La gestione corrente dell’infezione cronica da HCV:

la progressione verso la cirrosi

Simona Landonio

I Div Mal inf

H Sacco Milano

HCV Natural History

Viganò M et al Gastroenterology 2007;133:835-842

Overall survival: cirrhosis at baseline is the only factor associated with reduced

survival

Viganò M et al Gastroenterology 2007;133:835-842

Ten-year Progression Rate of Chronic Hepatitis C to Cirrhosis

Viganò M et al Gastroenterology 2007;133:835-842

Patients

still at risk 8

0

26

0

26

1

25

6

247 23

1

260 19

4

18

3

202 17

2

Months0 24 48 9672 120

Progression rate x yr = 2.4%

100

40

20

0

10

30

• età

•Fibrosi basale

Factors Associated With Increased Risk Of Cirrhosis In Patients With HCV

McCombs, JAMA Intern Med 2014;174:204–212

Patient characteristic CirrhosisHepatocellular

Carcinoma

(n=123,988) (n=128,481)

Events, No. (%) 17,926 (14.5%) 4,517 (3.5%)

Male sex 1.35 (1.21–1.50) 3.41 (2.39–4.88)

Age 1.02 (1.02–1.02) 1.07 (1.07–1.07)

Race White

Black

Other

1 (reference)

0.54 (0.52–0.56)

0.73 (0.70–0.76)

1 (reference)

0.73 (0.68–0.78)

0.80 (0.74–0.87)

HCV genotype 1

2

3

Other

1 (reference)

0.64 (0.61–0.68)

1.24 (1.18–1.31)

0.87 (0.75–1.00)

1 (reference)

0.52 (0.46–0.58)

1.63 (1.47–1.79)

0.77 (0.57–1.04)

Diabetes at baseline 1.38 (1.32–1.44) 1.31 (1.21–1.42)

Achieved undetectable

viral load0.62 (0.54–0.73) 0.62 (0.42–0.81)

The Long-Term Outcome of HCV Compensated Cirrhosis

A Cohort Study of 214 Patients in Milan

Sangiovanni A et al, Hepatology 2006;43:1303-10

Cu

mu

lative

pro

ba

bili

ty o

f e

ve

nts

0

25

50

100

0 1 32 4 5 6 87 9 10 1211 13 1514 Years

HCC

Gi haemorrhage

Ascites

Jaundice

PSE

Annual Incidence rate

HCC 3.9%

Ascites 2.9%

Jaundice 2.0%

GI haemor. 0.7%

PSE 0.1%

Annual mortality rate 4%

Causes of Mortality Significantly Associated with HCVThe REVEAL HCV Cohort Study

Causes of death Multivariate-adjusted HR (95% CI)

All causes 1.89 (1.66–2.15)

All liver-related 12.48 (9.34–16.66)

HCC 21.63 (14.83–31.54)

All extrahepatic diseases 1.35 (1.15–1.57)

All cancer, except HCC 1.32 (1.00–1.74)

Cardiovascular diseases 1.50 (1.10–2.03)

Nephritis/nephrosis 2.77 (1.49–5.15)

Lee et al, J Infect Dis 2012;206:469-77

24000 pz

1095 HCV

Follow up

16.2 anni

Development and Validation of a Comorbidity Scoring System for Patients with Cirrhosis

Survival probabilities in the Danish Patient Registry cohort, by CirCom group

Jepsen et al, Gastroenterology 2014;146:147-56

CirCom score (validated in 4,656 HCV-RNA+)

- COPD

- AMI

- PAD

- Epilepsy

- Substance Abuse

- Heart Failure

- Non Meta Cancer

- Meta cancer

- CKD

Follow up

2.5 anni

• Results

• 58 pts enrolled

• Mean time between the two biopsies:42.6 months (95%CI 33.7-51.5)

• 27/58 patients (46.5%) showed LFP; 9/58 (15.5%) progressed at least 2 stages. 5 patients developed cirrhosis.

MULTIVARIATE ANALYSIS FOR RISK FACTORS FOR LFP

OR LI 95%CLS 95%

CP

Riduzione CD4 3.99 1.25 12.76 0.020

ALT>150UI/l 3.10 0.85 11.31 0.087

Time to progression related to

decrease of CD4 cells

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 1920

50

100CD4 decrease

no CD4 decrease

time (months)

Perc

ent

fre

e o

f

prog

ress

ion

Median survival

38

92

P value <0.02

Expected time to chirrosis accordingantiretroviral therapy

0,0

1,0

2,0

3,0

4,0

5,0

6,0

0 10 20 30 40 50

TIME (YEARS)

