Is Azvudine Comparable to Nirmatrelvir-Ritonavir in Real-World Efficacy and Safety for Hospitalized Patients with COVID-19? A Retrospective Cohort Study

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Public health and economic systems are facing a tremendous burden globally, which can be attributed to the ongoing COVID-19 pandemic [1]. At the end of 2022, China had just suffered an intense wave of COVID-19 caused by the current dominant strain, Omicron, which showed high transmissibility and immunologic escape [2, 3]. Early initiation of antivirals brought the pandemic under control by reducing the risks of mortality and disease progression. Although numerous drugs have been developed, there are still very few approved antivirals available for COVID-19 [4]. Unlike in other countries, azvudine and nirmatrelvir-ritonavir were more extensively used during the winter 2022 epidemic in China due to their earlier approval by the National Medical Products Administration (NMPA) than other antivirals [5, 6].

Nirmatrelvir-ritonavir has been authorized for emergency use by many countries [7]. In China, it had been granted conditional approval for the treatment of non-hospitalized patients with COVID-19 with mild to moderate symptoms since February 2022 [5]. According to the EPIC-HR trial, nirmatrelvir-ritonavir reduced hospitalization and mortality rates by approximately 88% when initiated within 5 days of symptom onset compared to placebo [8]. Besides, its efficacy and safety have been extensively researched in other real-world studies, including comparisons with control groups [9‐11] or other antivirals [12‐16]. However, several concerns remain regarding the use of nirmatrelvir-ritonavir, including multiple drug–drug interactions [17] and a rebound of COVID-19 after antiviral treatment cessation [18].

Azvudine, another promising antiviral against COVID-19, was previously approved as an anti-HIV drug [19]. It was granted conditional authorization by the NMPA to treat COVID-19 in China on July 25, 2022 [6]. Unfortunately, limited published information is available regarding the use of azvudine in clinical practice. In a preliminary randomized controlled trial (n = 20), azvudine showed a shorter time to first nucleic-acid negative conversion (T_FNANC) vs. placebo [20]. Further phase 3 multicenter randomized placebo-controlled studies demonstrated that patients with COVID-19 who received azvudine had a lower viral load, a shorter time to symptom improvement, and a lower risk of progression or death vs. control [21, 22]. Although there are some acceptable efficacy and safety profiles of azvudine for treating COVID-19, evidence investigating its real-world outcomes is scarce. Only three real-world reports that compare azvudine with placebo have been published [23] or posted on the MedRxiv website for public comment [24, 25].

To date, there have been limited comparative studies between azvudine and nirmatrelvir-ritonavir, except for two studies that focused on viral load dynamics or other clinical efficacy outcomes [26, 27]. Therefore, a comparison of azvudine and nirmatrelvir-ritonavir is urgently needed. In this retrospective cohort study, we aimed to make a systematic head-to-head comparison of the efficacy and safety of azvudine and nirmatrelvir-ritonavir in hospitalized adult patients with COVID-19 in China. We hypothesized that azvudine is comparable to nirmatrelvir-ritonavir in real-world efficacy and safety for hospitalized patients with COVID-19.

Overall, 1571 patients with confirmed COVID-19 were admitted to our hospital, among whom we identified 495 patients who received nirmatrelvir-ritonavir or azvudine. Of these participants, we excluded 25 individuals who initiated antiviral treatment beyond 5 days after symptom onset, 15 with outcomes of death or critical illness occurring less than 3 days after therapy initiation, 5 participants who had previously taken antivirals before the study, 2 with drug contraindications, 7 with severe renal diseases, 2 with severe liver diseases, and 11 individuals who were lost to follow-up. Finally, a total of 428 participants were included in the final analysis, comprising 272 nirmatrelvir-ritonavir recipients and 156 azvudine recipients (Fig. 1).

As shown in Table 1, the majority of the baseline characteristics were well balanced between the two groups prior to matching. The mean age of the participants was 77.31 (± 12.86) years, with a majority (62.15%) being male. Age, sex, BMI, severity of COVID-19, smoking and drinking status, diabetes, and cardiovascular disease were not significantly different between the two groups. The proportions with chronic lung disease (20.96% vs. 9.62%, P = 0.003) and tumor and immunosuppression (30.88% vs. 15.38%, P < 0.001) appeared to be higher in the nirmatrelvir-ritonavir group compared to the azvudine group. Participants in the nirmatrelvir-ritonavir group exhibited significantly lower levels of LTM (P < 0.001) and higher levels of CRP (P < 0.001) compared to those in the azvudine group. The mean follow-up time for all patients was 27.84 days. After matching, we included 143 recipients of azvudine and 143 matched recipients of nirmatrelvir-ritonavir, resulting in balanced baseline characteristics between the two groups.

