prognosi nel paziente con epatite · i nuovi farmaci per hcv: frequenza della patologia, evidenze...

I NUOVI FARMACI PER HCV:FREQUENZA DELLA PATOLOGIA EVIDENZE DIFREQUENZA DELLA PATOLOGIA, EVIDENZE DI

EFFICACIA E SICUREZZA, STRATEGIE DI GESTIONE

ISTITUTO SUPERIORE DI SANITÀCNESPS ‐ Farmacoepidemiologia

La prognosi nel paziente con epatite CG. Taliani

Sapienza Università di Romap

Hepatitis CHepatitis C

• Natural history

• Not only a liver disease

• A “curable” diseaseA curable disease

• What HCV “cure” means• What HCV cure means…..

Natural History of HCV InfectionNatural History of HCV InfectionExposureExposure

(Acute Phase)(Acute Phase)~20 year progression ~20 year progression

l d hl d h

ResolvedResolved20%20%

15% 15% 85%85% rate accelerated with rate accelerated with HIV, HBV, alcoholHIV, HBV, alcohol

ChronicChronic20%20%

55 i l ii l i

CirrhosisCirrhosis

ESLDESLD HCCHCC6%/yr6%/yr 4%/yr4%/yr55--year survival in year survival in

patients with HCC patients with HCC is < 5%is < 5%22

Transplant/deathTransplant/death33––4%/yr4%/yr

is < 5%is < 5%

Time (Time (yryr))

HCC = hepatocellular carcinomaHCC = hepatocellular carcinoma

1010 2020 3030 4040

HCC = hepatocellular carcinomaHCC = hepatocellular carcinomaESLD = endESLD = end--stage liver diseasestage liver disease

Di Di BisceglieBisceglie A, et al. A, et al. HepatologyHepatology. 2000;31:1014. 2000;31:1014--1018.1018.

Factors AssociatedFactors Associatedith Ad d Fib iith Ad d Fib iType of Factor Well Established Factors

with Advanced Fibrosiswith Advanced FibrosisType of Factor Well Established Factors

•Age at infectionHost

g•Duration of infection•Male genderB li fib i•Baseline fibrosis

•HIV infectionViral •HIV infection•HBV infection

External •Heavy alcohol use

Bialek SR, et al. Clin Liver Dis. 2006;10:697-715.

Risk of Fibrosis Progression Risk of Fibrosis Progression ggIncreases with AgeIncreases with Age

910

essi

on

789

f pr

ogre

456

e ri

sk o

f

234

Rel

ativ

e

01

(19- 24) (25 - 29) (30 34) (35 - 39) (40 - 44) (45 - 49) (50 - 54) (55 - 59) (60 - 64) (65 - 69) (70 +)

Ryder S et al. Gut .2004;53:451-55.

The The longlong‐‐termterm outcomeoutcome ofof HCV HCV compensatedcompensatedcirrhosiscirrhosis: a 17: a 17 yr followyr follow upup ofof 214214 PtsPtscirrhosiscirrhosis: a 17: a 17‐‐yr followyr follow‐‐up up ofof 214 214 PtsPts

100

of events

50

100

Annual Incidence rate

HCC 3.9%

obability

o

25

HCC

Ascites

HCC 3.9%Ascites 2.9%Jaundice 2.0%GI bleeding 0.7%EPS 0 1%

ulative pro 25

GI bleeding

JaundiceEPS 0.1%

Cumu

0

Years

GI bleeding

EPS

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Years214 196 168186 153 142 129 110116 96 89 6674 57 3648

214 196 164184 152 144 134 114122 100 89 6975 60 4054214 197 163182 151 142 133 105114 92 86 6874 60 3955Pts still

at risk

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

214 198 171188 160 151 142 122129 105 94 7381 64 4258214 198 173190 162 152 146 122129 108 98 7784 66 4359

