Il danno d’organo provocato dal Virus C

Gloria Taliani 8 Maggio 2014

Malattie Infettive e TropicaliSapienza Università di Roma Policlinico Umberto I, Roma

Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione

Natural History of HCV Infection

Stable80% (68%)

HCCLiver failure25% (4%)

Slowlyprogressive75% (13%)

Resolved15%

Acute HCV

Cirrhosis20% (17%)

Chronic HCV85%

CD8+ CD4+

Cytokines(IL-2, IFN-TNF-, TGF-PDGF)Cell killing

Kupffer cell

Hepatocytes

Hepatic stellate cells

TGF-Activation

Fibrosis

Death

Hepatitis C Disease Pathogenesis

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.

The long-term outcome of HCV compensated cirrhosis: a 17-yr follow-up of 214 Pts

Cum

ulati

ve p

roba

bilit

y of

eve

nts

25

50

100

0

Years

HCC

GI bleeding

Ascites

Jaundice

EPS

214 196 168186 153 142 129 110116 96 89 6674 57 3648

214 198 171188 160 151 142 122129 105 94 7381 64 4258214 196 164184 152 144 134 114122 100 89 6975 60 4054214 197 163182 151 142 133 105114 92 86 6874 60 3955

214 198 173190 162 152 146 122129 108 98 7784 66 4359

Sangiovanni A et al Hepatology 2006

Annual Incidence rate

HCC 3.9% Ascites 2.9% Jaundice 2.0% GI bleeding 0.7% EPS 0.1%

Pts still at risk

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

Effect of Inflammation on Fibrosis Progression in HCV Patients

Change in Fibrosis Score According to Necrosis Score at Baseline

Piecemeal Necrosis Score at Baseline0-1 2-3 > 4

Patients, n 30 66 27Mean change in fibrosis score per yr

0.05 0.19 0.37

Ghany MG, et al. Gastroenterol. 2003;124:97-104.

Patients Developing Cirrhosis According to Initial Level of Fibrosis

Yano M, et al. Hepatology. 1996;23:1334-1340.

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 ± portal-portal bridging

42.9

3.0-3.45 (n = 15) Septal + regions of partial nodular regeneration

100

Factors Associated With Advanced Fibrosis

Adjusted Odds Ratio (95% CI)

1.0 15.00.01

3.444

Risk Factor

Age at entry (≥ 60 years)

Duration of infection (≥ 25 years)

BMI (≥ 30)

History of diabetes

AST (≥ 80 U/L)

AFP (≥ 15 µg/L)

Grades 2 and 3 steatosis

1.750

1.917

2.251

4.032

3.875

2.790

• Retrospective study of 460 pts with chronic hepatitis C (41% F3-4)• Multivariate analysis of factors associated with F3-4

Hu S, et al. J Clin Gastro. 2009

P Value

.0334

.0378

.0173

.0304

.0087

.0383

.0378

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

Hui JM, et al. Gastroenterol. 2003;125:1695-1704.

HO

MA-

IR

Fibrosis Score

55

44

33

22

11

00F0F0 F1F1 F2F2 F3F3 F4F4

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

Hezode C, et al. Hepatology. 2005;42:63-71.

Odds Ratio of Accelerated Fibrosis Progression Rate* (95% CI)

1.0 10.00.01

1.3

Cannabis Use

Occasional

3.4

P Value

Daily

.57

.005

*Compared with median progression rate of cohort: 0.074 Metavir U/yr.

Alcohol Consumption Increases Risk of Cirrhosis in HCV Patients

*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.