During the follow-up period, the incidence of all-cause mortality at day 28 was 5.51% in the nirmatrelvir-ritonavir group and 5.77% in the azvudine group. After adjusting for potential confounders in model 3, we observed no significant difference in all-cause 28-day mortality between the two groups. This suggests that azvudine may be noninferior to nirmatrelvir-ritonavir with respect to 28-day mortality (adjusted HR 1.41; 95% CI 0.56–3.56; P = 0.471), although there was a slightly lower mortality rate among nirmatrelvir-ritonavir recipients compared to those receiving azvudine (Table 2 and Fig. 2). The finding was consistent with the PSM analysis (crude HR 1.27; 95% CI 0.47–3.42; P = 0.631). Age (adjusted HR 1.06; 95% CI 1.01–1.11), BMI (adjusted HR 1.31; 95% CI 1.16–1.47), and severe illness type (adjusted HR 3.63; 95% CI 1.42–9.30) were identified as significant predictors of mortality in the study population (Supplementary Table S2).

Likewise, similar results were observed for secondary outcomes. During the 28-day follow-up period, the transfer rate to a critical condition was 6.99% in the nirmatrelvir-ritonavir group and 8.33% in the azvudine group, while P_NANC was 79.41% in the nirmatrelvir-ritonavir group and 84.62% in the azvudine group. The results regarding the risk of progression to a critical condition (adjusted HR 1.67; 95% CI 0.78–3.60; P = 0.189) and P_NANC (adjusted HR 0.87; 95%CI, 0.69–1.09; P = 0.220) within 28 days suggest that azvudine may be similarly effective in these outcomes as compared to nirmatrelvir-ritonavir, although there is a slight tendency for azvudine to perform slightly worse (Table 2 and Fig. 2). These results agree with those in the PSM analyses: risk of progression to a critical condition (crude HR 1.31; 95% CI 0.58–3.00; P = 0.517) and P_NANC (crude HR 0.83; 95% CI 0.64–1.07; P = 0.146). Meanwhile, age (adjusted HR 1.06; 95% CI 1.02–1.11), BMI (adjusted HR 1.18; 95% CI 1.06–1.31), and severity of COVID-19 (adjusted HR 4.58; 95% CI 2.05–10.24) were identified as potential risk factors for critical progression of COVID-19 (Supplementary Table S3), and a history of tumor and immunosuppression (adjusted HR 0.72; 95% CI 0.55–0.94) could be a risk factor for reduced P_NANC at day 28 (Supplementary Table S4).

Among the continuous outcomes, significant differences were observed in T_FNANC, with a significantly longer duration noted in the azvudine group as compared to the nirmatrelvir-ritonavir group (β 2.53; 95% CI 0.76–4.29; P = 0.005) (Table 2). There was no statistically significant difference in hospital stay duration between the azvudine and nirmatrelvir-ritonavir groups (β − 0.82; 95% CI − 2.78 to 1.15; P = 0.414). These were consistent with the PSM analysis results: T_FNANC (β 2.77; 95% CI 0.80–4.75; P = 0.006) and the length of hospital stay (β − 1.73; 95% CI − 3.98 to 052; P = 0.133). Additionally, a higher level of D-dimer was found to be associated with a longer T_FNANC (β 0.28; 95% CI 0.03–0.52) (Supplementary Table S5), while older individuals were observed to have prolonged hospital stays (β 0.13; 95% CI 0.05–0.21) (Supplementary Table S6). Despite comparable outcomes in most aspects, azvudine was found to be inferior to nirmatrelvir-ritonavir in terms of T_FNANC.

