Nirmatrelvir/ritonavir reduces risk of severe COVID-19 in outpatients, regardless of vaccination status
28 Aug 2024
Nirmatrelvir/ritonavir is effective against the composite outcome of hospitalization or mortality ≤35 days after COVID-19 diagnosis in nonhospitalized adults with COVID-19, regardless of vaccination status, according to a systematic review and meta-analysis of cohort studies.
“Evidence on the effects of oral antivirals in randomized controlled trials has been extensive, but a dearth of evidence exists on the effects of these therapies in vaccinated subgroups,” wrote the researchers. “Additionally, early systematic reviews of observational studies of nirmatrelvir/ritonavir had several limitations as they did not explicitly include studies that accounted for patient-level vaccination status, and their search results are outdated [search last performed in January 2023].”
In the current study, researchers searched MEDLINE, EMBASE, Scopus, Web of Science, WHO COVID-19 Research Database, and medRxiv for reports published from 1 January 2022 to 8 November 2023. They included 30 cohort studies on 2,537,674 nonhospitalized adults with COVID-19 (untreated controls, n=2,027,387; oral antivirals, n=510,287). Of these, 462,279 patients received nirmatrelvir/ritonavir and 48,008 patients received molnupiravir. The primary outcome was a composite of hospitalization or mortality ≤35 days after COVID-19 diagnosis. [J Antimicrob Chemother 2024;doi:10.1093/jac/dkae163]
“We had moderate certainty that nirmatrelvir/ritonavir probably reduced risks of the composite primary outcome [risk ratio (RR), 0.62; 95 percent confidence interval (CI), 0.55–0.70; I2=0 percent] and mortality [RR, 0.31; 95 percent CI, 0.21–0.44; I2=63 percent] and low certainty that nirmatrelvir/ritonavir slightly reduced the risk of hospitalization [RR, 0.54; 95 percent CI, 0.42–0.68; I2=80 percent] in the overall population,” noted the researchers.
Molnupiravir slightly reduced the composite primary outcome (RR, 0.75; 95 percent CI, 0.67–0.85; I2=32%; low certainty) in the overall population and in unvaccinated patients, but probably made little to no difference in terms of hospitalization (RR, 0.82; 95 percent CI, 0.70–0.97; I2=63 percent; moderate certainty). “We had very low certainty about the effect of molnupiravir on mortality [RR, 0.36; 95 percent CI, 0.26–0.51; I2=64 percent],” added the researchers.
Notably, there were consistent associations between studies reporting RR (unvaccinated: 0.46; vaccinated: 0.64; psubgroup difference=0.47) and HR (unvaccinated: 0.59; vaccinated: 0.55; psubgroup difference=0.52) and limited evidence of effect modification by vaccination status against the composite primary outcome with nirmatrelvir/ritonavir, but the results were inconsistent with molnupiravir between studies reporting RR (unvaccinated: 0.75; vaccinated: 0.79; psubgroup difference=0.78) and HR (unvaccinated: 0.60; vaccinated: 1.16; psubgroup difference=0.08).
In five studies, risk difference (RD) estimates against the composite primary outcome for nirmatrelvir/ritonavir were 1.21 percent in vaccinated patients and 1.72 percent in unvaccinated patients. In two studies, the corresponding RD estimates for molnupiravir were -0.01 percent and 1.73 percent, respectively.
“Nirmatrelvir/ritonavir is effective against the composite outcome of severe COVID-19 independent of vaccination status,” concluded the researchers. “Molnupiravir has inconsistent evidence of effectiveness, notably among vaccinated adults. Further research and reassessment of molnupiravir use among vaccinated adults are warranted.”
“Evidence on the effects of oral antivirals in randomized controlled trials has been extensive, but a dearth of evidence exists on the effects of these therapies in vaccinated subgroups,” wrote the researchers. “Additionally, early systematic reviews of observational studies of nirmatrelvir/ritonavir had several limitations as they did not explicitly include studies that accounted for patient-level vaccination status, and their search results are outdated [search last performed in January 2023].”
In the current study, researchers searched MEDLINE, EMBASE, Scopus, Web of Science, WHO COVID-19 Research Database, and medRxiv for reports published from 1 January 2022 to 8 November 2023. They included 30 cohort studies on 2,537,674 nonhospitalized adults with COVID-19 (untreated controls, n=2,027,387; oral antivirals, n=510,287). Of these, 462,279 patients received nirmatrelvir/ritonavir and 48,008 patients received molnupiravir. The primary outcome was a composite of hospitalization or mortality ≤35 days after COVID-19 diagnosis. [J Antimicrob Chemother 2024;doi:10.1093/jac/dkae163]
“We had moderate certainty that nirmatrelvir/ritonavir probably reduced risks of the composite primary outcome [risk ratio (RR), 0.62; 95 percent confidence interval (CI), 0.55–0.70; I2=0 percent] and mortality [RR, 0.31; 95 percent CI, 0.21–0.44; I2=63 percent] and low certainty that nirmatrelvir/ritonavir slightly reduced the risk of hospitalization [RR, 0.54; 95 percent CI, 0.42–0.68; I2=80 percent] in the overall population,” noted the researchers.
Molnupiravir slightly reduced the composite primary outcome (RR, 0.75; 95 percent CI, 0.67–0.85; I2=32%; low certainty) in the overall population and in unvaccinated patients, but probably made little to no difference in terms of hospitalization (RR, 0.82; 95 percent CI, 0.70–0.97; I2=63 percent; moderate certainty). “We had very low certainty about the effect of molnupiravir on mortality [RR, 0.36; 95 percent CI, 0.26–0.51; I2=64 percent],” added the researchers.
Notably, there were consistent associations between studies reporting RR (unvaccinated: 0.46; vaccinated: 0.64; psubgroup difference=0.47) and HR (unvaccinated: 0.59; vaccinated: 0.55; psubgroup difference=0.52) and limited evidence of effect modification by vaccination status against the composite primary outcome with nirmatrelvir/ritonavir, but the results were inconsistent with molnupiravir between studies reporting RR (unvaccinated: 0.75; vaccinated: 0.79; psubgroup difference=0.78) and HR (unvaccinated: 0.60; vaccinated: 1.16; psubgroup difference=0.08).
In five studies, risk difference (RD) estimates against the composite primary outcome for nirmatrelvir/ritonavir were 1.21 percent in vaccinated patients and 1.72 percent in unvaccinated patients. In two studies, the corresponding RD estimates for molnupiravir were -0.01 percent and 1.73 percent, respectively.
“Nirmatrelvir/ritonavir is effective against the composite outcome of severe COVID-19 independent of vaccination status,” concluded the researchers. “Molnupiravir has inconsistent evidence of effectiveness, notably among vaccinated adults. Further research and reassessment of molnupiravir use among vaccinated adults are warranted.”