La prognosi nel paziente con epatite C

I NUOVI FARMACI PER HCV:
FREQUENZA DELLA PATOLOGIA EVIDENZE DI
FREQUENZA DELLA PATOLOGIA, EVIDENZE DI EFFICACIA E SICUREZZA, STRATEGIE DI GESTIONE ISTITUTO SUPERIORE DI SANITÀ
CNESPS ‐ Farmacoepidemiologia
La prognosi nel paziente con epatite C
G. Taliani
Sapienza Università di Roma
p
Hepatitis C C
• Natural history
• Not only a liver disease
• A “curable”
curable disease
disease
• What HCV HCV “cure”
cure means…..
means
Natural History of HCV Infection
Exposure
(Acute Phase)
15%
~20 year progression
rate accelerated
l
d with
h
HIV, HBV, alcohol
85%
Chronic
Resolved
20%
Cirrhosis
5-year survival
i l in
i
patients with HCC
is < 5%2
6%/yr
ESLD
4%/yr
HCC
3–4%/yr
Transplant/death
Time (yr
(yr))
10
HCC = hepatocellular carcinoma
ESLD = end
end--stage liver disease
Di Bisceglie A, et al. Hepatology. 2000;31:1014
2000;31:1014--1018.
20
30
40
Factors Associated
with
ith Advanced
Ad
d Fibrosis
Fib
i
Type of Factor
Type of Factor
Well Established Factors
Well Established Factors
Host
•Age at infection
g
•Duration of infection
•Male gender
•Baseline fibrosis
B li fib i
Viral •HIV infection
•HIV
infection
•HBV infection
External
•Heavy alcohol use
Bialek SR, et al. Clin Liver Dis. 2006;10:697-715.
Relative
e risk off progre
ession
Risk of Fibrosis Progression
g
Increases with Age
10
9
8
7
6
5
4
3
2
1
0
(19- 24)
(25 - 29)
(30 34)
(35 - 39)
Ryder S et al. Gut .2004;53:451-55.
(40 - 44)
(45 - 49)
(50 - 54)
(55 - 59)
(60 - 64)
(65 - 69)
(70 +)
Cumu
ulative pro
obability o
of events
The long‐‐term outcome of HCV The long
HCV compensated
compensated
cirrhosis:: a 17‐
cirrhosis: a 17
cirrhosis
: a 17‐yr follow
yr
yr follow‐
follow‐up up of 214 up of
214 Pts
214 Pts
100
Annual Incidence rate
50
HCC
Ascites
Jaundice
GI bleeding
EPS
25
3.9%
2.9%
2.0%
0.7%
0 1%
0.1%
HCC
Ascites
Jaundice
GI bleeding
GI bleeding
EPS
0
Pts still at risk
0
1
2
3
4
5
6
7
8
9
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
10
11
12
13
14
15 Years
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
The natural history of liver disease: a simplified
i lifi d view
i
Development of HCC
Increasing
liver fibrosis
Crhonic Liver
Disease
Alcohol
Viral Hepatitis
Cholestatic
NASH Autoimmune
Compensated
cirrhosis
Decompensated
cirrhosis
OLT Death
Variceal Hemorrhage Ascites
Encephalopathy
Jaundice
Garcia-Tsao, 2008
Box plots of one and two‐year survival rates
i Child P h class
in Child–Pugh
l A, B and C
A B dC
(D’Amico G et al, J Hepatol 06)
Hepatitis C C
• Natural history
• Not only a liver disease
• A “curable”
curable disease
disease
• What HCV HCV “cure”
cure means…..
means
Kaplan–Meier curves of cumulative event rate of
d
dementia
i in the groups
i h
with and without
ih d ih
HCV infection from matched 11‐year HCV cohorts
Cumu
ulative eveent rate (%
%)
Matched Cohort
HCV –
HCV+
Logrank P < 0.001.
(Chiu et al. European J Neurology in press)
58.570 pairs matched
with a 1:1 ratio by: sex, age, income, i
urbanization, diabetes,
Hypertension
Hypertension, hypercholesterolemia, chronic obstructive
pulmonary disease and depressive disorder.
depressive disorder.