0

20

40

60

80

100

10 20 30 40Years Following Exposure†

Cirr

hosi

s (%

)

HCVHCV + alcohol*

6

1812

58

31

64

40

85P < .01 P < .01

P < .01

100 %Survival at 1 year 80 % 45 %

Com

pens

ated

Dec

ompe

nsat

ed

Stage 1

Stage 2

Stage 3

Stage 4

No varices

No ascites

Varices

No ascites

Ascites +/-

varices

Bleeding +/-

ascites

7%

6.6%

7.6%

1-year mortality rate according to clinical stages

Classification from a systematic review of 118 studies

4.4%

4%

1%

3.4%

20%

57%D’Amico G et al J Hepatol 2006

DEATH

Survival Probability in HCV Patients With Cirrhosis

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.

Compensated

After first major complication

Survival Probability100

Pat

ien

ts (

%)

80

60

40

20

01200 12 24 36 48 60 72 84 96 108

MosPatients at Risk384 376 342 288 236 165 126 79 52 39 25 65 39 21 11 7 4 4 3 3 2 1

Cirrhosis

The impact of SVR on histological outcome of HCV-induced cirrhosis

Maylin S et al Gastroenterology 2008

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

Comparison of liver fibrosis stage between pre-treatment and post-treatment paired liver biopsy in 126 patients

Post-treatment specimens were

collected a median of 6 months after

treatment cessation

Mallet V et al Ann Int Med 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.

Cumulative incidence of esophageal varices in 149 IFN ± RBV-treated patients with compensated HCV-induced cirrhosis according

to response to therapy

Bruno S, et al Hepatology 2010

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

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)

0 24 48 72 96 120 144 1680

20

40

60

80

100

months

% w

ith li

ver c

ompl

icat

ions

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

Patients at risk

SVR

no SVR

liver-related complications Liver mortality

Bruno S et al Hepatology 2007

0 24 48 72 96 120 144 1680

20

40

60

80

100

months%

su

rviv

al

to l

ive

r-re

late

d d

ea

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

Patients at risk

SVR

no SVR

(p: 0.001 by log-rank test) (p: 0.001 by log-rank test)

Survival Outcomes in Pts With CHC and Advanced Fibrosis

P < .001P < .001

P < .001 P < .001

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

30

20

10

00

All

-Cau

se

Mo

rtal

ity

(%)

1 2 3 4 5 6 7 8 9 10Yrs

All-Cause Mortality

With SVR

Pts at Risk, nWithout SVRWith SVR

405192

393181

382168

363162

344155

317144

295125

25088

20756

16440

13528

30

20

10

00

Liv

er-

Rel

ated

M

ort

alit

y o

r L

iver

T

ran

spla

nta

tio

n (

%)

1 2 3 4 5 6 7 8 9 10Yrs

Liver-Related Mortality or Liver Transplantation

With SVR

Pts at Risk, n Without SVRWith SVR

405192

392181

380168

358162

334155

305144

277125

22988

18756

14640

11928

30

20

10

00

Hep

ato

cell

ula

r C

arci

no

ma

(%)

1 2 3 4 5 6 7 8 9 10Yrs

Hepatocellular Carcinoma

With SVR

Pts at Risk, n Without SVRWith SVR

405192

390181

375167

349161

326152

294142

269124

22986

19154

15139

12227

30

20

10

00

Liv

er

Fai

lure

(%

)

1 2 3 4 5 6 7 8 9 10Yrs

Liver Failure

With SVR

Pts at Risk, n Without SVRWith SVR

405192

384180

361166

337160

314152

288141

259123

21688

18456

14340

11328

Achieving Sustained Virologic Response: Impact on Long-Term Outcomes in HIV/HCV-Coinfection

OverallMortality

Lo

ng

-Ter

m O

utc

om

e R

ate

(per

10

0 p

erso

n/y

ears

)

Liver-RelatedMortality

LiverDecompensation

0.46*0.46*(0.06,1.65)(0.06,1.65)

Hepato-carcinoma

LiverTransplantation

**PP=0.003, =0.003, ††PP=0.028, =0.028, ‡‡PP<0.001, and <0.001, and §§PP=0.034 versus not attaining a sustained virologic response.=0.034 versus not attaining a sustained virologic response.n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.n=711 HIV/HCV-coinfected patients receiving interferon (peg or conventional) + ribavirin.

