Hepatitis C Virus and Metabolism

Transcription

1 AISF Annual Meeting Roma, Febbraio 2017 Hepatitis C Virus and Metabolism Salvatore Petta Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy salvatore.petta@unipa.it

2 Salvatore Petta, MD, PhD Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S., University of Palermo, Italy salvatore.petta@unipa.it Advisory Boards and/or Speaker for Gilead, AbbVie, Janssen, Bristol-Myers Squibb, Merck Sharp and Dohme

3 Epidemiology of HCV Infection Obesity Dyslipidemia Diabetes Kidney Diseases Hypertension Cardiovascular Diseases

4 HCV Rete Sicilia (data at 12 Feb 2017) Variable 10,918 patients, 49.1% 1 with cirrhosis, mean age 62.8 years Entire cohort <65 years (N=5,083) 65 years (N=5,835) Male gender 57.4% 68.1% 48.1% BMI 30, n (%) 13.2% % 12.8% Diabetes 25.2% % 30.4% Arterial hypertension 42.5% % 56.3% Cardiovascular disease 5.1% 5 2.3% 7.2% Chronic Kidney Disease 3.8% 6 2.3% 4.8% Psychiatric disorder 11.7% % 11.2% Lymphoproliferative disorder 1.7% 8 1.5% 1.7% 1 data relative to 9005 pts; 2 data relative to 8387 pts; 3 data relative to 7587 pts; 4 data relative to 7672 pts ; 5 data relative to 7364 pts; 6 data relative to 7335 pts; 7 data relative to 7368 pts; 8 data relative to 5358 pts

5 HCV Viral Entry Zhu et al, WJG 2014

6 Lipid Droplets play a Key Role in HCV Infection Filipe et al, Trend Mol Med 2015

7 Dyslipidemia/ Obesity Diabetes/ IR Steatosis Does HCV Induce Cardio-metabolic Alterations? Do Metabolic Alterations Affect Natural History of HCV patients?

8 Dyslipidemia/ Obesity

9 Lipid Profile, Obesity and HCV Infection Marzouk et al, GUT 2007

10 Obesity and HCV Infection VAI score, a marker of adipose tissue dysfunction, was independently associated with higher viral load in 236 patients with G1 HCV infection Petta S et al, Hepatology 2010

11 Dorso Cervical Fat and CHC Petta S, et al J HEP 2013

12 HVPG and Liver Decompensation in Cirrhosis: Is there a role for Obesity? N=30 N=47 N=41 BMI (HR 1.06; 95%C.I ) was an independent predictor of decompensation after adjusting for albumin, Mayo endstage liver disease score, etiology, treatment group, HVPG and albumin. Berzigotti et al, Hepatology 2015

13 Diabetes/ IR

14 Endogenous glucose production (EGP) and glucose disposal in hepatitis C without MS (euglycemic hyperinsulinemic clamp + tracers infusion + indirect calorimetry, n=14) 3 non-3 Vanni et al, Hepatology 2009

15 HCV and Diabetes The Third NHANES Survey, 9841 persons >20 years of age HCV neg HCV pos Subjects > 40 yrs: OR for T2DM 3.77 (95%CI: ) After nine years of follow up, in HCV-infected pts : High risk for T2DM: 12 fold increase in incidence of diabetes Low risk for T2DM: no increased incidence MEHTA et al, Ann Intern Med 2000

16 Chronic HCV infection and risk for diabetes: a community-based prospective study (REVEAL Cohort: n=16,928 anti-hcv- vs. 930 anti-hcv+; 180,244 PY; median FU 11.0 yrs) Adjusted HR 1.53 ( ) Adjusted for ALT HR 1.40 ( ) LIN et al, Liver Int 2016 July 16 [Epub ahead of print]

17 HCV Infection and Diabetes Bugianesi et al, J Hep 2012

18 IR Affects Outcomes of in Chronic Hepatitis C p< n= % n= % 15.8% Advanced fibrosis (>3 by Scheuer) NO IR IR NO DIABETES DIABETES Petta S et al, AJG 2008

