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Stefano Fagiuoli
U.S.C. Gastroenterologia Epatologia e Trapiantologia
Ospedale Papa Giovanni XXIII - Bergamo
Il Trattamento dell’Epatite C nelfuturo prossimo
0
20
40
60
80
100
IFN
6 or
12 mo
IFN+RBV
6 mo
IFN+RBV
12 mo
PEG
2a/b+RBV
12 mo
TVR+PEG
+RBV
6-12 mo
LDV/SOF
2-6 mo
62-63
19-2823
20
0
87
20112011 2013 2013
SV
R R
ate
(%
)
1 – pooled data from ION-1, ION-2, and ION-3
Jeffers L, et al. Hepatology 2004; 39: 1702-1708; Conjeevaram H, et al. Gastroenterology 2006; 131: 470-477; Muir A, et al. N Engl J Med 2004; 350: 2265-71; McHutchison J, et al. Gastroenterology 2000; 119: 1317-1323; Poordad F, et al. N Engl J Med 2011; 364: 1195-206; Bacon B, et al. N Engl J Med 2011; 364: 1207-17; Jacobson I, et al. N Engl J Med 2011; 364: 2405-16; Zeuzem S, et al. N Engl J Med 2011; 364: 2417-28; Manns M, et al. Lancet 2014; 384: 414-426; Jacobson I, et al. Lancet 2014; 384: 403-413; Lawitz E, et al. N Engl J Med 2013; 368:1878-87; Afdhal N, et al. N Engl J Med 2014; 370: 1889-98; Afdhal N, et al. N Engl J Med 2014; 370: 1483-1493; Kowdley K, et al. N Engl J Med 2014; 370: 1879-88.
SMV+PEG
+RBV
6-12 mo
63
2014
SOF+PEG
+RBV
3 mo
951
SVR Rates for Approved Therapies in HCV GT 1 TN or TE
Years are not to scale
42-61
BOC+PEG
+RBV
6-12 mo
20041998 1998
At present
The benchmark for acceptable HCV treatment outcome
is set to > 90%
3
SVR for Approved Therapies in HCV
SVR > 90%
< Toxicity
> Tolerability
Must haves
Short duration
One size fits all: pangenotypic
High barrier to resistance Helpful
Requirements for HCV Therapy
No drug–drug interactions
Low pill burden
Nice
bonus
SVR:
Clinical
Outcomes
Prevent Decompensation
Delay Liver-Related Death
Delay/prevent HCC
Prevent (Improve) Extrahepatic disorders
Cirrhosis regression
Slowing progression of PH
HCV Cirrhosis Natural History: can we modify it ?
But……
With some Caveats……
Hepatology. 2012;56:532-543.
Cirrhosis !
Less fibrosis….. but still Cirrhosis !
Cumulative incidence of hepatic decompensation and hepatic mortality according to:absence (stage 1) or presence (stage 2) of varices in 2 cohorts of HCV patients with
compensated cirrhosis
Gomez EV, et al. J Hepatol 2013Bruno S, et al. Am J Gastroenterol 2009
n= 352 patients n= 402 patients
Clinical Decompensation
Liver-related mortality
Gomez EV, et al. J Hepatol 2013Bruno S, et al. Am J Gastroenterol 2009
n= 352 patients n= 402 patients
Clinical Decompensation
Liver-related mortality
Cumulative incidence of hepatic decompensation and hepatic mortality according to:absence (stage 1) or presence (stage 2) of varices in 2 cohorts of HCV patients with
compensated cirrhosis
The Impact of “Cirrhosis Regression” on Clinical Events
?
Liver-related events Liver-related events
The Impact of “Cirrhosis Regression” on Clinical Events
Liver-related events Liver-related events
?
