Effectiveness of nirmatrelvir/ritonavir and molnupiravir in non-hospitalized adults with COVID-19: systematic review

Abstract

<p>To determine the effectiveness of nirmatrelvir/ritonavir and molnupiravir among vaccinated and unvaccinated non-hospitalized adults with COVID-19. Methods: Observational studies of nirmatrelvir/ritonavir or molnupiravir compared to no antiviral drug treatment for COVID-19 in non-hospitalized adults with data on vaccination status were included. We searched MEDLINE, EMBASE, Scopus, Web of Science, WHO COVID-19 Research database, and medRxiv for reports published between 1 January 2022 and 8 November 2023. The primary outcome was a composite of hospitalization or mortality up to 35 days after COVID-19 diagnosis. Risk of bias was assessed with ROBINS-I. Risk ratios (RR), hazard ratios (HR) and risk differences (RD) were separately estimated using random-effects models. Results: We included 30 cohort studies on adults treated with nirmatrelvir/ritonavir (n=462,279) and molnupiravir (n=48,008) in the systematic review and 22 studies in the quantitative synthesis. Nirmatrelvir/ritonavir probably reduced the composite outcome (RR 0.62, 95% CI 0.55–0.70; I²=0%; moderate certainty) with no evidence of effect modification by vaccination status (Psubgroup=0.47). In five studies, RD estimates against the composite outcome for nirmatrelvir/ritonavir were 1.21% (95% CI 0.57% to 1.84%) in vaccinated and 1.72% (95% CI 0.59% to 2.85%) in unvaccinated subgroups. Molnupiravir may slightly reduce the composite outcome (RR 0.75, 95% CI 0.67–0.85; I²=32%; low certainty). Evidence of effect modification by vaccination status was inconsistent among studies reporting different effect measures (RR Psubgroup=0.78; HR Psubgroup=0.08). In two studies, RD against the composite outcome for molnupiravir were −0.01% (95% CI −1.13% to 1.10%) in vaccinated and 1.73% (95% CI −2.08% to 5.53%) in unvaccinated subgroups. Conclusion: Among cohort studies of non-hospitalized adults with COVID-19, nirmatrelvir/ritonavir is effective against the composite outcome of severe COVID-19 independent of vaccination status. Further research and a reassessment of molnupiravir use among vaccinated adults are warranted.<br></p>