Risk of acute liver injury following the nirmatrelvir/ritonavir use

Background: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as adverse events of nirmatrelvir/ritonavir users in the EPIC-HR trial. Aim: To quantify the risk and severity of acute liver injury (ALI) associated with nirmatrelvir/ritonavir use. Methods: This self-controlled case-series study was conducted using electronic medical records of patients with confirmed diagnosis of SARS-CoV-2 infection between 26th February 2022 and 12th February 2023 in Hong Kong. Results: Among 2 409 848 patients with SARS-CoV-2 infection during the study period, 153 853 were prescribed with nirmatrelvir/ritonavir, of whom 834 (.5%) had incident ALI (moderate: 30.5%; moderate to severe: 18.9%; severe or fatal: 5.8%). Compared with the non-exposure period, risk of ALI increased significantly during the pre-exposure period (IRR = 38.13, 95% CI = 29.29–49.62) and remained elevated during the five-day nirmatrelvir/ritonavir treatment (IRR = 20.75, 95% CI = 17.06–25.25) and during wash-out period (IRR = 16.27, 95% CI = 13.23–20.01). Compared to the pre-exposure period, risk of ALI was not increased during the five-day nirmatrelvir/ritonavir treatment period (IRR =.54, 95% CI =.43–.70). Compared to 5469 non-nirmatrelvir/ritonavir users with incident ALI, nirmatrelvir/ritonavir users had less severe ALI by the severity index (p <.001) and peak INR (1.7 vs. 2.3; p <.001). ALI cases with nirmatrelvir/ritonavir use had lower risk of all-cause death (29.1% vs. 39.1%; OR =.64; p <.001) and no increase in risk of liver decompensation (1.0% vs. 1.3%; OR =.62; p =.230) compared to non-users. Conclusion: The risk of ALI associated with nirmatrelvir/ritonavir treatment for COVID-19 was elevated in the pre-exposure period, but not following nirmatrelvir/ritonavir initiation. ALI following nirmatrelvir/ritonavir treatment were mostly mild and less severe than ALI events in non-nirmatrelvir/ritonavir users.