Protease inhibitor-based direct-acting antivirals are associated with increased risk of aminotransferase elevations but not hepatic dysfunction or decompensation

ABSTRACT Background & Aims Cases of acute liver injury (ALI) have been reported among chronic hepatitis C virus-infected initiators of protease inhibitor (PI)-based direct-acting antiviral (DAA) regimens, predominately with decompensated cirrhosis in whom these therapies are contraindicated. No analyses have evaluated if initiators of PI versus non-PI-based DAAs have higher risk of ALI, by advanced hepatic fibrosis/cirrhosis. We compared the risk of three ALI outcomes among PI-based and non-PI-based DAA initiators, by baseline FIB-4. Methods We conducted a cohort study of 18,498 initiators of PI-based DAA therapy (paritaprevir/ritonavir/ombitasvir +/- dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) matched 1:1 on propensity score to non-PI-based DAA initiators (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAA therapy, we determined development of: 1) alanine aminotransferase (ALT) >200 U/L, 2) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and 3) hepatic decompensation. We used Cox regression to determine hazard ratios (HRs) with 95% confidence intervals of each ALI outcome in PI versus non-PI initiators within groups defined by baseline FIB-4 (≤3.25; >3.25). Results Among persons with baseline FIB-4 ≤3.25, PI initiators had higher risk of ALT >200 U/L (HR, 3.98 [2.37-6.68]), but not severe hepatic dysfunction (HR, 0.67 [0.19-2.39]) or hepatic decompensation (HR, 1.01 [0.29-3.49]), compared to non-PI-initiators. For those with baseline FIB-4 >3.25, PI initiators had higher risk of ALT >200 U/L (HR, 2.15 [1.09-4.26]), but not severe hepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepatic decompensation (HR, 0.87 [0.41-1.87]), compared to non-PI initiators. Conclusion While risk of incident ALT elevations was increased among PI-based DAA initiators in both FIB-4 groups, risk of severe hepatic dysfunction and hepatic decompensation did not differ between PI and non-PI-based DAA initiators in either FIB-4 group. Lay Summary Cases of liver injury have been reported among patients treated with protease inhibitor-based direct-acting antivirals for hepatitis C infection, but it is not clear if risk of liver injury among people starting these drugs is increased compared to those starting non-protease inhibitor-based therapy. In this study, persons who initiated protease inhibitor-based treatment had higher risk of liver inflammation than non-protease inhibitor-based initiators, regardless of the presence of pre-treatment advanced liver fibrosis/cirrhosis. However, the risk of severe liver dysfunction and decompensation were not higher for protease inhibitor-based initiators.