Alfredo ALBERTI How to predict outcome in hepatitis

Alfredo ALBERTI

How to predict outcome in hepatitis C patients Alfredo Alberti Department of Clinical and Experimental Medicine Venetian Institute of Molecular Medicine University of Padova ITALY Paris , January 22 nd 2007

Natural History of Hepatitis C Acute Hepatitis C 10 - 30 years Chronic Hepatitis 50 - 85 % Cirrhosis 20 - 30 % Decompensation 6 - 10 % HCC 5 - 10 % Death 5 - 10 %

ASSESSING PROGNOSIS IN HEPATITIS C • Progression to cirrhosis and end stage liver disease in a minority of cases • Often takes decades • Not linear • Difficult to predict in the individual case • Cofactors may play a major role

CLINICAL IMPLICATIONS OF ASSESSING “SHORT” TERM PROGNOSIS (3 -5 yrs) IN A PATIENT WITH HCV • To treat or not to treat , or to postpone therapy waiting for new drugs, particularly for “borderline” or “difficult-to-treat” patients or with some contraindication • How to monitor • Life style counselling

How to Predict Outcomes in Patients with Chronic HCV Need to Define (A) (B) Actual stage of liver disease Spead of Disease Progression (Where it is) (How fast is going) Fibrosis Stage Fibrogenesis Rate + Prognosis

STAGES IN CHRONIC HCV INFECTION • • THE EARLY “HISTOLOGICAL” STAGES No significant fibrosis (F 0 -F 1) Intermediate fibrosis (F 2) Severe fibrosis (F 3) Histological cirrhosis (F 4) THE LATE “CLINICALLY OVERT” STAGES • Compensated cirrhosis without portal hypertension with portal hypertension • Decompensated cirrhosis

Incidence of HCC in Chronic Hepatitis C According to Stage of Fibrosis (490 IFN untreated patients) Cumulative incidence (%) 70 F 4 60 50 40 F 3 30 20 F 2 10 F 0 -1 0 0 1 2 3 4 5 6 7 8 9 10 years Yoshida et al. , Ann Intern Med 1999

How to Define Stage Compensated disease stage of liver fibrosis F 0 I F 1 S F 2 H F 3 A F 4 K F 5 F 6 F 0 M E T A V I R LIVER BIOPSY F 1 FIBROTEST F 2 APRI F 3 FIBROSCAN F 4 and many others

Sequential Algorithm for Fibrosis Evaluation (SAFE-Biopsy) in Compensated Hepatitis C APR I No fibrosis (low NPV) Grey Zone Sebastiani et al J Hepatol 2006 Significant fibrosis (high PPV) FIBROTEST F 0 -F 1 (low NPV) Liver biopsy Significant fibrosis (high PPV) Liver biopsy not needed 45 -70% reduction in biopsies with >95% diagnostic accuracy Biopsy and non-invasive markers agonists and not antagonists

PROGRESSION OF HEPATIC FIBROSIS IN CHRONIC HEPATITIS C (Poynard et al Lancet 1997; 349: 825 -832) Influenced by Male sex Age Alcohol Fibrosis 4 3 Rapid Medium 2 Slow 1 Absent 10 Years 20 30

CROSS-SECTIONAL vs LONGITUDINAL STUDIES CROSS-SECTIONAL advanced mild Vs. disease identified variables : causes or effects ? LONGITUDINAL STUDIES non progressors vs. progressors May underestimated “dynamic” variables

The Changing View on Major Cofactors Affecting Hepatitis C Outcomes Candidates in the early 90’ Candidates in the late 90’ candidates in the new Millenium THE VIRUS ENVERONMENTAL COFACTORS THE HOST HCV genotypes Viral Load HCV quasispecies Alcohol Coinfections (HBV - HIV) Age / gender Race / genetics Metabolic syndrome

HCV-RNA and GENOTYPE as PROGNOSTIC MARKERS 7 -10 yr outcome in initially mild CHC (longitudinal study in 177 cases) Boccato et al JVH 2006, Boccato et al 2007 HCV-1 HCV-2 HCV-3 < 800. 000 IU > 800. 000 IU % fibrosis progression 1 -2 points > 2 points 33% 11% 37% 13% 30% 15% 28% 14% 33% 11%

