1. Trends in Treatment of Recurrent Hepatitis C After Liver Transplantation Kate Forgan-Smith KA Stuart 1,4, C Tallis 1,4 GA Macdonald 1,3,4, J Fawcett 2,3 Departments of Gastroenterology and Hepatology 1 and Hepatobiliary Surgery 2, University of Queensland 3, Queensland Liver Transplant Service 4, Princess Alexandra Hospital, Brisbane

2. Projected Prevalence of HCV Cirrhosis and Complications Number of Cases 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 0 Year 195019601970198019902000201020202030 Hepatocellular Carcinoma (HCC) Decompensated Cirrhosis Davis GL et al. Gastroenterology. 2010;138(2):513-521

4. Background HCV-related cirrhosis develops in 20–30% of liver transplant (LT) recipients within 5 years and impacts upon graft and patient survival Sustained virological response (SVR) improves survival compared to partial responders and untreated patients Berenguer M. J Hepatology 49: 2008: 247 – 287 Berenguer M. Liver Transplantation 19: 2013: 69-77.

5. Treatment of HCV after Liver Transplantation Currently, anti-viral therapy (AVT) is most often commenced at the time of established recurrent HCV in the acute, or more commonly chronic phase to achieve viral eradication and/or reduce disease progression -IFN monotherapy – SVR <5% -IFN & Ribavirin – SVR 20% -Peg-IFN & Ribavirin – SVR 33% Uncertainties remain regarding: Duration and timing of AVT Optimal drug doses Role of growth factor support DAA based therapy Berenguer M. J Hepatology 49: 2008: 247 - 287

6. Aims and Methodology This is a single centre retrospective review of all adult LT recipients at the Princess Alexandra Hospital who had antiviral therapy post LT for recurrent HCV infection The aims were to review the outcomes and adverse effects (AE) of antiviral therapy for recurrent HCV. Patient demographic, clinical, laboratory and histological data were obtained on review of medical records.

7. Patient Demographics Age (year; median, range) 52 (31 – 68) Gender (M:F)39 : 13 Ethnicity84% Caucasian BMI (kg/m 2 ; median, range)26.4 (20 – 46) Diabetes mellitus (n, %)14 (24%) Presence of HCC at LT (n, %)22 (38%) 1995-2003: 282 adult liver transplants and 65 (23%) with HCV 2004-2013: 239 adult liver transplants and 83 (35%) with HCV 52 patients (total of 58 treatments) were identified who had received antiviral treatment for HCV between 1999 and February 2013 (35% of HCV liver transplant recipients)

8. Patient Clinical Characteristics IFN ± RBVPeg-IFN ± RBVDAA triple therapy Year of AVT 1999 – 20032004 – 20132012 – 2013 Patient (N) 9454 Age (yr, median, range) 51 (46 – 56)53 (39 – 68)52 (40 – 59) Gender (M:F) 6 : 335 : 102 : 2 Immunosuppression (Tacro/Cyclo/other) 6/3/029/12/34/0/0 Time since LT (mo, median, range) 60 (2 – 300) 24 (5 – 276) 11 (5 – 96)

9. Patients Started on HCV AVT Year Started AVT Number of patients

10. Liver and Virological Factors by Treatment Group IFN ± RBV (n = 9) Peg-IFN ± RBV (n = 45) DAA triple therapy (n = 4) METAVIR: Fibrosis: 0/1/2/3/4 (n) 0/0/3/6/01/18/19/7/00/0/3/1/0 METAVIR: Activity: 0/1/2/3 (n) 0/0/2/71/19/17/80/0/2/2 HCV viral load (log 10 IU/mL) 6.36.66.7 HCV Genotype (1/2/3) 7/1/124/2/193 G1a, 1 G1b Treatment Experienced (n, %) 3 (33.3%) (IFN only) 18 (40%) (11/18 Peg-IFN) 100% (3x NR, 1x relapse)

11. Antiviral Treatment: Outcomes IFN ± RBV (n = 9) Peg-IFN ± RBV (n = 45) DAA triple therapy (n = 4) Duration of Therapy (median, range in week) 25 (3 – 48)48 (12 – 104) 1 on treatment indefinitely 48 (12 – 48) SVR: Overall (%) SVR by HCV genotype (n, %) 22.2% 1: 1/7 (14%) 2: 0/1 (0%) 3: 1/1 (100%) 42.2% 1: 6/24 (25%) 2: 1/2 (50%) 3: 12/19 (63.2%) 75% TPV: 3/3 (100%) BOC: 0/1 (0%)

12. Antiviral Treatment: Adverse Effects IFN ± RBV (n = 9) Peg-IFN ± RBV (n = 45) DAA triple therapy (n = 4) Adverse effects: Haematological Psychological Other 100% 89% 44% 22% 82% 53% 29% 13% 100% 75% 0% Use of G-CSF, EPO or RBC transfusion (n, %) 3 (33%)10 (22%)3 (75%) Discontinuation rate (n, %) 7 (78%)15 (33%)1 (25%) Dose Reduction – Combined (n, %) PEG-IFN (n, %) Ribavirin (n, %) 3 (33%) 1 (11%) 2 (22%) 28 (62%) 10 (22%) 20 (44%) 3 (75%) 1 (25%) 3 (75%)

13. Antiviral Treatment after Liver Transplantation: Labour Intensive and Expensive Peg-IFN ± RBV (n = 45) DAA triple therapy (n = 4) Number of OPD visits (median, range) 11 (6 – 50) 21 (12 – 29) Number of blood tests (median, range) 24 (8 – 98) 49 (24 – 72) Cost of 1 representative patient Laboratory: Pharmacy (including EPO, G-CSF): $1699.11 $19,765.70 $5842.52 $148,767.65

14. Conclusions 33% adult LT recipients had HCV infection and 1/3 of affected patients received AVT post LT. Peg-IFN & RBV had become the standard of care for recurrent HCV post-LT. In our centre, there was a trend towards starting AVT sooner, at an earlier stage of fibrosis after LT and for longer compared to patients treated with IFN & RBV. –Learning curve effect reflecting physician comfortability –Lower discontinuation rates SVR rates are comparable to published data with better results in non-Genotypic 1 HCV patients

15. Conclusions DAA based AVT is labour intensive, costly and accompanied by a high rate of adverse effects. We acknowledge that new DAA regimens will replace PEG-IFN and 1 st generation DAA based regimens as treatment for HCV after LT. Even though expensive, the costs will likely be offset by less monitoring, shorter duration and fewer adverse effects.

16. Acknowledgements Dr Katherine Stuart Maree Jarrett and Sue Rixon, Liver Transplant Co-ordinators, Queensland Liver Transplant Service Departments of Gastroenterology and Hepatology, Hepatobiliary Surgery and Queensland Liver Transplant Service, Princess Alexandra Hospital Department of Gastroenterology and Hepatology, Townsville Hospital Liver Transplant recipients

17. Eligibility Criteria – DAAs post LT Chronic Genotype 1 HCV infection and liver biopsy demonstrating HCV recurrence: -> F2 within 12 months of LT or, -fibrosing cholestatic hepatitis or, -> F3 greater than 12 months post LT and previously failed Peg-IFN/RBV therapy. Absence of contraindications to protease inhibitor/Peg-IFN RBV Patient’s case discussed at the Integrated Liver Transplant Meeting with agreement by all Transplant Hepatologists to use DAA triple therapy