19 Esophageal Varices in HCV Cirrhosis: Is there a role for Insulin Resistance? Cammà C, Petta S et al, Hepatology 2009

20 HCC Development in HCV : Is there a role for Diabetes? 4302 HCV patients followed for a median of 8.2 yrs Diabetes (HR 1.73, 95%CI ) independently predicted HCC development together with age, male gender, alcohol intake, cirrhosis and no SVR Arase et al, Hepatology 2013

21 Decompensation and death in HCV: Is there a role for Diabetes? 2132 HCV patients 348 patients with HCVrelated Cirrhosis Hepatic Decompensation Huang et al, Hepatology 2014 Death Elkrief et al, Hepatology 2014

22 Steatosis

23 Steatosis Prevalence in Chronic Hepatitis C Asselah T et al, Gut 2006

24 Pathogenesis of Steatosis in CHC Insulin Resistance >liver FFA influx de novo lipogenesis G1 G3 Steatosis >>Lipogenesis <<Lipid degradation <<Lipid Secretion PNPLA3 TM6SF2?? Oxidative Stress

25 NASH and Severity of Fibrosis in CHC Variable Multiple Logistic Regression N=434 NASH=87 OR (95% CI) p value Age (yrs) 1.03 ( ) Cholesterol (mg/dl) 0.98 ( ) <0.001 HOMA 1.18 ( ) Histology at Biopsy Severe Necroinflammatory activity NASH 2.16 ( ) ( ) 0.03 NASH was diagnosed in presence of steatosis, ballooning and perisinusoidal fibrosis (Bedossa Score) Petta S et al, APT 2015

26 HCC Occurrence Steatosis and risk of Fibrosis Progression and HCC in CHC Fibrosis Progression HCC Occurrence n=103 G1 81 G3 22 Fartoux L et al, Hepatology 2005 Ohata K et al, Cancer 2003

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28 HCV and Kidney Damage Model 1: age, gender, race/ethnicity; Model 2: model 1 and baseline GFR; Model 3: model 2 and comorbidities; Model 4: model 3 and systolic BP, diastolic BP, and body mass index; Model 5: model 4 and sociodemographic parameters Molnar et al, Hepatology 2015

29 Development and Validation of a Comorbidity Scoring System for Patients with Cirrhosis Survival probabilities in the Danish Patient Registry cohort, by CirCom group CirCom score (validated in 4,656 HCV-RNA+) - COPD - AMI - PAD - Epilepsy - Substance Abuse - Heart Failure - Non Meta Cancer - Meta cancer - CKD Jepsen et al, Gastroenterology 2013

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31 Prevalence of Carotid Plaques (%) Intima-media Thiknes (mm) Carotid Atherosclerosis in G1 CHC Patients Compared to Controls p<0.001 p< N= 174 G1CHC N= 174 controls N= 174 G1CHC N= 174 controls Petta et al, Hepatology 2011

32 HCV and Cerebro-Cardiovascular Events Petta S et al, Gastroenterology 2016

33 HCV and Cardiovascular Mortality Petta S et al, Gastroenterology 2016

34 HCV and Cardiovascular Damage: A plausible Hypothesis Petta S et al, Gut 2014

35 Development and Validation of a Comorbidity Scoring System for Patients with Cirrhosis Survival probabilities in the Danish Patient Registry cohort, by CirCom group CirCom score (validated in 4,656 HCV-RNA+) - COPD - AMI - PAD - Epilepsy - Substance Abuse - Heart Failure - Non Meta Cancer - Meta cancer - CKD Jepsen et al, Gastroenterology 2013

36 Dyslipidemia/ Obesity Diabetes/ IR Steatosis Does HCV Eradication Improve Cardio-metabolic Alterations? What Meaning for Metabolic Alterations after SVR?