The results of the stratification and interaction analyses are presented in Supplementary Figs. S1–S5. The absence of a statistically significant interaction effect between azvudine and nirmatrelvir-ritonavir was demonstrated across all subgroups. In the subgroup analysis of the all-cause 28-day mortality and length of hospital stay outcomes, no significant differences were observed among any of the subgroups (Supplementary Figs. S1 and S5). In the subgroup analysis of the risk of progressing to a critical condition, as for participants “with tumor and immunosuppression”, the azvudine group showed a significantly higher risk than nirmatrelvir-ritonavir group (adjusted HR 4.39; 95% CI 1.34–14.41, P = 0.021); on the other hand, for participants “without tumor and immunosuppression”, the risk in azvudine and nirmatrelvir-ritonavir group showed no significant difference (P = 0.445) (Supplementary Fig. S2). In the “severe” subgroup, the azvudine group showed a significantly lower P_NANC compared to the nirmatrelvir-ritonavir group (adjusted HR 0.43; 95% CI 0.19–0.95, P = 0.038); while in the “mild-to-moderate” subgroup, there was no significant difference in P_NANC between the azvudine and nirmatrelvir-ritonavir groups (P = 0.609) (Supplementary Fig. S3). A significantly longer T_FNANC was observed in the azvudine group compared to the nirmatrelvir-ritonavir group in all of the age and BMI subgroups. The differences were particularly pronounced in “younger” (β 4.87; 95% CI 0.19–9.55; P = 0.047) or “obese” (β 3.55; 95% CI 0.42–6.69; P = 0.028) subgroups (Supplementary Fig. S4). We also observed that T_FNANC was significantly longer in the “male” (β 3.24; 95% CI 0.83–5.66; P = 0.009), “severe ill type” (β 6.38; 95% CI 1.46–11.29; P = 0.015), “non-smoking” (β 2.50; 95% CI 0.69–4.31; P = 0.007), “non-drinking” (β 2.41; 95% CI 0.60–4.23; P = 0.009), “without diabetes” (β 1.89; 95% CI 0.02–3.76; P = 0.049), “with cardiovascular disease” (β 3.76; 95% CI 0.38–7.14; P = 0.031), and “without tumor and immunosuppression” (β 2.68; 95% CI 0.78–4.59; P = 0.006) subgroups by comparing azvudine and nirmatrelvir-ritonavir (Supplementary Fig. S4).

The results of sensitivity analyses are presented in Table 2 and Supplementary Tables S7–S8. Consistent findings were obtained from multilevel regression models (Table 2) and complete data analyses with missing values excluded (Supplementary Tables S7 and S8), indicating the robustness and stability of the results.

After 28 days of follow-up, similar incidences of adverse events were observed in the nirmatrelvir-ritonavir and azvudine groups (4.41% vs. 3.21%, P = 0.538) (Table 3). Among patients who received nirmatrelvir-ritonavir, the most common adverse events were elevated liver enzymes (1.84%), followed by gastrointestinal disorders (1.10%) and skin rash (0.74%). Other adverse effects included dizziness, weakness, shortness of breath, sweating, and dry throat (all 0.37%). Similarly, the adverse effects observed during azvudine therapy were gastrointestinal disorders (1.92%), elevated liver enzymes (1.28%) and skin rash (0.64%).

This study investigated the efficacy and safety profiles of azvudine and nirmatrelvir-ritonavir in a representative cohort of 428 hospitalized adult patients with COVID-19 in China with a follow-up period exceeding 28 days. Results showed that initiation of azvudine was potentially non-inferior to nirmatrelvir-ritonavir in 28-day mortality, risk of progression to a critical condition, P_NANC, length of hospital stay, and the incidence of adverse reactions, whereas nirmatrelvir-ritonavir demonstrated a superior T_FNANC compared to azvudine. In summary, the results indicate that azvudine may exhibit comparable efficacy and safety to nirmatrelvir-ritonavir in certain outcomes among hospitalized adult patients with COVID-19 in China.

To date, only two studies have compared azvudine with nirmatrelvir-ritonavir, and those studies focused solely on viral load dynamics or clinical efficacy outcomes [26, 27]. Our study revealed that the azvudine group exhibited a prolonged T_FNANC compared to the nirmatrelvir-ritonavir group, which is consistent with previous studies that focused on viral load dynamics outcomes [26]. In addition, our investigation found that azvudine and nirmatrelvir-ritonavir had comparable efficacy profiles, although the latter showed slightly better all-cause mortality, risk of progression to a critical condition, and P_NANC. The results of our study regarding all-cause mortality and risk of progression to a critical condition are not entirely consistent with previous studies, which showed that the azvudine groups had a significantly lower incidence rate of composite disease progression and tended towards a nonsignificantly reduced all-cause mortality rate compared to the nirmatrelvir-ritonavir groups [27]. This inconsistency in results may be attributed to differences in the study population, outcome measures, or follow-up time. Firstly, our study was conducted in hospitalized patients with COVID-19 in Zhejiang Province of China from December 20, 2022 to January 31, 2023, while the prior research was carried out in Hunan Province during the period from December 5, 2022 to January 31, 2023, so the study population was slightly different. Secondly, the risk of progression to a critical condition outcome in our study was defined as individuals who experience respiratory failure requiring mechanical ventilation, develop shock, or suffer from multiple organ failures necessitating treatment in the ICU (Supplementary Table S1), while the incidence rate of composite disease progression in the prior study was a composite disease progression outcome that included all-cause death, intensive care unit admission, initiation of invasive mechanical ventilation, and need for high-flow oxygen therapy. Thirdly, we performed a 28-day follow-up for the two outcomes, whereas the previous study had a follow-up time of 38 days. Nevertheless, the results of our study provide interesting and controversial findings regarding the clinical efficacy of azvudine and nirmatrelvir-ritonavir.