Increased Risk of Cirrhosis and ESLD in HIV-HCV Coinfected Patients Histologic Cirrhosis Decompensated Liver Disease Eyster Makris Soto Telfer Pol Makris Benhamou Lesens Combined 0. 76 1. 0 2. 07 10. 83 0. 61 1. 0 Relative Risk (95% CI) Clin Infect Disease. Graham GS et al. The University of Chicago Press. 2001. 33. 562 -569. 6. 14 10 175. 32

HBV coinfection as Cause of Progression of Chronic Hepatitis C • Fong et al, Hepatology 1991 • Pontisso et al, Gastroenterology 1993 • Crespo et al, Am J Gastroenterol, 1994 Progression to cirrhosis x 2. 1 - 6. 6 • Liaw et al, Hepatology 1995 • Zarski et al, J Hepatol 1998 • Sagnelli et al, Hepatology 2000 Progression to HCC x 5. 6 - 136 • Benvegnù et al 2004 Occult (anti-HBc positive) HBV coinfection may also play a role in carcinogenesis

Fibrosis Progression in initially mild chronic hepatitis C correlates with age at diagnosis 58 54 o Age at entry 50 o 46 o 42 38 34 o Boccato et al 2006 30 0 1 2 3 Grades of fibrosis progression over 7 -10 years of observation ©

Age at infection and Fibrosis progression rate in chronic HCV Ishak unit / year Wright et al Gut 2003 - 2. 5 - 2. 0 - 1. 5 - 1. 0 - 0. 5 - 0. 0 Age at time of infection (years)

Fibrosis Progression in initially mild chronic hepatitis C correlates with Mean ALT During Follow-up 200 180 160 Mean ALT during follow-up o 140 120 100 o 80 o 60 Boccato et al 2006 o 40 0 1 2 3 Grades of fibrosis progression over 7 -10 years of observation ©

Progression of Liver Fibrosis in HCV Carriers with Normal or Elevated ALT % with fibrosis progression Hui, 2003 (High ALT) p = 0. 06 (Normal ALT) years of follow-up % with progression to severe fibrosis (High ALT) p = 0. 01 (Normal ALT) years of follow-up

LONG TERM FOLLOW-UP IN HCV CARRIERS WITH INITIALLY NORMAL ALT • 185 HCV patients with normal ALT (3 x 2 month apart) • Final results of 10 -15 year follow-up (mean 11. 3 yrs) ALT at inclusion (UNL=50 IU/L) <20 IU/L % cases last observation cirrhosis HCC 27% 0% 0% 21 -30 IU/L 33% 5% 0% 31 -50 IU/L 40% 10% 4% Boccato et al 2007

Reactivation of Hepatitis C After 6 Years of Persistently Normal ALT GRADE 8 STAGE 3 ALT (IU/L) 200 P. P. o 43 yrs + 100 NORMAL GRADE 2 STAGE 0 50

ALT Flare in HCV Carriers with Initially ( 6 mo) Normal ALT Author N° cases FU (yrs) % ALT flare Puoti et al, 2002 880 1. 8 21. 5 % Martinot-Peignoux et al, 2001 24 3. 5 21 % Tsuy et al, 2001 120 3. 6 23. 3 % Persico et al, 2000 37 4. 1 23 % Hui et al, 2003 40 6. 3 27. 5 % Boccato et al, 2004 45 7. 3 33 %

HEPATITIS RECRUDESCENCE IN A CARRIER OF HCV 2 WITH PNALT FOLLOWED BY BIOCHEMICAL REACTIVATION Rumi et al J Viral Hepatitis 2002; 9: 71 -74) 1 st liver biopsy (1994) grading 4, staging 1 2 nd liver biopsy (1999) grading 6, staging 5

Disease Progression in HCV Patients presenting with PNALT and having ALT reactivation Initial Biopsy F 0 F 1 F 2 -F 3 7 -10 yrs Final Outcome F 0 25% F 1 56% F 2 -3 19% F 1 11 % F 2 61 % F 3 -4 28 % F 2 5% F 3 66 % F 4 29 % HCC 9 % Alberti et al 2007

RISK FACTORS FOR DISEASE PROGRESSION IN HCV CARRIERS WITH INITIALLY PNALT • • • F 2 in initial biopsy ALT >50% UNL BMI > 32 Alcohol ALT FLARES OR STABLE REACTIVATION

