Boehringer Ingelheim- sponsored Satellite Symposium. HCV Beyond the Liver

Boehringer Ingelheim- sponsored Satellite Symposium HCV Beyond the Liver

HCV AS A METABOLIC MODIFIER: STEATOSIS AND INSULIN RESISTANCE Francesco Negro University Hospital of Geneva Switzerland

Clinical introduc=on Background Liver histology shows various degrees of steatosis Steatosis is GT dependent HCV infec>on is associated with diabetes Ques>on Clinical significance For liver disease progression? Sign of a different underlying metabolic disease? Associa>on with HCV? Effect on liver disease or course of DM/IR? Link to cardiovascular effects? Effect on response to HCV treatment? Long- term course? BeNer aoer HCV cure? DM, diabetes mellitus; GT, genotype; HCV, hepa>>s C virus; IR, insulin resistance

Prevalence of liver steatosis (%) 60 50 40 30 20 10 HCV genotype and liver steatosis n=1383 without risk factors (BMI <25 kg/m 2, no alcohol, no T2D) 80 100 Grade 0 70 Grade 1 90 Grade 2 Grade 3 Prevalence of liver steatosis (%) 80 70 60 50 40 30 20 10 Grade 0 1 Grade 2 3 RR=4.81 p=2.33x10-27 0 GT- 1 GT- 2 GT- 3 GT- 4 0 Non- 3 GT GT- 3 RR, rela>ve risk; T2D, type 2 diabetes Leandro G et al. Gastroenterology 2006;130:1636 1642

HCV- induced steatosis: Does it ma\er? Steatosis induced by HCV (mostly HCV- GT- 3a): Does not accelerate fibrosis progression 1,2 Does not increase insulin resistance Does not impair the virological response to IFN- α- based regimens 3 Associa>on with HCC 4? Role in HCV life cycle 5? 1. Bochud P- Y et al. J Hepatol 2009;51:655 666 2. Bugianesi E et al. Hepatology 2006;44:1648 1655 3. Poynard T et al. Hepatology 2003;38:75 85 4. Kurosaki M et al. Hepatol Res 2010;40:870 877 HCC, hepatocelluar carcinoma; IFN, interferon 5. Clément S et al. Hepatology 2011;54:38 49 6. Peyrou M et al. J Hepatol 2013 (in press)

Metabolic not viral steatosis affects SVR 100 90 80 p=0.34 Steatosis No steatosis SVR (%) 70 60 50 40 30 20 10 p<0.001 p<0.001 0 GT- 3 non- GT- 3 GT- 1, 4, 5 or 6 (n=134) (n=900) (n=746) Patients received PegIFN/RBV SVR, sustained virological response Poynard T et al, Hepatology 2003;38:75 85

HCV infec=on and risk of diabetes: A systema=c review and meta- analysis Number of studies OR 95% CI Unadjusted, retrospec=ve 14 2.03 1.52 2.54 Adjusted, retrospec=ve 7 1.68 1.15 2.20 Unadjusted, longitudinal 3 1.71 1.36 2.06 Adjusted, longitudinal 4 1.67 1.28 2.06 Adjusted, retrospec=ve, HCV vs HBV 3 1.80 1.20 2.40 Unadjusted, mono- infected vs HIV co- infected 4 1.82 1.27 2.38 CI, confidence interval; HBV, hepatitis B virus; HIV, human immunodeficiency virus; OR, odds ratio White D et al. J Hepatol 2008;49:831 844

HCV is associated with an increased prevalence of T2D in persons >40 The third NHANES (n=9841, 8.4% with T2D, 2.1% HCV+) Prevalence of type 2 diabetes (%) 35 30 25 20 15 10 5 years Adjusted OR for T2D 3.77 (95% CI 1.81 7.87) HCV+ HCV- 0 20 29 30 39 40 49 50 59 60 69 Age (years) NHANES, National Health and Nutrition Examination Survey Mehta S et al. Ann Intern Med 2000;133:592 599

HCV increases the incidence of T2D in high- risk pa=ents (>60 years, BMI >35 kg/m 2 ) The Atherosclerosis Risk in Communi=es (ARIC) Study Prospec>ve, community- based, case cohort study 1084 T2D- free persons aged 44 65 years (HCV+ 0.8%) 548 developed T2D over 9 years of follow- up Risk group HCV n Incident T2D cases HR (95% CI) Low - 545 212 1 Low + 8 1 0.48 (0.05 4.4) High - 524 329 1 High + 7 6 11.6 (1.39 96.6) HCV precedes diabetes! BMI, body mass index; HR, hazard ratio Mehta S et al. Hepatology 2003;38:50 56

HOMA- IR and C- pep=de levels are higher in chronic HCV- infected pa=ents than in matched chronic HBV- infected pa=ents CHC (n=240) CHB (n=80) p Male sex (%) 166 (69.2) 61 (76.3) NS Age (year) 41.2±6.5 40.5±12.4 NS BMI (kg/m 2 ) 23.8±3.3 23.9±3.1 NS WC (cm) 88.7±10.7 88.8±9.0 NS F3 F4 (%) 51 (21.3) 16 (20.0) NS HOMA- IR 2.8±2.9 1.7±1.1 <0.001 C- pep=de (pg/ml) 2.6±1.4 1.8±0.6 <0.001 Values are mean ±SD or frequency (%) NS, non-significant; WC, waist circumference Moucari R et al. Gastroenterology 2008;134:416 423

