A multicenter retrospective cohort study conducted across ten hospitals in Henan Province, China has found that azvudine demonstrates effectiveness comparable to nirmatrelvir/ritonavir (Paxlovid) in treating hospitalized patients with SARS-CoV-2 infection and pre-existing chronic liver diseases.
Study Design and Patient Population
Researchers analyzed data from 37,606 hospitalized patients with SARS-CoV-2 infection, identifying 1,355 azvudine recipients and 373 nirmatrelvir/ritonavir recipients who met the inclusion criteria of having pre-existing chronic liver diseases. To balance baseline characteristics and minimize selection bias, the study employed a 2:1 propensity score matching approach.
The final analysis included 674 patients in the azvudine group and 364 patients in the nirmatrelvir/ritonavir group. Patients' chronic liver conditions included hepatitis, cirrhosis, autoimmune hepatitis, nonalcoholic fatty liver disease (NAFLD), and metabolic-associated fatty liver disease (MAFLD).
Key Findings on Effectiveness
The primary analysis revealed no significant difference between azvudine and nirmatrelvir/ritonavir regarding all-cause death (p=0.34) within the 30-day follow-up period. The crude incidence rate of all-cause death was 10.94 per 1,000 person-days in the azvudine group versus 12.74 per 1,000 person-days in the nirmatrelvir/ritonavir group.
After adjusting for covariates through multivariate Cox regression analysis, the hazard ratio for all-cause death in the azvudine group was 0.80 (95% CI: 0.574-1.128, p=0.208) compared to the nirmatrelvir/ritonavir group, indicating no statistically significant difference between the treatments.
For the secondary outcome of composite disease progression (including application of high-flow nasal cannula oxygen therapy, mechanical ventilation, ICU admission, and all-cause death), the results similarly showed no significant difference between the two treatment groups (p=0.32). The crude incidence rate was 22.06 per 1,000 person-days for azvudine versus 19.13 per 1,000 person-days for nirmatrelvir/ritonavir.
Subgroup Analysis Reveals Important Differences
Notably, subgroup analysis revealed that azvudine demonstrated superior effectiveness specifically for patients with comorbid primary malignant tumors. For this patient subgroup, azvudine was associated with a significantly lower risk of all-cause death compared to nirmatrelvir/ritonavir (HR: 0.21; 95% CI: 0.09-0.48).
Additionally, azvudine showed better outcomes for patients who began treatment more than 5 days after symptom onset (HR: 0.50; 95% CI: 0.28-0.90), suggesting it may be particularly beneficial for patients with delayed treatment initiation.
Safety Profile Comparison
The safety evaluation revealed that both medications had acceptable safety profiles. Patients receiving azvudine showed a relatively lower risk of increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) compared to those receiving nirmatrelvir/ritonavir, suggesting potentially better liver function outcomes with azvudine.
Dynamic monitoring of liver function parameters over 15 days post-treatment showed that ALT levels were above normal range in both groups, with AST levels gradually decreasing in both treatment arms. Gamma-glutamyl transpeptidase (GGT) levels were elevated in both groups, with azvudine showing a slower recovery rate, though the difference was not statistically significant except at the 12-day mark.
Supporting Evidence from Additional Studies
These findings align with a separate single-center retrospective study conducted at the First Affiliated Hospital of Soochow University between December 2022 and February 2023. This study, which employed a 1:3 propensity score matching to compare 521 azvudine recipients with 207 nirmatrelvir/ritonavir recipients, found no significant differences in discharge rates with improvement (88.9% vs. 87.9%, p=0.816) or median improvement time (5.0 days vs. 5.5 days, p=0.732).
The Soochow University study also found comparable rates of high-flow nasal cannula use, non-invasive mechanical ventilation, invasive mechanical ventilation, and disease progression between the two treatment groups.
Clinical Implications
These findings have important implications for clinical practice, particularly in regions where cost considerations may influence treatment decisions. Azvudine, as the first Chinese-developed oral anti-COVID-19 agent, may offer a cost-effective alternative to nirmatrelvir/ritonavir with comparable effectiveness for most patients with chronic liver diseases.
The superior effectiveness of azvudine for patients with comorbid primary malignant tumors is particularly noteworthy. Researchers hypothesize that this advantage may be related to azvudine's unique mechanism of action. Unlike nirmatrelvir/ritonavir, which is a protease inhibitor combination, azvudine is a nucleoside analog that inhibits RNA-dependent RNA polymerases. Additionally, azvudine has been found to concentrate in the thymus with its active form after oral administration, potentially protecting immune function—a critical factor for patients with both liver disease and malignancy.
Study Limitations
The authors acknowledge several limitations to their research. As a retrospective study, there exists potential for non-randomized treatment selection bias, though propensity score matching was employed to balance baseline characteristics. The inclusion of severe/critical patients beyond guideline reference may introduce selection bias, and the cohort is representative only of Henan province, limiting generalizability to other regions and ethnicities.
Additionally, real-world drug choice may be influenced by factors such as drug availability, clinician preferences, cost-effectiveness, and patient affordability. The study also lacked information on specific treatment duration, which could affect clinical outcomes.
Conclusion
This multicenter retrospective cohort study provides valuable evidence that azvudine offers effectiveness comparable to nirmatrelvir/ritonavir for hospitalized SARS-CoV-2 infected patients with pre-existing chronic liver diseases. The findings suggest that azvudine may be particularly beneficial for patients with comorbid primary malignant tumors and those with delayed treatment initiation.
While further randomized controlled trials with larger samples are needed to confirm these findings, this study provides important guidance for clinicians selecting antiviral treatments for this vulnerable patient population during the ongoing COVID-19 pandemic.
