Alfredo Marzano

Gastroepatologia

Ospedale San Giovanni Battista

Università di Torino

Convegno regionale AES 2015

Alghero 22 maggio

Epatite B

Gestione della cirrosi scompensata

Caso clinicoPresentazione

• Ricovero reparto ottobre 2014• C.A., uomo, 63 anni, Domodossola, guardia giurata;• Potus (1L/die); fumo (20/die)• ECA HBV nota dal 1981. Mai trattato• 2004 ECT (non lesioni focali, IP ND); EGDS: no varici;• 2004-5-6 exeresi polipi colon; dolicocolon;• 2014: diagnosi cirrosi compensatano terapia

• Ricovero 17/10/2014 altro Osp. per febbricola, ascite, ittero(wbc 4600, hb 12.1, mcv 98, plts 64000, INR 2.69, ast 768, alt589, ggt 196, BT 13.34, BD 10.36), alb 2.7, HBsAg+ 0.49 UI ,antiHBs 7.5 UI, IgM HBc pos, antiHBe+, HCV-, HIV -;

• TC : ascite in cirrosi, VP pervia. No terapia antivirale.

Subclinical portal hypertension

0

12

10

5

24

PortalHypertension

(mmHg)

Portal hypertension = HVPG > 5 mmHg

Clinically significative portal hypertension >10 mmHg; decompensation > 12 mm Hg

Chronic hepatitis

Compensated Cirrhosis

Subclinical portal hypertension

VaricesBleeding

PSE

Ascites

SBP

0

12

10

5

24

PortalHypertension

(mmHg)

Portal hypertension = HVPG > 5 mmHg

Clinically significative portal hypertension >10 mmHg; decompensation > 12 mm Hg

Chronic hepatitis

Decompensated Cirrhosis

Varices Bleeding

PSE

Ascites

SBP

Decompensated CirrhosisChronic or Acute-on-Chronic Evolution

VaricesBleeding

PSE

Ascites

SBP

0

12

10

5

24

Portal

Hypertension

(mmHg)

Chronic Acute-on-Chronic

HBV reactivation

Evolution progressive acute

Ingresso in reparto 24/10/2015

EO: ittero, ascite, (no PBS), spiders+++, condizioninutrizionali scadute (peso 65 Kg, H 178 cm), crat0.82, hb 10.8, glic 112, wbc 4140, bt 19.3, ast 151, alt135, ggt 78, alb 2.9, INR 2.69, aFP 13, qHBsAg 0.49UI, HBV DNA 7575 UI, anti-HDV neg, HCV RNA neg.

Decorso

MELD 28

• Valutazione preliminare chirurgo OLT;• Gruppo A-• TC con ricostruzione vascolare (non trombosi portale, non

lesioni focali)• EGDS: GC severa• Entecavir 0.5 mg 1 co/die (24/10)• Bilancio OLT• Plasma, albumina, compenso dell’ascite (- 5 Kg 1/11)

R Fontana. Gastroenterology 2002;123:719-727.

25 patients

129

patients

0

20

40

60

80

100X

X XXX

XX X

XX

XXX

XXX

XXXX X

X

X

0 6 12 18 24 30 36 42

No Survival

Survival

Overall

Survival in Decompensated Cirrhosis

(LAM)

Mortality in the first 6 months(Chronic Evolution or Acute-on-Chronic)

Decompensation in HBV related cirrhosis antiviral therapy and evaluation for liver transplantation

Months

Cirrhosis

ETV and TNF First line (A1)

PEG Only well compensated cirrhosis

LAM NO

HBV DNAEvery 3M during the first year and until HBV DNA neg (risk of reacerbation)

HCC Monitoring is mandatory (B1)

DiscontinuationOnly after 12M of consolidation after anti-HBe serocoversion or HBsAg loss and antiHBs seroconversion

Decompesated NUC + LT evaluation

EASL. J Hepatol. 2012;57:167-185

Decompensated cirrhosis

Mutimer DJ, Gut 2012

86% Improved

14% Not Improved50% Improved/Stabilized

14% Not Improved

30% Death*

2% No F/U

N = 176 (226)

