Since its discovery in December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused more than 7 million deaths worldwide, according to the World Health Organization (WHO), making it one of the deadliest viruses in human history (COVID-19 Deaths, 2024). Its associated disease, COVID-19, prompted a global response, with significant efforts to develop treatments and preventive measures, particularly vaccines (Dolgin, 2022). These vaccines effectively reduced the severity of illness, hospitalisation rates, and mortality in various populations (Mohammed et al., 2022). Consequently, the COVID-19 emergency officially ended on 5 May 2023 (Assistant Secretary for Public Affairs, 2023).

However, certain populations remain at high risk of developing severe forms of COVID-19. For these vulnerable groups, early antiviral therapies (i.e., administered within 5 days from symptom onset) have been evaluated to prevent progression to severe disease, hospitalisation, and death (Bellino, 2022). In Italy, two antiviral treatments are currently authorised for symptomatic COVID-19 outpatients at high risk of severe disease: intravenous remdesivir (RDV - Veklury^®) and oral nirmatrelvir/ritonavir (NRM/RTV - Paxlovid^®) (AIFA, 2023c; 2023b; Bakheit et al., 2023). According to the Italian Medicines Agency (Agenzia Italiana del Farmaco - AIFA), these drugs are indicated for adult patients who do not require additional oxygen and have at least one significant risk factor for severe disease progression. These include active oncological or hematological diseases, chronic kidney or respiratory conditions, immunodeficiencies, obesity, heart and vascular diseases, uncontrolled diabetes, liver disease, haemoglobinopathies, and neurodevelopmental or neurodegenerative disorders (AIFA, 2020). In clinically vulnerable patients, favourable data on the combination of antiviral drugs or antiviral and monoclonal agents emerged (Mazzitelli et al., 2024; Rotundo et al., 2024). Moreover, the efficacy of such antivirals in preventing disease progression was maintained despite the Omicron variants’ lower pathogenicity than the previous ones (Mazzitelli et al., 2023b).

The recommended dosage of RDV in adults and adolescents is a single loading dose of RDV 200 mg administered by intravenous infusion on day 1 and 100 mg administered once daily by intravenous infusion on the following 2 days. Due to the intravenous nature, RDV is usually administered in a hospital or ambulatory setting, prescribed by specialists such as infectious disease clinicians (AIFA, 2023c), which requires a dedicated staff. While RDV was initially approved for inpatient use, it is also indicated for outpatients (adults and pediatric patients weighing at least 40 kg) who do not require supplemental oxygen but are at increased risk of progressing to severe COVID-19 (AIFA, 2023c). On the contrary, NRM/RTV is an oral treatment that can be easily taken at home, with a dose of 300 mg nirmatrelvir and 100 mg ritonavir, twice daily for 5 days (AIFA, 2023b). However, prescribing NRM/RTV requires a prior pharmacological anamnesis to exclude the presence of any interactions with chronic comedications (AIFA, 2023b). Molnupiravir was another drug used to treat COVID-19 disease, whose manufacturer withdrew its application for marketing authorisation in June 2023 (AIFA, 2023a).

Zur et al. (2024) compared RDV, NRM/RTV and Molnupiravir through a network meta-analysis with “hospitalisation” and “adverse events” to measure their difference in efficacy and safety. This network meta-analysis showed that RDV is more effective than NRM/RTV, and there is a trend for greater safety for RDV than NRM/RTV. However, their analysis included studies with heterogeneous outcomes, some of which did not report adverse events, limiting conclusions about treatment safety.

Through a comprehensive network meta-analysis, this article aims to evaluate the evidence on the efficacy and safety of the already available antiviral treatments RDV and NRM/RTV for symptomatic COVID-19 outpatients. Additionally, it provides a budget impact analysis to assess the financial implications of these treatments in healthcare systems, focusing on their cost-effectiveness and overall value in the management of high-risk COVID-19 patients.

The cost-effectiveness analysis between these two treatments in this specific setting was conducted to assess whether the superior efficacy of RDV over NRM/RTV, as reported by Zur et al. (2024), could translate into cost savings despite its higher cost and intravenous administration. Unlike Zur et al., our network meta-analysis includes only studies comparing RDV and NRM/RTV to the standard of care, excluding those on Molnupiravir. Additionally, our network meta-analysis focuses solely on serious adverse events for therapy’s safety, while Zur et al. (2024) considered all adverse events. This methodological distinction may explain why we did not observe a statistically significant difference in hospitalisation risk between RDV and NRM/RTV, whereas Zur et al. found RDV to be superior. At the University Hospital of Padua, our findings suggest that both antivirals are more effective than standard of care, analysing hospitalisation events in predominantly vaccinated populations (Mazzitelli et al., 2023b; 2023a).

