Ursodeoxycholic acid is associated with a reduction in SARS-CoV-2 infection and reduced severity of COVID-19 in patients with cirrhosis.

BACKGROUND AND AIMS: Studies have demonstrated that reducing farnesoid X receptor activity with ursodeoxycholic acid (UDCA) downregulates angiotensin-converting enzyme in human lung, intestinal and cholangiocytes organoids in vitro, in human lungs and livers perfused ex situ, reducing internalization of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into the host cell. This offers a potential novel target against coronavirus disease 2019 (COVID-19). The objective of our study was to compare the association between UDCA exposure and SARS-CoV-2 infection, as well as varying severities of COVID-19, in a large national cohort of participants with cirrhosis. METHODS: In this retrospective cohort study among participants with cirrhosis in the Veterans Outcomes and Costs Associated with Liver cohort, we compared participants with exposure to UDCA, with a propensity score (PS) matched group of participants without UDCA exposure, matched for clinical characteristics, and vaccination status. The outcomes included SARS-CoV-2 infection, symptomatic, at least moderate, severe, or critical COVID-19, and COVID-19-related death. RESULTS: We compared 1607 participants with cirrhosis who were on UDCA, with 1607 PS-matched controls. On multivariable logistic regression, UDCA exposure was associated with reduced odds of developing SARS-CoV-2 infection (adjusted odds ratio [aOR] 0.54, 95% confidence interval [CI] 0.41-0.71, p < 0.0001). Among patients who developed COVID-19, UDCA use was associated with reduced disease severity, including symptomatic COVID-19 (aOR 0.54, 95% CI 0.39-0.73, p < 0.0001), at least moderate COVID-19 (aOR 0.51, 95% CI 0.32-0.81, p = 0.005), and severe or critical COVID-19 (aOR 0.48, 95% CI 0.25-0.94, p = 0.03). CONCLUSIONS: In participants with cirrhosis, UDCA exposure was associated with both a decrease in SARS-CoV-2 infection, and reduction in symptomatic, at least moderate, and severe/critical COVID-19.

Comparison of infection-induced and vaccine-induced immunity against COVID-19 in patients with cirrhosis.

BACKGROUND AND AIMS: Immunity to SARS-CoV-2 can be infection or vaccine-induced. Cirrhosis is associated with vaccine hyporesponsiveness, but whether there is decreased immunity after SARS-CoV-2 infection in unvaccinated patients with cirrhosis is unknown. The objective of our study was to compare infection-induced and vaccine-induced immunity against COVID-19 among patients with cirrhosis. METHODS: This was a retrospective cohort study among US Veterans with cirrhosis between November 27, 2020, and November 16, 2021, comparing a vaccine-induced immunity group, defined as participants without a documented SARS-CoV-2 infection but fully vaccinated with two doses of an mRNA vaccine, and infection-associated immunity group, defined as unvaccinated participants who had a positive SARS-CoV-2 polymerase chain reaction (PCR). Both groups were propensity score matched for observed characteristics, including location, and the date of the immunity acquiring event, to control for the community prevalence of COVID-19 variants. The outcome was a positive SARS-CoV-2 PCR more than 60 days after previous infection in the infection-induced, or after full vaccination in the vaccine-induced immunity group. RESULTS: We compared 634 participants in the infection-induced immunity group with 27,131 participants in the vaccine-induced immunity group using inverse propensity of treatment weighting. Vaccine-induced immunity was associated with a reduced odds of developing SARS-CoV-2 infection (adjusted hazard ratio [aHR], 0.18; 95% confidence interval [CI], 0.16-0.20, p < 0.0001). On multivariable logistic regression, vaccine-induced immunity was associated with reduced odds of developing symptomatic (adjusted odds ratio [aOR], 0.36; 95% CI, 0.33-0.41, p < 0.0001), moderate/severe/critical (aOR, 0.27; 95% CI, 0.22-0.31, p < 0.0001), and severe or critical COVID-19 (aOR, 0.20; 95% CI, 0.16-0.26, p < 0.001), compared with infection-induced immunity. CONCLUSIONS: In participants with cirrhosis, vaccine-induced immunity is associated with reduced risk of developing COVID-19, compared with infection-induced immunity.

Third dose of COVID-19 mRNA vaccine appears to overcome vaccine hyporesponsiveness in patients with cirrhosis.

BACKGROUND & AIMS: Cirrhosis is associated with immune dysregulation and hyporesponsiveness to several vaccines including those against COVID-19. Our aim was to compare outcomes between patients with cirrhosis who received 3 doses of either the Pfizer BNT162b2 mRNA or Moderna mRNA-1273 vaccines to a propensity-matched control group of patients at similar risk of infection who received 2 doses. METHODS: This was a retrospective cohort study of patients with cirrhosis who received 2 or 3 doses of a COVID-19 mRNA vaccine at the Veterans Health Administration. Participants who received 3 doses of the vaccine (n = 13,041) were propensity score matched with 13,041 controls who received 2 doses, and studied between July 18, 2021 and February 11, 2022, when B.1.617.2 (delta) and B.1.1.529 (omicron) were the predominant variants. Outcomes were aggregated as all cases with COVID-19, symptomatic COVD-19, with at least moderate COVID-19, or severe or critical COVID-19. RESULTS: Receipt of the third dose of a COVID-19 mRNA vaccine was associated with an 80.7% reduction in COVID-19 (95% CI 39.2-89.1, p <0.001), an 80.4% reduction in symptomatic COVID-19, an 80% reduction in moderate, severe or critical COVID-19, (95% CI 34.5-87.6%, p = 0.005), a 100% reduction in severe or critical COVID-19 (95% CI 99.2-100.0, p = 0.01), and a 100% reduction in COVID-19-related death (95% CI 99.8-100.0, p = 0.007). The magnitude of reduction in COVID-19 was greater with the third dose of BNT 162b2 than mRNA-1273 and among participants with compensated rather than decompensated cirrhosis. CONCLUSIONS: Administration of a third dose of a COVID-19 mRNA vaccine was associated with a more significant reduction in COVID-19 in patients with cirrhosis than in the general population, suggesting that the third dose can overcome vaccine hyporesponsiveness in this population. LAY SUMMARY: Cirrhosis is associated with decreased responsiveness to several vaccines, including those against COVID-19. In this study of 26,082 participants with cirrhosis during the delta and omicron surge, receipt of the third dose of the vaccine was associated with an 80% reduction in COVID-19, a 100% reduction in severe/critical COVID-19, and a 100% reduction in COVID-19-related death. These findings support the importance of a third dose of mRNA vaccine among patients with cirrhosis.