Association of Molnupiravir and Nirmatrelvir-Ritonavir with Reduced Mortality and All-cause Sepsis in Hospitalized Patients Infected with Omicron Variant of SARS-CoV-2: A Territory-Wide Prospective Cohort Study

Abstract Object This study evaluates the association between antivirals (Molnupiravir and Nirmatrelvir-Ritonavir) and all-cause and respiratory mortality and organ dysfunction among high-risk COVID-19 patients during an Omicron outbreak. Methods Two cohorts, Nirmatrelvir-Ritonavir vs. control and Molnupiravir vs. control, were constructed with inverse probability treatment weighting to balance baseline characteristics. Cox proportional hazards models evaluated the association of their use with all-cause mortality, respiratory mortality, and all-cause sepsis (a composite of circulatory shock, respiratory failure, acute liver injury, coagulopathy, and acute liver impairment). Patients recruited were hospitalized and diagnosed with the COVID-19 Omicron variant between February 22, 2022 to April 15, 2022, and followed up until May 15, 2022. Results The study included 17,704 patients. There were 4.67 and 22.7 total mortalities per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio, -18.1 [95%CI, -23.0 to -13.2]; hazard ratio, 0.18 [95%CI, 0.11–0.29]). There were 6.64 and 25.9 total mortalities per 1000 person-days in the Molnupiravir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, -19.3 [95%CI, -22.6 to -15.9]; hazard ratio, 0.23 [95%CI, 0.18–0.30]). In all-cause sepsis, there were 13.7 and 35.4 organ dysfunction events per 1000 person-days in the Nirmatrelvir-Ritonavir and control groups respectively before adjustment (weighted incidence rate ratio per 1000 person-days, -21.7 [95%CI, -26.3 to -17.1]; hazard ratio, 0.44 [95%CI, 0.38–0.52]). There were 23.7 and 40.8 organ dysfunction events in the Molnupiravir and control groups respectively before adjustment (weighted incidence ratio per 1000 person-days, -17.1 [95%CI, -20.6 to -13.6]; hazard ratio, 0.63 [95%CI, 0.58–0.69]). Conclusions Among COVID-19 hospitalized patients, use of either Nirmatrelvir-Ritonavir or Molnupiravir compared with no antiviral use was associated with a significantly lower incidence of 28-day all-cause and respiratory mortality and sepsis.