No SVR
SVR
No SVR
SVR
Pa
tie
nts
aliv
e (
%)
Survival after P/R treatment in 440 patients with HCV cirrhosis, CTP A 5-6 (mean follow-up time 7.7 yrs)
No SVR
SVR
No SVR
SVR
Log rank p = 0.003Log rank p = 0.001
Esophageal varicesbefore P/R
No esophageal varicesbefore P/R
Di Marco V, et al. submitted
LDV+SOF+RBV in G1/G4 HCV patients with decompensated cirrhosis
-6
-4
-2
0
2
4
-6
-4
-2
0
2
4
n=5 n=5 n=2 n=3
(+10)
CPT B CPT C
12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*
*Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.
Flamm, AASLD, 2014, Oral #239
LDV+SOF+RBV in G1/G4 HCV patients with decompensated cirrhosis
-6
-4
-2
0
2
4
-6
-4
-2
0
2
4
n=5 n=5 n=2 n=3
(+10)
CPT B CPT C
12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*
*Missing FU-4: n=2 CPT B 12 wk; n=4 CPT B 24 wk; n=2 CPT C 12 wk; n=7 CPT C 24 wk.
Flamm, AASLD, 2014, Oral #239
36% not improved 35% not improved
Death due to Cirrhosis and HCC after P/R treatments
Eradication of HCV: What about CURE ???
Point of NO RETURN ????
The ……“Too late point”…….?
Factors associated with increased risk of cirrhosis and HCC in patients with HCC
Clinical
Outcomes
Extrahepatic Benefit ????
Extrahepatic Benefit of SVR
Antiviral Treatment and Extrahepatic Outcomes in HCV
End Stage Renal Disease
Hsu et al, Gut 2015; 64: 495-503
Ischemic Stroke
p=0,001
p=0,001p=0,027
p= ns
Acute Coronary Syndrome
Autoimmune Diseases
SVR in diabetics
…….The EARLIER, the WIDER we treat HCV
the better the OUTCOME……
Increasing Use of High SVR Therapy (~ 90%) will Eliminate HCV in the US by 2029
No more
patients
available
to treat
200,000Treated
150,000
100,000
50,000
0
160,000
120,000
80,000
40,000
0
Cured
Razavi H, et al. Hepatology. 2013;57:2164-2170.
EPAC survey 31-12-2013 - Chronic Hepatitis C in Italy
Total expected patients
337-375.000
Patients with diagnosis not attending
to authorized centers87-95000 *
Patients with diagnosis attending to authorized centers
220-250000
Patients without diagnosis ???
Patients excluded:• patients with fatal comorbidities (i.e. neoplasms including HCC)• patients with decompensated cirrhosis (Child C) • older patients (> 85 years old)• pediatric patients
HCV-HIV coinfected patients30000
*Including:• Patients managed by general practitioners• Patients referring to SERD• Incarcerated (25000)• Immigrants• Patients with more than one code
Fibrosis stage % Number of Patients
F0 - F1 45 136.350 / 151.650
F2 15 45.450 / 50.550
F3 11,5 34.845 / 38.775
F4 – Cirrhosis 28,5 86.355 / 96.045Child A 65-77% 62.429-73.954
Child B 15-22% 14.406-21.130
Child C 4-8% 3.482-7.684
F3 + F4 40 131.200 / 134.820
EPAC survey 31-12-2013 - Chronic Hepatitis C in Italy
Widespread
Number and proportion of HCV treatments according to drug price* & estimated prevalence of CHC
Italian patients (#)
Price per Treatment €
Number of Patients treatable according to
budget *
% patients treated x year #
Time required to treat all patients
(Years)
50000 20000 6 16.5
40000 25000 7.5 13.2
30000 33000 10 10
25000 40000 12 8.25
20000 50000 15 6.6
15000 66000 19.7 5
10000 100000 30.3 3
5000 200000 60.6 1.6
2000 Egypt/Indian
500000 all 1
* Budget 1x109 € (or less?) # : ~ 337.000 HCV estimated Italian patients
Tema costo-beneficio
• Nuove terapie COSTOSE≈ 30-35.000 €
• Risorse Limitate ????
• Selezione pazienti ?Deferral informato?
Riflessioni………..