CPT A = 40%, B = 38%, C = 22%

43%Transplanted

21% Removed from

Wait List

36% Still Wait Listed

*All deaths occurred prior to 6 months

Schiff et al. Liver Transpl; 2007

ADV treatment of decompensated Cirrhosis

HBV-related Acute-on-chronic liver failure

Garg H et al, Hepatology 2011

TDF

VaricesBleeding

PSE

Ascites

SBP

0

12

10

5

24

Portal

Hypertension

(mmHg)

HBV-related Acute-on-chronic liver failure

Mitauchi T et al, Int J Med Sci 2013

Lai J et al, Hepatob Pan Dis Int 2013

ETV

Acute-on-chronic liver failure

Clinical experience: entecavir

Marengo & Marzano Antiviral Therapy 2013

Prognostic scores in cirrhosis

Post-

Liv

er

Tra

nspla

nta

tion

mort

alit

y

*

0

10

20

30

40

50

60

70

CHILD UNOS MELD

CHILD 5 8 12 15UNOS 1 3 2B 2A

MELD <20 20-29 30-39 >40

Decompensation

Mortality

R Fontana. Gastroenterology 2002;123:719-727.

25 patients

129

patients

0

20

40

60

80

100X

X XXX

XX X

XX

XXX

XXX

XXXX X

X

X

0 6 12 18 24 30 36 42

No Survival

Survival

Overall

Survival in Decompensated Cirrhosis

(LAM)

Mortality in the first 6 months(Chronic Evolution or Acute-on-Chronic)

Decompensation in HBV related cirrhosis antiviral therapy and evaluation for liver transplantation

Months

LT for HBV-related cirrhosis in US and Europe

Decompens.

vs

HCC

Van Bommel, Liver Int 2013; Burra, J Hepatol 2013

HCC

Dec

Decorso 1

• Riduzione HBV DNA (1065 UI il 6/11), incrementoBT (21) e INR (3.19); episodio di EPS risolto conriduzione diuretici e idratazione

MELD 31• Dimesso 11/11/2015 con indicazione al

completamento del bilancio in ambulatorio OLT.Inserito in LAT 17/11/2015

MELD 28 BT 5.5, creat 0.94, INR 1.59

OLT 2666 (!) 16/12/2014

Donatore 0+; HBsAg+

• Estubato G1;

• Rigetto 27/12;

• Anemia da autoanticorpi (siero Antilinfocitario);CMV (terapia), colangite (EC,SH)stop 30/1/2015;

• EBV alto titolo (2.044.600 cp/ml 13/1)TCPTLD(RTX);

• Chiusura Kehr 28/1;

• PPD+piraldina

Profilassi post-OLT

• HBIG 20,000 UIStop G7

• ETV 0.5 mg/die

Decorso post-OLT

• Dimesso 6/2/2015 (52 gg degenza): wbc 3850, hb9.5, plts 115, BT 5.1, ast 76, alt 108, ggt 562, aph268;

• 17/3/2015: non sintomi; funzione midollare nn, EBVDNA neg, CMV neg, colangio-RMN stenosianastomotica;

• 4/5/2015 ERCP: sfinterotomia e protesi.

• In programma biliodigestiva.

• HBsAg+

Biochimica e virologia

17/12 27/12 15/1 2/2 9/2 26/2 17/3

HBsAg neg pos 12.6 8.67 11.15 8.33 5.81

antiHBs 300 neg neg neg neg neg neg

antiHBe pos pos pos pos pos pos

HBV

DNA

neg neg neg 35 UI neg neg neg

AST 76 30

ALT 108 21

GGT 562 98

APH 268 37

CREAT 1.06 0.98

BT 5.4 0.5

INR 1.13 1.0

ETV+HBIG ETV

2429 pts

Prophylaxis of hepatitis B recurrence after LT

Cholangitas, Am J Transpl 2013

Liver transplantation:

HBIg-free schedules22.5->37% HBsAg+

Cholangitas, Am J Transpl 2013

Treatment of patients with cirrhosis

Patients with

cirrhosis

• PEG-IFN may increase the risk of bacteraemic infection and hepatic decompensation

in patients with advanced cirrhosis

• Among NAs, TDF or ETV are preferred because of their potency and minimal risk of

resistance

• LAM should not be used

• Close monitoring of HBV DNA every 3 months at least during the first year of therapy

and until HBV DNA undetectability is important

Patients with

decompensated

cirrhosis

• Patients should be treated in specialized liver units and may be candidates for liver

transplantation

• NA treatment is indicated irrespective of HBV DNA level to prevent reactivation

