*Purpose: An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). Establishment of HCV infection in uninfected recipients is near-universal with the requirement for post-transplant antiviral treatment. Prevention of HCV infection with a simplified regimen would be preferable.

*Methods: HCV-uninfected organ recipients were treated with ezetimibe 10 mg (an HCV entry inhibitor) and glecaprevir/pibrentasvir 300 mg/120 mg one dose before and once daily for 7 days after transplantation from HCV-infected donors. HCV RNA was assessed daily for 14 days and then weekly to 12 weeks post-transplant. The primary endpoint was prevention of HCV infection as evidenced by undetectable serum HCV RNA 12 weeks after transplant.

*Results: 30 patients received transplants (13 lung, 10 kidney, 6 heart and 1 kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 4.90 log₁₀IU/mL (range 1.18-7.13 log₁₀IU/mL) and included different HCV genotypes (9 genotype 1, 2 genotype 2, 5 genotype 3 and 2 genotype unknown). The treatment regimen was 100% effective in preventing HCV infection in the recipients and all 30 patients remain HCV RNA negative at last follow-up (median 27 weeks, range 5-45 weeks post-transplant). Low-level viremia was transiently detectable in 20 (67%) recipients in the early post-transplant period but never beyond day 11. Treatment was well tolerated, with transient ALT and CK elevations noted during treatment that resolved with treatment completion. Two recipients died of unrelated causes and neither were ever viremic for HCV.

*Conclusions: Ezetimibe combined with glecaprevir/pibrentasvir given one dose before and for 7 days after transplant was a completely effective and simplified regimen for preventing transmission of HCV infection in recipients of different organs from HCV-infected donors (registration NCT04017338).

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