Beyond HCV cure: reversibility of liver damage · Beyond HCV Cure: reversibility of liver damage...

Beyond HCV cure:

reversibility of liverdamage

Massimo Puoti

SC Malattie Infettive

ASST GRANDE OSPEDALE

METROPOLITANO NIGUARDA

MILANO

Beyond HCV Cure: reversibility of liver damage

• Regression of necroinflammatory changes and regression of fibrosis

• Cirrhosis: is the the point of no return ?

• Clinical Progression of advanced liver disease

• Regression of portal hypertension

• Regression of decompensation

• HCV cure and HCC

2








3

INTERACTION WITH CELLULAR

REGULATORY MECHANISMS

VIRUS REPLCATION

REVERSIBLE LIVER DAMAGE

PRO-ONCOGENESIS

Fib

rosi

sSt

age

Time (and patient’s age)

Viral Hepatitis

Alcohol

NASH

Phase of slow progression

Phase of rapid progression

High relevance of genetic factors: some patients do not progress beyond this stage

Reduction of apoptosis leads toa maximal hyperplasia of ECM-producing cells

Liver Fibrosis: a Dynamic Path

Reduced anti-oxidant and immune responses withaging

Biochemical changes in ECM composition and structure

Progressive IncreaseIn Tissue Stiiffness

Fibrosis stage

1

10

100

F1 F2 F3 F4

Fibrosis stage (Metavir)

Elas

tici

ty (

kPa)

Castera L. et al. Gastroenterology 2005

Mild FibrosisModerate FibrosisSevere FibrosisCirrhosis

Fibrosis progression in chronic hepatitis C

Long term asymptomatic process

Progression speed change over time and is heterogeneous across the liver tissue

The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with

liver cirrhosis SU Kim, HJ Oh, IR. Wanless, S Lee, YN Park, J Hepatol 2012

4a 4b 4c

LAENNEC SCORING SYSTEM

THE LAENNEC SCORE OF CIRRHOSIS AND ITS PROGNOSTIC VALUE








8

Histological outcome during long-term tenofovir treatment

Marcellin P, et al. Lancet 2013

• 348 patients with paired biopsies before and after 5 yearstreatment with tenofovir DF (centralized reading)

• 87% (304/348) of patients had global histological improvement (> 2 ↘ Knodell index and no ↗ Ishak fibrosis score)

• 51% (176/348) of patients had fibrosis regression (≥1 unit ↘ in Ishak score) and 96% had prevention of fibrosis progression

• Cirrhosis (Ishak ≥5) regression occurred in 71/96 of patients (74%) with cirrhosis at baseline

Long-term suppression of HBV can lead to

regression of fibrosis and cirrhosis

Distribution of Metavir fibrosis stages in pre-treatment and post-treatment liver biopsies

61% patients with F4 at baseline had cirrhosis regressionto lower METAVIR stages

F4

F3

F2

F1

Pre-treatment Post-treatment

38 2 (5%)

7 (18%)

14 (37%)

15 (39%)

Nu

mb

er

of

pati

en

ts

40

20

10

30

0

D’Ambrosio et al Hepatology. 2012

Area of fibrosis (%)

Baseline Bx After SVR

0

2.5

5

7.5

10

12.5

15

17.5

20

22.5

25

Morphometry 1 Morphometry 2

• 38 patients, Hepatitis C cirrhosis, Child-Pugh A

• 24/48 weeks standard bitherapy and SVR

• Paired biopsy, mean interval : 6 years

Courtesy by Prof M Colombo

Drivers of Cirrhosis regression

Remodelling of

portal tract

Liver cell regeneration

Thinning of fibrous septa

CIRRHOSIS : POINT OF NO RETURN

1. « OLD » CIRRHOSIS (cross-link collagens and elastic fibers)

2. MICRONODULAR ATROPHIC CIRRHOSIS (CLD withrepeated burst of necrosis and regeneration)

3. VASCULAR THROMBOSIS (portal or central) block the remodeling of blood flow from a perinodularto a translobular pathway

LAENNEC SCORING SYSTEM AND CIRRHOSIS REGRESSION

4a 4b 4c

• Thick fibrous septa

• Atrophic nodules








17

?

