Il danno d’organo provocato dal Virus C
Gloria Taliani 8 Maggio 2014
Malattie Infettive e TropicaliSapienza Università di Roma Policlinico Umberto I, Roma
Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione
Natural History of HCV Infection
Stable80% (68%)
HCCLiver failure25% (4%)
Slowlyprogressive75% (13%)
Resolved15%
Acute HCV
Cirrhosis20% (17%)
Chronic HCV85%
CD8+ CD4+
Cytokines(IL-2, IFN-TNF-, TGF-PDGF)Cell killing
Kupffer cell
Hepatocytes
Hepatic stellate cells
TGF-Activation
Fibrosis
Death
Hepatitis C Disease Pathogenesis
Influence of HIV-1 replication and its treatment on the liver in HCV coinfection
Kim RY and Chung RT GASTROENTEROLOGY 2009;137:795– 814
Advanced Liver Disease
• Histologic– Bridging fibrosis
• Ishak 3/6-4/6• Metavir 3/4
– Cirrhosis • Ishak 5/6-6/6• Metavir 4/4
Ishak KG, et al. J Hepatol. 1995;22:696-699.Bedossa P, et al. Hepatology. 1996;24:289-293.
Complications of Advanced Liver Disease
• Clinical– Portal hypertension
• Thrombocytopenia, varices, nodular liver
– Impaired hepatic function• Albumin, bilirubin, INR
• Decompensation– Ascites– Encephalopathy– Variceal hemorrhage– Jaundice
Sangiovanni A, et al. Hepatology. 2006;43:1303-1310.
The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts
Cum
ulati
ve p
roba
bilit
y of
eve
nts
25
50
100
0
Years
HCC
GI bleeding
Ascites
Jaundice
EPS
214 196 168186 153 142 129 110116 96 89 6674 57 3648
214 198 171188 160 151 142 122129 105 94 7381 64 4258214 196 164184 152 144 134 114122 100 89 6975 60 4054214 197 163182 151 142 133 105114 92 86 6874 60 3955
214 198 173190 162 152 146 122129 108 98 7784 66 4359
Sangiovanni A et al Hepatology 2006
Annual Incidence rate
HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding 0.7% EPS 0.1%
Pts still at risk
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Effect of Inflammation on Fibrosis Progression in HCV Patients
Change in Fibrosis Score According to Necrosis Score at Baseline
Piecemeal Necrosis Score at Baseline0-1 2-3 > 4
Patients, n 30 66 27Mean change in fibrosis score per yr
0.05 0.19 0.37
Ghany MG, et al. Gastroenterol. 2003;124:97-104.
Patients Developing Cirrhosis According to Initial Level of Fibrosis
Yano M, et al. Hepatology. 1996;23:1334-1340.
Fibrosis Score Description of Fibrosis Patients Progressing to Cirrhosis
by Year 10, %
≤ 1.9 (n = 27) None; too mild to alter portal tract size
29.6
2.0-2.9 (n = 28) Portal/periportal ± portal-portal bridging
42.9
3.0-3.45 (n = 15) Septal + regions of partial nodular regeneration
100
Factors Associated With Advanced Fibrosis
Adjusted Odds Ratio (95% CI)
1.0 15.00.01
3.444
Risk Factor
Age at entry (≥ 60 years)
Duration of infection (≥ 25 years)
BMI (≥ 30)
History of diabetes
AST (≥ 80 U/L)
AFP (≥ 15 µg/L)
Grades 2 and 3 steatosis
1.750
1.917
2.251
4.032
3.875
2.790
• Retrospective study of 460 pts with chronic hepatitis C (41% F3-4)• Multivariate analysis of factors associated with F3-4
Hu S, et al. J Clin Gastro. 2009
P Value
.0334
.0378
.0173
.0304
.0087
.0383
.0378
Insulin Resistance Associated With More Rapid Fibrosis Progression in HCV Pts
• In 260 HCV-infected subjects, insulin resistance independently associated with stage of fibrosis– OR: 1.3; P < .001 for trend
Hui JM, et al. Gastroenterol. 2003;125:1695-1704.
HO
MA-
IR
Fibrosis Score
55
44
33
22
11
00F0F0 F1F1 F2F2 F3F3 F4F4
Cannabis Use Significantly Associated With Faster Rate of Fibrosis Progression
• 270 untreated HCV-infected patients undergoing liver biopsy evaluated for risk factors of rapid fibrosis progression– 52.2% noncannabis users; 14.8% occasional cannabis users; 33.0%
daily cannabis users
Hezode C, et al. Hepatology. 2005;42:63-71.
Odds Ratio of Accelerated Fibrosis Progression Rate* (95% CI)
1.0 10.00.01
1.3
Cannabis Use
Occasional
3.4
P Value
Daily
.57
.005
*Compared with median progression rate of cohort: 0.074 Metavir U/yr.
Alcohol Consumption Increases Risk of Cirrhosis in HCV Patients
*Excessive alcohol intake characterized as > 40 g/day for women and > 60 g/day for men.†Duration of exposure defined as either first blood transfusion before 1990 or from the year of initial intravenous drug use.
Wiley TE, et al. Hepatology. 1998:28:805-809.
0
20
40
60
80
100
10 20 30 40Years Following Exposure†
Cirr
hosi
s (%
)
HCVHCV + alcohol*
6
1812
58
31
64
40
85P < .01 P < .01
P < .01
100 %Survival at 1 year 80 % 45 %
Com
pens
ated
Dec
ompe
nsat
ed
Stage 1
Stage 2
Stage 3
Stage 4
No varices
No ascites
Varices
No ascites
Ascites +/-
varices
Bleeding +/-
ascites
7%
6.6%
7.6%
1-year mortality rate according to clinical stages
Classification from a systematic review of 118 studies
4.4%
4%
1%
3.4%
20%
57%D’Amico G et al J Hepatol 2006
DEATH
Survival Probability in HCV Patients With Cirrhosis
Fattovich G, et al, Morbidity and mortality in compensated cirrhosis type C: A retrospective follow-up study of 384 patients. Gastroenterology, 1997: 112, , 463-472.
Compensated
After first major complication
Survival Probability100
Pat
ien
ts (
%)
80
60
40
20
01200 12 24 36 48 60 72 84 96 108
MosPatients at Risk384 376 342 288 236 165 126 79 52 39 25 65 39 21 11 7 4 4 3 3 2 1
Cirrhosis
The impact of SVR on histological outcome of HCV-induced cirrhosis
Maylin S et al Gastroenterology 2008
Post-treatment
Pre-treatment F0 F1 F2 F3 F4
F0 1 2 0 0 0
F1 14 16 7 0 0
F2 7 23 12 2 4
F3 0 5 12 7 4
F4 0 1 2 6 5
Comparison of liver fibrosis stage between pre-treatment and post-treatment paired liver biopsy in 126 patients
Post-treatment specimens were
collected a median of 6 months after
treatment cessation
Mallet V et al Ann Int Med 2008
Rate (%) of patients with hystological regression of cirrhosis after the achievement of SVR in
HCV-induced disease
96 patients with biopsy-proven cirrhosis (METAVIR score F4); treated with IFN; posttreatment liver biopsy.
The median follow-up was 118 months (interquartile range, 86 to 138 months).
Eighteen patients had regression of cirrhosis.
Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCV-induced cirrhosis according
to response to therapy
Bruno S, et al Hepatology 2010
Patients still at risk
No SVR 115 89 65 35 7 0
SVR 34 30 27 17 7 0
* Years since initiation of antiviral treatment
Impact of SVR on long-term outcome in 848 patients with HCV-related histologically-proven cirrhosis (stage 1)
treated with IFN MT (14 yers FU)
0 24 48 72 96 120 144 1680
20
40
60
80
100
months
% w
ith li
ver c
ompl
icat
ions
SVR 124 119 116 108 70 41 12 no SVR 759 702 634 527 345 207 34
Patients at risk
SVR
no SVR
liver-related complications Liver mortality
Bruno S et al Hepatology 2007
0 24 48 72 96 120 144 1680
20
40
60
80
100
months%
su
rviv
al
to l
ive
r-re
late
d d
ea
thSVR 120 115 112 105 66 38 11no SVR 728 680 629 541 369 234 47
Patients at risk
SVR
no SVR
(p: 0.001 by log-rank test) (p: 0.001 by log-rank test)
Survival Outcomes in Pts With CHC and Advanced Fibrosis
P < .001P < .001
P < .001 P < .001
Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.
30
20
10
00
All
-Cau
se
Mo
rtal
ity
(%)
1 2 3 4 5 6 7 8 9 10Yrs
All-Cause Mortality
With SVR
Pts at Risk, nWithout SVRWith SVR
405192
393181
382168
363162
344155
317144
295125
25088
20756
16440
13528
30
20
10
00
Liv
er-
Rel
ated
M
ort
alit
y o
r L
iver
T
ran
spla
nta
tio
n (
%)
1 2 3 4 5 6 7 8 9 10Yrs
Liver-Related Mortality or Liver Transplantation
With SVR
Pts at Risk, n Without SVRWith SVR
405192
392181
380168
358162
334155
305144
277125
22988
18756
14640
11928
30
20
10
00
Hep
ato
cell
ula
r C
arci
no
ma
(%)
1 2 3 4 5 6 7 8 9 10Yrs
Hepatocellular Carcinoma
With SVR
Pts at Risk, n Without SVRWith SVR
405192
390181
375167
349161
326152
294142
269124
22986
19154
15139
12227
30
20
10
00
Liv
er
Fai
lure
(%
)
1 2 3 4 5 6 7 8 9 10Yrs
Liver Failure
With SVR
Pts at Risk, n Without SVRWith SVR
405192
384180
361166
337160
314152
288141
259123
21688
18456
14340
11328
Achieving Sustained Virologic Response: Impact on Long-Term Outcomes in HIV/HCV-Coinfection
OverallMortality
Lo
ng
-Ter
m O
utc
om
e R
ate
(per
10
0 p
erso
n/y
ears
)
Liver-RelatedMortality
LiverDecompensation
0.46*0.46*(0.06,1.65)(0.06,1.65)
Hepato-carcinoma
LiverTransplantation
**PP=0.003, =0.003, ††PP=0.028, =0.028, ‡‡PP<0.001, and <0.001, and §§PP=0.034 versus not attaining a sustained virologic response.=0.034 versus not attaining a sustained virologic response.n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.
3.123.12(2.16,4.37)(2.16,4.37)
1.651.65(0.98,2.16)(0.98,2.16)
4.334.33(3.16,5.8)(3.16,5.8)
0.830.83(0.38,1.58)(0.38,1.58)
1.021.02(0.50,1.82)(0.50,1.82)
0.930.93(0.44,1.70)(0.44,1.70)
0.230.23††
(0.01,1.27)(0.01,1.27)0.230.23‡‡
(0.01,1.27)(0.01,1.27) 00(0,0.84)(0,0.84)
00§§
(0,0.84)(0,0.84)
0.230.23(0.01,1.27)(0.01,1.27)
NewAIDS
Conditions
GESIDA 3603 Cohort: 711 pts treated for HCV
Berenguer J. et al. Hepatology 2009.
