1. Liver transplantation for HCV infection R3 양 인 호 /Prof 김 병 호

2. Epidemiology HCV infection causes about 40 percent of all chronic liver disease in US HCV associated cirrhosis is the m/c indication for orthotopic liver transplantation (OLT) among US adults - 우리나라에서는 10%, 점차 증가하는 추세

3. Forman LM et al. The association between hepatitis C infection and survival after orthotopic liver transplantation. Gastroenterology 2002;122(4):889-96.

4. Natural history Recurrence of HCV occurs in over 95% of patients Reinfection occurs during reperfusion of the allograft in the OR Viral titers reach pretransplant levels within 72 hours Peripheral monocytes harbor virus and acts as as source for reinfection of the donor liver Histologic evidence of recurrent disease is present in the majority of patients 1 year after OLT 11-37% have moderate fibrosis at this time point Median time to recurrent cirrhosis : 8-10 yrs Rapid progressors develop recurrent cirrhosis within 3-5 years

6. Recipient factors Older age : associated with reduced survival but not disease progression Women : the risk of advanced fibrosis is higher than men HCV/HIV coinfection vs. HCV monoinfection : 3 yr patient survival rates 60% vs. 79% : 3 yr graft survival rates 53% vs. 74% Interleukin(IL)-28B polymorphisms - recipient IL28B non-CC polymorphisms : severe cholestatic hepatitis - donor IL28B-CC polymorphisms : higher ALT and HCV RNA levels in the early post-LT period : higher rates of fibrosis at 1 year post-LT and higher rates of graft loss

7. Donor factors Elderly donor : most consistently associated with progressive HCV disease and graft loss → Elderly donors are recommended not to be utilized in HCV-infected patients Donors with cardiac death : higher rates of complications, HCV recurrence and severity, compared to livers from brain death donors Anti-HCV positive donors - no worse outcome compared to anti-HCV negative donors - except if donor has evidence of fibrosis or is older

8. Transplant related factors CMV infection - a/w more severe fibrosis - most important risk factor : lack of effective CMV-specific immunity - CMV D+/R- patients are at highest risk → extended course of CMV prophylaxis is suggested Treated acute rejection - a/w severity and risk of posttransplant cirrhosis - receipt of anti-rejection treatment (steroid boluses, anti- lymphocyte preparations) → mild rejection is not recommended to be treated with steroid boluses, rather with increased maintenance immunosuppression

10. Diagnosis Presence of persistently detectable post-LT HCV RNA Gold standard : Liver biopsy - elevated liver enzymes can be due to conditions other than HCV recurrence - preservation injurys - acute/chronic rejections - steatohepatitis - biliary complications Most transplant centers utilize annual biopsies or annual noninvasive tests to monitor disease activity and fibrosis to determine the appropriate timing for antiviral therapy

12. Noninvasive tests of fibrosis severity

13. Treatment Goal : prevent liver-related complications : prevent graft loss Basic treatment approach : pre-LT antiviral therapy -prevent post-LT HCV infection : post-LT antiviral therapy - eradicate infection in those with established recurrence

14. Pre-LT antiviral Tx Combination of peg-interferon + ribavirin Sustained virologic response (SVR) : HCV RNA undetectable at least 6 months - when achieved prior to LT, eliminated risk of HCV infection Candidates - compensated or mildly decompensated cirrhosis (MELD < 18) Contraindication - Advanced decompensation : Child-Pugh class B+ or C, MELD ≥ 18

15. Pre-LT antiviral Tx Treatment is discontinued in 20-35% due to adverse effect - including infectious complications - risk factors : high Child-Pugh score, high MELD score, presence of ascites, low baseline albumin Triple therapy : peg-interferon + ribavirin + protease inhibitor (telaprevir or boceprevir) - safety and efficacy not yet been evaluated

16. Post-LT antiviral Tx Achievement of sustained viral clearance - a/w improved histology in the majority of patients and higher rates of graft survival Recommendation - stage 2/4 fibrosis - mod to severe necroinflammation - cholestatic hepatitis Higher SVR rates among those with milder histologic disease

18. Post-LT antiviral Tx Protease inhibitors + peg interferon + ribavirin - likely improve SVR rates - drug interactions with calcineurin inhibitors (CNI) and mTOR inhibitors Daclatasvir - NS5A inhibitor - predicted not to have any anticipated drug interactions with CNI

19. Post-LT antiviral Tx Complications of interferon → immunological complications - acute rejection - chronic rejection - autoimmune-like hepatitis (plasma cell hepatitis) Overall incidence : 7.2% Lower graft survival (38.5% vs 85.6%)