Il danno d’organo provocato
dal Virus C
Gloria Taliani
8 Maggio 2014
Malattie Infettive e Tropicali
Sapienza Università di Roma
Policlinico Umberto I, Roma
Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione
Natural History of HCV Infection
Acute HCV
Resolved
15%
Chronic HCV
85%
Stable
80% (68%)
Cirrhosis
20% (17%)
Slowly
progressive
75% (13%)
HCC
Liver failure
25% (4%)
Hepatitis C Disease Pathogenesis
CD4+
CD8+
Cell killing
Cytokines
(IL-2, IFN-TNF-a, TGF-PDGF)
TGF-
Death
Kupffer cell
Hepatocytes
Activation
Hepatic stellate cells
Fibrosis
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.
Cumulative probability of events
The long-term outcome of HCV compensated
cirrhosis: a 17-yr follow-up of 214 Pts
100
Annual Incidence rate
50
HCC
Ascites
Jaundice
GI bleeding
EPS
25
3.9%
2.9%
2.0%
0.7%
0.1%
HCC
Ascites
Jaundice
GI bleeding
EPS
0
Pts still
at risk
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
214
214
214
214
214
196
197
196
198
198
186
182
184
188
190
168
163
164
171
173
153
151
152
160
162
142
142
144
151
152
129
133
134
142
146
116
114
122
129
129
110
105
114
122
122
96
92
100
105
108
89
86
89
94
98
74
74
75
81
84
66
68
69
73
77
57
60
60
64
66
48
55
54
58
59
36
39
40
42
43
Sangiovanni A et al Hepatology 2006
Years
Effect of Inflammation on Fibrosis
Progression in HCV Patients
Change in Fibrosis Score According to Necrosis Score
at Baseline
Patients, n
Mean change in
fibrosis score
per yr
Piecemeal Necrosis Score at Baseline
0-1
2-3
>4
30
66
27
0.05
Ghany MG, et al. Gastroenterol. 2003;124:97-104.
0.19
0.37
Patients Developing Cirrhosis
According to Initial Level of Fibrosis
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 ± portalportal bridging
42.9
3.0-3.45 (n = 15)
Septal + regions of partial
nodular regeneration
100
Yano M, et al. Hepatology. 1996;23:1334-1340.
Factors Associated With Advanced
Fibrosis
•
•
Retrospective study of 460 pts with chronic hepatitis C (41% F3-4)
Multivariate analysis of factors associated with F3-4
Risk Factor
Adjusted Odds Ratio (95% CI)
3.444
Age at entry (≥ 60 years)
P Value
.0334
Duration of infection (≥ 25 years)
1.750
.0378
BMI (≥ 30)
1.917
.0173
2.251
History of diabetes
AST (≥ 80 U/L)
4.032
AFP (≥ 15 µg/L)
3.875
Grades 2 and 3 steatosis
.0087
.0383
2.790
0.01
Hu S, et al. J Clin Gastro. 2009
.0304
1.0
.0378
15.0
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
HOMA-IR
5
4
3
2
1
0
F0
F1
F2
Fibrosis Score
Hui JM, et al. Gastroenterol. 2003;125:1695-1704.
F3
F4
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
Cannabis Use
Odds Ratio of Accelerated Fibrosis
Progression Rate* (95% CI)
1.3
Occasional
.57
3.4
Daily
0.01
1.0
.005
10.0
*Compared with median progression rate of cohort: 0.074 Metavir U/yr.
Hezode C, et al. Hepatology. 2005;42:63-71.
P Value
Alcohol Consumption Increases Risk of
Cirrhosis in HCV Patients
100
Cirrhosis (%)
80
P < .01
P < .01
64
58
60
P < .01
85
40
40
20
0
HCV
HCV + alcohol*
31
18
12
6
10
20
30
Years Following Exposure†
40
*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.
100 %
Survival at 1 year 80 %
45 %
1-year mortality rate according to clinical stages
Compensated
Classification from a systematic review of 118 studies
Stage 1
1%
No varices
No ascites
7%
Stage 2
4.4%
3.4%
Varices
No ascites
4%
DEATH
Decompensated
6.6%
Stage 3
Ascites +/-
20%
varices
7.6%
Stage 4
Bleeding +/ascites
57%
D’Amico G et al J Hepatol 2006
Survival Probability in HCV Patients
With Cirrhosis
Compensated
Survival Probability
100
After first major
complication
Patients (%)
80
60
40
20
0
0
12
24
36
48
60 72
Mos
84
Patients at Risk
384 376 342 288 236 165 126 79
65 39 21 11
7
4
4
3
96 108 120
52
3
39
2
25
1
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.
Cirrhosis
The impact of SVR on histological
outcome of HCV-induced cirrhosis
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
Post-treatment
specimens were
collected a median
of 6 months after
treatment
cessation
Comparison of liver fibrosis stage between pre-treatment and
post-treatment paired liver biopsy in 126 patients
Maylin S et al Gastroenterology 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.
Mallet V et al Ann Int Med 2008
Cumulative incidence of esophageal varices in 149 IFN ± RBVtreated patients with compensated HCV-induced cirrhosis according
to response to therapy
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
Bruno S, et al Hepatology 2010
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)
(p: 0.001 by log-rank test)
80
60
40
no SVR
20
SVR
0
0
24
48
Patients at risk
SVR
no SVR
72
96
120
144
months
124
759
119
702
116
634
108
527
70
345
41
207
12
34
liver-related complications
168
% survival to liver-related death
% with liver complications
100
(p: 0.001 by log-rank test)
SVR
100
no SVR
80
60
40
20
0
0
24
48
72
120
728
115
680
112
629
105
541
Patients at risk
SVR
no SVR
96
120
144
38
234
11
47
months
66
369
Liver mortality
Bruno S et al Hepatology 2007
168
20
10
With SVR
0
0 1 2 3 4 5 6 7 8 9 10
Yrs
Hepatocellular
Carcinoma (%)
Pts at Risk, n
Without SVR 405 393 382 363 344 317 295 250 207 164 135
With SVR
192 181 168 162 155 144 125 88 56 40 28
30
Hepatocellular Carcinoma
P < .001
20
10
0
With SVR
0 1 2 3 4 5 6 7 8 9 10
Yrs
Pts at Risk, n
Without SVR 405 390 375 349 326 294 269 229 191 151 122
With SVR
192 181 167 161 152 142 124 86 54 39 27
Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.
