Future of liver transplantation in viral hepatites

Transcription

1 Future of liver transplantation in viral hepatites Prof. Luiz A. Carneiro D`Albuquerque M.D.. P.h.D. Professor Titular Transplante de Orgãos do Aparelho Digestivo Departamento de Gastroenterologia Hospital das Clínicas da Universidade de São Paulo. Brasil

2 HCFMUSP Epidemiologia -Tx de Fígado 2% 1% 2% 3% 92% CIRROSE COLANGITE ESCLEROSANTE SÍNDROME DE BUDD-CHIARI PAF OUTRAS LTx Waiting list 10% 7% 10% Virus B 2% 1%1% 1% Virus C 51% VHC ÁLCOOL VHB CRIPTOGÊNICA AUTOIMUNE CBP VHB+VHC VHB+VHD CB 2ÁRIA 17%

3 HCV- Natural history Acute HCV Resolved 15% Chronic HCV 85% Stable 80% (68%) Cirrhosis 20% (17%) Slowly progressive 75% (13%) HCC Liver failure 25% (4%)

4 Natural history old scenario Universal virologicrecurrence 20-54% development of bridging fibrosis and cirrhosis in 5 years Overall response to PegIFN and ribavirin: 39% (10-59%) High rates of side effects Berenguer & Schuppan. J Hepatol 2013:58:

5 HCV treatment 100 PegIFN DAAs Standard IFN 1991 RBV IFN 6 mos 16 IFN 12 mos IFN/RBV 6 mos IFN/RBV 12 mos PegIFN 12 mos PegIFN/ RBV 12 mos PegIFN/ RBV/ DAA Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD. DAA + RBV ± PegIFN

6 108 relt for HCV recurrence (7 centers in France, 1 in Spain) Song et al. World J Gastroenterol 2016

7 Drug-drug interactions EASL Guidelines, 2015 Saab et al. J Clin Transl Hepatol 2016;4:32 38

8 Treat before or after LT? Pre-LT treatment ü May obviate the need for LT (MELD<20?) ü Reduce frequency of hospitalizations because of liverrelated complications (MELD<20?) ü Improve tolerability of HCC therapy ü Avoid DDIs with immunosuppressives post-lt Post-LT treatment ü No episodes of rejection ü No immune modulation ü Higher SVR rates than pre-lt (if treated before cirrhosis) ü More DAA treatment options (restored liver and renal function) ü Prevents graft loss because of recurrent disease McCaughan et al. Hepatology 2015; 62(Suppl 1): 738A. Chen & Terrault. Curr Opin Organ Transplant 2016, 21: Coilly A et al. Hepatology 2015; 62:257A

9 In the era of DDAs What are the new frontiers on liver transplantation? What the total volume of liver transplantation will be affected? What are the changes on the management of hepatitis C infected?

10 With direct antiviral agentsàhcv infection will account for a lower proportion of indications for LT HCV-infected with cirrhosis will continue to be at risk of developing HCC after SVR DAA may not affect the global volume of LT due to the current gap between donors and recipients Use of HepC donnors and DAA after LT treatment???

11 Evolução -Tx Fígado Waiting list: 10% VHB Pre- HBIG era: 90% recurrence >70% graft loss Debatable transplant indication Post-HBIG era: 1991, Muller et al: First reported case with HBIG 1993, Samuel et al: recurrence at 3 years 75% without HBIG 74% HBIG for 2 months 36% HBIG for 6 months 1996, Grelleer et al: Lamivudine as prophylaxis 18% recurrence in 6 months 41% recurrence in 3 years 1998, Makowitz et al: HBIG + Lamivudine No recurrence in 1 year Hepatol Int Recurrence : 7%

12 Evolução -Tx Fígado Current practice recommendations for liver transplant for HBV: Undetectable HBV viral loads before transplant Potent antivirals (entecavir and tenofovir) Use of HBIG Hepatol Int Recurrence : 7%

13 HBV antihbc + donors Prevalence of antihbc + donors 2-9% U.S. 7-12% Europe and Japan 53-57% China and Taiwan Cholongitas E, Papatheodoridis GV, Burroughs AK. Liver grafts from anti-hepatitis B core positive donors: A systematic review. JHepatol 2010; 52:

14 Rates of de novo HBV Without prevention strategies ü 58% (81/140) in non-immunes ü 18% (6/34) in previously vaccinated ü 14% (5/35) in receptors with isolated antihbc+ ü 4% (3/70) in naturally immune receptors With prevention strategies (lamivudine and/or HBIG): ü 11% in non-immunes ü 2% in previously vaccinated ü 3% in receptors with isolated antihbc+ ü 4% (3/70) in naturally immune receptors

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16 Graft survival

17 Results Graft survival With/ without NUCs

18 Proposal for Donnor anti-hbc+ Recepient antihbc+ / anti-hbs+ Recepient antihbc+ only Recepient vaccin anti-hbs+ Recepient naïve anti-hbc- anti-hbs- Yes àaccept No LAMIVUDINA

19 Yellow fever??? BRAZIL: Yellow fever outbreak from January- March 2017 in Minas Gerais State 392 confirmed cases, 140 confirmed deaths

