From December 1, 2022, to January 31, 2023, we collected data from 4077 patients with COVID-19 in our hospital. After applying the exclusion criteria, a total of 2862 patients were included in this study. Of these, 1,490 received azvudine treatment, while 1372 received standard treatment. The flowchart of the entire study process is detailed in Fig. 1.

Flowchart of COVID-19 patient selection

Table 1 displays the baseline demographic and clinical characteristics of the patients. Preliminary data indicated differences between the two groups in several variables. Specifically, the azvudine group had a higher proportion of males, older age, and more severe cases compared to the control group. To ensure comparability between the groups, we adjusted for variables with P < 0.05 in the univariate Cox regression analysis (S1) and conducted 1:1 propensity score matching (PSM).

After PSM, we identified 920 patients receiving azvudine treatment and 920 patients in the control group for analysis. The baseline characteristics of both groups remained balanced, with a standardized mean difference (SMD) < 0.1 (S2, S4). In addition, after inverse probability of treatment weighting (IPTW) matching, a total of 2867 azvudine-treated patients and 2877 patients receiving standard treatment were included, with an SMD < 0.1 (S3, S4).

In the original cohort analysis, no significant impact on the 28-day mortality rate was observed in hospitalized patients with COVID-19 (15.8% vs. 21.8%, P = 0.065) (Fig. 2A). However, after adjusting for confounding factors using PSM and IPTW, azvudine significantly improved the 28-day mortality rate in hospitalized patients with COVID-19 (20.9% vs. 19.2%, P = 0.003 and 21.8% vs. 23.7%, P = 0.039, respectively) (Fig. 2B, C).

All cause mortality outcomes in azvudine recipients and control group. A Original queue; B after propensity score matching; C after inverse probability of treatment weighting

To further investigate the relationship between azvudine treatment and patient mortality rates, we compared patients in different clinical subtypes. In mild COVID-19 patients, azvudine treatment did not significantly alter the 28-day mortality rate (3.3% vs. 21.0%, P = 0.086) (Fig. 3A). However, in patients with moderate (12.9% vs. 9.5%, P = 0.043), severe (37.2% vs. 39.8%, P = 0.014), and critical conditions (64.9% vs. 46.4%, P = 0.008), those receiving azvudine intervention exhibited significantly different 28-day survival rates compared to those receiving standard treatment (Fig. 3B–D).

28-day mortality rate of various clinical types in COVID-19 patients. A Mild. B Moderate. C Severe. D Critical

When administered to severe and critical patients, azvudine showed a more significant reduction in mortality rates at 7 days (10.1% vs. 1.7% and 34.7% vs. 8.1%, respectively) and 14 days (23.0% vs. 8.4% and 46.5% vs. 22.9%, respectively) (Fig. 3C, D). These data indicate that azvudine can improve the survival rates of patients with COVID-19, particularly for severe and critical patients.

Based on Cox regression analysis, in the original cohort, azvudine treatment reduced 7-day (1.09/1000 people vs. 5.06/1000 people, P < 0.001) and 14-day (3.35/1000 people vs. 5.65/1000 people, P = 0.001) mortality rates. However, the effect on 28-day mortality (4.38/1000 people vs. 5.65/1000 people, P = 0.065) was not significant (Table 2).

Post-propensity score matching, the azvudine group demonstrated significantly improved all-cause mortality rates at 7 days (0.80/1000 people vs. 6.29/1000 people, P < 0.001), 14 days (3.42/1000 people vs. 7.26/1000 people, P < 0.01), and 28 days (4.33/1000 people vs. 7.29/1000 people, P = 0.003). This finding aligns with results following IPTW adjustment.

Subgroup analysis based on COVID-19 clinical grading revealed that in mild patients, azvudine reduced mortality within 7 days (HR: 0.04, 95% CI 0.00–0.74, P = 0.030), but not significantly at 14 days (HR: 1.02, 95% CI 0.34–3.07, P = 0.968) or 28 days (HR: 0.98, 95% CI 0.34–2.84, P = 0.966). In moderate, severe, and critical patients, azvudine significantly reduced mortality rates at 7, 14, and 28 days, with greater effectiveness observed in critical patients.