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.