Risk of acute liver injury following the nirmatrelvir/ritonavir use

Abstract

AbstractBackgroundElevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as adverse events of nirmatrelvir/ritonavir users in the EPIC‐HR trial.AimTo quantify the risk and severity of acute liver injury (ALI) associated with nirmatrelvir/ritonavir use.MethodsThis 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.ResultsAmong 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.ConclusionThe 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.