Lee et Al. J Infect Dis 2012; 206: 469‐477
Lee et Al. J Infect Dis 2012; 206: 469‐477
Hepatitis C C
• Natural history
• Not only a liver disease
• A “curable”
curable disease
disease
• What HCV HCV “cure”
cure means…..
means
A SVR is Durable in Patients with HCV Infection
Treated with PegIFNalfa2a and Ribavirin
with PegIFNalfa2a and Ribavirin
Patients outcomes 4 years after therapy
Durrable SVR
R (%)
100
99.1%
100%
99.1%
98.8%
99%
80
60
40
20
0
All pts
All
pts
n=1343
HCV monoinfected
HCV monoinfected
Mono tx
ALT
n=166
Swain MG et al. Gastroenterology 2010
Combo tx
ALT
n=998
Combo tx
PNALT
n=79
HIV‐HCV
HIV
HCV
n=100
Hepatitis C C
• Natural history
• Not only a liver disease
• A “curable”
curable disease
disease
• What HCV HCV “cure”
cure means…..
means
Mortality ratio of 2889 patients with chronic hepatitis C Followed for 65 months (1986
(1986‐1998)
1998)
Overall deaths Liver-related
Liver related Liver-unrelated
deaths
deaths
Patients
Untreated
No
No.
30
Interferon treated
56
All
7
SVR
49
Non SVR
SMR
No
No.
SMR
1.9 (1.3-28) 23 13.5 (8.6-20.3)
0.9 (0.7-1.1) 35 4.7 (3.3-6.5)
0 4 (0
0.4
(0.1-0.7)
1-0 7) 2 0
0.8
8 (0
(0.1-3.0)
1-3 0)
1.1 (0.8-1.5) 33 6.5 (4.5-9.1)
Yoshida et al Gastroenterology 2002;133:483‐491
No
No.
SMR
7 0.5 (0.2-1.0)
21 0.4 (0.2-0.6)
5 0.3
0 3 (0
(0.1-0.7)
1-0 7)
16 0.4 (0.2-0.7)
Van Der Meer et Al, JAMA 2012; 308: 2584‐93
Cumulative rates of incidence of lym
mphoma ((%)
HCV Elimination Reduces The Incidence of Malignant Lymphoma
f
li
h
Persistent Infection (n=2161)
SVR (n=1048)
4
3
Log‐rank test p=0.0159
1.49%
2
0.36%
1
0
2.56%
0
0%
0%
0%
5
10
15 Years
Follow‐up duration (years)
p
(y
)
Kawamura Y, et al. Am J Med 2007;120:1034-1041
The impact of SVR on histological
outcome
t
off HCV-induced
HCV i d
d cirrhosis
i h i
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
P
tt t
t
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
Improvement in Fibrosis at Week 72 Following Start of HCV Therapy Varied With Response to Treatment
Me
ean Fibrosiss Change (Metavir SStage)
0
SVR
Relapse
NR
‐0.2
‐0.4
‐0.6
‐0.8
‐1.0
‐1.2
Patie
ents With Im
mproveme
ent in FFibrosis ≥ 1
1 Stage (%))
100
90
80
70
60
50
40
30
20
10
0
SVR
Everson GT, et al. Aliment Pharm Ther. 2008;27:542‐551.
