Antiviral agents for COVID-19: A post-pandemic systematic review of randomized controlled trials.

Background : After years of the pandemic of SARS-CoV-2 infection, some cases with severe symptoms of COVID-19 are still presenting. Therapeutic alternatives that provide a clear benefit for severe cases remain lacking. Aim : To assess the best available evidence on the efficacy of antiviral therapy for severe COVID-19 and to synthesize the results. Methodology : A systematic review was designed. PubMed publications until December 2025 were searched. Randomized clinical trials (RCTs) of interventions with antiviral agents, with control groups that received placebo or standard of care (SOC) in patients with severe COVID-19 hospitalized or in the intensive care unit (ICU), were selected. The primary outcome was all-cause mortality; other secondary results were considered. Results : A total of 43 studies were identified, involving 12,052 patients. The severity distribution was 35.6%, 52.0%, and 12.4% for mild, moderate, and severe cases, respectively. Ten antiviral agents were evaluated. The results showed a decrease in mortality among patients treated with remdesivir (RR 0.83; 95% CI0.74-0.93; p=0.001), molnupiravir (RR 0.16; 95% CI 0.04-0.73; p=0.02), and nirmatrelvir (RR 0.05; 95% CI 0.00-0.91; p=0.04). Conclusions : According to the results, some antivirals (remdesivir, molnupiravir, nirmatrelvir) reduced all-cause mortality among patients with COVID-19 compared with placebo or SOC.