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

Abstract

Objective: 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). 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 (RR 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.

Conclusions: 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.

Registration: PROSPERO CRD42023429232.

Figure 1.

PRISMA flow diagram of studies in the systematic review of oral antiviral treatment of adult outpatients with COVID-19. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

Relative effectiveness of nirmatrelvir/ritonavir (a) and molnupiravir (b) in the overall cohort populations (considered as a confounder) against the composite outcome, hospitalization and mortality. The size of the data markers (blue squares) reflects the weight of each study and its contribution to the pooled estimate. CI, confidence interval. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Relative effectiveness of nirmatrelvir/ritonavir among vaccinated and unvaccinated subgroups against (a) composite outcome (RR), (b) composite outcome (HR), (c) hospitalization (RR) and (d) hospitalization (HR). The size of the data markers (blue squares) reflects the weight of each study and its contribution to the pooled estimate. CI, confidence interval. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Relative effectiveness of molnupiravir among vaccinated and unvaccinated subgroups against (a) composite outcome (RR), (b) composite outcome (HR) and (c) mortality (HR). The size of the data markers (blue squares) reflects the weight of each study and its contribution to the pooled estimate. CI, confidence interval. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 5.

Absolute RD for nirmatrelvir/ritonavir for all outcomes among adults overall (a); composite outcome (b) and mortality (c) stratified by vaccination status. Absolute RD for molnupiravir for all outcomes among adults overall (d) and for the composite outcome stratified by vaccination status (e). The size of the data markers (blue squares) reflects the weight of each study and its contribution to the pooled estimate. CI, confidence interval. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.