FIBROSIS HAART

SINGLE OR DUAL

NO THERAPY

Non parametric ANOVA P=0.87

Macias J et al Hepatology 2015; 61 (5): 1503-11

RISK OF LIVER DECOMPENSATION AMONG HIV/HCV COINFECTED PATIENTS WITH MILD FIBROSIS IN THE SHORT-TERM

1492 pazienti Follow up 6 anni

Macias J et al Hepatology 2015; 61 (5): 1503-11

Mortalità 1,8% anno

Rischio scompenso 1,5% anno

Variables Associated with HCV Worsening

Older age

Male gender

HCV gt

Hepatic Inflammation

Steatosis/BMI

Alcohol

Tobacco

HBV

HIV

Not modifiable

Modifiable

Cirrhosis Regression In HCV Patients Responding To Interferon-based Therapy

StudyPatients

with cirrhosis (n)

Months from SVR

Stagingsystem

Regression rates

Reichard, et al. 1999

3 24−96 Scheuer 3 (100%)

Arif, et al. 2003 6 6–72 Ishak 5 (83%)

George, et al. 2009 8 56 Ishak 6 (75%)

Poynard, et al. 2002 37 < 24 Metavir 25 (68%)

D’Ambrosio, et al. 2012

38 48–104 Metavir 23 (61%)

Everson, et al. 2008 40 6 Metavir 20 (50%)

Shiratori, et al. 2000 24 12–120 Metavir 11 (46%)

Mallet, et al. 2008 39 11 Metavir 17 (44%)

Pol, et al. 2004 17 NA Metavir 4 (24%)

SVR and Mortality: IFN Era Long-term follow-up study of pts with chronic HCV infection and

advanced fibrosis or cirrhosis (N = 530 treated 1990-2003; median follow-up: 8.4 yrs)[1]

Baseline factors significantly associated with all-cause mortality:

– Older age

– Genotype 3 (2-fold increase in mortality and HCC)

– Higher Ishak fibrosis score

– Diabetes

– Severe alcohol use

SVR also reduces all-cause mortalityeven in absence of cirrhosis[2]

1. van der Meer AJ, et al. JAMA. 2012;308:2584-2593. 2. Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.

10-Yr Cumulative

Incidence5

04

03

02

01

00

Pts

(%

)

SVR

No SVR

8.9

26.0

1.9

27.4

5.1

21.8

Clinical Event Number/Total Patients Reference

SVR (+) SVR (-)

Diabetes 26/1167

(2.2%)

117/1175

(9.9%)

Arase et al 2009

Malignant

lymphoma

0/2161

(0%)

25/1048

(12.6%)

Kawamura et al

2007

Improved

Neurocognitive

Functions*

8/8 100% 0/6 0% Byrnes et al

2012

* Improved Brain Metabolism: basal ganglia Cho/Cr and ml/Cr ratios

Extrahepatic Clinical Benefits of a SVR in Patients with Chronic Hepatitis C

An SVR Improves Post-treatment Liver Fibrosis Stage

Post treatment

Pre-TX F0 F1 F2 F3 F4

F0 1 2 0 0 0

F1 14 16 7 0 0

F2 7 23 12 2 0

F3 0 5 12 7 4

F4 0 1 2 6 5

126 HCV SVR patients with a post-TX liver biopsy mean follow-up 3.3 years (0.5–18 yrs)

Maylin S, et al. Gastroenterology 2008;135:821–829

An SVR Improves Post-treatment Liver Fibrosis Stage

Post treatment

Pre-TX F0 F1 F2 F3 F4

F0 1 2 0 0 0

F1 14 16 7 0 0

F2 7 23 12 2 0

F3 0 5 12 7 4

F4 0 1 2 6 5

126 HCV SVR patients with a post-TX liver biopsymean follow-up 3.3 years (0.5–18 yrs)

Maylin S, et al. Gastroenterology 2008;135:821–829

Fibrosis stage:

-Improve 56%

-Unchange 32%

-Worse 12%

Liver biopsy 17 months after SVR:

cirrhosis regression in 17/35 (49%)

Number at risk

Non-resp.

Resp.

0

0

20

40

60

80

100

24 48 72 96 120

Month

Liv

er-

rela

ted

eve

nts

(%)

p=0.002

61

35

Non-responder

Responder

59

35

52

33

43

33

32

27

22

18

No events among

reversers

Number at risk

Non-reversers

Reversers

0

0

20

40

60

80

100

24 48 72 96 120

Month

Liv

er-

rela

ted

eve

nts

(%)

p=0.01

78

18

Non-reverser

Reverser

76

18

69

16

60

16

47

12

30

10

The Impact Of Cirrhosis Regression On Clinical Events

Mallet V, et al. Ann Intern Med 2008;149:399–403

No. at riskNo SVRSVR

00

5

10

15

20

30

1 2 3 4 5 6 7 8 9 10Time (years)

