Evaluating the Effectiveness of Antivirals for COVID-19 in the Post-vaccine, Omicron Era: A Systematic Review and Meta-analysis

Introduction: Randomized controlled trials (RCTs) of oral antivirals for COVID-19 conducted early in the pandemic had favorable results in unvaccinated populations. We conducted a systematic review and meta-analysis of the effectiveness of nirmatrelvir-ritonavir and molnupiravir against hospitalization and death in vaccinated populations in the post-Omicron era. Methods: We systematically searched PubMed, Embase and the Cochrane library for RCTs conducted from January 2020, and observational studies in adults who were vaccinated conducted from January 2022. We performed a random effects meta-analysis using the inverse variance method with subgroup analysis by age (<65 vs ≥65 years) and study quality (excluding vs including studies at serious risk of bias). Results: We identified 43 studies (8 RCTs, 35 observational). Two RCTs were in vaccinated populations in which no association between treatment with nirmatrelvir-ritonavir and a reduction in death, or treatment with molnupiravir and a reduction in hospitalization or death, was observed. In the meta-analysis of observational studies, nirmatrelvir-ritonavir was associated with a reduction in hospitalization (n = 11; odds ratio (OR): 0.60; 95% CI .54-.67, hazard ratio (HR): 0.69; 95% CI .62-.76) and mortality (n = 9; OR: 0.33, 95% CI .22-.48; HR: 0.56, 95% CI .36-.87). Molnupiravir was not associated with a significant reduction in hospitalization (n = 5; OR = 0.83; 95% CI .65-1.07) with mixed results for mortality (n = 9; OR = 0.61; 95% CI .41-.91; HR = 0.65; 95% CI .42-1.01). Conclusions: In vaccinated populations, RCTs have not demonstrated a reduction in hospitalization or death among populations treated with nirmatrelvir-ritonavir or with molnupiravir. However, RCTs of nirmatrelvir-ritonavir had limited statistical power to detect clinically important differences. Observational studies of nirmatrelvir-ritonavir, but not molnupiravir, consistently suggested a benefit against these outcomes. Clinical Trail Registration: PROSPERO (CRD420251266532).