20 Case refferred as acute liver failure Listed as priority Nephrology à Dialysis Neurosurgery à Catheter ICP Worsening of ICH and Shock Refractory Jan 8th, 2017 Fulminant hepatitis? Alt mental stat. Jan 9th, 2017 Fulminant hepatitis + AKI MELD 40 FLUCONAZOLE Jan 10th, 2017 Fulm. hep. + ICH + AKI Jan 11th, 2017 Death CEFOTAXIME

21 POST-MORTEM EXTERNAL LABORATORY (COLLECTED BEFORE REFERRAL TO HC-ICU) LEPTOSPIROSIS SEROLOGY: NEG - YELLOW FEVER SEROLOGY: POSITIVE - PCR YELLOW FEVER: POSITIVE - TO TRANSPLANT OR NOT TO TRANSPLANT? - BLOOD VIRAL LOAD SUPPOSED TO BE MAXIMUM 7 DAYS HOWEVER: REAL-TIME PCR POSITIVE IN TISSUES AT NECROPSY: HEART, KIDNEYS, LIVER

22 Dengue fever in HBV cirrhosis CHILD B 7 MELD 14 Exames 23/02 19/03 02/04 Hb 14, Plaq Leuco (47S/40L) Ureia Cr 0,56 0,91 2,5 ALT AST GGT FA Alb 3,4 2,8 2,4 INR 1,36 1,41 1, (70S/8Ly) BT/BD 2,8/1,9 13,5/11,3 32,7/29,4 CHILD C 11 MELD 34

23 Dengue in a cirrhotic patient Hepatic decompensation due to dengue fever in a compensated cirrhotic patient due to HBV MELD score 14 à 39 à 22 Transplanted 6 months later with MELD score 26 Few data regarding natural history of dengue in cirrhotic patients Debatable liver transplant indication when decompensated

24 Viral hepatites Where we come from and where we are? HCV related and alcoholic cirrhosis With or without HCC HBV related cirrhosis, biliary disease, vascular diseases of the liver and acute liver failure > lower number of indications for transplantation Non- alcoholic steatohepatitis (NASH) emerged as a growing cause of end-stage liver disease and HCC in North America By contrast, HBV and, to a lesser extent, HCV-related cirrhosis remain the main indications for liver transplantation in Asia

25 Hepatitis C nowadays - 30% of global LT volume is related to HCV, but: - New DAAs can cure HCV infection in almost all cases - DAAs can prevent progression to cirrhosis - Sustained virological response (SVR) associated with cirrhosis regression and decreased decompensation rate - HCV eradication also reduces risk of HCC development Is it the end of LT for HCV?

26 Hepatitis C in the future - Indications for transplantation because of HCV will continue to decrease in the future - DAAs could avoid 4400 transplants between 2013 and 2022 in France - Reduction of 88% and 42% in transplants in HCV-infected patients with HCC and decompensated cirrhosis - However, it is unlikely that DAAs will affect global LT volume in years, because ratio between candidates and donors generally exceeds 2 in Western Countries Durand F Liver International 2017

27 LT in a future without HCV - The burden of alcohol-related liver disease is likely to increase - NASH may become the major indication of LT in the future because of increasing obesity prevalence - New indications for LT may arise in malignant disease: cholangiocarcinoma and colorectal liver metastases - LT will still be dictated by the number of donors instead of number of candidates Durand F Liver International 2017

28 Hepatitis E and Hepatitis A Virus Very few patients require emergency transplantation and the epidemiology of hepatitis A may not markedly change in the future In contrast, acute liver failure because of hepatites E virus (HEV) infection is an emerging indication for transplantation in Europe. HEV seems to be a marginal cause of acute liver failure in the USA. Treatment is based on ribavirin Durand F Liver International 2017

29 Conclusions East: HBV still a major indication of LT West: HCC remain the main indication of LT in HBVinfected patients HCV-related LT will decrease due to DAAs Retransplantation for HCV will virtually disappear in the near future But the numbers of donors will still dictate the volume of LT

30 VACCINE REPORTS Carla Vizzotti, MD,* Jorge González, Angela Gentile, MD, Analía Rearte, MD,* Margarita Ramonet, MD, María Cristina Cañero-Velasco, MD, María Eugenia Pérez Carrega, MD,* Analía Urueña, MD* and Máximo Diosque, MD* Background: After a country wide outbreak occurred during , 1 dose of hepatitis A vaccine was introduced into Argentinian regular immunization schedule for all children aged 12 months in June The aim of this study was to assess the impact of this novel intervention. Methods: A longitudinal analysis was done of hepatitis A virus (HAV) infection rates reported to the National Epidemiological Surveillance System from 2000 to Occurrence of fulminant hepatic failure (FHF) and liver transplantation industrialized countries and associated with improvements in public health standards and with vaccination programs. 3 6 Although vaccines against hepatitis A are safe, effective and cost effective when implemented universally in childhood, the high cost and a 2-dose schedule may explain the lack of widespread use of these vaccines Given the high immunological response to the first dose of vaccine and the expectation for longlasting protection induced by immunological memory, the use of a single-dose vaccination strategy Vizzotti et al FIGURE 1. FIGURE 2. evaluate the impact of this strategy as well as to recommend the need for a second dose.

31 São Paulo University Medical School Thank you

32 UNIVERSIDADE DE SÃO PAULO FACULDADE DE MEDICINA DEPARTAMENTO DE GASTROENTEROLOGIA Obrigado