alfredo alberti. how to predict outcome in hepatitis c patients alfredo alberti department of...
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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
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