In real-world clinical practice, the choice between RDV and NRM/RTV for early COVID-19 treatment is primarily dictated by patient-specific factors, particularly concomitant chronic medications and comorbidities. Among the two, NRM/RTV has stricter eligibility criteria due to its well-documented drug-drug interactions, which frequently made RDV the only feasible option. However, in cases where both treatments were viable, NRM/RTV was overwhelmingly preferred by physicians due to its oral administration, which avoids the need for repeated hospital visits. Given these prescribing patterns, our cost-effectiveness analysis focuses on patients who received NRM/RTV, as they represent the subgroup that could have been treated with either therapy, allowing for a meaningful economic comparison. This approach aligns with real-world clinical decision-making and highlights potential opportunities for cost savings.

An interesting finding from the sensitivity analysis revealed an opposite trend for efficacy, potentially influenced by the different patient selection processes in the two study designs. In RCTs, patient selection is more rigorous, ensuring that the sample meets all eligibility criteria, while real-world studies have less control over patient characteristics, possibly including patients with varying, usually worse, health statuses. For instance, vaccination status could significantly impact efficacy outcomes. In fact, the different results of the sensitivity analysis may be due to the lack of vaccinated patients in the RCTs, which are present in observational studies. The observational study of Ganatra et al. (2023) showed a 60% reduction in relative risk reduction in the hospitalisation for any cause in the NRM/RTV group compared to placebo. Instead, for RDV the data for vaccinated patients are much more limited (Andrews et al., 2024). Due to the potential different efficacy and safety of these drugs among different patients, these two antiviral therapies cannot be prescribed to every patient with a mild-to-moderate form of COVID-19. In particular, NRM/RTV has many drug interactions. Thus, NRM/RTV is not recommended for patients on polytherapy, while only RDV can be administered to patients with chronic kidney disease (Cheng et al., 2022; Gulick et al., 2024). To better apply these findings, sub analyses across different patient populations are recommended, allowing for the selection of the most cost-effective therapy tailored to individual patient characteristics.

Cost analysis indicated that from a healthcare perspective, treating 1,000 patients with NRM/RTV could result in savings of €550,854.46 compared to RDV. Both antiviral therapies demonstrate improved efficacy when administered within 48 h of symptom onset, which could further enhance clinical outcomes and cost-effectiveness by reducing hospitalizations (Andrews et al., 2024). However, the included studies did not provide sufficient data to conduct a sensitivity analysis specifically evaluating this time-dependent effect within our network meta-analysis. Given the significant implications of early treatment initiation, future research should explore the potential benefits of administering antivirals within the first 48 h of diagnosis, assessing both clinical efficacy and economic impact to better inform healthcare decision-making. The limitations of this analysis are the absence of a societal cost perspective, costs to clinics such as scheduling patients on short notice, and opportunity costs, which would likely further favour NRM/RTV due to differences in administration settings. RDV requires a 3-day outpatient treatment, where both the patient and the caregiver would spend at least 1 h per day receiving drug administration, as estimated in the time-flow analysis (Supplementary Table S1). This outcome will be reviewed in the future if oral RDV will be available (McCarthy, 2023).

Overall, the early treatment interventions had a significant positive impact on healthcare resources, as shown by Pierre et al. (2023). However, in the comparison between early treatments for COVID-19 the budget impact analysis supports NRM/RTV, with several limitations preventing a longer-term estimate. One key uncertainty is the upcoming price renegotiationing for both antivirals in 2025, which could significantly alter the cost comparison between these treatments. Additionally, the future number of patients expected to receive these therapies was approximated due to limited data. Specifically, the number of vulnerable patients eligible for treatment in the examined region was unavailable, and historical data from the early period when these therapies were first indicated are skewed by health policies aimed at containing SARS-CoV-2, which are no longer in place. Furthermore, the early COVID-19 treatments prescribed by primary care physicians—a smaller subset compared to those prescribed by specialists—were not accounted for in this analysis. Another limitation is that the cost analysis was performed from an Italian healthcare perspective using Italian salaries and prices. While our budget impact analysis was conducted within the Italian healthcare system, the methodology can be applied to other settings by adjusting cost parameters such as personnel salaries, hospitalization expenses, and drug pricing to reflect local healthcare conditions.

In order to decide which one is better, a network meta-analysis with a larger number of studies should be performed, possibly with a direct comparison of the two drugs. A limitation of our study was that we not consider the indirect costs of treatment, which could have contributed to a better cost analysis. Another factor that could have made the analysis more accurate was to categorise the costs of serious adverse events by type of adverse event. Furthermore, the outcomes of therapies among the different eligible patient targets must be analysed more specifically to implement a more accurate choice in clinical practice and a better evaluation of adverse events costs. In conclusion, to choose which antiviral therapy to administer, physicians should consider the prescribing indications, which limit the use of NRM/RTV more than RDV due to its high rate of interactions with other drugs, and in cases where early therapy can be chosen for COVID-19, NRM/RTV is currently the best choice in economic terms.