COVID-19, caused by the SARS-CoV-2 virus, has significantly impacted global health, especially among the older population due to their age-related decline in immune function and a higher prevalence of comorbidities (Bartleson et al., 2021). Older individuals were particularly susceptible to severe outcomes from COVID-19 due to their weakened immune response and higher likelihood of having underlying health conditions that exacerbate the severity of the disease (Sanyaolu et al., 2020; Bartleson et al., 2021). Epidemiological data have revealed that individuals aged 65 years and over accounted for more than 60% of hospital admissions and a considerable proportion of ICU admissions in Northern Italy, indicating higher hospitalization and mortality rates in this demographic (Azzolina et al., 2022). Notably, a mortality rate as high as 30% has been observed in patients aged 80 and above, in stark contrast to less than 5% for those below 60 (Bonanad et al., 2020). Among these patients, prolonged hospital stays and an increased need for ventilatory support have been frequently observed, along with a higher incidence of post-hospitalization complications (O'Mahoney et al., 2023). Additionally, the presence of comorbidities such as hypertension, diabetes, and chronic respiratory diseases significantly exacerbated the risk of severe outcomes (Sanyaolu et al., 2020). Therefore, the development and evaluation of COVID-19 treatments have been necessitated to specifically include older patients, ensuring the representativeness of data for this particular group. Therefore, in the development and evaluation of COVID-19 treatments, older patients must be specifically included to ensure the research findings represent this important demographic.

In 2022, China experienced a significant breakthrough in COVID-19 treatment. This progress was marked by the National Medical Products Administration (NMPA) and the National Healthcare Security Administration (NHSA) approving the clinical use of two oral medications, Nirmatrelvir-Ritonavir and Azvudine (Zhu, 2023). These agents, which were included in the medical reimbursement list, were extensively utilized during the winter 2022 outbreak. Nirmatrelvir was formulated with Ritonavir, a pharmacokinetic enhancer. It targeted SARS-CoV-2’s main protease, known as Mpro or 3CLpro (Hashemian et al., 2023). This action was key in blocking the virus’s ability to process polyprotein precursors, thus hindering viral replication (V'Kovski et al., 2021). The combination’s enhanced efficacy was due to Ritonavir inhibiting the metabolism of Nirmatrelvir through CYP3A, increasing its plasma levels (Dian et al., 2023). In February 2022, Nirmatrelvir-Ritonavir was approved by the NMPA as the first treatment for mild to moderate COVID-19 cases in China primarily for adult patients (Shi et al., 2023). Azvudine, identified as a synthetic nucleoside analog, was recognized for its effects exerted through phosphorylation within cells, leading to the formation of its active metabolite, Azvudine triphosphate. It received conditional authorization from the NMPA for treating COVID-19 in China on 25 July 2022 (Zhu, 2023).

Previous studies have provided empirical data on the use of Nirmatrelvir-Ritonavir and Azvudine in the treatment of COVID-19, especially in older populations (Wee et al., 2023). Nirmatrelvir-Ritonavir showed effectiveness in reducing the disease’s severity and mortality (Talic et al., 2021; Nyberg et al., 2022; Hughes et al., 2023; Jing et al., 2023; Najjar-Debbiny et al., 2023). Azvudine has also shown generally good effectiveness and safety in early stages of infection, but more real-world multi-center data were still needed (Chen and Tian, 2023b). Other options besides these two drugs also exist, and have demonstrated potential therapeutic value in early infection (Mazzitelli et al., 2023a; Mazzitelli et al., 2023b; Grundeis et al., 2023; Kip et al., 2023; Wong et al., 2023). One such drug, Remdesivir, works by inhibiting COVID-19 replication by interfering with viral RNA synthesis (Grundeis et al., 2023). Monoclonal antibody treatment neutralizes the virus by targeting surface proteins, thereby reducing the severity of symptoms caused by infection (Kip et al., 2023; Lin et al., 2023). Similarly, Molnupiravir disrupts viral replication by introducing errors into the viral genome (Teli et al., 2023; Mazzitelli et al., 2023a; Wong et al., 2023; Mazzitelli et al., 2023b). Although these pharmacological interventions expand the scope of treatment, additional studies are needed to characterize their safety in older groups. Furthermore, due to regulatory approval, Nirmatrelvir-Ritonavir and Azvudine have achieved wider adoption in clinical settings in China than alternative medicines.

The principal objective of this study was to compare the safety and effectiveness of Nirmatrelvir-Ritonavir and Azvudine in the treatment of older patients with early infection of COVID-19. The differences in treatments, outcomes, and adverse effects of the two medications were specifically assessed and analyzed in this study. This comparison would provide valuable insight into the optimal management of early infection of COVID-19 in older patients, a demographic that remains at high risk of severe disease and complications.

This study compared the safety and effectiveness of Nirmatrelvir-Ritonavir and Azvudine in older patients hospitalized with COVID-19. A cohort of 375 subjects was selected from a pool of patients at a tertiary hospital in China during the peak of the pandemic. During that time, both Nirmatrelvir-Ritonavir and Azvudine had already been approved for clinical use and were widely available. Our main findings indicate that there is no significant difference between Azvudine and Nirmatrelvir-Ritonavir in reducing the risk of mortality. However, Azvudine may perform better in reducing nucleic acid conversion time and lowering viral load, as well as demonstrating slightly better safety in older patients.