“DecompensatingEvent” Stage 3

Bleeding

Stage 4First nonbleeding

decompensation

Stage 5Second

decompensation

Death orOLT

SEPSISRenalFailure

Compensated Cirrhosis Decompensated Cirrhosis

Stage 1

Stage 2

No VaricesNo Ascites

VaricesNo Ascites

HVPG: 5-12 mm Hg HVPG > 12 mm Hg

Modified from Arvaniti V. et al., Gastroenterology 2010; 139:1246-1256

Hepatocellular carcinoma

HVPG: < 5 mm Hg

F0 Fibrosis

F3 Fibrosis

Non-cirrhotic

HCV clearance

The impact of HCV eradication changes according to disease stage

HCV clearance

HCV clearance

HCV clearance








19

Occurrence of EV

Progression of EV

V. Di Marco et al. Gastroenterology 2016

Effect of viral eradication on occurrence/progression of

esophageal varices in patients with HCV cirrhosis after Peg/RBV

Afdhal, et al. EASL 2016; Poster #LBP518

46 had paired HVPG at baseline and end-of-treatment

9 had follow-up HVPG at 48 weeks post-treatment

Wk 48EOT

Wk 96SVR48

Pretreatment

Mean 29% decrease in HVPG

HVPG <12 mmHg in 1/3 pts *Patients with HVPG ≤12 mmHg at EOT; each bar represents 1 patient

0

-20

-40

-60

*Patients with HVPG ≤12 mmHg at EOT; each bar represents 1 patient

Baseline MELD

<10 mmHg

≥10 mmHg

*

*

*

HVPG % change at PTW48 in patients with BL HVPG ≥12 mmHg who achieved SVR12 (n=9)

8/9 had >20% HVPG

ΔH

VP

G f

rom

BL

(%)

SOF+RBV for 48 weeks in CTP-A/B + HVPG >6mmHg

HCV ERADICATION RESULTS IN REDUCTION OF HEPATIC VENOUS PRESSURE GRADIENT

48 WEEKS AFTER END OF TREATMENT; FINAL RESULTS OF THE STUDY OF SOF + RBV IN

PATIENTS WITH CIRRHOSIS AND PORTAL HYPERTENSION

Mandorfer M,et al.. J Hepatol 2016.

Sustained virologic response to interferon-free therapies

ameliorates HCV-induced portal hypertension








23

DAA Studies in Decompensated Cirrhosis (CTP-B/C)*

SOLAR-1 SOLAR-2 ASTRAL-4 ALLY-1

LDV/SOF+RBV

LDV/SOF+RBV

SOF/VEL±RBV

DCV+SOF+RBV

Number with outcomes 93 81 250 39

Last Assessment SVR4 SVR24 SVR12 SVR12

% CTP score improved% CTP score worsened

67%8%

77%6%

47%11%

76%12%

% MELD score improved% MELD score worsened

67%17%

73%16%

54%25%

40%40%

% MELD improved in CTP B% MELD worsened in CTP B

64%17%

65%20%

54%25%

43%43%

% MELD improved in CTP C% MELD worsened in CTP C

70%18%

83%11%

──

67%0%

*Only SVR patients are included

Hepa-C Registry: SVR, Safety, and Deaths With HCV Tx in Advanced Liver Disease

Predictor

SAE Death (On Study)

OR

(95% CI)

Multiv.

P Value

OR

(95% CI)

Multiv.

