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 22nd 2007

Natural History of Hepatitis C

Acute Hepatitis CAcute Hepatitis CAcute Hepatitis CAcute Hepatitis C

Chronic Hepatitis Chronic Hepatitis 50 - 85 %50 - 85 %

Chronic Hepatitis Chronic Hepatitis 50 - 85 %50 - 85 %

Cirrhosis 20 - 30 %Cirrhosis 20 - 30 %Cirrhosis 20 - 30 %Cirrhosis 20 - 30 %

DecompensationDecompensation6 - 10 %6 - 10 %

DecompensationDecompensation6 - 10 %6 - 10 %

HCCHCC5 - 10 %5 - 10 %HCCHCC

5 - 10 %5 - 10 %

DeathDeath5 - 10 %5 - 10 %DeathDeath

5 - 10 %5 - 10 %

10 - 30 years

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

Need to Define

(A) (B)

Actual stage of liver disease

Spead of Disease

Progression(Where it is) (How fast is going)

Fibrosis

Stage + FibrogenesisRate

Prognosis

How to Predict Outcomes in Patients with Chronic HCV

STAGES IN CHRONIC HCV INFECTION

THE EARLY “HISTOLOGICAL” STAGES• No significant fibrosis (F0-F1)• Intermediate fibrosis (F2)• Severe fibrosis (F3)• Histological cirrhosis (F4)

THE LATE “CLINICALLY OVERT” STAGES• Compensated cirrhosis without portal hypertension with portal hypertension• Decompensated cirrhosis

Incidence of HCC in Chronic Incidence of HCC in Chronic Hepatitis C According to Stage Hepatitis C According to Stage

of Fibrosisof Fibrosis

0 1 2 3 4 5 6 7 8 9 100

10

20

30

40

50

60

70

years

F4

F3

F2

F0-1

Cu

mul

ativ

e in

cide

nce

(%

)

(490 IFN untreated patients) (490 IFN untreated patients)

Yoshida et al., Ann Intern Med 1999

How to Define Stage

F0 F0 LIVER BIOPSY

F1

F2

F3

F4

F5

F6

METAVIR

F1

F2

F3

F4

FIBROTEST

APRI

FIBROSCAN

and many others

I

S

H

A

K

Compensated disease

stage of liver fibrosis

Sequential Algorithm for Fibrosis Evaluation (SAFE-Biopsy) in Compensated Hepatitis C

APR I

No fibrosis(low NPV)

Significant fibrosis

(high PPV)

Grey Zone

FIBROTEST

Significant fibrosis

(high PPV)

F0-F1(low NPV)

Liver biopsy not neededLiver biopsy

Sebastiani et al J Hepatol 2006

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)

Years10 20 30

RapidMedium

Slow

4

3

2

1

Fib

rosi

s

Absent

Influenced by Male sex Age Alcohol

CROSS-SECTIONAL vs LONGITUDINAL STUDIES

CROSS-SECTIONAL

milddisease

Vs.advanced 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’THE VIRUS

HCV genotypes

Viral Load

HCV quasispecies

Candidates

in the late 90’

ENVERONMENTAL

COFACTORS

Alcohol

Coinfections (HBV - HIV)

candidates

in the new MilleniumTHE HOST

Age / gender

Race / genetics

Metabolic syndrome

HCV-RNA and GENOTYPEas PROGNOSTIC MARKERS

% fibrosis progression

1-2 points > 2 points

HCV-1 33% 11%

HCV-2 37% 13%

HCV-3 30% 15%

< 800.000 IU 28% 14%

> 800.000 IU 33% 11%

7-10 yr outcome in initially mild CHC (longitudinal study in 177 cases)

Boccato et al JVH 2006, Boccato et al 2007

Increased Risk of Cirrhosis and ESLD in HIV-HCV Coinfected

PatientsHistologic CirrhosisHistologic Cirrhosis Decompensated Liver DiseaseDecompensated Liver Disease

0.760.76 1.01.0 2.072.07 10.8310.83

CombinedCombined

0.610.61 1.01.0 6.146.14 1010

CombinedCombined

Relative Risk (95% CI)Relative Risk (95% CI)

MakrisMakris

SotoSoto

PolPol

BenhamouBenhamou

EysterEyster

TelferTelfer

MakrisMakris

LesensLesens

175.32175.32

Clin Infect Disease.Clin Infect Disease. Graham GS et al. The University of Chicago Press. 2001. 33. 562-569. Graham GS et al. The University of Chicago Press. 2001. 33. 562-569.

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

• Liaw et al, Hepatology 1995

• Zarski et al, J Hepatol 1998

• Sagnelli et al, Hepatology 2000

• Benvegnù et al 2004

Progression to cirrhosis x 2.1 - 6.6

Progression to HCC x 5.6 - 136

Occult (anti-HBc positive) HBV coinfection may also play a role in carcinogenesis

58

54

50

46

42

34

38

o

o

o

Grades of fibrosis progression over 7-10 years of observation0 1 2 3

Fibrosis Progression in initially mild chronic hepatitis C correlates with age at diagnosis

A g e

at entry

30

o

©

Boccato et al 2006

<20 21-30 31-40 41-50 >50

- 0.0

- 0.5

- 1.0

- 1.5

- 2.0

- 2.5

Age at time of infection (years)

Ishak unit / year

Age at infection and Fibrosis progression rate in chronic HCV

Wright et al Gut 2003

200

180

160

140

100

120

60

80

40

o

o

o

o

Mean ALT

during

follow-up

Grades of fibrosis progression over 7-10 years of observation

0 1 2 3

Fibrosis Progression in initially mild chronic hepatitis C correlates with Mean ALT During Follow-up

