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 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
(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 Hepatitis C
According to Stage of Fibrosis
(490 IFN untreated patients)
Cumulative incidence (%)
70
F4
60
50
40
F3
30
20
F2
10
F0-1
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
F0
I
F1
S
F2
H
F3
A
F4
K
F5
F6
F0
M
E
T
A
V
I
R
LIVER BIOPSY
F1
FIBROTEST
F2
APRI
F3
FIBROSCAN
F4
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
F0-F1
(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
Slow
2
1
Absent
10
Years
20
30
CROSS-SECTIONAL vs LONGITUDINAL STUDIES
CROSS-SECTIONAL
advanced
mild
Vs.
disease
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
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
<20
21-30
31-40
41-50
Age at time of infection (years)
>50
Fibrosis Progression in initially mild chronic hepatitis C
correlates with Mean ALT During Follow-up
200
180
160
o
Mean ALT
140
during
follow-up
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
80
% with fibrosis progression
Hui, 2003
(High ALT)
60
p = 0.06
40
(Normal ALT)
20
0
0
80
2
4
6
8
years of follow-up
10
% with progression to severe fibrosis
12
(High ALT)
60
40
p = 0.01
20
(Normal ALT)
0
0
2
4
6
8
years of follow-up
10
12
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





GRADE 2
STAGE 0
50
NORMAL
 



 
1992
1993

1994
 
 
1995

1996

  
1997
1998
1999
2000
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 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
F0
F1
F2-F3
7-10 yrs
Final Outcome
F0
25%
F1
56%
F2-3 19%
F1
11 %
F2
61 %
F3-4 28 %
F2
5%
F3
66 %
F4
29 %
HCC 9 %
Alberti et al 2007
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
(7-10 yr follow-up of 177 cases)
HCV1
HCV2
HCV3
(87 cases)
(51 cases)
(39 cases)
ns
ns
ns
Age at entry
0.05
0.05
Ns
ALT profile
0.05
0.05
0.05
Histologic
activity in 1° Bx
Liver steatosis
0.05
0.05
ns
0.05
0.05
ns
BMI at entry
0.05
0.05
ns
Viral Load
Steatosis in Mild Chronic Hepatitis C
135 patients with F0/F1 (A1) in initial biopsy,
untreated, rebiopsed after 62 ± 28 mo
STEATOSIS
46%
5-10%
22%
11-30%
11%
> 30%
13%
PROGRESSION TO F3/F4
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
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.....
Microarrays of host genes
Present/Future
Send in
the 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
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