Sangiovanni A et al Hepatology 2006Sangiovanni A et al Hepatology 2006

The natural history of liver disease: i lifi d ia simplified view

Increasingliver fibrosis

Development of HCC

Compensatedcirrhosis

Decompensatedcirrhosis

OLT Death

Crhonic LiverDisease

AlcoholViral Hepatitis Variceal Hemorrhage AscitesCholestatic

NASH Autoimmune

EncephalopathyJaundice

Garcia-Tsao, 2008

Autoimmune

Box plots of one and two‐year survival ratesi Child P h l A B d Cin Child–Pugh class A, B and C

(D’Amico G et al, J Hepatol 06)


• Natural history




Kaplan–Meier curves of cumulative event rate ofd i i h i h d i hdementia in the groups with and without HCV infection from matched 11‐year HCV cohorts

Matched Cohort

HCV –%)

HCV+

entrate (% 58.570 pairs matched

with a 1:1 ratio by: i

ulative eve sex, age, income,

urbanization, diabetes,Hypertension

Cumu

Logrank P < 0.001.Hypertension, hypercholesterolemia, chronic obstructivechronic obstructivepulmonary disease and depressive disorder.

(Chiu et al. European J Neurology in press)

depressive disorder.

Lee et Al. J Infect Dis 2012; 206: 469‐477


• Natural history




A SVR is Durable in Patients with HCV InfectionTreated with PegIFNalfa2a and RibavirinTreated with PegIFNalfa2a and Ribavirin

Patients outcomes 4 years after therapy

99.1% 98.8% 99.1% 99%100

100%

60

80

R (%

)

40

60

rable SV

R

0

20

All pts HCV monoinfected HIV HCV

Dur

All ptsn=1343

HCV monoinfected HIV‐HCVn=100

Mono txALT

Combo txALT

Combo txPNALT

Swain MG et al. Gastroenterology 2010

n=166 n=998 n=79


• Natural history




Mortality ratio of 2889 patients with chronic hepatitis C Followed for 65

months (1986‐1998)months (1986 1998)

Overall deaths Liver-related Liver-unrelatedOverall deaths

SMRNo

Liver related deaths

SMRNo

deaths

SMRNoPatients

Untreated 30 1.9 (1.3-28)

SMRNo.

23 13.5 (8.6-20.3)

SMRNo.7 0.5 (0.2-1.0)

SMRNo.Patients

Interferon treatedAllSVR

567

0.9 (0.7-1.1)0 4 (0 1-0 7)

352

4.7 (3.3-6.5)0 8 (0 1-3 0)

215

0.4 (0.2-0.6)0 3 (0 1-0 7)SVR

Non SVR 7

490.4 (0.1-0.7)1.1 (0.8-1.5)

233

0.8 (0.1-3.0)6.5 (4.5-9.1)

516

0.3 (0.1-0.7)0.4 (0.2-0.7)

Yoshida et al Gastroenterology 2002;133:483‐491

Van Der Meer et Al, JAMA 2012; 308: 2584‐93

HCV Elimination Reduces The Incidence f li h

(%)

of Malignant Lymphomamph

oma (

Persistent Infection (n=2161)SVR (n=1048)4

nce of lym

32.56%Log‐rank test p=0.0159

of incide

2 1.49%

tive rates

1 0.36%

0%0% 0%

Cumula 0 0 5 10 15 Years

Follow‐up duration (years)

0% 0%

p (y )

Kawamura Y, et al. Am J Med 2007;120:1034-1041

The impact of SVR on histological t f HCV i d d i h ioutcome of HCV-induced cirrhosis

P t t t tPost-treatment

Pre-treatment F0 F1 F2 F3 F4

Post-treatment specimens were

collected a median of 6 months after

F0 1 2 0 0 0

F1 14 16 7 0 0

of 6 months after treatment cessation

F1 14 16 7 0 0

F2 7 23 12 2 4

F3 0 5 12 7 4F3 0 5 12 7 4

F4 0 1 2 6 5

Comparison of liver fibrosis stage between pre-treatment and

Maylin S et al Gastroenterology 2008

post-treatment paired liver biopsy in 126 patients

Improvement in Fibrosis at Week 72 Following Start of HCV Therapy

Varied With Response to Treatment

100

ent in

)

0SVR Relapse NR

80

90

100

mprovem

e1 Stage (%

)

s Cha

nge

Stage) ‐0.4

‐0.2

50

60

70

ents W

ith Im

Fibrosis ≥ 1

ean Fibrosis

(Metavir S

‐0.8

‐0.6

30

40

50

PatieF

Me

‐1.2

‐1.0

0

10

20

Everson GT, et al. Aliment Pharm Ther. 2008;27:542‐551.