Relapse
NR
SVR AND PORTAL HYPERTENSION IN
PATIENTS WITH COMPENSATED CIRRHOSIS
218 EV free
f
cirrhotics
i h ti
SVR 22.8%
22 8%
Endoscopy every 3 ys
FU 11.4 ys
% developing
esophageal varices
SVR
0%
No SVR
39.1%
Untreated
31.8%
Bruno et al., Hepatology 2010
Impact of SVR on long‐term outcome Impact of SVR on long‐
in 848 patients with HCV‐‐related in 848 patients with HCV
histologically‐‐proven cirrhosis histologically
(stage 1
stage 1) treated with IFN MT
) treated with IFN MT
% w ith live r c o m p lica tio n s
100
CUMULATIVE INCIDENCE OF LIVERRELATED COMPLICATIONS
307 cases with F3 or F4
(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
41
207
12
34
168
months
124
759
119
702
116
634
108
527
70
345
liver‐‐related complications
liver
related complications
Bruno S et al Hepatology 2007
Cardoso AC et al.,
al J Hepatol 2010
% surviva
al to liver-rela
ated death
Impact of SVR on long‐
Impact of SVR on long‐term outcome in
outcome in 848 patients with outcome in 848 patients with 848 patients with
HCV‐‐related HCV
related histologically
histologically‐‐
proven cirrhosis (stage 1
proven cirrhosis (stage
proven cirrhosis (
(stage 1) stage 1)
1) )
treated with IFN MT
307 cases with F3 or F4
SVR
100
no SVR
80
60
(p: 0.001 by log‐rank test)
40
20
0
0
24
48
72
120
728
115
680
112
629
105
541
P ti t att risk
Patients
i k
SVR
no SVR
CUMULATIVE INCIDENCE OF
LIVER-RELATED DEATH
96
120
144
38
234
11
47
168
months
66
369
Liver mortality
Cardoso AC et al., J Hepatol 2010
Bruno S et al Hepatology 2007
All-Cause
Morrtality (%)
20
Without SVR
10
With SVR
0
0
1 2
3 4
5 6
Yrs
7 8
9 10
Hep
patocellularr
Carc
cinoma (%
%)
Pts at Risk,
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
Hepatocellular Carcinoma
P < .001
001
30
20
Without SVR
10
With SVR
0
0
1 2
3 4
5 6
Yrs
7 8
9 10
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.
30
Liver-Related Mortality or Liver
T
Transplantation
l t ti
20
P < .001
Without SVR
10
With SVR
0
0
1 2
3 4
5 6
Yrs
7 8
9 10
Pts at Risk,
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
Liverr Failure (%
%)
All-Cause Mortality
P < .001
30
Live
er-Related
Mortality or Live
er
Transp
plantation (%)
Survival Outcomes in Pts With CHC and Advanced
Fibrosis With/Without SVR
Liver Failure
30
P < .001
001
20
Without SVR
10
With SVR
0
0
1 2
3 4
5 6
Yrs
7 8
9 10
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
Event-free survival according to response to therapy
in 102 patients with HCV-induced
HCV induced cirrhosis and
portal hypertension (stage 2)
% off Patients W
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 Annual rate of HCC occurrence (% person‐years) in patients with HCV‐related
person‐years) in patients with HCV‐related cirrhosis according to IFN treatment
Median
follow up
follow-up
time: 14.4
years
Bruno S et al Am J Gastroenterol 2009
HCC occurrence in patients with HCV‐related cirrhosis according to SVR
cirrhosis according to SVR
Singal AK Clin Gastroenterol Hepatol 2009
CUMULATIVE INCIDENCE OF HEPATOCELLULAR CARCINOMA
307 cases with
ith F3 or F4
Cardoso AC et al., J Hepatol 2010
Association of SVR With the Development of HCC in HCV infection
in HCV infection
Forest plot of adjusted hazard effects in persons at all stages of fibrosis
Morgan RL et al. Ann Intern Med 2013
Association of SVR With the Development of HCC in HCV infection
in HCV infection
Forest plot of adjusted hazard effects in Persons with advanced liver disease
Morgan RL et al. Ann Intern Med 2013
Association of SVR With the Development of HCC in HCV infection
in HCV infection
Forest plot of adjusted hazard effects in Persons with advanced liver disease
absolute reduction in
HCC risk was 4.2% (CI, 4.0% to 4.9%) for patients
%) f
i
achieving an SVR
an SVR
Morgan RL et al. Ann Intern Med 2013
HEPATOCELLULAR CARCINOMA (HCC) INCIDENCE IN CHRONIC HEPATITIS C PATIENTS (CHC) ACCORDING TO
CHRONIC HEPATITIS C PATIENTS (CHC) ACCORDING TO SUSTAINED VIROLOGIC RESPONSE (SVR)
1371 patients
1371
patients
Diagnosed 1989‐2011
Treated
HCC‐incidence
F4/SVR: 7.7% F4/non‐SVR 21.9% (p = 0.003)
F3/SVR : 1.4%
non SVR: 5 6%
non‐SVR: 5.6% (p = 0.04).