P Value

CP A vs

B/C

2.16

(1.29-3.64).004

1.73

(0.39-7.64).034

MELD1.31

(1.2-1.43)< .001

1.34

(1.16-1.53)< .001

MELD

≥ 18NR .171 NR < .001

Platelets0.99

(0.98-0.99).008

1.002

(0.99-1.02).151

Platelets

< 100,000

2.94

(1.8-4.8)< .001 NR .711

3000 100 200

0.0 0

0.2 5

0.5 0

0.7 5

1.0 0

Time (days)

Kaplan-Meier Survival Estimates

MELD < 18 MELD ≥ 18

92%

99% 99% 97%

78%68%

P < .001

Fernàndez-Carrillo, et al. EASL-ILC 2016 GS01

studies n. pts Meld baseline

HCC rate SVR12 Reaching delisting criteria*

delisted

ITACOPS (Italy) 1 216 13(6-24)

47% NA 40% NA

Coilly (France) 151 10±5(6-32)

56% 88% 26% 6%

Deterding (Germany)

88 NA 0% 74% 38% NA

Proportion of patients reaching delisting criteria in real life cohorts

* MELD < 15 in studies from Italy and France; Transition from Child B-C to A in Germany

Martini s. et al. Hepatol 2015; 62 (S1); Coilly et al. Hepatol 2015; 62 (S1); Deterding et al. APT 2015; 42: 889-901

Belli L, et al. J Hepatol 2016

103 patients listed for decompensated HCV in 11 centres Treated with SOF/RBV, SOF/LDV, SOF/DCV, median f/u 52 wks 34 deactivated for improvement 19 delisted

Variable % Delisting

Baseline MELD<1616–20>20

25/51 (49%)7/38 (18%)2/13 (15%)

Baseline Predictors • Cumulative incidence of inactivation

MELD <16 Δ MELD = 4 Δ alb = 0.8

MELD = 16–20 Δ MELD = 4 Δ alb = 0.8

MELD >20 Δ MELD = 4 Δ alb = 0.8

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 12 24 36 48 60 72 84 96 108 wks

MELD <16 Δ MELD = 2 Δ alb = 0.5

MELD = 16–20 Δ MELD = 2 Δ alb = 0.5

MELD >20 Δ MELD = 2 Δ alb = 0.5

Predictors of Clinical Outcome in CTP-B,CBaseline MELD and Δ MELD, Albumin after 12 wks

Variable HR (IC95%) p-value

Δ MELD at 12 wks

1.349 (1.2–1.51)

<0.0001

Δ albumin at 12 wks

0.307 (0.13–0.72)

0.0069

Ontreatment Predictors

Long-term Follow-up of >1,000 HCV Patients With Compensated or Decompensated Cirrhosis Who Achieved SVR Following Treatment

With Sofosbuvir-Based Regimens

*Cirrhosis status determined prior to treatment with SOF-based regimen resulting in SVR. BMI, body mass index;GT, genotype; IL28B,

interleukin-28B; Q, quartile.Muir A, AASLD, 2016, #880

Demographics and Disease Characteristics

Cirrhosis Registry Study (DALTON-C): Interim Results

N=1067

Dem

ogr

aph

ics

Mean age, y (range) 59 (33–83)

Male, n (%) 712 (67)

Race, n (%)White 915 (86)

Black 92 (9)

Hispanic/Latino 145 (14)

Region, n (%)

North America 840 (78)

Europe 149 (14)

Australia/New Zealand 71 (7)

Patient source, n (%)Clinical study 834 (78)

Clinical practice 233 (22)

Mean BMI, kg/m2 (Q1, Q3) 30 (26, 33)

Dis

eas

e c

har

acte

rist

ics

Mean time since HCV diagnosis, y (range) 14 (1–51)

Cirrhosis, n (%)* 1064 (>99)

Decompensated 201 (19)

HCV GT, n (%)

1 592 (55)

2 49 (5)

3 148 (14)

4–6 43 (4)

Missing 235 (22)

Median platelets, x103/μL (range) 133 (20–626)

Assessments

• Every 6 mo: HCV RNA; labs, CPT, MELD; any occurrence

within preceding 6 mo of HCC, death, liver transplant, and

hepatic events, and results of endoscopy or biopsy (if

performed); health-related QoL questionnaires

• Baseline and yearly thereafter: Transient elastography

• Baseline and Week 240: Endoscopy

• End of study: Liver biopsy (optional)

