1. Hepatitis B and C Infections and Liver Transplantation Seyed Moayed Alavian Professor of Gastroenterology and Hepatology Editor in-chief of Hepatitis Monthly E mail: editor@hepatmon.com editor@hepatmon.com 2016 Sari Meeting

2. Hepatitis B and Hepatitis D Infections before and after Liver Transplant

3. Presentation of a case A 45 years man with HBV infection and MELD 18 transplanted and he had history of using Tenefovir for a short time and irregular. What is your plan for prevention of HBV recurrence after liver transplantation?

4. Indications for Liver Transplantation in Adults: Etiologies of End-Stage Liver Disease in Iran Chronic Hepatitis B/ Acute fulminant Chronic Hepatitis C Non-alcoholic steato-hepatitis Autoimmune Hepatitis Metabolic and genetic disorders ….

5. Patients with HBV-related cirrhosis who are eligible for transplantation can be conceptually divided into those with high versus low risk of reinfection. High-risk patients include patients with cirrhosis who are HBe Ag positive or HBe Ag negative but with high serum HBV DNA levels, and patients with antiviral drug-resistance prior to transplant. Low-risk patients include patients with fulminant HBV, co- infection with HDV, and cirrhotic patients who are HBe Ag negative with low serum HBV DNA levels Campos-Varela I, et al. Does pre-liver transplant HBV DNA level affect HBV recurrence or survival in liver transplant recipients receiving HBIg and nucleos(t)ide analogues? Ann Hepatol. 2011

6. Oral therapy such as Tenefovir for of HBV infection in decompensated cirrhosis is highly effective in suppressing HBV and : Potentially delaying the need for transplantation Improve and Stabilize liver function Prevent hepatocellular carcinoma And the most important reducing the risk of recurrent HBV infection after OLT Impact of HBV therapy before liver transplantation

7. The 1-year survival probability for HBV patients improved from 71% in 1987–1991 to 87% in 1997– 2002, and the 5-year survival probability increased from 53% in 1987–1991 to 76% in 1997–2002. Evolution of Survival After Liver Transplant between recipients with HBV hepatitis and those with other diagnosis Kim WR et al. Liver Transpl. 2004;10:968 5 HBIG LAM

8. Management of HBV cirrhosis; how to manage and prepare for surgery Dindoost P, Jazayeri SM, Alavian SM. Hepatitis B immune globulin in liver transplantation prophylaxis: an update. Hepat Mon. 2012 In the Surgery time: HBIG first day 10,000 IU IV Then 5000 daily for the first week, reduce to 2500 daily in the second week Adjust according to result of Anti HBs Ab Week 2,3,4: weekly 5,000 I.U if HBs Ab less than 300 I.U/ml Use of fixed dose in setups where Anti HBs Ab level monitoring is not readily available Month 2 until year one, Monthly 5000 I.U Intention is to have Anti HBs Ab level of 300 in the first three months HBV DNA before transplantation should be negative with anti-viral drugs If before transplantation HBV DNA is positive, the HBs Ab title should be more than 100 long life

9. Liver Transplantation for HDV infection The outcome of transplantation for chronic hepatitis D is superior to that for chronic hepatitis B. Better course The reinfection is significantly lower for HDV than for HBV and the clinical course of recurrent hepatitis is milder than for HBV. If hepatitis D recurs In the new liver without the expression of hepatitis B (an unusual serologic profile in imunocomponent persons but common in transplant pts.) liver injury is limited. The management is not basically different from other HBV cirrhotic - In Delta patients: - HBIG should never be stopped, risk of Delta reactivation

10. Hepatitis C and Liver Transplantation

11. Introduction Recurrence of HCV infection among patients, who undergo liver transplantation with detectable HCV RNA is still a major concern with morbidity and allograft loss after transplantation. Approximately 30% of HCV transplanted patients develop acute severe recurrent hepatitis progressing rapidly to liver cirrhosis and increased risk of death. In patients with end stage liver disease in the waiting list for liver transplantation, it is advised to start DAA as soon as possible.

12. Natural History of HCV infection 5 years After OLT

13. Patterns Of HCV Recurrence After OLT Fibrosing Cholestatic HCV Recurrence Chronic Hepatitis Linear Rate Of Fibrosis Progression Delayed Onset Progression 5% 25%*65%* * At 5 years follow-up

14. Opportunities to Intervene with Antiviral Therapy Biggins SW, Terrault NA. Infect Dis Clin N Am 2006; 20:155

15. Management of HCV Disease Prior to 2014  Antiviral therapy is primarily given post-LT  Annual biopsies used to monitor for fibrosis change  Treat early severe recurrence and those with progression (F2 or more)  Mainstay of treatment = peg-IFN, ribavirin and Protease inhibitors (PIs)

16. Every Step of HCV Replication Can be Targeted Manns MP et al. Nat Rev Drug Discov. 2013

17. Sofosbuvir A “Game Changer” For Management of Recurrent HCV Disease  Positives  Excellent tolerability  No DDI with immunosuppression  Consistent HCV RNA suppression on treatment  Negatives  Renal insufficiency requires dose reduction  Unknown dosing if on dialysis  Cost and access

18. HCV treatment in patients on the liver transplant waiting list Several proof of concept studies have shown – Safety – Efficacy – Compensated liver disease – Mild-to-moderately decompensated cirrhosis Safe prevention of post liver transplant recurrence

19. HCV treatment in patients on the liver transplant waiting list Interferon-based therapies – Interferon and Ribavirin – Sofosbovir-based triple therapy – Daclatasvir-based triple therapy Good results, however, toxicities of INF still present.

20. Days HCV RNA Negative Prior to LT and Rate of Recurrence No Recurrence (n=28)Recurrence (n=10) Median days of HCV RNA undetectable No recurrence: 95 Recurrence: 5.5 p <0.001 >30 days TND

21. In the case of post liver transplantation recurrence of HCV, treatment should be started two to four months after liver transplantation to pass the initial critical period. After the advent of DAAs, satisfactory virological responses with minimal side effects were observed in this setting.

22. Test Management of Hepatitis C Virus in Patients with Liver Transplantation Alavian SM, et al. Recommendations for the Clinical Management of Hepatitis C in Iran: A Consensus-Based National Guideline. Hepat Mon. 2016

23. Conclusions Treatment Strategies in Wait-Listed Patients with Chronic HCV Pros  Uniformly prevent post-LT HCV infection  May reverse / improve liver function allowing avoidance of liver transplantation Cons  Improvement insufficient to avoid LT but reduces MELD to range less likely to get LT  HCC patients needed to be transplanted, regardless Antiviral Therapy for 12-24 wks Follow-up Liver Transplantation SVR Candidates with renal insufficiency (HRS) limited options for treatment

24. Conclusion Today, Liver Transplantation is possible and more safe in new era of new drugs and better conterol of viral replication of HCV and HBV infections