T. Purevsambuu et al. EASL 2014; abstr Oral 125
F0 2/SVR 0.2% F0–2/SVR
0 2%
Non‐SVR 2.9% (p = 0.01).
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)
C
Cumulativ
ve HCC
Occurren
O
nce (%)
12
12.2%
(5.3-19.1)
> 60 yrs of age
45 60 yrs of age
45-60
< 45 yrs of age
10
9.7%
(5.8-13.6)
8
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.
LIVER EVENT-FREE SURVIVAL ACCORDING TO STAGE
OF CIRRHOSIS AT THE TIME OF ANTIVIRAL THERAPY
Fernandez-Rodriguez 2010
SVR
no SVR
no-SVR
SVR
ALBUMIN>3.9g
/no varices
Fernandez‐Rodriguez et al. Fig.7
ALBUMIN<3.9
/varices
no-SVR
Cumulative probability of survival of SVRs versus
Non SVRs and controls in patients with
Decompensated HCV cirrhosis
C umulativve probab
bility of su rvival
1
SVR
09
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
Cirrhosis and Portal Hypertension Study (SOF+RBV)
Laboratory and Clinical Event Changes
SOF+RBV Observation 24 weeks
Platelets (10
Pl
t l t (103/µL)
/ L)
20
15
10
5
0
‐5
5
‐10
‐15
17
p=0.003
0,6
0,5
04
0,4
0,3
0,2
0,1
0
‐0,1
‐0,2
p=NS
1
1
‐1
‐9
CTP A
ALT (U/L)
ALT (U/L)
Alb i ( /dL)
Albumin (g/dL)
p=0.001
0,5
13
0
0
0,4
‐20
‐40
0
‐60
‐80
‐0,1
CTP A
CTP B
20
p=0.001
Ascites
‐72
‐75
CTP A
CTP B
CTP B
Hepatic Encephalopathy
SOF + RBV
n=25
Observation
n=25
SOF + RBV
n=25
Observation
n=25
Baseline
6
9
5
2
Week 12
5
8
3
3
Week 24
0
7
0
4
Patients n
Patients, n
Afdhal N, EASL, 2014, O68
Duration of Undetectable HCV RNA Before
T
Transplant
l t Predicted
P di t d Lack
L k off Recurrence
R

64% of pts HCV RNA negative 12 wks
post-LT (93% at LT)

Continuous days TND pre-LT only
factor predicting HCV recurrence in
multivariate analysis
> 30 days TND
No recurrence (n = 28)
Recurrence (n = 10)
– Only 1/24 pts with > 30 days TND
experienced recurrence
Median days TND (P < .001)
 No recurrence: 95
 Recurrence: 5.5
0
30
60
90
120 150 180 210 240 270 300 330
Days With HCV RNA Continuously TND Prior to Liver Transplant
Curry MP, et al. AASLD 2013. Abstract 213. Reproduced with permission.
Conclusions
l i
• HCV multiorgan, curable disease
• Natural history multifaceted
•A
Antiviral
ti i l treatment potentially
t t
t t ti ll capable
bl of f
reverting hepatic and extra
and extra‐hepatic
hepatic
damage
• HCC surveillance in advanced fibrosis
20
Without SVR
10
With SVR
0
0 1 2 3 4 5 6 7 8 9 10
Yrs
He
epatocellular
Carcinoma ((%)
Pts at Risk,
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
Without SVR
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-Related
Liver Transplantation
P < .001
30
20
Without SVR
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
Liv
ver Failure (%)
All Cause Mortality
All-Cause
P < .001
30
Liverr-Related
Mortality or Liverr
Transpllantation (%
%)
All-Cause
Morrtality (%)
Survival Outcomes in Pts With CHC and
Ad
Advanced
d Fib
Fibrosis
i With/With
With/Withoutt SVR
Liver Failure
30
P < .001
20
Without SVR
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