The Coronavirus Disease 2019 Rebound Study: A Prospective Cohort Study to Evaluate Viral and Symptom Rebound Differences in Participants Treated With Nirmatrelvir Plus Ritonavir Versus Untreated Controls

Abstract

Background The uptake of nirmatrelvir plus ritonavir (NPR) in patients with COVID-19 has been limited by concerns around the rebound phenomenon despite the scarcity of evidence around its epidemiology. The purpose of this study was to prospectively compare the epidemiology of rebound in NPR-treated and untreated participants with acute COVID-19 infection. Methods We designed a prospective, observational study in which participants who tested positive for COVID-19 and were clinically eligible for NPR were recruited to be evaluated for either viral or symptom clearance and rebound. Participants were assigned to the treatment or control group based on their decision to take NPR. Following initial diagnosis, both groups were provided 12 rapid antigen tests and asked to test on a regular schedule for 16 days and answer symptom surveys. Viral rebound based on test results and COVID-19 symptom rebound based on patient-reported symptoms were evaluated. Results Viral rebound incidence was 14.2% in the NPR treatment group (n=127) and 9.3% in the control group (n=43). Symptom rebound incidence was higher in the treatment group (18.9%) compared to controls (7.0%). There were no notable differences in viral rebound by age, gender, pre-existing conditions, or major symptom groups during the acute phase or at the 1-month interval. Conclusion This preliminary report suggests that rebound after clearance of test positivity or symptom resolution is higher than previously reported. However, notably we observed a similar rate of rebound in both the NPR treatment and control groups. Large studies with diverse participants and extended follow-up are needed to better understand the rebound phenomena.

A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound

“…Notably, antiviral therapy is not a risk factor for rebound in our model or in clinical cohorts if administered late during infection 36 . However, high viral load shedding is a risk factor for rebound in our model, as suggested in other studies 37 .…”

“…However, the use of nirmatrelvir/ritonavir in real-world cohorts has identified viral rebound as a significant issue. Viral rebound occurred in 14.2% of individuals in one large cohort and was usually associated with recrudescence of symptoms, though protection against hospitalization and death appeared to be maintained (6) and remains significant despite high rates of population immunity due to vaccination and prior infection (7) . Similar rates of viral rebound were observed between molnupiravir and nirmatrelvir, suggesting the rebound effect is not drug-specific and may pertain to characteristics of SARS-CoV-2 infection and treatment duration (8) .…”

SARS-CoV-2 virologic rebound with nirmatrelvir-ritonavir therapy

“…Data are conflicting about whether nirmatrelvir-ritonavir (N-R) is associated with virologic rebound (VR). [1][2][3][4][5][6][7] However, precise estimation of VR incidence with and without N-R use has been limited by infrequent and short-term sampling, symptomatic reporting, and absence of culture data.…”

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

“…We speculate that the more extensive interactions of the ketoamide adduct or the azetidinyl group may provide a degree of redundancy in binding that is absent in NTV. The possibility of NTV resistance arising is especially concerning given the routine occurrence of rebound cases after NTV treatment ( 104 , 105 ) and prolonged treatments of immunocompromised patients ( 48 , 49 ), because these persistent infections provide favorable conditions for mutations to arise.…”