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Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune-mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct-acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA-IGD (1 case: 2 controls—33 vs 66). Among all treated between 2014 and 2016, DAA-IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid-induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P< .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA-IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation.

Interferon treatment of hepatitis C virus (HCV) infection after liver transplantation (LT) can result in immune‐mediated graft dysfunction (IGD). The occurrence of, risk factors for, and outcomes of IGD with direct‐acting antiviral (DAA) therapy have not been reported. We conducted a multicenter study of HCV+LT recipients who did or did not develop DAA‐IGD (1 case: 2 controls—33 vs 66). Among all treated between 2014 and 2016, DAA‐IGD occurred in 3.4% (33/978). IGD occurred only after treatment completion (76.0 [IQR, 47.0;176]). Among those treated, 48% had plasma cell hepatitis, 36% acute cellular rejection, 6% chronic rejection, and 9% combined findings. Median time to liver enzyme resolution was 77.5 days (IQR, 31.5;126). After diagnosis, hospitalizations, steroid‐induced hyperglycemia, and infection occurred in a higher percentage of cases vs controls (33% vs 7.5%, 21% vs 1.5%, 9% vs 0%; all P< .05). Only one IGD patient died and none required retransplant. A multivariate regression analysis found that liver enzyme elevations during and soon after DAA therapy completion correlated with subsequent IGD. In conclusion, while DAA‐IGD is uncommon, liver enzyme elevations during or after DAA therapy may be a sign of impending IGD. These indicators should guide clinicians to diagnose and treat IGD early before the more deleterious later clinical presentation. In this multicenter cohort, immune‐mediated graft injury related to direct‐acting anti‐HCV therapy after liver transplantation was uncommon but associated with higher morbidity than those without this complication, and could be predicted by persistent liver test abnormalities during and soon after therapy completion.