BACKGROUNDSimnotrelvir has demonstrated potent anti-viral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In a Phase II/III study, Simnotrelvir plus ritonavir (S/R, co-packaged) shortened the time to the resolution of symptoms in adult COVID-19 patients. However, real-world data on effectiveness of simnotrelvir/ritonavir against SARS-CoV-2 during XBB omicron variant surges are still limited.STUDY DESIGN AND METHODSThis was a nationwide, multicenter, prospective, observational real-world study at 42 sites in China. Adult patients with mild to moderate COVID-19 and at disease onset were eligible for participation. Patients were grouped in S/R group (treated with S/R) and control group (not receiving oral antivirals for COVID-19). The primary endpoint was the COVID-19-related hospitalization or all-cause mortality within 28 days. Secondary endpoints included the time from confirmed SARS-CoV-2 infection to negative conversion, and the time to resolution of COVID-19 symptoms. Besides, serious adverse events (SAE), adverse drug reactions (ADR) and combined medication were reported. Propensity Score-Matched (PSM) analysis (1:1) was performed for adjustment for baseline variables. Hazard ratios (HR) and adjusted risk ratios (aRR) were estimated using the Cox and Modified poisson regression, respectively.RESULTSBetween June 6, 2023 and December 27, 2023, 3522 patients were enrolled. S/R was associated with a reduced incidence of COVID-19-related hospitalization (6/1896 [0.3%] vs. 43/1408 [3.1%]; HR: 0.110, 95% confidence interval [CI]: 0.043 to 0.283, p<0.001 vs control), consistently with the results after PSM (4/1381 [0.3%] in S/R vs. 40/1381 patients [2.9%]; aRR: 0.12; 95% CI: 0.05, 0.29; P<0.001). No deaths occurred in both S/R and control groups. Matched Patients over 65 and patients with risk factors who received S/R achieved significantly reduced risk of COVID-19 related hospitalization (aRR: 0.032; 95% CI: 0.004, 0.268; aRR: 0.034; 95% CI: 0.005, 0.252, respectively; all P<0.001). Furthermore, S/R shortened the median time to viral clearance by 1 day (6.0 vs 7.0 days; 95% CI: -2.0 to -1.0; P<0.001) and reduced the median time to symptom resolution by 2 days (8.0 days vs 10.0 days; 95% CI: -2.0 to -1.0; P<0.001). Besides, the proportion of patients in the S/R group using combined medication was significantly lower than that in the control group (30.2% vs 49.4%). Subgroup analysis showed potential protective effect of S/R in the elderly and patients with more than 1 risk factor.CONCLUSIONIn real world, S/R significantly reduced the incidence of COVID-19-related hospitalization, demonstrated favorable safety profiles, and less use of combined medication.