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

Heng Zhao^1,2Wanting Meng¹Xing Lv¹Shaokui Si²Shunjun Wu¹Jing Li¹Zhigui Cai¹Ruoqi Jin¹Ling Yang¹Chenyao Li¹Liqiang Song^1*

• ¹Department of Pulmonary and Critical Care Medicine, Xijing Hospital of Air Force Medical University, Xi'an, China
• ²Department of Pulmonary and Critical Care Medicine, The 987th Hospital of the PLA Joint Service Support Force, Baoji, China

Background: Patients with severe or critical COVID-19 remain at 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 a nirmatrelvir/ritonavir group or a non-antiviral group according to 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 the non-antiviral group, n=213), those in the nirmatrelvir/ritonavir group had significantly lower 28-day mortality than the non-antiviral group (6.9% vs. 15.5%; P = 0.002), as well as reduced in-hospital mortality (8.1% vs. 16.0%; P = 0.003). After multivariable adjustment, nirmatrelvir/ritonavir use remained independently associated with a reduced risk of 28-day (aHR = 0.346, 95% 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 reduced mortality risk was particularly evident in patients aged ≥65 years, non-smokers, and those without chronic lung disease or hypertension, with critical illness, and initiating treatment within 5 days of symptom onset. The median post-baseline hospitalization duration was longer in the nirmatrelvir/ritonavir 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.