Long-term Follow-up of >1,000 HCV Patients With Compensated or Decompensated Cirrhosis Who Achieved SVR Following Treatment

With Sofosbuvir-Based Regimens

Cirrhosis Registry Study (DALTON-C): Interim Results

Shift in CPT Classification

*Only 1 patient with CPT B cirrhosis prior to treatment has reached >42 mo since start of treatment; this patient had CPT A cirrhosis at last assessment. †Only 1 patient with CPT C cirrhosis prior to treatment has reached >36 mo since start of treatment; this patient had CPT A cirrhosis at last assessment.

The majority of patients maintained or improved their CPT category relative to pretreatment through up to 36 (CPT C) or 42 (CPT B) months relative to treatment start

Overall improvements in key laboratory components such as mean bilirubin and mean albumin were observed

Muir A, AASLD, 2016, #880

100

80

60

40

20

00-6 6-12 12-18 18-24 24-30 30-36 36-42

172 173 119 112 57 29 10

CPT B Cirrhosis Pretreatment*

Time Interval from Start of Treatment (months)

Pa

tie

nts

, %

100

80

60

40

20

00-6 6-12 12-18 18-24 24-30 30-36

24 24 13 14 13 8

CPT C Cirrhosis Pretreatment†

Time Interval from Start of Treatment (months)

Pa

tie

nts

, %CPT A

CPT BCPT C

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30

Genetic

instability

Prolonged

expression

of viral genes

HBx, LHBs

Host immune responses

Inflammation

Oxydative stress

Cirrhosis

HCV

HBV(overt or occult)

Genetic

instability

Prolonged

expression

of viral genes Core,

NS3, NS5a

Cell proliferation

Apoptosis

Modifications of the

epigenome

Integration of HBV DNA

Into host chromosomes :

Insertional mutagenesis

of cellular genes

HCC carcinogenesis

Direct and indirect roles of hepatitis viruses

AP1, NFkB

b-catenin

HCC DevelopmentHCCProgression

mi-RNA122 Immune control

?

Non-tumour cells can promote HCC metastasis via release of MVs: innate immune cells produce MVs harbouring

CD11b–CD18, which can be taken up by HCC cells and promote their capacity of migration, invasion, attachment

to the endothelium and metastasis. Non-tumour cells can also produce MVs with antitumoral properties.

Lemoinne S et al. Nature Reviews Gastroenterology & Hepatology 11, 350–361 (2014)

Eradication of HCV and risk of HCC: a meta-analysis of IFN-based studies

Morgan et al, Ann Int Med 2013;158:329-337

Forest Plot Of Adjusted Hazard Effects In Persons At All Stages Of Fibrosis

Enrolled

Discontinued

Completed

Ongoing

99.7% (5414/5433) maintenance of SVR 0.1% (6 patients) late relapse and 0.2% (12 patients) reinfection HCC:

− SVR Registry : 0.3% (16/5433) overall; 1.2% (13/1086) among cirrhotics− Sequence Registry: 0.9% (5/536) overall; 3.4% (4/117) among cirrhotics

N=5433

n=56

N=432771 (0–156) Weeks

N=536

n=51

N=11544 (0–159) WeeksMedian f/u from EOT

in parent study (range)

n=1050 n

Non-SOF studies D/C 336

LTFU 247

W/D consent 235

Rolled into dedicated cirrhosis registry 172

HCV RNA ≥LLOQ 18

Death 15

Signed consent but ineligible 14

Investigator decision 13

n=370 nStarted HCV treatment 290W/D consent 40LTFU 30Death 4Investigator decision 3Signed consent but ineligible 2Non-SOF study D/C 1

SVR Registry Sequence Registry

Long-Term Follow-Up of CHC Patients Treated with DAAs

Lawitz, EASL 2016, Poster FRI-166

SOF±PegIFN±RBV (18 studies)