Achieved SVRAchieved SVRDid not achieve SVRDid not achieve SVR
Event-free survival according to response to therapy in 102 patients with HCV-induced cirrhosis and
portal hypertension (stage 2)
Di Marco V et al J Hepatol 2007
0 6 12 18 24 30 36 42 48 54 600
20
40
60
80
100
Months
% o
f Pati
ents
With
out E
vent
s Li
ver-
rela
ted
SVR (16 pts)
NR (86 pts)
p= 0.006 by log rank test
Cumulative probability of survival of SVRs versus Non SVRs and controls in patients with decompensated HCV-induced cirrhosis
0,5
0,6
0,7
0,8
0,9
1
0 6 12 18 24 30 36 42
months
Cu
mu
lativ
e p
rob
abili
ty o
f su
rviv
al
SVR
NonR
Ctrl
p= 0.07
Iacobellis A et al J Hepatol 2007
Factors Associated With Greater Benefit or Greater Risk of Treatment in Cirrhotics
Factors Associated With Greater Benefit of Therapy
Factors Associated With Greater Risks of Therapy
↓ Child-Pugh score
↓ MELD score
↑ Platelet count
↑ Albumin level
↓ Age
↑ Child-Pugh score
↑ MELD score
↓ Platelet count
↓ Albumin level
↑ Age
Deaths and AEs in the first 6 month of follow-up according to treatment or not
OR=0.7
OR=0.6
OR=0.6
OR=0.9
OR=2.4 (1.02 – 5.77)
OR=2.9 OR=1.2
OR=1.9
Iacobellis A et al J Hepatol 2007
Singal AK Clin Gastroenterol Hepatol 2010
HCC occurrence in patients with HCV-related cirrhosis according to SVR
Meta-analysis: Risk of HCC in HCV Pts With Advanced Fibrosis Following SVR
• 1000 patients with bridging fibrosis or cirrhosis who achieved SVR following IFN-based HCV therapy followed for median of 5.7 yrs
• Cirrhotics at greatest risk of HCC following SVR
Van der Meer AJ, et al. AASLD 2013. Abstract 143.
Cu
mu
lati
ve H
CC
O
ccu
rren
ce (
%)
Cirrhosis
Bridging Fibrosis
P = .064
8-Yr HCC Rate, % (95% CI)
8.5(5.8-11.2)
1.8(0-4.3)
Yrs
12
10
8
6
4
2
00 1 2 3 4 5 6 7 8
Age as a Risk Factor for HCC Following SVR in HCV Pts With Advanced Fibrosis
Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission.
• HCC risk increased with age; highest for those > 60 yrs
Cu
mu
lati
ve H
CC
O
ccu
rren
ce (
%)
12
10
8
6
4
2
00 1 3 4 5 6 72 8
Yrs
> 60 yrs of age45-60 yrs of age< 45 yrs of age
P = .006
12.2%(5.3-19.1)
9.7%(5.8-13.6)
2.6%(0-5.5)
8-Yr HCC Rate, % (95% CI)
ESLD
Child-Pugh B
Portal hypertension – high risk
Cirrhosis – treatment candidate
Liver disease is not optimally represented by Child-Pugh stage (A, B, or C) or MELD score
Cirrhosis: A Continuous Spectrum of Disease
Severity of Disease Increases Need for HCV Therapy but Also Impairs Response
May not need immediate treatment
BUT • Easier to treat• High likelihood of response
Advanced disease/ cirrhosis
Mild disease
Greater need for treatment BUT
• Response to current IFN-based therapy may be
impaired
DAA Classes and Subclasses: antiviral potency and resistance barrier according to HCV genotype
Drug Class Subclass 1 b 1a 2 3 4
Protease inhinbitors
1st Generation first wave i.e. Telaprevir/Boceprevir 1st Generation 2nd wave i.e.Faldaprevir/Simeprevir/ 2nd GenerationMK5172 §
NS5a Inhibitor
1st GenerationDaclatasvir Ledipasvir ABT 267 2nd Generation MK 8742 GS 5816
NN Polymerase Inhibitors
ABT 333 GS 9669 Deleobuvir Nucleos/tides Polymerase inhibitors
2nd Generation : Sofosbuvir 33 High Moderate Low Very low
Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione