Effectiveness of Nirmatrelvir/Ritonavir for Outpatients in the Era of Omicron, Vaccination, and Previous Infection: A Meta-analysis

BACKGROUND: Since the benefit of nirmatrelvir-ritonavir (N-R) may have changed in contemporary patients, we assessed the effectiveness of N-R for preventing hospitalization and death among outpatients with COVID-19 in the Omicron era. METHODS: This was a meta-analysis of cohort studies comparing rates of hospitalization and/or mortality in outpatients treated with N-R compared with untreated patients. Analysis was limited to studies conducted since December 2021 that performed an adjusted multivariate analysis. Quality was assessed using the Newcastle-Ottawa Scale. Summary estimates of adjusted relative risks (aRR) with 95% confidence intervals (CI) and prediction intervals (PI) were calculated overall and for prespecified subgroups. Heterogeneity was summarized visually and with τ and 95% PIs. Absolute effects were estimated by applying pooled aRRs to baseline risks to obtain absolute risk reductions (ARRs) and numbers needed to treat (NNTs). RESULTS: Forty-seven studies (10,791,211 patients) were included. Pooled aRRs were 0.54 (95% CI, 0.43-0.68) for all-cause hospitalization and 0.45 (0.36-0.56) for COVID-19 hospitalization. Pooled RRs were 0.30 (0.23-0.39) for all-cause mortality and 0.43 (0.32-0.59) for COVID-19 mortality. PIs were < 1.0 for COVID-19 hospitalization (0.21-0.96), all-cause mortality (0.11-0.83), and any mortality (0.13-0.88), indicating likely benefit in future studies in similar settings. Subgroup analyses showed larger effects earlier in the Omicron period for hospitalization (RR 0.46 vs 0.68; p = 0.0049) and the composite outcome (0.45 vs 0.68; p = 0.0078), and a smaller mortality reduction among immunocompromised patients (RR 0.26 vs 0.11; p = 0.034). The estimated NNT to prevent a COVID-19 hospitalization for patients at low risk (0.16%), moderate risk (2.2%), and high risk (8.9%) of hospitalization based on a validated risk score were 1148, 84, and 20 respectively. DISCUSSION: N-R is associated with reduced hospitalization and death. Absolute risk reductions of hospitalization are small in low-risk patients but clinically meaningful in moderate- and high-risk patients.