• Gregory E Edelstein, Julie Boucau, Rockib Uddin, Caitlin Marino, May Y Liew, Mamadou Barry, Manish C Choudhary, Rebecca F Gilbert, Zahra Reynolds, Yijia Li, Dessie Tien, Shruti Sagar, Tammy D Vyas, Yumeko Kawano, Jeffrey A Sparks, Sarah P Hammond, Zachary Wallace, Jatin M Vyas, Amy K Barczak, Jacob E Lemieux, Jonathan Z Li, and Mark J Siedner.
• Brigham and Women's Hospital, Boston, Massachusetts (G.E.E., Y.K., J.A.S.).
• Ann. Intern. Med. 2023 Dec 1; 176 (12): 157715851577-1585.

BackgroundData are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir-ritonavir (N-R) and virologic rebound (VR).ObjectiveTo compare the frequency of VR in patients with and without N-R treatment for acute COVID-19.DesignObservational cohort study.SettingMulticenter health care system in Boston, Massachusetts.ParticipantsAmbulatory adults with acute COVID-19 with and without use of N-R.InterventionReceipt of 5 days of N-R treatment versus no COVID-19 therapy.MeasurementsThe primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL.ResultsCompared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected.LimitationsObservational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission.ConclusionVirologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus.Primary Funding SourceNational Institutes of Health.

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