Liver transplant: what is left after the viruses

Riunione Monotematica A.I.S.F. 2016 The Future of Liver Disease: Beyond HCV is there a Role for Hepatologist? Milan 15 th 2016 Liver transplant: what is left after the viruses Stefano Ginanni Corradini Liver Transplant Unit Sapienza Università di Roma Email: stefano.corradini@uniroma1.it

Stefano Ginanni Corradini TITOLO:Liver transplant:what is left after the viruses Università Sapienza di Roma Il sottoscritto dichiara di non aver avuto negli ultimi 12 mesi conflitto d interesse in relazione a questa presentazione e che la presentazione non contiene farmaci in studio o ad uso off-label

What is left after the viruses in the liver transplant field? (the role of transplant hepatologists) no fear of post-transplant viral recurrence how will the spared donors be used to transplant more patients with other end-stage liver diseases? will a subgroup of HCV eradicated patients (other than alcoholics) still deserve a liver transplant? how will the spared donors ameliorate the ITT (including access to transplant) outcomes of liver transplantation?

Liver transplant activity in Europe over time Viral Crypto/Others Alcoholic

Waitlist registrations for NASH and ALD increased over time UNOS DATABASE, new liver transplant waitlist registrants 2004-2013 NASH category = diagnosis of NASH + obese (body mass index >30 kg/m2) patients with cryptogenic cirrhosis (CC) NASH, as defined in the study, demonstrated a 170% increase in prevalence from 804 in 2004 to 2174 in 2013 among new liver transplant waitlist registrants NASH Alcoholic Gastroenterology 2015;148:547 555

Obese cirrhotic patient outcomes after liver transplantation World J Hepatol 2015;7:1484-1493

Obese cirrhotic patient overall survival after liver transplantation Limitations: o significant heterogeneity (not unexpected given the use of non-randomized studies utilized) o potential confounding variables (differences in immunosuppression, surgical skills, post operative care) Subset analysis that corrected for BMI based on the degree of ascites. The adjusted BMI was not independently predictive of poor patient survival Liver International 2015;35:164-70

Obese cirrhotic patient outcomes after liver transplantation Morbid obese patients have worse short-term outcomes The more recent trend in better outcomes may reflect better patient selection (comorbidities!) and improved care More long-term data looking at 5 years and beyond are needed World J Hepatol 2015;7:1484-1493

Diabetes comorbid with obesity is associated with poor survival after liver transplantation Multicenter (Australia and New Zealand; n=617) Dry body mass index was calculated following adjustment for ascites Concomitant diabetes and obesity but not each condition in the absence of the other is associated with reduced post-liver transplant survival. Journal of Gastroenterology and Hepatology 2016;31: 1016 1024

Future challenges for Transplant Hepatologists: sarcopenia, sarcopenic obesity and bariatric surgery Future challenges for Transplant Hepatologists: obesity diabetes hypertension hyperlipidaemia cardiovascular disease sarcopenia Sarcopenic obesity is a known risk factor for mortality in cirrhotic patients Sarcopenia is a known risk factor for poor outcomes after liver transplantation What about the effect of sarcopenic obesity on liver transplant outcomes? Timing of sleeve gastrectomy (SG): 1. pretransplant SG (cirrhosis severity, adhesion between the staple line of the stomach and the left lobe of the liver) 2. combined liver transplant and SG (LTSG) 3. SG in the posttransplant setting (immunosuppression, late beneficial effects of surgery) Unknown long-term effect of SG on sarcopenia [Mastino D et al. Obes Surg 2016 Feb 29]

Nonalcoholic Steatohepatitis Is the Most Rapidly Growing Indication for Liver Transplantation in Patients With Hepatocellular Carcinoma in the U.S HEPATOLOGY 2014;59: 2188-2195

HCC in NAFLD patients has different characteristics then in HCV positive patients multicenter observational prospective study of NAFLD-related HCC (NAFLD-HCC; n=145) vs hepatitis C virus (HCV)-related HCC (n=611) enrolled in secondary care Italian centers Compared to HCV, HCC in NAFLD patients had: a larger volume more often an infiltrative pattern was detected outside specific surveillance Cirrhosis was present in only about 50% of NAFLD-HCC patients, in contrast to the near totality of HCV-HCC. HEPATOLOGY, 2016;63: 827-838

