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………..