1. L.A. Lesmana Department of Medicine, University of Indonesia, Jakarta

2. NALFD – AASLD definition 2012 Evidence of hepatic steatosis, by imaging or by histology, No causes for secondary hepatic fat accumulation Chalasani N, et al. Gastroenterology 2012;142:1592-1609.

3. Prevalence of NAFLD in the Asia-Pacific region Country Percentage of NAFLD Country Percentage of NAFLD Japan 9 – 30% Japan 9 – 30% China 5 – 18% China 5 – 18% Korea 18 % Korea 18 % India 5 – 28% India 5 – 28% Indonesia 30% Indonesia 30% Malaysia 17 % Malaysia 17 % Singapore 5% Singapore 5% Amarapurkar. Asia Pacific Working Party on NAFLD 2006

4. Insulin Resistance and Hepatitis p<0.005 Imazeki et al. Liver Int 2008:355-62

5. Current Evidence

6. Prevalence of steatosis in CHB StudiesYearCountryNumber of casess Prevalence of steatosis (%) Altlparmak et al.2005Turkey16439 Gordon et al.2005Australia1776 Thomopulos et al.2006Greece23318 Bondini et al2007USA15332 Peng et al2008China15327 Rastogi et al2011India35034 Lesmana et al2012Indonesia17430 Thomopoulos KC, et al. Eur J Gastroenterol Hepatol 2006;18:233-7 Altlparmak E, et al. World J Gastroenterol 2005;11:3056-9. Gordon A, et al. J Hepatol 2005;43:38-44. Peng D, et al. J Gastroenterol Hepatol 2008;23:1082-8. Bondini S, et al. Liver Int 2007;27:607-11. Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9. Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

7. Factors associated with FL in CHB Fatty Liver (-) (n=100) Fatty Liver (+) (n=64) p-value Mean age (years)33.2 + 11.7037.9 + 10.090.006 Mean BMI (kg/m 2 )25.3 + 3.9327.8 + 3.700.000 Male sex, n(%)60 (53.1)53 (46.9)0.008 Mean AST (U/L)76.5 + 56.1470.0 + 54.610.469 Mean ALT (U/L)131.6 + 109.39113.5 + 68.190.686 Mean cholesterol (mg/dL)162.2 + 38.8)184.9 + 34.50.000 Mean triglyceride (mg/dL)102.5 + 44.66133.7 + 65.960.004 HBeAg positive, n(%)42 (41.4)17 (27.0)0.059 Mean viral load (pg/mL)1,628.24781.550.067 Fibrosis stage 2-3, n(%)20 (20)11 (17.2)0.754 HAI 9-17, n(%)36 (36)23 (35.9)0.772 Altlrmak E, et al. World J Gastroenterol 2005;11:3056-9.

8. Insulin Resistance in CHB HOMA-IR <1.64 (n=35) HOMA-IR > 1.64 (n=34) p-value Mean BMI (kg/m 2 )21.8 + 3.724.0 + 4.40.029 Mean waist circumference (cm)80.1 + 8.685.1 + 10.20.089 Median triglyceride (mg/dL)90.0110.00.016 Median fasting insulin (μU/mL)5.011.7<0.001 Fasting glucose (mg/dL)8553<0.001 Fibrosis F2-F4, n(%)21 (60.0)15 (54.2)0.232 HAI >6, n(%)11 (31.4)10 (29.4)0.717 Steatosis grade 1-220 (57.2)21 (61.8)0.873 Median HBV-DNA (log copies/mL)5.146.20.324 HBeAg positive, n(%)13 (37.1)13 (38.2)1.000 Kumar M, et al. Am J Gastroenterol 2009;104:76-82.

