Efficacy and safety of antiviral treatments for symptomatic COVID-19 outpatients: Systematic review and network meta-analysis

Background: Remdesivir, molnupiravir, and nirmatrelvir/ritonavir are three antiviral agents approved by FDA emergency authorization for treating mild to moderate symptomatic COVID-19 adult outpatients at high risk for hospitalization and death. Objectives: To compare the efficacy and safety of these antivirals based on updated published RCT and real-world data. Study design: This systematic review followed the preferred reporting items for systematic reviews and meta-analysis framework guidelines. We searched all publications up to January 2023. RRs and 95% CIs for death, hospitalization, and adverse events were calculated. Results: Six RCTs and seven cohort studies were included, with 1,456,523 participants, of whom 50,979 were treated with antivirals. Remdesivir was associated with the lowest probability of hospitalization and death compared to nirmatrelvir/ritonavir and molnupiravir (P-scores 0.99 and 0.90, respectively, for remdesivir, 0.64 and 0.55, respectively for nirmatrelvir/ritonavir, and 0.26 and 0.49, respectively for molnupiravir). Based on indirect comparisons, remdesivir was associated with a statistically significant decreased risk for hospitalization compared to molnupiravir (RR 0.09; 95% CI 0.02–0.40) and to nirmatrelvir/ritonavir (RR 0.11; 95% CI 0.03–0.73). No statistically significant difference was found between antivirals in the mortality risk reduction and the risk for side effects. Conclusions: This is the most comprehensive network meta-analysis integrating RCTs and real-world data. In our indirect comparison, remdesivir was associated with the highest efficacy in preventing hospitalization among high risk symptomatic COVID-19 outpatients, compared to nirmatrelvir/ritonavir and molnupiravir. This finding supports current guidelines, and may have importance when deciding which antiviral to use, together with other important factors.