• (PEG-)IFN is contraindicated

• ETV or TDF should be used

– ETV dose for patients with decompensated cirrhosis is 1 mg once daily

– Lactic acidosis has been reported to develop in some NA (particularly ETV)

treated patients with advanced decompensated cirrhosis (MELD score >20),

therefore clinical and laboratory parameters should be closely monitored

Patients after liver

transplantation

• Pre-transplant therapy with a potent NA with a high barrier to resistance is

recommended for all HBsAg+ patients undergoing liver transplantation

EASL Clinical Practice Guidelines. J Hepatol 2012

Treatment of CHB Italian update 2011

Marengo & Marzano Antivir Ther 2013

100%

TDF

Marengo & Marzano APT 2014 (submitted)

Marcellin P; The Lancet 2013

Regression of histological cirrhosis

N=57N=57

* Median time of long-term biopsy: 6 years (range: 3–7 years)

Long-term entecavir therapy results

in the reversal of fibrosis/cirrhosis

Chang TT, Hepatology 2010

Antiviral Therapy reduces Portal Hypertension

Hepatic Venous Pressure Gradient (HVPG) decreasein cirrhotic patients with significant (> 10 mm Hg) portal hypertension

treated with lamivudine

Manolakopoulos S et al, J Hepatol 2009

Antiviral Therapy reduces Portal Hypertension

Debernardi Venon W et al; AISF 2013

5/7 (71%) OV disappearance

Antiviral Therapy reduces Portal Hypertension

Koga H et al. Hepatol Res 2007

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120 Months

27 24 19 9 4 3

80%

2127 15 8 4

27 26 23 2

0

14 92427 21 18 14

12%

EV progression

EV regression

0

20

40

60

80

100

0 12 24 36 48 60 72 84 96 108 120

Patients

at risk80 78 74 62 45 3380 6778 56 39

8%

EV progression

Changes of esophageal varices (EV) in compensated

cirrhotics treated with LAM±TDF for 10 years

No varices at baseline (n=80)

Lampertico et al, submitted 2013

F1 varices at baseline (n=27)

Overall, EV worsening rate per year: 0.9%*

* 6 of 7 progressors (86%) had either LMV-R and/or HCC

Hepatology 2013

Marengo, Antiviral Therapy 2013

Decompensation Death

* 2 CH

CH

Cirrhosis

Clinical experience with III gen NUCs:

Entecavir 100 pts (55 compensated cirrhosis)

HCC

Hepatology 2013

Results

0

5

10

15

20

HVPG basal

HVPG aftertherapy

mmHg

P< 0.02

Debernardi V & Marzano.

Personal data

Liver fibrosis and portal hypertension in HBV related cirrhosis

long term responders to antiviral therapy

Mean

0

20

40

60

80

100

LSPS < 0.62

LSPS > 0.62

LSPS ≤ 0.62 after therapy has 100% NPV for predicting an HVPG < 6 mmHg

HVPG

< 6 mmHg > 6 mmHg

% pts

44 pts

30 pts

Results

Liver fibrosis and portal hypertension in HBV related cirrhosis

long term responders to antiviral therapy

Debernardi V & Marzano.

Personal data

Incidence of HCC: 14.8%

HCC vs no HCC: no significant difference in ALT, LS, Ø spleen, PLTS, qHBsAg

≤ 0.62 > 0.62

HCC 4/11 (36%) 7/11 (63%)*

qHBsAg (mean) 147.09 909.92*

LS ≥ 11 0/4 (mean 5.8) 6/7 (mean 16.3)*

ALT (mean) 23 42*

Ø spleen (cm) 10.1 13.4*

PLTS 185000 116000*

* p < 0.05 vs patients group with LSPS ≤0.62

Liver fibrosis and portal hypertension in HBV related cirrhosis

long term responders to antiviral therapy

Debernardi V & Marzano.

Personal data

LSPS

Epatite B

Gestione della cirrosi scompensata

Conclusioni

• tutti i cirrotici vanno trattati con NUC

• in caso di scompenso: NUC, trattamento delle

complicanze legate all’ipertensioine portale ed al

profilo emodinamico + bilancio OLT