ritonavir and Sepsis

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. Two cohorts, Nirmatrelvir-Ritonavir versus control and Molnupiravir versus 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 and April 15, 2022, and followed up until May 15, 2022. 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]). 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-days all-cause and respiratory mortality and sepsis.

Topics: Antiviral Agents; COVID-19; COVID-19 Drug Treatment; Humans; Multiple Organ Failure; Ritonavir; SARS-CoV-2; Sepsis

The pathophysiology of sepsis involves excessive lymphocyte apoptosis, which correlates with adverse outcomes, and disordered cytokine production, which may promote host injury. As the protease inhibitor (PI) class of antiretroviral agents is known to prevent apoptosis in vitro, we evaluated their effect on survival, lymphocyte apoptosis, and consequent cytokine production in mice with sepsis induced by cecal ligation and perforation. Mice pretreated with PIs have improved survival (67%; P<0.0005) compared with controls (17%) and a significant (P<0.05) reduction in lymphocyte apoptosis. Even mice receiving therapy beginning 4 h after perforation demonstrated improved survival (50%; P<0.05) compared with controls. PI therapy is also associated with an increase in the Th1 cytokine TNF-alpha (P<0.05) early in sepsis and a reduction in the Th2 cytokines IL-6 and IL-10 (P<0.05) late in sepsis; despite no intrinsic antibacterial effects, PI also reduced quantitative bacterial blood cultures. The beneficial effects of PI appear to be specific to lymphocyte apoptosis, as lymphocyte-deficient Rag1-/- mice did not experience benefit from treatment with PI. Thus, inhibition of lymphocyte apoptosis by PI is a candidate approach for the treatment of sepsis.

Topics: Administration, Oral; Animals; Apoptosis; Cecum; Cytokines; Drug Evaluation, Preclinical; Enterococcus; Escherichia coli; Female; Genes, RAG-1; Germ-Free Life; Intestinal Perforation; Lymphocytes; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbial Sensitivity Tests; Nelfinavir; Protease Inhibitors; Pseudomonas aeruginosa; Ritonavir; Sepsis; Spleen; Streptococcus bovis; Thymus Gland