©

Boccato et al 2006

0

20

40

60

80

0 2 4 6 8 10 12

0

20

40

60

80

0 2 4 6 8 10 12

Progression of Liver Fibrosis in HCV Carriers with Normal or Elevated ALT

% with fibrosis progression

% with progression to severe fibrosis

years of follow-up

years of follow-up

(High ALT)

(High ALT)

(Normal ALT)

(Normal ALT)

p = 0.06

p = 0.01

Hui, 2003

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 % last observation

at inclusion cases cirrhosis HCC(UNL=50 IU/L) <20 IU/L 27% 0% 0%

21-30 IU/L 33% 5% 0%

31-50 IU/L 40% 10% 4%

Boccato et al 2007

1992 1993 1994 1995 1996 1997 1998 1999 2000

50

100

200

ALT (IU/L)

P.P. o 43 yrs

+

GRADE 2STAGE 0

GRADE 8STAGE 3

NORMAL

Reactivation of Hepatitis C After 6 Years of Persistently Normal ALT

ALT Flare in HCV Carriers with Initially (6 mo) Normal ALT

AuthorN°

casesFU

(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 HCV2 WITH PNALT FOLLOWED BY BIOCHEMICAL REACTIVATION Rumi et al J Viral Hepatitis 2002;9:71-74)

1st liver biopsy (1994)

grading 4, staging 1

2nd liver biopsy (1999)

grading 6, staging 5

Disease Progression in HCV Patients presenting with PNALT and having ALT reactivation

Initial Biopsy Final Outcome

F1 11 %F1 F2 61 %

F3-4 28 %

F2 5 %F2-F3 F3 66 %

F4 29 %HCC 9 %

F0 25%F1 56%F2-3 19%

F0

Alberti et al 2007

7-10 yrs

RISK FACTORS FOR DISEASE PROGRESSION IN HCV CARRIERS

WITH INITIALLY PNALT

• F2 in initial biopsy• ALT >50% UNL• BMI > 32• Alcohol • ALT FLARES OR STABLE REACTIVATION

Variables associated with fibrosis progression in initially mild CHC

HCV1(87 cases)

HCV2(51 cases)

HCV3(39 cases)

Viral Load ns ns ns

Age at entry 0.05 0.05 Ns

ALT profile 0.05 0.05 0.05

Histologic activity in 1° Bx

0.05 0.05 ns

Liver steatosis

0.05 0.05 ns

BMI at entry 0.05 0.05 ns

(7-10 yr follow-up of 177 cases)

Steatosis in Mild Chronic Hepatitis C

STEATOSIS 46%

5-10% 22%

11-30% 11%

> 30% 13%

PROGRESSION TO F3/F4 16%

Steatosis 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%

135 patients with F0/F1 (A1) in initial biopsy,untreated, rebiopsed after 62 ± 28 mo

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 FIBROSISHCV type 1 with similar duration of infection

(12 - 14 years)

No steatosis Grade of steatosis p<

1-2 3-4

N° Patients 28 18 12

Fibrosis score 1.43±0.15 1.58 ± 0.47 2.63±0.33 0.001

Yearly rate 0.12±0.01 0.14 ± 0.01 0.23±0.03 0.0001

Adinolfi et al Hepatology 2001

INSULIN RESISTANCE CONTRIBUTES TOFIBROSIS PROGRESSION IN HEPATITIS C

Hui et al Gastroenterology 2003

Insulin Resistance but not Liver Steatosisaffects Fibrosis stage in HCV-3 patients

Bugianesi et at Hepatology 2006

Fibrosis Progression and Gender/Aging

Martino et al, Hepatology 2004

PREMENOPAUSAL

fibrosisvs

POSTMENOPAUSAL

fibrosis

Pregnancy HRT yes

vs vs

Nulliparous HRT no

Family History and Outcome of Chronic HCV Infection

Family history ofadvanced liver disease

(any ethiology)N°

% cirrhosis

MedianTime to

Cirrhosis F / year

NO 946 12.8% 25 yrs 0.125

p <0.001

YES 237 30.8% 11 yrs 0.750

Data from 1186 patients with HCV infection

On Stage of Basic Research for Disease Determinants

Send in the Clones

Send in the Genes

HCV-J SNVSVAHDASGKRVYYLTRDPTTPLARAAWETVRHTPVNSWLGNIIMYAPTLWARMILMTHFFSILLAQEQLEKALDCQIYGACYSIEPLDLPQIIERLHGLSAFSLHSY 

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....................R.................N......S.................W.....Pt 11 TMA+ .....................A.......................R.......R.................N......S.................W..... 

 

Sequencing of virus clones(searching for BAD Viruses)

Microarrays of host genes(searching for BAD Signatures)

Past

Present/Future

THE PATIENT WITH HCV-RELATED CIRRHOSIS

Niederau et al Hepatology 1998

Variables associated with disease worsening and Variables associated with disease worsening and HCC development in HCV related cirrhosisHCC development in HCV related cirrhosis

• Older age

• Male gender

• ALT and AFP profile

• Platelet count

• Bilirubin level

• HBV coinfectionHBV coinfection

• Alcohol intakeAlcohol intake

• Liver SteatosisLiver Steatosis

• Tobacco smokingTobacco smoking

NEGATIVE PROGNOSTIC VARIABLESAFFECTING “NATURAL” AND “THERAPY-

RELATED” OUTCOMES IN PATIENTS WITH HCV

Natural course Response to therapy

HCV Load

HCV genotype

Age

Stage of disease

Insulin resistance

HIV-HBV

Alcohol

* * * * * * * * * * * *

nono

CONCLUSIONS

Prognosis still difficult to define individually

Need to consider age, stage of fibrosis, disease activity and ALT profile

Major negative cofactors are alcohol, HIV, HBV, obesity and Insulin resistance

More to be learnt on host genetics