9. Demographic Factors VariableSteatosis (+) (n=118) Steatosis (-) (n=232) p value Mean age35.5 + 10.527.9 + 14.0<0.001 Male : Female108 : 10192 : 400.045 Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9. VariableSteatosis (+) (n=52) Steatosis (-) (n=122) p valueOR (95%CI) Mean age42.6 + 10.540.0 + 11.20.150- Male : Female (%)73.1 : 26.949.2 : 50.80.0042.81 (1,38-5,69) Medistra Hospital. Unpublished data 2007-2009

10. Biochemical and Viral Factors VariableSteatosis (+) (n=118) Steatosis (-) (n=232) p value Median ALT (U/mL)62680.620 HBeAg positive (%)48.857.20.106 Median DNA (copies/mL)69 x 10 4 750 x 10 4 0.025 HBV genotypes (n=80): A B C D A+C A+D A+C+D 12.6% 0 81.2% 3.1% 0 14.5% 2.1% 64.6% 2.1% 12.5% 2.1% 0.567 Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9.

11. Metabolic Parameters VariableSteatosis (+) (n=118) Steatosis (-) (n=232) p value Mean BMI (kg/m 2 )25.2 + 4.820.4 + 3.5<0.01 Mean FBS (mg/dL)94.1 + 19.686.9 + 13.90.091 Mean TG (mg/dL)138.8 + 62.188.0 + 27.90.002 Mean cholesterol (mg/dL)171.8 + 43.5139.3 + 37.60.017 Mean insulin (IU/L)13.0 + 9.19.1 + 6.00.027 Median HOMA-IR2.7 (0.96-11.75)1.9 (0.19-6.7)0.048 Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9. BMI: body mass index; FBS: fasting blood sugar; TG: triglycerides; HOMA-IR: Homeostatic Model of Assessment – Insulin Resistance

12. Histological Features Rastogi A. et al. Indian J Pathol Microbiol 2011;54:454-9. VariableSteatosis (+) (n=118) Steatosis (-) (n=232) p value Mean HAI score4.8 + 2.64.5 + 2.90.286 Mean fibrosis score1.7 + 1.11.5 + 1.10.170 HAI: histological activity index

13. Data in Medistra Hospital VariableSteatosis (+) (n=118) Steatosis (-) (n=232) p value Mean BMI (kg/m 2 )25.1 + 3.722.7 + 3.3<0.001 Waist circumference (cm)88.3 + 11.079.0 + 10.1<0.001 Mean ALT (U/L)49.8 + 26.771.7 + 102.90.132 Log HBV-DNA (copies/mL)5.92 + 1.996.07 + 2.080.675 Liver stiffness (kPa)8.3 + 6.39.5 + 10.20.468 HBeAg-positive (%)42.345.10.736 Genotype C (%)32.419.80.138 Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

14. Histological Features Fibrosis stage Inflammatory grade p = 0.849p = 0.624 Lesmana LA, et al. Acta Med Indones 2012;44:35-9.

15. Predictors of Steatosis in CHB CountryNSteatosisPredictors Altlparmak, et al (2005)Turkey16439%Older age, BMI, high cholesterol and triglyceride Gordon, et al (2005)Australia1776%Waist circumference, FPG, C- peptide Thomopoulos, et al (2006)Greece23318%FPG, BMI> 25 kg/m 2 Bondini, et al (2007)USA6419%Obesity, waist circumference, hypergension, dyslipidemia, older age Cindoruk, et al (2007)Turkey14034%BMI, total cholesterol, hypertriglyceridemia Peng, et al (2008)China15327%BMI, Age ALT Rastogi, et al (2011)India35034%Triglyceride Lesmana, et al (2012)Indonesia17430%Waist circumference

16. Fatty Liver vs. SVR Rates Cindoruk M, et al. J Clin Gastroenterol 2007;41:513-7. FL did not affect IFN-based treatment outcomes (p > 0.005)

17. ALT HBeAg+ HBV DNA Immune Escape/ Reactivation Inactive Carrier Status HBeAg – Chronic HBV HBeAg + Chronic Hepatitis B Immune Tolerant Immune Control Immune Clearance Immune control – treatment not required Immune control – inactive disease HBeAg–

18. Summary: NAFLD in CHB NAFLD is commonly found in about one-third of patients. NAFLD in CHB is strongly associated with metabolic factors, e.g.: body mass index (BMI), obesity, insulin resistance, dyslipidemia. NAFLD is not associated with liver fibrosis or histological activity index. NAFLD may not affect treatment response. In patients with CHB and NAFLD with elevated ALT in clinical practice is not easy to distinguish whether the high ALT is due to CHB or NAFLD.

