*Purpose: Two recent pilot trials have shown that transplanting hepatitis C (HCV) viremic kidneys in to HCV negative recipients is feasible. These trials used 12 weeks of direct-acting anti-viral (DAA) therapy to treat donor-derived HCV viremia. We conducted an open-label single-center nonrandomized trial (ClinicalTrials.gov: NCT03249194) in two phases to determine the feasibility of using ultra short-term DAA prophylaxis before and after kidney transplantation from deceased HCV-infected viremic donors to non-HCV-infected recipients (D+/R- transplants).

*Methods: Waitlisted HCV negative kidney transplant candidates with expected wait time of >2 years, with age>60 years, or any age with at least two co-morbidities (diabetes, heart disease, peripheral vascular disease or stroke) without significant liver fibrosis assessed by transient elastography were enrolled. After administration of short course (2-4 days) prophylactic Sofusbuvir/Velpatasvir (SOF/VEL), patients were screened for HCV RNA at Days 3, 7, 14, 21, 28, 42, Months 3, 6 and 12. Development of viremia triggered a full 12 week course of DAA therapy.

*Results: Overall, 25 patients (mean age=60 years; 36% females; 60% African-American) received D+/R- transplants. The mean wait time to transplant from enrollment was 28 days and the mean donor KDPI was 59%. The median donor viral load was 5.6E+05 IU/mL (IQR:1.08E+03-1.98E+07) although 5 samples could not be analyzed possibly due to degradation. 67% were Genotype (GT) 1a, 22% were GT 3 and 11% were GT 2. At a median follow-up of 4.6 months (IQR: 1.8-15months) post-transplant, both patient and graft survivals were 100%. Average kidney function as measured by eGFR was 57±16mL/min/1.73m2. There were two episodes (8%) of acute T-cell mediated rejection that were reversed with therapy. There were no cases of liver dysfunction. In Phase I, ten D+/R- recipients received one dose of pangenotypic SOF/VEL immediately pre-transplant and then one dose on post-transplant Day 1. Viral transmission rate was 30% (3/10; All GT1a). Of these 3, two patients achieved sustained virologic response with a subsequent course of DAA while one patient (with NS3/4A and NS5A resistance mutations) did not. In Phase II, 15 D+/R- patients received two additional doses of SOF/VEL on Days 2 and 3 post-transplant. Viral transmission rate decreased to 13%, with only two patients acquiring HCV (one GT2 and one GT3). Both patients have undetectable viral loads after initiating 12 weeks of DAA therapy.

*Conclusions: Our data suggests that ultra-short duration DAA prophylaxis was largely effective in preventing donor-derived HCV transmission and has the potential of resulting in significant cost-savings by avoiding DAA therapy in a large majority of D+/R- transplants.

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