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Nirmatrelvir-Ritonavir Rebound – COVID-19 Strikes Again

December 26, 2023

Written by Nick Zelt

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Treatment of COVID-19 with nirmatrelvir-ritonavir (N-R) was associated with virologic rebound (VR) in a prospective observational trial. Viral loads were high enough to cause transmission, though it remains unclear if certain patients may require longer insolation periods or how to identify those patients without significant retesting.

Baby (please don’t) come back.
Rumours of VR, resurgence of COVID-19 viral replication, and sometimes clinical disease after treatment with N-R have been circulating for some time.  Until now, data on virologic rebound have been largely retrospective, based on case reports and a single prospective home-based testing study.

These authors performed a sub-analysis from data collected for POSITIVES (Post-vaccination Viral Characteristics Study), a prospective observational cohort study. COVID-19 positive patients who were treated with N-R (n = 72) or received no treatment (n = 55) self-collected nasal swabs 3 times per week for at least 2 weeks or until viral loads were undetectable. The primary outcome was VR within 20 days, with viral load cut-offs based on previous data correlating these levels to a risk of transmission. 

Patients taking N-R were more likely to have VR (21%) compared to those without treatment (2%), absolute difference 19% (95%CI 9-29, p = 0.001). The N-R group was older, received more COVID-19 vaccinations and had more immunosuppression. After multivariable logistic regression to account for demographic data, only N-R use was associated with VR, aOR 10 (95%CI 1.13 to 88.74, p = 0.038). No instances of drug resistance mutations were detected post N-R treatment.

How will this change my practice?
I thought this would change my advice about isolation periods. Sadly, it will not, since the overall number of days to negative culture was similar when comparing all N-R patients to the no-therapy group. I can’t even suggest those with return of symptoms isolate for longer because only half the patients with VR reported symptoms, and only 30% of patients reporting rebound symptoms had VR. Interestingly, when authors limited their collection strategy to only the specific time points measure in the EPIC-HR study, 81% of VR events would not have been detected. Another reason to be skeptical of industry-run studies even when they appear thorough.

SARS-CoV-2 Virologic Rebound With Nirmatrelvir-Ritonavir Therapy : An Observational Study. Ann Intern Med. 2023 Dec;176(12):1577-1585. doi: 10.7326/M23-1756. Epub 2023 Nov 14.