Liver International ISSN 1478-3223

LIVER TRANSPLANTATION

Boceprevir in liver transplant recipients Sammy Saab1,2, Vignan Manne2, Sherona Bau2, Justin A. Reynolds3, Ruby Allen2, Leonard Goldstein2, Francisco Durazo1,2, Mohammed El-Kabany1,2, Steven Han1,2 and Ronald W. Busuttil2 1 Departments of Medicine, The University of California, Los Angeles, CA, USA 2 Departments of Surgery, The University of California, Los Angeles, CA, USA 3 Department of Medicine, Mayo Clinic, Scottsdale, Arizona, USA

Keywords hepatitis C – liver transplant – protease inhibitors

Correspondence Sammy Saab, MD, MPH, AGAF Pfleger Liver Institute UCLA Medical Center 200 Medical Plaza, Suite 214 Los Angeles, CA 90095, USA Tel: 310-206-6705 (V) Fax: 310-206-4197 (F) e-mail: [email protected] Received 7 February 2014 Accepted 18 March 2014 DOI:10.1111/liv.12548

Abstract Background: There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease in liver transplant recipients. Methods: We retrospectively evaluated the safety and efficacy in liver transplant recipients treated for recurrent hepatitis C genotype 1 with the combination of peginterferon, ribavirin and boceprevir. Results: Twenty liver transplant recipients were treated for recurrent hepatitis C. Baseline alanine aminotransferase, total bilirubin and HCV RNA values (± SD) were 67.5 (±50.9) mg/dl, 1.78 (±1.99) U/L, and 16 955 510 (±21 620 675) IU/ml. Anaemia was a common adverse event requiring epoetin in 16 of 20 recipients and ribavirin dose reductions in 17 of 20 recipients. One-third of recipients required a blood transfusion. Filgrastim was used in 11 of 20 patients (55%) and eltrombopag in two of 20 recipients (10%) over the course of treatment. Serum creatinine level increased significantly from a baseline value of 1.33 mg/dl to 1.59 mg/dl at week 20 of boceprevir (P < 0.005). The overall sustained viral response (SVR) was 50%. Of the 14 patients who had a viral load less than 1000 IU/ml at week 4 of boceprevir, the SVR was 71%. The SVR was 83% of the 11 patients who had undetectable viral levels at week 4 of boceprevir. Conclusions: Antiviral therapy utilizing boceprevir in liver transplant recipients requires close monitoring. Anaemia and neutropenia were common requiring growth factors in most recipients. On-treatment viral responses appear promising but longterm data are needed.

Hepatitis C virus (HCV) related liver disease is also the most common indication for liver transplantation in the United States (1), accounting for approximately 40% of all liver transplants performed annually (2). Unfortunately, recurrent HCV after transplant is near universal and is associated with diminished graft survival and cirrhosis in up to 30% of transplant recipients within 5 years (3). Overall, HCV-infected liver transplant recipients have a shorter survival as compared to nonHCV recipients (4). Pegylated interferon (PEG) used in combination with ribavirin (RBV) has been studied in the post-transplant setting for treatment of recurrent HCV. However, the rate of sustained virological response (SVR) is approximately 30% in genotype 1 HCV-infected patients (5). In those who are treated and do demonstrate sustained virological response, improved survival as well as histological stability or improvement has been observed (6, 7). There has been increasing interest in utilizing NS3/ 4A protease inhibitors, boceprevir and telaprevir, in the treatment of liver transplant recipients (8–11). Liver International (2014) © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Widespread use has been limited by concerns regarding adverse effects and drug-drug interactions. Boceprevir and telaprevir are both strong inhibitors of CYP3A, and in studies of healthy patients administered a single dose of tacrolimus in the setting of standard telaprevir dosing, tacrolimus levels rose to 70-fold their expected levels (4.6-fold with telaprevir and cyclosporine) (12). Boceprevir is metabolized by CYP3A as well as aldo-ketoreductase, which produces inactive keto-reduced metabolites. When co-administered with tacrolimus or cyclosporine according to a similar study design as that done by Garg et al., tacrolimus levels rose to 17-fold their expected levels (2.7-fold with boceprevir and cyclosporine) (13). Because of the low rates of SVR in post-transplant patients using PEG/RBV, we developed a protocol utilizing boceprevir along with peginterferon and ribavirin in liver transplant recipients with recurrent hepatitis C disease. We report our early experience using boceprevir and highlight the early efficacy, safety and drug interactions.

1

Boceprevir for recurrent HCV after transplant

Methods Patient Population and Data Collection

We performed a retrospective chart review of all liver transplant recipients treated with peginterferon alfa-2a (PEG), ribavirin (RBV) and boceprevir (BOC) for recurrent hepatitis C disease at the University of California Los Angeles Medical Center seen between September 2011 and January 2013. Patients identified for our study were adults with genotype 1 HCV recurrence after liver transplantation (LT) with the following inclusion criteria: (i) aged 18–70 years at beginning of antiviral treatment; (ii) HCV viraemia after LT with pathologic evidence of HCV recurrence on liver biopsy and strong indication for antiviral treatment (history of fibrosing cholestatic hepatitis, minimum stage 2 fibrosis or extrahepatic manifestation of HCV) and (iii) a stable regimen of cyclosporine and mycophenylate mofetil. Exclusion criteria were evidence of allograft rejection on biopsy within 6 months of starting antiviral therapy, contraindications to PEG/RBV use, or evidence of decompensated liver disease (e.g. ascites, encephalopathy). All LT patients at our institution who met these inclusion criteria between September 2011 and January 2013 were treated with BOC in addition to PEG/RBV. Data on demographics (age, gender, race/ethnicity), body mass index (BMI), history of prior antiviral therapy, baseline laboratory values, pathologic specimens and HCV RNA levels were recorded by chart review. Descriptive statistics were used. Distribution of the results was presented as mean ± SD. ANOVA was used to compare repeated measures. A P value of

Boceprevir in liver transplant recipients.

There has been increasing interest in using protease inhibitors with pegylated interferon and ribavirin to treat recurrent hepatitis C (HCV) disease i...
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