19. Current Evidence

20. Risk factors of FL in Chronic Hep C ParameterHCV (n=75)HCV+ FL (n=69)p value Obesity2552<0.05 Diabetes821<0.05 Hypertension1425<0.05 Hypertriglyceridemia1533<0.05 Metabolic syndrome2863<0.001 Fatty liver is associated with features of metabolic syndrome in patients with chronic hepatitis C virus infection. Sanyal AJ, et al. Am J Gastroenterol 2003;98:2064-71

21. IR and Liver Fibrosis in CHC Taura N, et al. Am J Gastroenterol 2006;101:2752-9. Insulin resistance is associated with more advanced fibrosis in patients with chronic hepatitis C virus infection p = 0.002

22. HCV GENOTYPE DISTRIBUTION HCV genotype 1b is predominant in Indonesia Utama A, et al. Liver Int 2010;30:1152-60. Subjects: 68 chronic hepatitis, 48 cirrhosis, and 34 HCC Method: core sequence analyses %

23. Relapse rate are higher in patients infected with HCV genotype 3 who have an RVR Shah SR, et al. Clin Gastroenterol Hepatol 2011;9:688-93.  RVR: rapid virologic response (HCV RNA <43 IU/mL at week-4 )  SVR: sustained virologic response (HCV RNA <15 IU/mL at week-48 p=0.001

24. Steatosis is the strongest independent predictor of relapse in patients infected with HCV genotype 3 who have an RVR Shah SR, et al. Clin Gastroenterol Hepatol 2011;9:688-93. OR: 3.0; 95%CI: 1,5-6.1; p=0.003 Steatosis vs. no steatosis HCV RNA > vs. < 400.000 IU/mL BMI > vs < 30 kg/m2 Age > vs <45 years GGT > vs < ULN OR: 2.5; 95%CI: 1,0-6.3; p=0.04 OR: 2.2; 95%CI: 1,0-4.8; p=0.04 OR: 2.2; 95%CI: 1,2-4.2; p=0.02 OR: 2.1; 95%CI: 1,1-4.1; p=0.03 -2 -1 0 1 2 3 4 5 6 7 8

25. HCV infection and Metabolic Syndrome There is no evidence for association between HCV infection and metabolic syndrome. The 2 conditions occur together at a higher rate than would occur by chance, although HCV infection has been associated with type2 diabetes mellitus. The serum lipid profile of patients with HCV infections is characterized by decreased level of cholesterol and sometimes triglycerides,in contrast to metabolic syndrome Negro F. Gastroenterology 2012;142:1288-92

26. HCV and Lipid Metabolism that may lead to steatosis of hepatocytes Negro F. Gastroenterology 2012;142:1288-92.

27. HCV might affect insulin signaling in hepatocytes contributing to Insulin Resistance Negro F. Gastroenterology 2012;142:1288-92.

28. Possible Clinical Outcomes Insulin resistance in CHC have substantial impact on the morbidity and mortality : Accelerated progression of liver fibrosis Increase type 2 diabetes Reduced virological response to antiviral therapy Increase incidence of cardiovascular events  need further study Bugianesi E, et al. J Hepatol 2012;56(Suppl ):S56-S65

29. Summary: NAFLD in CHC NAFLD is frequently found in CHC Its present is genotype specific, mostly genotype 1 and 3 Alcohol, central obesity, raised BMI are associated with more activity and more severe fibrosis Obesity reduces response to IFN-based treatment NAFLD may increase relapse rate among previously rapid virologic responders