3.123.12(2.16,4.37)(2.16,4.37)

1.651.65(0.98,2.16)(0.98,2.16)

4.334.33(3.16,5.8)(3.16,5.8)

0.830.83(0.38,1.58)(0.38,1.58)

1.021.02(0.50,1.82)(0.50,1.82)

0.930.93(0.44,1.70)(0.44,1.70)

0.230.23††

(0.01,1.27)(0.01,1.27)0.230.23‡‡

(0.01,1.27)(0.01,1.27) 00(0,0.84)(0,0.84)

00§§

(0,0.84)(0,0.84)

0.230.23(0.01,1.27)(0.01,1.27)

NewAIDS

Conditions

GESIDA 3603 Cohort: 711 pts treated for HCV

Berenguer J. et al. Hepatology 2009.

Achieved SVRAchieved SVRDid not achieve SVRDid not achieve SVR

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

portal hypertension (stage 2)

Di Marco V et al J Hepatol 2007

0 6 12 18 24 30 36 42 48 54 600

20

40

60

80

100

Months

% o

f Pati

ents

With

out E

vent

s Li

ver-

rela

ted

SVR (16 pts)

NR (86 pts)

p= 0.006 by log rank test

Cumulative probability of survival of SVRs versus Non SVRs and controls in patients with decompensated HCV-induced cirrhosis

0,5

0,6

0,7

0,8

0,9

1

0 6 12 18 24 30 36 42

months

Cu

mu

lativ

e p

rob

abili

ty o

f su

rviv

al

SVR

NonR

Ctrl

p= 0.07

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

↓ MELD score

↑ Platelet count

↑ Albumin level

↓ Age

↑ Child-Pugh score

↑ MELD score

↓ Platelet count

↓ Albumin level

↑ Age

Deaths and AEs in the first 6 month of follow-up according to treatment or not

OR=0.7

OR=0.6

OR=0.6

OR=0.9

OR=2.4 (1.02 – 5.77)

OR=2.9 OR=1.2

OR=1.9

Iacobellis A et al J Hepatol 2007

Singal AK Clin Gastroenterol Hepatol 2010

HCC occurrence in patients with HCV-related cirrhosis according to SVR

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

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

Cu

mu

lati

ve H

CC

O

ccu

rren

ce (

%)

Cirrhosis

Bridging Fibrosis

P = .064

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

8.5(5.8-11.2)

1.8(0-4.3)

Yrs

12

10

8

6

4

2

00 1 2 3 4 5 6 7 8

Age as a Risk Factor for HCC Following SVR in HCV Pts With Advanced Fibrosis

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

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

Cu

mu

lati

ve H

CC

O

ccu

rren

ce (

%)

12

10

8

6

4

2

00 1 3 4 5 6 72 8

Yrs

> 60 yrs of age45-60 yrs of age< 45 yrs of age

P = .006

12.2%(5.3-19.1)

9.7%(5.8-13.6)

2.6%(0-5.5)

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

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

Cirrhosis: A Continuous Spectrum of Disease

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

Advanced disease/ cirrhosis

Mild disease

Greater need for treatment BUT

• Response to current IFN-based therapy may be

impaired

DAA Classes and Subclasses: antiviral potency and resistance barrier according to HCV genotype

Drug Class Subclass 1 b 1a 2 3 4

Protease inhinbitors

1st Generation first wave i.e. Telaprevir/Boceprevir 1st Generation 2nd wave i.e.Faldaprevir/Simeprevir/ 2nd GenerationMK5172 §

NS5a Inhibitor

1st GenerationDaclatasvir Ledipasvir ABT 267 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

Seminario Nadir 2014 - Iniziativa resa possibile grazie a fondi istituzionali dell’Associazione