All-

cau

se m

ort

alit

y (%

)

p<0.001

No SVR

SVR

405192

393181

382168

363162

344155

317144

295125

25088

20756

16440

13528

25

All-cause mortality

No. at riskNo SVRSVR

00

5

10

15

20

30

1 2 3 4 5 6 7 8 9 10Time (years)

Live

r-re

late

d m

ort

alit

y o

rLi

ver

tran

spla

nta

tio

n (

%) p<0.001

No SVR

SVR

405192

392181

380168

358162

334155

305144

277125

22988

18756

14640

11928

25

Liver-related mortalityor liver transplantation

Survival Outcomes In Patients With Advanced Hepatic Fibrosis Due To HCV

Van der Meer JAMA 2012;308:2584–93

The Impact Of An SVR On Development OfEsophageal Varices In HCV Cirrhotics

Bruno S, et al. Hepatology 2010:51;2069–2076 D’Ambrosio R, et al. Antivir Ther. 2011;16:677–84

Patients at riskNo SVRSVR

00

20

40

60

80

100

2 4 6 8 10 12 14 16 18 20

Years

Cu

mu

lati

ve in

cid

ence

(%

)

Log-Rank p<0.0001

11534

8930

6527

3517

77

00

Patients at riskNo SVRSVR

00

20

40

60

80

100

1 2 3 4 5 6 7 8

Years

Cu

mu

lati

ve in

cid

ence

(%

)

Log-Rank p=0.03

5357

5357

5256

4649

3643

2634

2020

711

33

6%

30%

Non SVR

SVR

Non SVR

SVR

Effects of SustainedViral Response in Patients WithHIV and ChronicHepatitis C and NonadvancedLiver Fibrosis

Berenguer J et al. J Acquir Immune Defic Syndr 2014;66:280–287)

695 patientsF0, 77; F1, 290; F2, 328274/695 with SVR. Median follow-up : 4.9 years

SVR riduce la mortalità

e il rischio di

scompenso anche in pz

con fibrosi moderata

ANRS HEPATHER: multicenter observational cohort study assessing short-term effects of DAAs on mortality in pts with HCV (N = 9295) Median follow-up: 24 mos

DAA treatment associated with decreased risk of death vs no DAA treatment in the short term

DAA Therapy and Risk of Mortality

Carrat F, et al. AASLD 2017. Abstract LB-28.

*8482 person-yrs. †10040 person-yrs.

All-Cause Mortality

(n = 6460)*

DAA- (n = 2835)†

1.0

0.98

0.96

0.94

0.92

0.90Su

rviv

al

Pro

bab

ilit

y

250 5 10 15 20 30Mos

DAA+

HR: 0.65 (95% CI: 0.45-0.95; P = .0258)

Impact of SVR with DAAs on Mortality and HCC

Backus, AASLD 2017, Oral 78

All-cause mortality rates and incident HCC rates in Veterans ± advanced chronic liver disease (ACLD) in the HCV registry treated with DAAs through Sept 2016

Achieving SVR after DAA treatment significantly reduced lower all-cause mortality in both

ACLD and non-ACLD patients and significantly reduced incident HCC rates in ACLD

patients

p<0.001p<0.001

SVR was associated with 80% reduction in mortality and 84% reduced incidence in HCC

SVR was associated with 59% reduction in mortality

Veterans Affairs HCV Clinical Case Registry

47/1308

644/39,918

39/135

72/597

140/871

397/13,153

195/1067

598/13,992

How Accurate Is Transient Elastography to

Monitor for Regression of Cirrhosis After

SVR?

D’Ambrosio R, et al. J Hepatol. 2013;59:251-256.

33 pts with HCV and biopsy-proven

cirrhosis who achieved SVR after IFN

based therapy

5 (38%) pts

regressed

(TE < 12 kPa)

19 (95%) pts

regressed

(TE < 12 kPa)

FibroScan and biopsy ~ 60 mos post

SVR

Biopsy

FibroScan

20 pts

regressed

(≤ F3)

13 pts had

persistent

cirrhosis (F4)

Diagnostic accuracy of TE for diagnosing post-SVR cirrhosis: 61% sensitivity, 95% specificity

Regression of Fibroscan scores to “sub-cirrhotic” levels does not ensure true cirrhosis regression

Post HCV SVR Liver Stiffness Measurement

(LSM) Not Predictive of HCC

828 patients without previous HCC from 2 French treatment centers May 2008 - Nov 2016; SVR: 94% (799/849)

LSM assessed by FibroScanbefore HCV therapy and ≥ 1 time during 12-48 wks of follow-up

Post-SVR HCC screening every 6 mos by ultrasound

Median LSM decrease from baseline to follow-up: -3.6 kPa (-6.2 to -1.1; P < .0001)

At median f/u of 6 mos, 2 patients died and 22 (2.8%) developed HCC

Factors assoc. with HCC in multivariate analysis: age, sex, diabetes, and baseline LSM, but NOT change in LSM

Shili S, et al. EASL 2018. Abstract PS-021.

