage any potential side effects. Paxlovid is administered under emergency use authorization (EUA) by the FDA and has been associated with reduced risk of severe disease and hospitalization for high-risk patients with early COVID-19 infection. Unfortunately, there have also been reports of rebound symptoms after treatment. But what do these rebound symptoms mean for viral shedding, infectivity, and patient isolation?

Paxlovid shoots…it hits the rim…but who has the rebound?
This was a case series of 7 patients who were treated with 5 days of Paxlovid and subsequently developed recurrent symptoms or had recurrent antigen test positivity after initially testing negative when their treatment course was complete. All 7 patients were fully vaccinated and had received at least 1 booster vaccine dose. Each of the patients reported symptom improvement and had a negative antigen test after treatment. In total, 6 of the 7 patients had symptom recurrence and the other patient had a positive antigen test after treatment but was asymptomatic. On average, rebound symptoms occurred around day 9 after a positive test or 4 days after completion of Paxlovid treatment. Viral load was detectable for a median of 12 days (range 9-15) after completion of Paxlovid, and live virus was identified up to 11 days after completion of treatment. Conversely, it was recently reported that untreated COVID-19 patients only shed virus for a median of 5 days after an initial positive test.

These data suggest that patients treated with Paxlovid who have rebound symptoms may be at high risk for continued viral shedding. Therefore, patients with recurrent symptoms may warrant additional isolation and monitoring, even after an initial negative antigen test. Thankfully, there were no resistance associated mutations in the 6 SARS-CoV-2 specimens that were sequenced. 

This study was a small case series of only 7 patients and had several limitations. Patients also enrolled after clinical rebound, so we don’t know the actual incidence of rebound symptoms after Paxlovid treatment. Larger studies are needed to determine the incidence, clinical course, and public health impact of rebound after Paxlovid treatment. However, based on these results, we may need to rethink guidelines for isolation and repeat testing for patients with rebound symptoms.

Edited and Peer-Reviewed by Sam Parnell

Characterization of virologic rebound following nirmatrelvir-ritonavir treatment for COVID-19. Clin Infect Dis. 2022 Jun 23;ciac512. doi: 10.1093/cid/ciac512. Online ahead of print.

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