Background: Allografts of viremic OLT are at high risk of dysfunction and failure. Conventional Rx outcomes with Pegylated interferon (P-IFN) + Ribavirin (RBV) are suboptimal. In pre-OLT settings, TVR, a serine protease-inhibitor, has shown good response in combination Rx (+ Peg-IFN + RBV), but there is no data in HCV-OLT. TVR increases FK exposure by 70-fold in normal subjects. Toxicity and/or rejection (ACR) can be detrimental and it is a major concern in OLT. Aim: To achieve HCV aviremia in OLT with TVR+ P-IFN + RBV Rx and a safe reduction in FK dosing while minimizing adverse events (AE). Methods: IRB-approved trial of HCV viremic OLT (n=18) was carried out. All OLT genotype 1 with HCVR histology (stages 0-3). OLT started on TVR+PIFN+RBV for 12 weeks with further PIFN+RBV Rx for 12-36 weeks (RGRx). Pre-study FK dose reduced 25-30-fold (daily to weekly) to keep FK target level of 4-5 ng/ml. Five days after stopping TVR, FK dosage was gradually titrated up. FK and HCV-RNA levels (while detectable) and clinical evaluations done weekly.

Results: Thirteen OLT (72%) were PIFN+RBV non-responders. No ACR episodes were detected during TVR Rx. One patient had ACR 2 months post Rx. Main AE was anemia (67%, FK level-independent) treated with procrit (n=12) and/or PRBC transfusions (n=8). One patient (stage 3 fibrosis) who became aviremic developed pneumonia-ARDS and died. No other severe AE were observed. Most patients had predictable levels of FK when dosed once a week.

The rate HCV-RNA negative levels achieved with TVR-based Rx is superior to conventional Rx (data not shown). At 24 weeks of RGRx, sustained virologic response was over 50%.

Conclusions: FK dosing adjustment in HCV-OLT under TVR Rx can be safely achieved with low toxicity and low ACR incidences. Anemia was the main AE and effectively treated. TVR with RGRx approach is safe, reproducible and predictable. Controlled studies are needed to confirm this initial experience.

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