Factor HR (95% CI) P Value

Age (per yr) 1.06 (1.02-1.10) .005

Diabetes 2.70 (1.12-6.51) .026

Baseline LSM

Per kPa 1.05 (1.02-1.07) < .0001

Qualitative baseline

LSM.005

8-12.5 vs < 8 1.59 (0.14-17.59)

≥ 12.5 vs < 8 10.44 (1.38-78.63)

Change in LSM, per kPa 0.99 (0.94-1.04) .705

HVPG Change Over Time

Afdhal, EASL, 2015, LP13

There were clinically meaningful improvements in portal hypertension in addition to improvements in liver biochemistry, CTP and MELD scores

The effect of SVR12 and viral suppression on HVPG is being monitored at 1 year post-treatment

Observation Period in Patients with BL HVPG ≥12 mmHg* (24

weeks)

Changes After Treatment in Patients with BL HVPG ≥12 mmHg

(n=33)

SOF+RBV in Compensated and Decompensated Cirrhotics with Portal Hypertension

-30

-20

-10

0

10

20

30

40

n=2

HV

PG

Ch

ange

(%

) n=2a

30

20

10

0

-10

-20

-30

-40

-50

-60

-70

-80H

VP

G C

han

ge (

%)

Patients with >20% decrease (8/33)

Baseline MELD Score

<10 ≥10

aPatients with HVPG ≤12 mm Hg at end of treatment

*No patient had HVPG ≤12 mm Hg at end of observation period

HVPG = hepatic venous pressure gradient A reduction in HVPG ≥20% or below the 12-mm Hg threshold markedly reduces the risk of variceal bleeding, and varicesmay decrease in size

a a a

RESIST-HCV: Long-term Outcomes

Following SVR to HCV DAA Therapy

Prospective cohort analysis of 4668 patients who started DAAs Mar 2015 - Dec 2016 (previous HCC or OLT excluded)

– 69% with CTP A cirrhosis; 8.8% with CTP B cirrhosis

– SVR: 90.7%; no SVR: 5%

– Primary endpoint: survival since initiating HCV DAAs

– Median follow-up: 72 wks

– Modified ITT analysis: N = 4468Calvaruso V, et al. EASL 2018. Abstract PS-149.

RESIST-HCV: Predictors of Mortality

in Patients Treated With HCV DAAs

SVR associated with reduced risk of liver-related mortality across disease stages, but benefit lower in CTP B cirrhosis

– Univariate HR for no SVR vs SVR in CTP B: 3.49; P= .036

Multivariate Cox Regression HR (95% CI) P Value

Independent predictors of liver-related mortality in CTP A cirrhosis

No SVR 18.50 (6.75-50.70) < .001

Albumin < 3.5 g/dL 6.01 (2.30-15.73) < .001

Independent predictors of cardiovascular mortality in DAA-treated patients

No SVR 10.56 (3.43-32.46) < .001

Diabetes 4.11 (1.30-12.98) .011

Calvaruso V, et al. EASL 2018. Abstract PS-149.

HCV DAA Therapy and Survival in Pts With Decompensated Cirrhosis

• Comparison of incidence of death in pts with hepatic decompensation in the SOLAR studies of SOF/LDV + RBV(n = 212) and pre-DAA era pts in OPTN meeting SOLAR criteria (model creation set, n = 2071; validation set, n = 899)

– Survival prediction model created using OPTN data to determine expected mortality for 1 yr in pts not receiving DAA therapy; model included age, albumin, HE grades 1/2 and 3/4, MELD, sodium

• 15 deaths in 1 yr in SOLAR study

• DAA therapy lowered risk of death by 60%

Kim WR, et al. AASLD 2017. Abstract LB-27.

(95% CI: 0.24-0.65)

45

40

35

30

25

20

15

10

5

0Cum

ula

tive N

o.

of D

eath

s

0 1 2 3 4 5 6 7 8 9101112Mos

SMR = 0.39

Observed

Expected

Benefits of Achieving SVR

↓ Cirrhosis

↓

Decompensation

↓ HCC

↓ Transplantation

↓ All-cause mortality

↑ QoL

↓ Malignancy

↓ Diabetes

↓ CVD

↓ Renal

↑ Neurocognitive

SVR

Improved

clinical

outcomes

Hepatic

Extrahepatic

Decreased

transmission

Smith-Palmer J, et al. BMC Infect Dis. 2015;15:19. Negro F, et al. Gastroenterology. 2015;149:1345-1360. George SL, et al. Hepatology. 2009;49:729-738.

…nella speranza di non avervi steso….

GRAZIE PER L’ATTENZIONE!!!!!