Nirmatrelvir/ritonavir reduced mortality in severe or critical COVID-19 patients: a multicenter retrospective cohort study

Background Patients with severe or critical coronavirus disease 2019 (COVID-19) remain at a high risk of mortality. Although nirmatrelvir/ritonavir has demonstrated efficacy in non-severe COVID-19 patients with high-risk factors, its effectiveness in hospitalized patients with severe or critical COVID-19 remains unclear. This study evaluates the effectiveness of nirmatrelvir/ritonavir in this specific population. Methods In this multicenter retrospective cohort study, we included adults hospitalized with severe or critical COVID-19 at three tertiary hospitals in Shaanxi Province between December 2022 and November 2023. Participants were non-randomly categorized into either the nirmatrelvir/ritonavir group or the non-antiviral group based on whether they received nirmatrelvir/ritonavir during hospitalization. The primary outcome was 28-day mortality, and secondary outcomes included in-hospital mortality and post-baseline hospitalization duration. Results Among the 386 patients (nirmatrelvir/ritonavir group, n = 173, and non-antiviral group, n = 213), those in the nirmatrelvir/ritonavir group had significantly lower 28-day mortality than those in the non-antiviral group (6.9% vs. 15.5%; p = 0.002). Additionally, the nirmatrelvir/ritonavir group had reduced in-hospital mortality rates (8.1% vs. 16.0%; p = 0.003). After multivariable adjustment, the use of nirmatrelvir/ritonavir remained independently associated with a reduced risk of 28-day mortality (adjusted hazard ratio (aHR) = 0.346, 95% confidence interval (CI): 0.175–0.687; p = 0.002) and in-hospital mortality (aHR = 0.374, 95% CI: 0.196–0.716; p = 0.003). Subgroup analyses suggested that the reduced mortality risk was particularly evident in patients aged ≥65 years, non-smokers, those without chronic lung disease or hypertension, those with critical illness, and those who initiated treatment within 5 days of symptom onset. The median post-baseline hospitalization duration was longer in the nirmatrelvir/ritonavir group than in the non-antiviral group (11.0 vs. 9.0 days; p = 0.019). Conclusion Nirmatrelvir/ritonavir was associated with significantly reduced mortality in patients hospitalized with severe or critical COVID-19, supporting its clinical use in this population.