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

Background & Aims:Cases of acute liver injury (ALI) have beenreported among chronic HCV-infected patients receiving prote-ase inhibitor (PI)-based direct-acting antiviral (DAA) regimens,but no analyses have compared the risk of ALI in patientsreceiving PI-vs.non-PI-based DAAs. Thus, we compared the riskof 3 ALI outcomes between patients (by baseline Fibrosis-4 [FIB-4] group) receiving PI-based or non-PI-based DAAs. Methods:We conducted a cohort study of 18,498 patientsreceiving PI-based DAA therapy (paritaprevir/ritonavir/ombi-tasvir +/- dasabuvir, elbasvir/grazoprevir, glecaprevir/pibrentasvir)matched 1:1 on propensity score to those receiving non-PI-basedDAAs (sofosbuvir/ledipasvir, sofosbuvir/velpatasvir) in the 1945-1965 Veterans Birth Cohort (2014-2019). During exposure to DAAtherapy, we determined development of: i) alanine amino-transferase (ALT) >200 U/L, ii) severe hepatic dysfunction (coa-gulopathy with hyperbilirubinemia), and iii) hepaticdecompensation. We used Cox regression to determine hazardratios (HRs) with 95% CIs for each ALI outcome within groupsdefined by baseline FIB-4 (<-3.25; >3.25). Results:Among patients with baseline FIB-4<-3.25, thosereceiving PIs had a higher risk of ALT >200 U/L (HR 3.98; 95% CI2.37-6.68), but not severe hepatic dysfunction (HR 0.67; 95% CI0.19-2.39) or hepatic decompensation (HR 1.01; 95% CI 0.29-3.49), compared to those receiving non-PI-based regimens. Forthose with baseline FIB-4 >3.25, those receiving PIs had a higherrisk of ALT >200 U/L (HR, 2.15; 95% CI 1.09-4.26), but not severehepatic dysfunction (HR, 1.23 [0.64-2.38]) or hepaticdecompensation (HR, 0.87; 95% CI 0.41-1.87), compared to thosereceiving non-PI-based regimens Conclusion:While risk of incident ALT elevations was increasedin those receiving PI-based DAAs in both FIB-4 groups, the risk ofsevere hepatic dysfunction and hepatic decompensation did notdiffer between patients receiving PI- or non-PI-based DAAs ineither FIB-4 group. Lay summary:Cases of liver injury have been reported amongpatients treated with protease inhibitor-based direct-acting an-tivirals for hepatitis C infection, but it is not clear if the risk ofliver injury among people starting these drugs is increasedcompared to those starting non-protease inhibitor-based ther-apy. In this study, patients receiving protease inhibitor-basedtreatment had a higher risk of liver inflammation than thosereceiving a non-protease inhibitor-based treatment, regardless ofthe presence of pre-treatment advanced liverfibrosis/cirrhosis.However, the risk of severe liver dysfunction and decompensa-tion were not higher for patients treated with protease inhibitor-based regimens. Published by Elsevier B.V. on behalf of European Association for theStudy of the Liver

Automated summary

Cases of acute liver injury have been reported among chronic HCV-infected patients receiving protease inhibitor-based direct-acting antiviral therapy, but the risk of severe hepatic dysfunction and decompensation did not differ significantly between patients receiving PI-based or non-PI-based DAAs in either Fibrosis-4 group.