SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir−ritonavir (N-R) and virologic rebound (VR). Objective: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. Design: Observational cohort study. Setting: Multicenter health care system in Boston, Massachusetts. Participants: Ambulatory adults with acute COVID-19 with and without use of N-R. Intervention: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. Measurements: The 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. Results: Compared 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. Limitations: Observational 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. Conclusion: Virologic 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 Source: National Institutes of Health.