HCV Hepa=c insulin resistance (post- insulin receptor interac=ons) 1,2 Extrahepa=c insulin resistance (mediated by soluble factors) 1,2 20 34% 66 80% Whole- body insulin resistance 1. Vanni E et al. Hepatology 2009;50:697 706 2. Milner K- L et al. Gastroenterology 2010;138:932 641

Cytokines? microrna? Lipids? Hepato- adipokines? Cytokines? Lipids? Skeletal muscle Role of immune cells in HCV- induced IR? Adipokines? Cytokines? Lipids? HCV- infected liver Adipokines? Cytokines? Adipose =ssue Kaddai V & Negro F. Exp Rev Gastroenterol Hepatol 2011;5:503 516

Clinical impact of HCV- associated glucose metabolism disturbances Accelerated liver fibrosis progression HCC Cardiovascular/renal diseases

IR and chronic HCV progression 260 chronic hepa>>s C pa>ents Subgroup of 121 pa>ents with fibrosis F0 F1 matched to 137 healthy volunteers by sex, BMI and waist- to- hip ra>o Independent predictors of HOMA- IR: BMI (p<0.001) Prior an>viral therapy failure (p<0.001) Portal inflamma>on (p<0.001) HCV- GT- 3 (p=0.01) By mul>variate analysis, the HOMA- IR score (but not steatosis) was independently associated with Fibrosis score (p<0.001) Progression rate (p=0.03) Hui J et al. Gastroenterology 2003;125:1695 1704

Cumula>ve development rate of HCC in HCV- infected pa>ents treated with IFN Retrospec>ve cohort, n = 4,302 Japanese pa>ents treated with IFN- α followed for an average of 8.1 years Cumula>ve incidence of HCC: 4.3% at 5 yrs, 10.5% at 10 yrs, and 19.7% at 15 yrs Risk factors for HCC occurrence (P < 0.05): advanced fibrosis, lack of SVR, male sex, age >50, excess alcohol intake, and type 2 diabetes (T2DM). T2DM caused a 1.73- fold increase in the development of HCC Arase Y et al, Hepatology 2013;57:964 973

IR decreases SVR in chronic HCV- infected pa>ents treated with IFN- α/ RBV HCV- 1: OR 2.43, 95% CI 1.41 4.20, p=0.004 1 100 HCV- 2/HCV- 3: χ 2 9.752, p<0.001 2 80 SVR (%) 60 40 20 0 HOMA- IR <2 HOMA- IR 2 4 HOMA- IR >4 IFN-α, interferon-α; RBV, ribavirin; SVR, sustained virological response ( 6 months after end of treatment) 1. Romero- Gomez M et al. Gastroenterology 2005;128:636 641 2. Poustchi H et al. J Hepatol 2008;48:28 34

HCV RNA and HOMA- IR decline during danoprevir monotherapy for TN HCV GT- 1 Cohort A n=10 Cohort B n=10 Cohort C n=10 Cohort D n=10 HCV RNA decline predicted by baseline HCV RNA, but not by HOMA- IR, sex, age, BMI, ALT or triglycerides Moucari R et al. Gut 2010;59:1694 1698

Effect of HOMA- IR on virological response to protease inhibitor- containing regimen: TN pa>ents (n=161, treatment-naive, GT-1 from telaprevir study C208) Baseline HOMA- IR index 100 <2 (n=80) 2 4 (n=44) >4 (n=23) Pa=ents with undetectable HCV RNA (%) 80 60 40 20 0 Week 4 Week 12 End of treatment SVR HOMA-IR, homeostasis model assessment of insulin resistance; TN, treatment naïve Serfaty L et al. Gut 2012;61:1473 1480

Insulin sensi>zers do not seem to improve virological response to IFN- α in HCV GT- 1 Standard care Pioglitazone plus standard care Week 4 Week 12 Week 24 Week 48 Median change in serum log 10 HCV RNA level from baseline 0-1 - 2-3 - 4-5 n= 71 60 72 59 72 60 73 62-2.1-2.1-4.1-4.0-4.4-4.7-4.4-4.5 Pa=ents (%) 70 60 50 40 30 20 10 0 63.0 57.5 49.3 46.8 41.6 33.8 16.4 6.5 Week 4 Week 12 Week 24 Week 48 Serum HCV RNA decline Pa=ents with undetectable HCV RNA Harrison SA et al. Hepatology 2012;56:464 473

HCV as a metabolic modifier HCV causes steatosis and IR The impact of HCV- induced steatosis is debated In persons at risk, HCV- induced IR may lead to type 2 diabetes Diabe>c HCV+ pa>ents have increased liver and extrahepa>c morbidity and mortality