Evaluating the effectiveness of antivirals for COVID-19 in the post-vaccine, Omicron era: A systematic review and meta-analysis
Citation
Laura J Edwards, Bette Liu, James G Wood, Nicola Stephens, Allen C Cheng
Open Forum Infectious Diseases, Volume 13, Issue 7, July 2026, ofag339. DOI: https://doi.org/10.1093/ofid/ofag339
Abstract
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)