SVR Relapse NR

SVR AND PORTAL HYPERTENSION IN

PATIENTS WITH COMPENSATED CIRRHOSIS

218 EV f i h ti SVR 22 8%218 EV free cirrhotics SVR 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 longImpact of SVR on long‐‐term outcome term outcome in 848 patients with HCVin 848 patients with HCV‐‐related related

CUMULATIVE INCIDENCE OF LIVER-RELATED COMPLICATIONS

histologicallyhistologically‐‐proven cirrhosis proven cirrhosis ((stage 1stage 1) treated with IFN MT) treated with IFN MT

307 cases with F3 or F4

100

ns

(p: 0.001 by log‐rank test)

60

80

com

plic

atio

n

20

40

with

live

r c

no SVR

0 24 48 72 96 120 144 1680

months

%

Patients at risk

SVR

SVR 124 119 116 108 70 41 12 no SVR 759 702 634 527 345 207 34

liverliver‐‐related complicationsrelated complications Cardoso AC et al J Hepatol 2010liverliver related complicationsrelated complications

Bruno S et al Hepatology 2007

Cardoso AC et al., J Hepatol 2010

Impact of SVR on longImpact of SVR on long‐‐term term outcomeoutcome in 848 patients within 848 patients with CUMULATIVE INCIDENCE OFoutcome outcome in 848 patients with in 848 patients with HCVHCV‐‐related related histologicallyhistologically‐‐proven cirrhosis (proven cirrhosis (stage 1stage 1))

CUMULATIVE INCIDENCE OF LIVER-RELATED DEATH

307 cases with F3 or F4proven cirrhosis (proven cirrhosis (stage 1stage 1) ) treated with IFN MTtreated with IFN MT

80

100

ated

dea

th SVR

no SVR

40

60

al to

live

r-re

la

(p: 0.001 by log‐rank test)

0 24 48 72 96 120 144 1680

20

% s

urvi

va

P ti t t i k

LiverLiver mortalitymortality

monthsSVR 120 115 112 105 66 38 11no SVR 728 680 629 541 369 234 47

Patients at risk

Bruno S et al Hepatology 2007

LiverLiver mortalitymortalityCardoso AC et al., J Hepatol 2010

Survival Outcomes in Pts With CHC and Advanced Fibrosis With/Without SVRFibrosis With/Without SVR

30 All-Cause Mortality 30er %) Liver-Related Mortality or Liver

T l t ti20

10l-Cau

se

rtal

ity (%

) P < .001

Without SVR

20

10er-R

elat

ed

lity

or L

ive

plan

tatio

n ( Transplantation

P < .001

Without SVR10

00

Al

Mo r

1 2 3 4 5 6 7 8 9 10Yrs

With SVR

Pts at Risk n

10

00

Live

Mor

taTr

ans p

1 2 3 4 5 6 7 8 9 10Yrs

With SVR

Pts at Risk nPts at Risk, nWithout SVRWith SVR

405192

393181

382168

363162

344155

317144

295125

25088

20756

16440

13528

Pts at Risk, n Without SVRWith SVR

405192

392181

380168

358162

334155

305144

277125

22988

18756

14640

11928

30r %)