LDV+SOF±RBV (12 studies)

SOF+VEL±RBV (6 studies)

SOF+VEL+GS-9857 (2 studies)

Non-SOF (6 studies)*

1773

2272

816

3

569

251

34

45

3

203

“Incidence and pattern of "de novo" hepatocellular carcinoma in HCV patients treated with oral DAAs”

A. Romano1, S. Piovesan1, G. Anastassopoulos1, L. Chemello1, L. Cavalletto1, F.P. Russo1, M. Gambato1, V.Vincenzi2, P. Scotton3, S. Panese4, D. Tempesta4, T. Bertin5, M. Carrara6, A. Carlotto7, F. Capra8, G.Carolo8, G. Scroccaro9, A. Alberti1,

Navigatore Study Group

1University of Padova, Padova, Italy; 2 Belluno Hospital, Belluno, Italy;3 Treviso Hospital, Treviso Italy; 4Venezia Mestre Hospital, Venezia, Italy;5 Vicenza Hospital, Vicenza, Italy; 6 Bussolengo Hospital, Bussolengo, Italy; 7 Santorso Hospital, Santorso, Italy; 8University of Verona, Verona,

Italy; 9 Veneto Region, Venezia, Italy

RESULTSCumulative Proportion of HCC in the different stages of liver disease

(Kaplan-Meier)

F3 vs Child-Pugh A vs Child-Pugh B; Mantel test p=0.05

Child-Pugh A vs Child Pugh B; Mantel test p=0.259

IncidenceF3 0.23 x 100 persons-year; 95% CI 0.01-1.27C-P A 1.64 x 100 persons-year; 95% CI 1.14 -2.28C-P B 2.92 x 100 persons-year; 95% CI 1.07- 6.36

Annual Incidence Rate of HCC in Untreated HCV patients: 3.9%

HEPATOLOGY 2006

Annual Incidence Rate of HCC in Untreated HCV patients:2.8%

HCC IN UNTREATED HCV PATIENTS

RESULTS

HCC Incidence in Cirrhotics by subgroups (Multivariate analysis)

Variables included were: gender, HCV genotype, APRI score, Child Pugh stage, DAAs regimens, SVR-12

Multivariate Cox’s regression (Forward stepwise selection)

HR 95% CI p

APRI score ≥ 2.5 1.83 0.89-3.75 0.099

SVR-12 0.20 0.09-0.41 0.001

HCC risk increased linearly by 10% at each 1 point increase in APRI value

PATTERNS OF HCC DEVELOPMENT DURING/AFTER DAA THERAPY

SINGLE HCC NODULE 20/41 (48,8%)

2-3 HCC NODULES 5/41 (12,2%)

> 3 HCC NODULES or INFILTRATIVE HCC 16/41 (39%)

With Portal Thrombosis 5/41 (12,2%)

With Extrahepatic Metastasis 4/41 (9,7%)

RESULTS

57.2

30.8

54.1

9.5

15.5 14.3

33.3

53.8

28.6

0

10

20

30

40

50

60

70

SVR yes SVR no SVR pending

SINGLE HCC NODULE

2-3 HCC NODULES

>3 NODULES/INFILTRATIVE

HCC PATTERNS IN RELATION TO SVR

%

0

10

20

30

40

50

60

70

80

90

100

0--3 4--6 7--12 13--18

SINGLE NODULE

2-3 NODULES

> 3 NODULES/INFILTRATIVE

MONTHS AFTER INITIATION OF DAAs THERAPY

PATTERNS OF HCC DEVELOPMENT IN RELATION TO TIMING OF DAA TREATMENT

%

Unexpected high incidence of hepatocellular carcinomain cirrhotic patients with sustained virologic response

following interferon-free direct-acting antiviral treatment

• AURIC: Austrian ribavirin/interferon-free cohort; ClinicalTrials. gov, NCT02628717 201 subject completed 48 weeks of FU

• 19 cases with HCC post DAAs calculated HCC incidence 8.1% per year

• 3 with history of HCC all treated with curative treatment and with SVR ;

