Viral SARS-CoV-2 Rebound Rates in Linked Commercial Pharmacy-Based Testing and Health Care Claims

Background Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs. Methods We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)–treated and untreated individuals during the Omicron era (December 2021–November 2022) and prior to the Omicron era (October 2020–November 2021). Results Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%–5.7%) in NMV-r–treated infections as compared with 1.5% (95% CI, 1.3%–1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%–2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%–4.8%). Viral rebounds to high RNA levels in NMV-r–treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r–treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%–1.2%). Conclusions Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.