Hepatocellular CarcinomaP < 001

30

%) Liver Failure

P < 00120

10

pato

cellu

lar

cino

ma

(% P < .001

Without SVR

20

10r Fai

lure

(% P < .001

Without SVR

00

Hep Car

c

1 2 3 4 5 6 7 8 9 10Yrs

With SVR

Pts at Risk, n

00

Live

r1 2 3 4 5 6 7 8 9 10

Yrs

With SVR

Pts at Risk, nPts at Risk, n Without SVRWith SVR

405192

390181

375167

349161

326152

294142

269124

22986

19154

15139

12227


405192

384180

361166

337160

314152

288141

259123

21688

18456

14340

11328

Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

Event-free survival according to response to therapy in 102 patients with HCV-induced cirrhosis andin 102 patients with HCV induced cirrhosis and

portal hypertension (stage 2)

100

80

100‐related

SVR (16 pts)

60

80

entsLiver‐ SVR (16 pts)

40

With

outE

v

20

f PatientsW NR (86 pts)

0 6 12 18 24 30 36 42 48 54 600

% of

p= 0.006 by log rank test

Di Marco V et al J Hepatol 2007

Months

Annual rate of HCC occurrence (% person‐years) in patients with HCV‐relatedperson‐years) in patients with HCV‐related

cirrhosis according to IFN treatment

Median follow-upfollow up time: 14.4

years

Bruno S et al Am J Gastroenterol 2009

HCC occurrence in patients with HCV‐related cirrhosis according to SVRcirrhosis according to SVR

Singal AK Clin Gastroenterol Hepatol 2009

CUMULATIVE INCIDENCE OF HEPATOCELLULAR CARCINOMA

307 ith F3 F4307 cases with F3 or F4

Cardoso AC et al., J Hepatol 2010

Association of SVR With the Development of HCC in HCV infectionin HCV infection

Forest plot of adjusted hazard effects in persons at all stages of fibrosis

Morgan RL et al. Ann Intern Med 2013


Forest plot of adjusted hazard effects in Persons with advanced liver disease



Forest plot of adjusted hazard effects in Persons with advanced liver disease

absolute reduction inHCC risk was 4.2% (CI, 4.0%

%) f ito 4.9%) for patientsachieving an SVRachieving an SVR


HEPATOCELLULAR CARCINOMA (HCC) INCIDENCE IN CHRONIC HEPATITIS C PATIENTS (CHC) ACCORDING TOCHRONIC HEPATITIS C PATIENTS (CHC) ACCORDING TO

SUSTAINED VIROLOGIC RESPONSE (SVR)

1371 patients1371 patientsDiagnosed 1989‐2011

Treated

HCC‐incidenceF4/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).

F0–2/SVR 0 2%

T. Purevsambuu et al. EASL 2014; abstr Oral 125

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 FibrosisSVR in HCV Pts With Advanced Fibrosis

• HCC risk increased with age; highest for those > 60 yrs• HCC risk increased with age; highest for those > 60 yrs

8-Yr HCC Rate, % (95% CI)

12

10> 60 yrs of age45 60 yrs of age

12.2%(5.3-19.1)

ve H

CC

nc

e (%

) 10

8

6

45-60 yrs of age< 45 yrs of age 9.7%

(5.8-13.6)

Cum

ulat

ivO

ccur

ren 6

4P = .006

2.6%C O 2

00 1 3 4 5 6 72 8

(0-5.5)

Van der Meer AJ, et al. AASLD 2013. Abstract 143. Reproduced with permission.

0 1 3 4 5 6 72 8Yrs

LIVER EVENT-FREE SURVIVAL ACCORDING TO STAGEOF CIRRHOSIS AT THE TIME OF ANTIVIRAL THERAPY

Fernandez-Rodriguez 2010

SVR

no-SVRno SVR

SVR

ALBUMIN>3.9g/no varices

ALBUMIN<3.9/varices no-SVR

Fernandez‐Rodriguez et al. Fig.7

Cumulative probability of survival of SVRs versus Non SVRs and controls in patients withNon SVRs and controls in patients with

Decompensated HCV cirrhosis

0 9

1

rviv

al SVRNonR

0,8

0,9

bilit

y of

su NonR

Ctrl

0,7

ve p

roba

b

p= 0.07

0,6

Cum

ulat

iv

0,50 6 12 18 24 30 36 42

months

C

months

Iacobellis A et al J Hepatol 2007

Laboratory and Clinical Event ChangesCirrhosis and Portal Hypertension Study (SOF+RBV)