The results indicate that, in the Nirmatrelvir-Ritonavir group, the duration of medication administration was mainly concentrated in the 5–10 days range, whereas in the Azvudine group, it was primarily in the 5-10 days and over 10-day ranges, with a significant difference observed (p < 0.001) (Table 2). According to existing clinical guidelines, Nirmatrelvir-Ritonavir was typically recommended for a 5-day course, while Azvudine was recommended for a 7-day course, with potential adjustments based on the patient’s condition in actual clinical practice. The findings suggested that the use of Nirmatrelvir-Ritonavir aligned more closely with standardized treatment recommendations. In contrast, the use of Azvudine in clinical practice remained in an exploratory and adjustment phase, indicating the need for more evidence to support its optimal use. Regarding the time from hospitalization to the initiation of antiviral therapy, both groups had a similar proportion of patients starting treatment within 5 days of hospitalization. This indicated that in clinical practice, regardless of the medication used, physicians tended to initiate antiviral therapy as early as possible to achieve better therapeutic outcomes. This was consistent with existing guidelines (Bryant, 2020; COVID-19 Treatment Guidelines Panel, 2024). Besides, the broad categories for duration of medication treatment, time from hospitalization to initiation of antiviral therapy, and number of prescribed doses were chosen to reflect clinical guidelines and typical practices, ensuring consistency across the study population. However, this approach may reduce the granularity of the findings suggesting that future studies consider more detailed categorizations to enhance interpretability.

In terms of safety, it was found that following treatment with Azvudine, there was a lower incidence of abnormal renal function (13.6% vs 7.2%, p = 0.045), and one or more adverse events (12.8% vs 5.2%, p = 0.009) compared to Nirmatrelvir-Ritonavir. These results suggest that Azvudine may have lower hepatotoxicity, nephrotoxicity, and metabolic impact in certain aspects. A study on Nirmatrelvir-Ritonavir, showed that Ritonavir was primarily metabolized in the liver, while Nirmatrelvir could accumulate in the kidney and increase the incidence of abnormal renal function (Lingscheid et al., 2022). This is a concern for older patients, who, with advancing age and the presence of comorbidities such as diabetes, hypertension, and cardiovascular diseases, a reduced renal excretion rate could exacerbate the occurrence of adverse events (Kellum et al., 2021). In a previous COVID-19 study involving patients with renal failure, Azvudine showed fewer adverse reactions related to abnormal renal function compared to the standard treatment group (patients receiving standard antiviral treatment, symptomatic treatment, nutritional support, and oxygen inhalation) (Shang et al., 2023). Above all, it is important to be cautious when administering either of these two medications in older COVID-19 patients, especially those with abnormal renal function. It is important to note that all adverse events identified in this study have been previously reported in the literature and were consistent with known safety profiles of the medications, and no new or unreported adverse events were observed in our study. This consistency provides further evidence of the reliability of existing data regarding the adverse effects of these medications and their applicability to older patients with COVID-19.

This study confirms that Azvudine and Nirmatrelvir-Ritonavir have comparable effectiveness in reducing mortality risk, with Azvudine potentially showing better performance in shortening nucleic acid negative conversion time and increasing ΔCt values (Table 5). This has been confirmed by the results of a large number of previous real-world studies and clinical trials, especially in Nirmatrelvir-Ritonavir, which was the first-line treatment medication worldwide (Lewnard et al., 2023; Wong et al., 2023). According to a large cohort study in the United States of America, Nirmatrelvir-Ritonavir effectively reduces the risk of hospitalization or death within 30 days of a positive outpatient SARS-CoV-2 test (Lewnard et al., 2023). Nirmatrelvir-Ritonavir treatment also resulted in significant reductions in hospitalization and mortality from COVID-19 in patients over 65 years of age due to its rapid ability to inhibit viral replication (Al-Obaidi et al., 2023). However, due to potential interactions with other medications (such as digoxin, cyclosporine, and verapamil), careful management and monitoring are required in clinical application. These interactions can alter the metabolism and effectiveness of the antiviral drug, potentially leading to suboptimal therapeutic outcomes or increased toxicity (Stone, J. H., et al., 2020). Particularly in older patients, who often have multiple comorbidities and complex medication regimens, the risk of adverse drug interactions is higher, necessitating a thorough review of their medication history and close monitoring during treatment (Rahman et al., 2020). Moreover, our study found that Azvudine showed better performance in nucleic acid negative conversion time and virus clearance, which is particularly relevant for patients who are also on multiple medications for chronic conditions. The fewer drug interactions associated with Azvudine make it a more suitable option for these patients, reducing the risk of adverse effects and improving treatment safety.