37 HCV Eradication by and cholesterol levels G3 patients underwent PEG-IFN/RBV G1 patients underwent SOF/RBV Hofer H et al, AM J Gastroenterol 2002 Meissner et al, Hepatology 2015

38 HCV Eradication by IFN and Steatosis G3 34 G1 28 Steatosis does not disappear after HCV clearance in G1 HCV Kumar D et al, Hepatology 2002

39 HCV Eradication by IFN-free and Genes involved in lipid homeostasis 8 G1 patients with paired biopsy after SOF-RBV Meissner et al, Hepatology 2015

40 HCV eradication by IFN and Insulin Resistance/Diabetes 50 HCV+ underwent PEG-IFN/RBVtherapy N=2842 HCV+ 143 developed diabetes ROMERO-GOMEZ et al, Gastroenterology 2005 Arase et al, Hepatology 2010

41 Suppression of serum HCV RNA by IFN-free regimens correlates with improved insulin sensitivity n = 30, HCV-1, treated with danoprevir n = 5, HCV-3a without MS, treated with SOF/LDV + RBV MOUCARI et al, Gut 2010;59: GASTALDI et al (ongoing clinical trial)

42 HCV Eradication by IFN-free regimens and glucose homeostasis Petta et al, Lancet Gastr Hep 2017 Meissner et al, Hepatology 2015

43 HCV Eradication by IFN or DAA and Kidney Failure Hsu et al, GUT 2015 Petta et al, Lancet Gastr Hep 2017

44 HCV Eradication by IFN and Myocardial Injury Abnormal Severity score assessed by thallium-201 myocardial scintigraphy was found in 87% of patients Independent factors related to higher pretreatment SS were histology activity index score and serum HCV RNA titer N=217 Maruyama et al, J Hep 2013

45 HCV Eradication by IFN/IFN-free and Cardiovascular Events 1323 Cirrhotic Patients followed for a median of 58.2 months (668 with SVR by IFN or DAA) Nahon et al, Gastroenterology 2016

46 The Natural History of CHC Metabolic Comorbidities CHC Modified from Petta S et al, Liv Int 2016

47 Diabetes and HCC Occurrence in HCV Cirrhosis 1323 Cirrhotic Patients followed for a median of 58.2 months (668 with SVR by IFN or DAA) Nahon et al, Gastroenterology 2016

48 The Natural History of CHC Metabolic Comorbidities CHC What Lipid to do? Anti- Diabetics Lowering Nash Drugs Anti- Coagulants Modified from Petta S et al, Liv Int 2016

49 Lifestyle intervention and HCC Risk Turati et al, JHep 2014

50 Weight Loss and Portal Hypertension 50 Compensated Overweight/Obese Cirrhotic Patients (18 virus-related) with Portal hypertension Underwent 16 Weeks Lyfestile Program Berzigotti et al, Hepatology 2017

51 Liver Decompensation and Death in HCV Cirrhosis: Is there a role for Statins? 685 statins users and 2062 nonusers (matched by propensity score) with HCV Cirrhosis Decompensation Death Statins use independently protected from decompensation (HR 0.55; 95% CI, ) after adjustment for age, FIB-4 index score, albumin, MELD and Child Statins use independently protected from death (HR 0.55; 95% CI, ) after adjustment for age, FIB-4 index score, albumin, MELD and Child Mohanty et al, Gastroenterology 2016

52 Death in HCV Cirrhosis: Is there a role for Metformin? Risk Factors for Death in 250 Cirrhotic Patients Zhang et al. Hep 2014

53 Conclusions HCV infection and metabolic alterations are commonly associated, data existing about the ability of HCV to induce them, and of metabolic alterations to affect the prognosis of HCVinfected patients HCV eradication could lead to some improvement in metabolic alterations The management of metabolic alterations after SVR could improve the prognosis of HCV-infected patients

54 Aknowledgments Prof. Antonio Craxì, Prof. Calogero Cammà, Prof. Vito Di Marco. Sezione di Gastroenterologia, Di.Bi.M.I.S., University of Palermo, Italy Prof. Giulio Marchesini University of Bologna Dr Luca Valenti, Prof.ssa Fargion, Dott.ssa Fracanzani, Dott.ssa Dongiovanni University of Milan Prof.ssa Elisabetta Bugianesi University of Turin Prof. Fabio Marra University of Florence Prof.ssa Erica Villa University of Modena Dr. Luca Miele, Prof. Grieco University of Rome Prof. Gianluca Svegliati Baroni University of Ancona Prof. Victor de Ledinghen University of Bordeaux Prof. Vincent Wong University of Hong Kong Dr. Quentin Anstee University of Newcastle Prof. Jacob George University of Sydney LITMUS European NAFLD Partners