Pl t l t (103/ L) Alb i ( /dL)

SOF+RBV Observation 24 weeks

ALT (U/L)

171520

0,50,4

0 40,50,6

Platelets (103/µL) Albumin (g/dL)

13 00

20

ALT (U/L)

p=0.003 p=0.001 p=0.001

1

‐1‐505

10

00

0,10,20,30,4

‐60

‐40

‐20p=NS

‐9

1

‐15‐105

CTP A CTP B

‐0,1‐0,2‐0,1

0‐72 ‐75‐80

CTP A CTP BCTP A CTP B

Ascites Hepatic Encephalopathy

Patients nSOF + RBV

n=25Observation

n=25SOF + RBV

n=25Observation

n=25Patients, n n=25 n=25 n=25 n=25

Baseline 6 9 5 2

Week 12 5 8 3 3

Week 24 0 7 0 4

Afdhal N, EASL, 2014, O68

Duration of Undetectable HCV RNA Before T l t P di t d L k f RTransplant Predicted Lack of Recurrence

64% of pts HCV RNA negative 12 wks post-LT (93% at LT)

> 30 days TND Continuous days TND pre-LT only

factor predicting HCV recurrence in multivariate analysisNo recurrence (n = 28)

Recurrence (n = 10)– Only 1/24 pts with > 30 days TND

experienced recurrence

Recurrence (n = 10)

Median days TND (P < .001) No recurrence: 95 Recurrence: 5.5

3300 30 60 90 120 150 180 210 240 270 300

Curry MP, et al. AASLD 2013. Abstract 213. Reproduced with permission.

3300 30 60 90 120 150 180 210 240 270 300Days With HCV RNA Continuously TND Prior to Liver Transplant

l iConclusions

• HCV multiorgan, curable disease

• Natural history multifaceted

A ti i l t t t t ti ll bl f• Antiviral treatment potentially capable of reverting hepatic and extra‐hepaticreverting hepatic and extra hepaticdamage

• HCC surveillance in advanced fibrosis

Survival Outcomes in Pts With CHC and Ad d Fib i With/With t SVRAdvanced Fibrosis With/Without SVR

30 All-Cause Mortality 30r %)

Liver-Related Mortality or30

20

10-Cau

se

rtal

ity (%

)

All Cause MortalityP < .001

Without SVR

30

20

10r-R

elat

ed

ity o

r Liv

e rla

ntat

ion

(% Liver Related Mortality or Liver Transplantation

P < .001Without SVR

10

00

All

Mo r

1 2 3 4 5 6 7 8 9 10Yrs

With SVR

Pts at Risk n

10

00

Live

rM

orta

lTr

ansp

l

1 2 3 4 5 6 7 8 9 10Yrs

With SVR

Pts at Risk, nPts at Risk, nWithout SVRWith SVR

405192

393181

382168

363162

344155

317144

295125

25088

20756

16440

13528


405192

392181

380168

358162

334155

305144

277125

22988

18756

14640

11928

30

lar

(%) Hepatocellular Carcinoma

P < .00130

(%) Liver Failure

P < .00120

10

epat

ocel

luar

cino

ma

(

Without SVR

With SVR

20

10

ver F

ailu

re

Without SVR

With SVR0

0

He C

1 2 3 4 5 6 7 8 9 10Yrs

With SVR


405192

390181

375167

349161

326152

294142

269124

22986

19154

15139

12227

00

Liv

1 2 3 4 5 6 7 8 9 10YrsPts at Risk, n

Without SVRWith SVR

405192

384180

361166

337160

314152

288141

259123

21688

18456

14340

11328

Van der Meer AJ, et al. JAMA. 2012;308:2584-2593.

With SVR 192 181 167 161 152 142 124 86 54 39 27 With SVR 192 180 166 160 152 141 123 88 56 40 28

prognosi nel paziente con epatite · i nuovi farmaci per hcv: frequenza della patologia, evidenze...

Documents