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. No comparative analyses have evaluated whether initiators of PI versus non-PI-based DAAs have higher risk of ALI events, stratified by advanced hepatic fibrosis/cirrhosis status.

We conducted a cohort study including 20,872 initiators of PI-based (paritaprevir/ritonavir/ombitasvir +/- dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir) and 54,315 initiators of non-PI-based DAA therapies (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). We determined development of: 1) alanine aminotransferase (ALT) >200 U/L, 2) severe hepatic dysfunction (coagulopathy with hyperbilirubinemia), and 3) hepatic decompensation, all within 12 months of DAA initiation. Cox regression was used to determine propensity score-adjusted hazard ratios (HRs) with 95% confidence intervals of each outcome in PI versus non-PI initiators, stratified by baseline advanced hepatic fibrosis/cirrhosis status by FIB-4.

Among persons with baseline FIB-4 ≤3.25, PI initiators had higher risk of ALT >200 U/L (HR, 3.75 [2.74-5.15]), but not severe hepatic dysfunction (HR, 1.51 [0.57-4.04]) or hepatic decompensation (HR, 0.59 [0.26-1.37]), compared to non-PI-initiators. For those with baseline FIB-4 >3.25, PI initiators did not have significantly higher risk of ALT >200 U/L (HR, 1.68 [0.89-3.19]), severe hepatic dysfunction (HR, 0.79 [0.46-1.37]), or hepatic decompensation (HR, 0.78 [0.45-1.35]) than non-PI initiators.

While risk of incident ALT elevations was increased among PI-based DAA initiators with FIB-4 ≤3.25, risk of severe hepatic dysfunction and hepatic decompensation did not differ between PI and non-PI-based DAA initiators in either FIB-4 stratum.