Variables associated with fibrosis progression in initially mild CHC (7 -10 yr follow-up of 177 cases) HCV 1 HCV 2 HCV 3 (87 cases) (51 cases) (39 cases) ns ns ns Age at entry 0. 05 Ns ALT profile 0. 05 Histologic activity in 1° Bx Liver steatosis 0. 05 ns BMI at entry 0. 05 ns Viral Load

Steatosis in Mild Chronic Hepatitis C 135 patients with F 0/F 1 (A 1) in initial biopsy, untreated, rebiopsed after 62 ± 28 mo STEATOSIS 46% 5 -10% 22% 11 -30% 11% > 30% 13% PROGRESSION TO F 3/F 4 Steatosis 16% Progression of fibrosis 4 yrs 6 yrs < 5% 1. 8% 5. 6% 5 -10% 3. 8% 17. 6% 11 -30% 6. 7% 30% > 30% 18. 1% 33. 2% Fartoux et al, Hepatology 2003

The Metabolic Cofactors affecting Liver Fibrosis in Hepatitis C BMI Obesity Steatosis NASH Diabetes (type 2) Insulin Resistance

LIVER STEATOSIS AND FIBROSIS HCV type 1 with similar duration of infection (12 - 14 years) No steatosis N° Patients 28 Fibrosis score 1. 43± 0. 15 Yearly rate 0. 12± 0. 01 Grade of steatosis 1 -2 3 -4 18 12 1. 58 ± 0. 47 2. 63± 0. 33 0. 14 ± 0. 01 0. 23± 0. 03 p< 0. 001 0. 0001 Adinolfi et al Hepatology 2001

INSULIN RESISTANCE CONTRIBUTES TO FIBROSIS PROGRESSION IN HEPATITIS C Hui et al Gastroenterology 2003

Insulin Resistance but not Liver Steatosis affects Fibrosis stage in HCV-3 patients Bugianesi et at Hepatology 2006

Fibrosis Progression and Gender/Aging Martino et al, Hepatology 2004 PREMENOPAUSAL fibrosis vs POSTMENOPAUSAL fibrosis Pregnancy HRT yes vs vs Nulliparous HRT no

Family History and Outcome of Chronic HCV Infection Data from 1186 patients with HCV infection Family history of advanced liver disease (any ethiology) NO N° % cirrhosis Median Time to Cirrhosis F / year 946 12. 8% 25 yrs 0. 125 p <0. 001 YES 237 30. 8% 11 yrs 0. 750

On Stage of Basic Research for Disease Determinants Sequencing of virus clones (searching for BAD Viruses) Past Send in the Clones HCV-J SNVSVAHDASGKRVYYLTRDPTTPLARAAWETVRHTPVNSWLGNIIM YAPTLWARMILMTHFFSILLAQEQLEKALDCQIYGACYSIEPLDLPQIIERLHGLSAFSLHSY Pt 2 TMA+ . D. . . . A. . . L. . . Q. . . Pt 4 TMA+ . D. . . . A. . . . Q. . . Pt 11 TMA+ . . . . A. . . . Q. . . HCV-J SPGEINRVASCLRKLGVPPLRVWRHRARSVRAKLLSQGGRAATCGKYLFNWAVKTKLKLTPIPAASQLDLSGWFVAGYNGGDIYHSLSRARPRWFMLCLLLL Pt 2 TMA+ . . . R. . . S. . . . W. . . Pt 4 TMA+ . . . . R. . . . . N. . . S. . . . W. . . Pt 11 TMA+ . . A. . . R. . . N. . . S. . . . W. . . Present/Future Send in the Genes Microarrays of host genes (searching for BAD Signatures)

THE PATIENT WITH HCV-RELATED CIRRHOSIS

Niederau et al Hepatology 1998

Variables associated with disease worsening and HCC development in HCV related cirrhosis • Older age • Male gender • ALT and AFP profile • Platelet count • Bilirubin level • HBV coinfection • Alcohol intake • Liver Steatosis • Tobacco smoking

NEGATIVE PROGNOSTIC VARIABLES AFFECTING “NATURAL” AND “THERAPY-RELATED” OUTCOMES IN PATIENTS WITH HCV Natural course HCV Load HCV genotype Age Stage of disease Insulin resistance HIV-HBV Alcohol no no * * * Response to therapy * * * *

CONCLUSIONS Ø Prognosis still difficult to define individually Ø Need to consider age, stage of fibrosis, disease activity and ALT profile Ø Major negative cofactors are alcohol, HIV, HBV, obesity and Insulin resistance Ø More to be learnt on host genetics