• 16 without history of HCC calculated HCC incidence 6.6% per year– 11 with SVR calculated HCC incidence 5.2% per year

– 5 without SVR

Kozbial K et al Journal of Hepatology 2016; 65: 856–868

Adjuvant interferon for early or late recurrence of hepatocellularcarcinoma and mortality from hepatocellular carcinoma

following curative treatment: A meta-analysis

Forest plot of the 11 studies on adjuvant interferon therapy for hepatitis C virus associated with

hepatocellular carcinoma patients following curative therapy. (A) overall mortality; (B) 1-year early

recurrence; (C) 2-year early recurrence; (D) late recurrence. CI, confidence interval.

Survival data based on SVR was reported in three studies (n = 107). Pooled data showed longer survival in patients with SVR compared with nonresponders (85%vs. 56%; P = 0.03)

HCC recurrence after DAAs therapy reported series

Author N of patients Median Time from HCC

cure to DAA initiationmonths

% patients treated with non curative

Incidence Duration of follow up

Curative Tx of relapse

Conti F et al1 59 13 10% 58%(36-84%)

24 weeks Not reported

Reig M et al.2 58 11.2 10% 56% 24 weeks 75%

Torres HAet al. 3

8 7.5 0 0 48 weeks N.A.

Zavaglia C et al. 4

31 19.3 13% 3.2% (1) 32 weeks N.R.

Zeng Q-L et al. 5

8 NR 0 0 64 weeks N.A.

1. Conti F et al. J Hepatol 2016; 65: 727–733 2 Reig et al. J Hepatol 2016 ; 65: 719–726 3 Torres HA et al. J Hepatol 2016; 65: 856–868 4.

Zavaglia C et al. J Hepatol 2017; 66: 236-237. 5 Zeng Q-L et al J Hepatol 2016; 65: 057–1071

HCC Recurrence After DAA Therapy

Cohort ANRS N with HCC N with HCC treated

with DAA

HCC Recurrence Rate in DAA –treated group

per 100 person-months

HCC Recurrence Rate in No-DAA group per 100

person-months

HEPATHER 267 189 0.73 0.66

CIRVIR 79 13 1.11 1.73

CUPILT (LT) 314 314 3.1 --

All included patients had therapies with curative potential (resection, RFA, LT) No evidence of increased risk of HCC recurrence in DAA-treated patients

Pol S et al J Hepatol 2016; 65: 734–740

HCV patients with cirrhosis (A5-6) from 3 Italian liver clinics

10% achieved SVR (IFN-based therapy)

Controls: age and sex-matched general Italian population

Overall Survival

Predictors of Death:

Male sex

Platelets <80K

Survival of patients with HCV cirrhosis and SVR to Peg/RBV is comparable to the general population

Bruno S et a.l Journal of Hepatology 2016

CP-A CirrhosisIFN-based therapyNo alcohol info

5.2% at 10 yrs13.6% at 20 yrs

10.3% at 10 yrs23.7% at 20 yrs

Hepatocellular Carcinoma Liver Decompensation

Survival of patients with HCV cirrhosis and SVR to Peg/RBV is comparable to the general population, but….

Bruno S et a.l Journal of Hepatology 2016

Ongoing liver damage: steatohepatitis, alcohol, drugs

Beyond HCV Cure: reversibility of liver damageKey Messages

• Necroinflammatory changes and early cirrhosis are reversible

• Cirrhosis regression is associated with reduced mortality and survival similar to the general population

• Advanced (Laennec stafe 4b-c cirrhosis) is a point of no return

• In irreversible cirrhosis portal hypertension can be reduced or stabilized

• Decompensation even if advanced (CTP stage C) can be reverted especially in the long term

• Oncogenesis is reduced by HCV eradication but the impact of modulation of inflammation given by HCV suppression on tumour progression is still controversial

• HCV cure has a key role in reversibility of liver damage but concomitant causes of liver damage should be identified and controlled

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