Furthermore, our study directly compared the safety of azvudine and nirmatrelvir-ritonavir in hospitalized adult patients with COVID-19, which has not been documented in previous research. The present analysis did not reveal any noteworthy variation in the incidence of adverse events among these groups, aligning with prior phase 2–3 investigations involving azvudine [21, 22] or nirmatrelvir-ritonavir [8] compared to their controls. Therefore, our findings suggest that both azvudine and nirmatrelvir-ritonavir are safe therapeutic options recommended by the guidelines [28].

Meanwhile, there are several noteworthy observations from subgroup analyses. Nirmatrelvir-ritonavir demonstrated superiority over azvudine in subgroups characterized by a male gender, severe illness status, non-smoking and non-drinking habits, cardiovascular disease or a history of tumor and immunosuppression with respect to outcomes such as the risk of progression to a critical condition, P_NANC and T_FNANC. The findings suggest that nirmatrelvir-ritonavir may confer advantages over azvudine in specific populations, which is a controversial and different result compared to what was found in the previous study [27]. Hence, more studies are needed to verify these results.

We also included patients with severe illness in order to provide an opportunity for those who developed severe disease within 5 days of onset to receive treatment. A previous multicenter randomized controlled trial was conducted to evaluate the efficacy and safety of nirmatrelvir-ritonavir in the treatment of adult patients with severe disease [29]. Therefore, we can gather valuable insights into patients’ preferences for antiviral therapy based on the severity of COVID-19.

A strength of this study lies in the utilization of a real-world hospitalized cohort, with data collection facilitated through an electronic medical record system. This approach enables close monitoring and documentation of clinical details, as well as systematic coverage of clinical outcomes. Another strength is our adjustment for potential confounding covariates in multiple models, as well as the performance of various analyses, including regression analysis, PSM analysis, subgroup analysis and sensitivity analysis, based on previous literature [30, 31]. This makes our findings more robust. One additional strength is that we systematically evaluated six clinical outcomes in hospitalized adult patients with COVID-19, including the safety outcomes, which are the most comprehensive outcome measures to date. However, several limitations need to be addressed. Firstly, this was a single-center study with participants only from China. Thus, the findings may not fully generalize to other countries, and further validation is required in wider geographic regions. Secondly, although we included consecutive cases, considered many confounders, and performed multiple analyses in this study, residual confounding and unmeasured confounders between the two groups remain a concern in a retrospective study. Thirdly, clinicians may prefer azvudine over nirmatrelvir-ritonavir for treating patients on multiple medications due to contraindications related to drug–drug interactions. Hence, we excluded patients with drug-related contraindications and those with severe renal or liver disorders to allow for a fair comparison between the two groups. Fourthly, it is noteworthy that although the discharge criteria protocols for patients with COVID-19 used by different consultants were similar, there may still have been some subtle differences resulting in slightly different lengths of hospital stay. Thus, generalization of the results of our length of hospital stay outcome to other healthcare settings should be carried out with caution. Finally, the sample size of azvudine may not be large enough due to the rigorous study design and the strict inclusion and exclusion criteria for patient enrollment. Also, our subgroup analyses may have been underpowered due to their relatively small sample sizes in certain patient subgroups. Further research with larger sample sizes is greatly needed in the future.

In conclusion, this retrospective cohort study of hospitalized patients with COVID-19 showed that azvudine probably possessed comparable efficacy and safety to nirmatrelvir-ritonavir, although it was less effective than nirmatrelvir-ritonavir in some outcomes. Our research supplements existing studies and provides additional evidence for the real-world comparison between azvudine and nirmatrelvir-ritonavir. Meanwhile, these results will help physicians reconsider the selection and prioritization of antiviral drugs. Larger sample sizes or multicenter clinical studies are warranted for further investigation.