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COVID-19 Rebound in Nirmatrelvir Plus Ritonavir Treatment and Control Groups: Prospective Cohort Study
Jacqueline K Kueper1, Kalyani Kottilil1, Giorgio Quer1
1Scripps Research Translational Institute, Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, United States, 1 858-784-1000.
Interactive Journal of Medical Research
|June 2, 2026
Summary
COVID-19 rebound, including viral and symptom recurrence, was observed in patients treated with nirmatrelvir plus ritonavir (NPR) and in untreated individuals. However, the incidence of rebound was significantly higher in the NPR group compared to the control group.
Area of Science:
- Virology
- Infectious Diseases
- Clinical Research
Background:
- COVID-19 rebound after nirmatrelvir plus ritonavir (NPR) treatment raises questions about direct-acting antiviral efficacy.
- NPR is a primary direct-acting antiviral therapy for COVID-19.
Purpose of the Study:
- To investigate the epidemiology of COVID-19 rebound in US outpatients.
- To compare rebound incidence between patients who independently chose NPR and an untreated control group.
Main Methods:
- Prospective, decentralized observational cohort study (August 2022 - December 2023).
- Included frequent COVID-19 rapid antigen testing and symptom surveys for 15 days.
- Primary outcome: incidence of viral and symptom rebound.
Main Results:
- Higher 15-day cumulative incidence of viral (15.8% vs 5.3%) and symptom (16.5% vs 8.4%) rebound in the NPR group versus controls.
- Among patients who cleared by day 15, viral rebound probability was higher in the NPR group (19.1%) than controls (7%).
- Symptom rebound probability was also higher in the NPR group (47.7%) compared to controls (16.9%).
Conclusions:
- COVID-19 rebound occurs in both NPR-treated and untreated outpatients.
- The incidence of both viral and symptom rebound is higher in the NPR group.
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