In 2022, Azvudine became China’s first oral SARS-CoV-2RdRP inhibitor for the treatment of COVID-19 in adults. Although there are not many reported studies, multiple studies confirmed that Azvudine had a faster nucleic acid negative conversion time compared with standard antiviral treatment (Ren et al., 2020; de Souza et al., 2023; Zhao et al., 2023). A phase III multi-center randomized clinical study also showed that Azvudine could shorten the time to symptom improvement and increase the proportion of patients with mild to moderate COVID-19 (Yu and Chang, 2022). In our study, it was found that Azvudine demonstrated better performance in the time for nucleic acid negative conversion time (HR = 1.659, 95% CI: 1.166 - 2.360, p = 0.005) and ΔCt values (HR = 1.346, 95% CI: 1.021 - 1.773, p = 0.035) (Table 5) compared to Nirmatrelvir-Ritonavir. However, another study conducted by Xiang et al. comparing the same two drugs in patients with mild symptoms, found that Nirmatrelvir-Ritonavir had a better effect than Azvudine (Zhao et al., 2023). This difference might stem from the varying mechanisms of action and effects of the two medications in different disease conditions, patient populations, or differing stages of COVID-19 infection.

In this study, ΔCt values were also selected as one of the vital indicators for assessing seroconversion during the early stage of COVID-19 (Juanola-Falgarona et al., 2022). These values were also selected as an outcome indicator to compare the antiviral effectiveness of Azvudine and Nirmatrelvir-Ritonavir in a prior study (Wang et al., 2024). Similarly, in a retrospective observational study in Hong Kong, ΔCt values were used to observe the viral load among symptomatic COVID-19 patients (Lin et al., 2023). Therefore, in this study, ΔCt values were also considered as one of the outcome measures, aimed at comparing the viral load in the two treatment groups during early infection. The crude model’s results provide an initial assessment of the treatment effects, which might be influenced by confounders and therefore may not accurately reflect the true effects of the drugs. In contrast, the partially adjusted model, by controlling for confounding factors, presents a clearer demonstration of treatment effectiveness, thereby enhancing the robustness and reliability of our findings. This approach helps mitigate biases. Studies by Zheng et al. (Zheng et al., 2022; Wang et al., 2024) have explored the use of crude and partially adjusted models to assess the effectiveness of antiviral medications under different conditions, further supporting the importance and necessity of employing partially adjusted models in our study.

This study has several key strengths that enhance the robustness and relevance of our findings. Firstly, our study specifically focused on older adults, a demographic that is particularly vulnerable to severe outcomes from COVID-19. This focus enhances the applicability of our findings to clinical practices aimed at improving care for this high-risk group. The patient population at the First Hospital of Shanxi Medical University is diverse, reflecting various geographic and socioeconomic backgrounds from Shanxi Province and similar regions in China. Patients had a wide range of COVID-19 severity, from mild to critical cases. The study focused on older adults (age ≥65) with multiple comorbidities, such as diabetes and cardiovascular diseases. As a tertiary hospital, it had access to advanced medical resources and treatments, including Nirmatrelvir-Ritonavir and Azvudine. This enhances the generalizability of our findings to similar tertiary hospital settings. Secondly, by directly comparing the two treatments within this critical population, our study provides valuable insights that can inform clinical decision-making and optimize treatment strategies for older patients with COVID-19. Although multiple studies worldwide have confirmed Nirmatrelvir-Ritonavir’s status as the drug of choice in the first-line treatment of COVID-19 due to its effectiveness and safety profile, there are relatively fewer studies on the use of Azvudine. Moreover, where Azvudine was the focus of the study or where literature provides a real-world head-to-head comparison of the effectiveness and safety of the two drugs (Chen and Tian, 2023a; Wei et al., 2023; Zhu, 2023), there is little research of their use in older patients, a particularly vulnerable group. Compared with young and middle-aged patients, the mortality rate of older COVID-19 patients was much higher (Kang and Jung, 2020; Liu et al., 2020) and warrants more attention. PSM was employed to balance baseline characteristics, and a retrospective study approach was used for comparative analysis. The safety and effectiveness of these medications were assessed using Kaplan-Meier methods, Cox proportional hazards models, subgroup analysis, and nomograms.

Although the current study is based on a small sample of patients, the results indicated no significant difference between Azvudine and Nirmatrelvir-Ritonavir in terms of all-cause 28-day mortality. However, Azvudine showed a certain advantage in shortening nucleic acid negative conversion time and increasing ΔCt values. When comparing the safety of the two drugs, the incidence of adverse events was lower in patients treated with Azvudine than in those treated with Nirmatrelvir-Ritonavir.

The small scale of the study and its focus on a specific period and region may limit the generalizability of the results to other groups of patients of a similar age. The impact of the number of combined medications on the effectiveness of Nirmatrelvir-Ritonavir and Azvudine treatment groups was analyzed, but a detailed analysis of specific medications was not performed. Additionally, the assessment of adverse events relied solely on medical records, which may not have fully captured their true incidence and severity. Furthermore, the lack of daily PCR testing, caused by the strain on medical resources during the pandemic, could introduce bias in the number of days to conversion to negative, potentially affecting the accuracy of our findings. Future research with larger sample sizes, standardized testing protocols, and more rigorously designed studies are needed to confirm and validate our findings and provide more robust evidence to support our conclusions.