Liver-Related Mortality or
Liver Transplantation
P < .001
30
20
10
With SVR
0
0 1 2 3 4 5 6 7 8 9 10
Yrs
Pts at Risk, n
Without SVR 405 392 380 358 334 305 277 229 187 146 119
With SVR
192 181 168 162 155 144 125 88 56 40 28
Liver Failure (%)
All-Cause Mortality
P < .001
30
Liver-Related
Mortality or Liver
Transplantation (%)
All-Cause
Mortality (%)
Survival Outcomes in Pts With CHC and
Advanced Fibrosis
Liver Failure
30
P < .001
20
10
With SVR
0
0 1 2 3 4 5 6 7 8 9 10
Yrs
Pts at Risk, n
Without SVR 405 384 361 337 314 288 259 216 184 143 113
With SVR
192 180 166 160 152 141 123 88 56 40 28
Achieving Sustained Virologic Response: Impact on Long-Term
Outcomes in HIV/HCV-Coinfection
GESIDA 3603 Cohort: 711 pts treated for HCV
Achieved SVR
Did not achieve SVR
4.33
Long-Term Outcome Rate
(per 100 person/years)
(3.16,5.8)
3.12
(2.16,4.37)
1.65
(0.98,2.16)
0.46*
0.23†
(0.06,1.65)
(0.01,1.27)
0.23‡
(0.01,1.27)
0
(0,0.84)
Overall
Mortality
1.02
0.83
Liver-Related
Mortality
Liver
Decompensation
Hepatocarcinoma
0§
(0.44,1.70)
0.23
(0.01,1.27)
(0,0.84)
Liver
Transplantation
*P=0.003, †P=0.028, ‡P<0.001, and §P=0.034 versus not attaining a sustained virologic response.
n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.
Berenguer J. et al. Hepatology 2009.
0.93
(0.50,1.82)
(0.38,1.58)
New
AIDS
Conditions
Event-free survival according to response to therapy
in 102 patients with HCV-induced cirrhosis and
portal hypertension (stage 2)
% of Patients Without Events Liver-related
100
80
SVR (16 pts)
60
40
NR (86 pts)
20
p= 0.006 by log rank test
0
0
6
12
18
24
30
36
Months
42
48
54
60
Di Marco V et al J Hepatol 2007
Cumulative probability of survival of SVRs versus
Non SVRs and controls in patients with
decompensated HCV-induced cirrhosis
Cumulative probability of survival
1
SVR
0,9
NonR
Ctrl
0,8
p= 0.07
0,7
0,6
0,5
0
6
12
18
24
30
36
42
months
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
 ↑ Child-Pugh score
 ↓ MELD score
 ↑ MELD score
 ↑ Platelet count
 ↓ Platelet count
 ↑ Albumin level
 ↓ Albumin level
 ↓ Age
 ↑ Age
Deaths and AEs in the first 6 month of follow-up
according to treatment or not
OR=2.4 (1.02 – 5.77)
20
OR=0.7
15
OR=0.6
10
OR=2.9
OR=1.2
OR=0.6
OR=1.9
OR=0.9
5
0
Ascites
EPS
Bleeding
HCC
I nfection
Severe
infection
Deaths
Deaths
related to
infection
Iacobellis A et al J Hepatol 2007
HCC occurrence in patients with HCV-related
cirrhosis according to SVR
Singal AK Clin Gastroenterol Hepatol 2010
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
Cumulative HCC
Occurrence (%)
12
10
Cirrhosis
8
6
8-Yr HCC Rate, %
(95% CI)
8.5
(5.8-11.2)
P = .064
4
Bridging Fibrosis
2
0
0
1
2
3
4
Yrs
5
Van der Meer AJ, et al. AASLD 2013. Abstract 143.
6
7
8
1.8
(0-4.3)
Age as a Risk Factor for HCC Following
SVR in HCV Pts With Advanced Fibrosis
• HCC risk increased with age; highest for those > 60 yrs
8-Yr HCC Rate, % (95% CI)
Cumulative HCC
Occurrence (%)
12
12.2%
(5.3-19.1)
> 60 yrs of age
45-60 yrs of age
< 45 yrs of age
10
8
6
9.7%
(5.8-13.6)
P = .006
4
2.6%
(0-5.5)
2
0
0
1
2
3
4
Yrs
5
6
7
8
Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission.
Cirrhosis: A Continuous Spectrum of Disease
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
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
Mild disease
 Greater need for treatment
 BUT
• Response to current
IFN-based therapy may be
impaired
Advanced disease/
cirrhosis
DAA Classes and Subclasses: antiviral potency and resistance barrier
according to HCV genotype
Drug Class
Subclass
1st Generation first wave i.e.
Telaprevir/Boceprevir
Protease inhinbitors
1st Generation 2nd wave i.e.
Faldaprevir/Simeprevir/
2nd Generation
MK5172 §
1st Generation
Daclatasvir Ledipasvir ABT 267
NS5a Inhibitor
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
1b
1a
2
3
4
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Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione