UDCA treatment against COVID‐19: Do we have enough clinical evidence for drug repurposing?

Abstract: Research Letter doi: 10.1111/joim.13711 UDCA treatment against COVID-19: Do we have enough clinical evidence for drug repurposing? Dear Editor, Ursodeoxycholic acid (UDCA), an off-patent drug used to treat liver disease [1–3], is able to block severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry into the cells downregulating ACE2 expression [4], a promising strategy to protect against infection. In this light, John et al. [5] have recently demonstrated that in patients with cirrhosis, UDCA exposure was associated with both a decrease in SARS-CoV-2 infection and a reduction in coronavirus disease 2019 (COVID19) severity confirming previous data published by Brevini et al. [4]. To investigate the impact of UDCA treatment in SARS-CoV-2 infection and COVID-19 outcomes in an unselected population of COVID19 patients, we used the administrative databases from Lombardy (Northern Italy), the first region of the Western world to experience a rapid increase in the number of COVID-19 cases and related deaths and the most populated Italian region. The analysis included patients from the first and second pandemic waves, where wild-type and alfa variants were predominant. To test the association of UDCA exposure in the prevention of SARS-CoV-2 infection, we selected 9617 patients with a diagnosis of liver diseases alive on 1 March 2020 (for more details on data source, see the Supporting Information section). The cohort was divided into two groups: UDCA users and UDCA non-users whether they received or not at least one prescription of UDCA before entering the cohort (Fig. 1, left side). Demographic data were recorded at the time of inclusion. History of comorbidities was collected in the four years before inclusion using hospital records as primary diagnosis and up to five co-existing conditions. Exposures to medications of interest were traced in the 12 months before entering the cohort (Supplementary Materials, ATC and ICD-9-CM codes). We used logistic regression models to estimate the incidence of SARS-CoV-2 infection in the following 3 months after UDCA exposure. Odds ratios (ORs) with 95% confidence intervals (CIs) were adjusted for baseline characteristics (age, sex, pre-existing conditions and medications) and by inverse probability treatment weighting (IPTW). Baseline characteristics of the UDCA users and UDCA non-users groups, with standardized mean differences (SMD) were described before and after IPTW (Tables S2 and S3). Good balance was observed after IPTW with SMD equally or less than 0.10 (Figs. S1 and S2). Our model demonstrated good goodness of fit (p-value for Hosmer–Lemeshow test were 0.61 and 0.08 for first and second pandemic wave, respectively) and led to a small variance of the effect estimate as the average of the inverse predicted probabilities was approximately equal to 1: IPTW [mean, median (q1, q3)] were [0.99, 0.97 (0.93, 1.05)] and [1, 0.98 (0.94, 1.04)] for first and second pandemic wave, respectively. No differences in risk of SARS-CoV-2 infection were observed between UDCA users and UDCA non-users according to the pandemic waves: first wave (OR 1.01; 95% CI 0.80– 1.29) and second wave (OR 0.91; 95% CI 0.65– 1.27). We also evaluate the impact of UDCA treatment on COVID-19 outcomes in patients becoming positive for SARS-CoV-2 between 1 March 2020 and 31 May 2021 (Fig. 1, right side) using a Cox proportional hazard model. Hazard ratios (HRs) and 95% CIs were adjusted for baseline characteristics (sex, age,..