Fadel Dadabaev, Idris Yakubu, B. Agegnehu, Vasco Pontinha, Irfan Moinuddin, A.M.S. Brown, Sara Sterling, A. Iaria, Ryan Marks, Taylor Sprague, Dhiren Kumar, Stephen R. Seelam, Richard K. Sterling, Gaurav Gupta
Background. Kidney transplantation using hepatitis C virus (HCV) nucleic acid test–positive donors for HCV-negative recipients (D + /R − ) has expanded in the direct-acting antiviral (DAA) era, but real-world outcomes with short-course prophylaxis remain limited. We report the largest cohort to date managed with a 7-d perioperative prophylactic DAA strategy. Methods. Single-center prospective observational study of 204 consecutive HCV nucleic acid test–positive donor to HCV-negative recipient kidney transplants performed between December 2018 and August 2025. All recipients received sofosbuvir/velpatasvir 400 of 100 mg daily for 7 d beginning on the day of transplantation. HCV RNA was monitored through 90 d posttransplant. Breakthrough viremia triggered full-course DAA therapy. Results. Donor-derived breakthrough viremia occurred in 15 of 204 recipients (7.4%; 95% confidence interval, 4.2%-11.9%). Most cases (93.3%) were detected by postoperative day 28. Nonstructural protein 5A resistance-associated substitutions were identified in 4 of 8 tested breakthrough cases. First-line retreatment achieved sustained virologic response (SVR) at 12 wk in 14 of 15 (93.3%); 1 patient required salvage therapy, yielding overall SVR at 12 wk of 15 of 15 (100%), although 93% required insurance prior authorization (median delay 36 d). One-year patient and graft survival were 96.6% and 94.1%, respectively, with stable graft function through 12 mo (mean estimated glomerular filtration rate 53.0 ± 22.0 mL/min/1.73 m 2 ). Conclusions. Seven-day perioperative sofosbuvir/velpatasvir prophylaxis achieved SVR after prophylaxis alone in >92% of D + /R − kidney transplant recipients, with favorable 1-y clinical outcomes. Given the nonstructural protein 5A resistance-associated substitutions observed, we have transitioned to 7-d glecaprevir/pibrentasvir prophylaxis; outcomes will be reported via the REFORM-HEPC registry. These findings provide real-world evidence supporting the feasibility of short-course antiviral prophylaxis in HCV-viremic donor kidney transplantation.