Residual risk of hepatocellular carcinoma after HCV eradication In 2030 projected eradication of HCV-related disease in Italy Immunological changes (in some patients)? Future Microbiol.(2015) 10(6), 977 988

Residual indications to liver transplantation after HCV eradication HCC Cirrhosis progression due to comorbidities: obesity diabetes Late mortality in 1/3 of HCV eradicated cirrhotics

Many severely obese transplanted patients were HCV positive and diabetics UNOS DATABASE, adult liver transplants perfomed between 2002 and 2011 All time prevalence of obesity in US liver transplanted pts was 33.1% LIVER TRANSPLANTATION 21:1286 1294, 2015

BMI distribution in HCV-related chronic hepatitis and non-ascitic cirrhotic out-patients at «Sapienza University» according to era 100% 90% 80% 17% 29% 9% 70% 60% 50% 40% 30% 35 30-34.9 25-29.9 18.5-24.9 20% 10% 0% Cirrhotics 2001-2003 Cirrhotics 2014-2015 Chronic hepatitis 2014-2015 S Ginanni Corradini unpublished data

Prevalence of diabetes in HCV-related cirrhosis and chronic hepatitis outpatients at «Sapienza University» according to era 100% 6% 90% 80% 29% 26% 70% 60% 50% 40% Diabetics Non-diabetics 30% 20% 10% 0% Cirrhotics 2001-2003 Cirrhotics 2014-2015 Chronic hepatitis 2014-2015 S Ginanni Corradini unpublished data

Curing HCV results in a reduced incidence of T2DM, and an improvement of T2DM-related clinical outcomes is possible in diabetic CHC patients who obtain SVR. However, a definite verdict is not possible The high therapeutic efficacy of novel antivirals will ensure that a large number of diabetic cirrhotic patients will achieve eradication; this will enable us to understand the relative contribution of the virus and of lifestyle (and genetics) on T2DM outcome. Meanwhile, we can hypothesise that only early diagnosis and treatment of HCV infection might be associated with regression of T2DM-related clinical manifestations and complications

Time dependent projections of the effect of dual (IFN+RIBA) or triple (IFN+RIBA+Telaprevir or Boceprevir for genotype 1) HCV therapy on liver transplant waiting list satisfaction for patients with HCV-related disease in France Listed no treatment HCC Listed no treatment Decompensated cirrhosis Listed dual and triple therapy Listed dual and triple therapy Transplants performed Transplants perfomed Digestive and Liver Disease 46 (2014) 157 163

Time dependent projections of the effect of dual (IFN+RIBA) or triple (IFN+RIBA+Telaprevir or Boceprevir for genotype 1) and DAAs (from 2015) HCV therapy on liver transplant waiting list satisfaction for patients with HCV-related disease in France HCC Decompensated cirrhosis Listed dual and triple therapy Listed DAAs Listed dual and triple therapy Transplants performed Transplants performed Listed DAAs Digestive and Liver Disease 46 (2014) 157 163

In Italy HCV eradication should allow to spare approximately 400-450 donors per year Viral 37% Viral 60% [HCV=46%; HBV=18%] Liver Match DLD 2011;43:155 164

Waitlist mortality and drop-outs are higher in France than in Italy Digestive and Liver Disease 46 (2014) 157 163

Conclusions The bulk of potential candidates to liver transplantation affected by obesity and/or diabetes (including also an unknown fraction of HCV eradicated) and/or sarcopenia is expected to rapidly increase in the next future These patients should be referred to a liver transplant center as early as possible (even in the pre-cirrhotic stage when obesity is severe/morbid) Transplant hepatologists should strictly interact with nutritionists and endocrinologists In the next years the tesoretto of liver donors spared from transplanting viral patients will allow to ameliorate the ITT outcomes of liver transplantation, provided that all patients have the same chances to be evaluated by transplant centers