Effectiveness of Nirmatrelvir/Ritonavir or Molnupiravir Use in Immunocompromised Patients on B-Cell–Depleting Therapy With COVID-19: A Target Trial Emulation Study

Abstract

Background. Immunocompromised patients, especially those receiving B-cell-depleting therapy (BCDT), remain at high risk for severe coronavirus disease 2019 (COVID-19). Although monoclonal antibodies showed benefit pre-Omicron, the real-world effectiveness of the oral antivirals in BCDT recipients is unclear. Methods. We emulated a target trial using the Cleveland Clinic electronic health record. Adult patients (≥18 years) with immune-mediated inflammatory diseases who received rituximab or ocrelizumab and tested positive for severe acute respiratory syndrome coronavirus 2 between 19 December 2021 and 30 June 2025 were eligible. The primary endpoint was hospitalization or death within 21 days; the secondary endpoint was death within 90 days. Propensity scores adjusted for confounding, and Weighted Cox regression models were used to evaluated treatment effects. Results. Among 255 853 COVID-19 cases, 876 met criteria for the nirmatrelvir/ritonavir cohort (411 treated, 465 untreated) and 566 for the molnupiravir cohort (91 treated, 475 untreated). In the nirmatrelvir/ritonavir cohort, 18 (4.4%) of treated versus 43 (9.2%) of untreated patients were hospitalized or died within 21 days. After weighting, nirmatrelvir/ritonavir reduced the hazard by 44% (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.31-0.99). In the molnupiravir cohort, 6 (6.6%) of treated and 46 (9.7%) of untreated patients met the primary endpoint; the weighted HR was 0.56 (95% CI, 0.24-1.33), not statistically significant. Conclusions. Early outpatient nirmatrelvir/ritonavir significantly lowers the risk of COVID-19-related hospitalization or death in patients on BCDT. Molnupiravir showed a nonsignificant trend toward benefit. These findings support prioritizing nirmatrelvir/ritonavir for high-risk immunocompromised populations.