Massimo Puoti Dept of Infectious Diseases

AO Ospedale Niguarda C Granda Milano

Management of End-stage Liver Disease

Disclosures

Massimo Puoti acted in a consultancy capacity for Abbvie, BMS, Boehringer

Ingelheim, Janssen, GSK, ViiV, Gilead Sciences, MSD as a speaker at company-sponsored events for Abbvie, BMS,

Boehringer Ingelheim, Janssen, Gilead Sciences, GSK, ViiV, Roche Diagnostics, MSD, Beckman,

During this lecture data on not licensed products and on off label

use of licensed products will be discussed

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Causes of death in the Swiss HIV Cohort study 2005-09

Ruppik M. et al. Changing patterns of causes of death in the SHCS 2005-2009. CROI 2011. Poster # 789. Available at: http://www.retroconference.org/2011/PDFs/789.pdf.

Chart1

80

73

72

42

30

13

4

7

8

28

31

9

38

11

Causes of Death

Foglio1

Causes of Death

Liver diseases80

AIDS73

Non AIDS Malignancies72

Non AIDS infections/sepsis42

Heart diseases30

CNS13

Kidney4

Gastro/pancreas7

Lung8

Suicide or psych.28

Substance use31

Accident or Homicide9

Other or not classified38

Unknown11

ESLD: definition End-stage liver disease (ESLD) is the final decompensation

phase in the liver trajectory. It is characterized by episodic, acute exacerbations, often

requiring hospitalization. Life-threatening complications, such as variceal

hemorrhage or hepatoma, combine with multiple debilitating symptoms, including ascites, extreme fatigue, pruritus, and cachexia.

Patients may also experience cognitive decline, ranging from mild chronic impairment to severe hepatic encephalopathy and coma.

Many suffer from psychological distress and depression.

Boyd K et al Hepatology 2012

Metavir F4 Ishak S 5-6

Metavir F4 Ishak S 6

Metavir F4 Ishak S 6

Metavir F4 Ishak S 6

Metavir F4 Ishak S 6

Biology: Fibrogenesis & angiogenesis Scar X-linking Acellular scar Nodule size

Insoluble scar & small nodules

Scars & large nodules

HVPG: > 5 > 10 > 12 > 12

Clinical: none none Varices formation Ascites (without VH)

VH (+ ascites)

Stage: Early stage cirrhosis Compensated (stage 1)

Compensated (stage 2)

Decompensated (stage 3)

Decomp (stage 4)

Stages according to DAmico et al, J Hepatol 2006;44: 217-31

F4 and beyond: cirrhosis is a progression of stages of increasing severity and non-reversibility

increasing vasodilatation

Staging of Liver disease: the pieces of the puzzle

Blood Tests & US

Fibroscan

Physical exam Biopsy

Diagnosis of Cirrhosis: Sign and Symptoms Physical examination

Jaundice

Spider naevi

Ginecomastia

Ascites and Hernias

Hepatic Encephalopathy

Palmar Erythema

F0 F1 F2 F3 F4

Cirrhosis with

Portal Hypertension

Decompensated Cirrhosis

AST/ALT ratio

PLT count

Age

GT

Cholesterol or N glycans

INR or ApoA1

Insulin Sensit. (HOMA)

INDIRECT MARKERS

OF FIBROSIS

Indirect markers of Fibrosis Single parameter

Platelet count < 150 x 109/L AST/ALT > 1

Combined scores Forns1:

Age, plt, GT, cholesterol APRI2:

AST, plt Fibroindex3:

plt, AST, GT FPI4:

AST, cholesterol, past alcohol intake, HOMA, age

FIB-45: plt, AST, ALT, age

Bonacini6 : ALT, AST, INR, plt,

Pohl7: ALT, AST, plt

AP8: age, plt

Glycocirrho test9: profile of serum proteins

N-glycans

1 Forns X et al Hepatology 2002; 2 Wai et al. Hepatology 2003; 3 Koda M et al Hepatology 2007; 4 Sud A et al Hepatology 2004 5 Sterling R et al Hepatology 2006; 6 Bonacini M et al Am J Gastroenterol 2007; 7 Poynard T et al J Viral Hepatitis 2007; 8 Callewaert N et al Nat Med 2004

Affected by: HIV per se ART

Liver Ultrasound Surface Nodularity and diagnosis of cirrhosis

liver surface appeared as a dotted or irregular line and/or the liver parenchyma was not homogeneous, with areas of different echogenicity, reflecting an underlying nodularity

Paggi S et al J Hepatology 2008 49: 564-71;

FIBROSCAN

Vibration controlled Transient Elastometry

Vibrating Probe: elastic wave propagates into liver tissue

US probe: measures the displacements induced by the propagation of the wave

FibroScan

2.5 cm

4 cm

1 cm

Explored volume

LB : 1/50,000 of the liver FibroScan : 1/500 of the liver

The probe induces an elastic wave through the liver

The velocity of the wave is evaluated in a region located from 2.5 to 6.5 cm below

the skin surface

Liver Stiffness Measurement by Transient Elastometry (FibroScan)

Stiffness in KPa median of 5-10 determination with IQR Measurement with IQR > 30% lower validity No reference normal range High intra and interobserver agreement (0.98) between

trained physicians or nurses (training=100 tests) 1 Pheasibility is influenced by BMI and steatosis 1 Results could be biased by:

the extent of necroinflammatory activity 2,3 Macronodular pattern of cirrhosis and perisinusoidal fibrosis4

Reflects the elevation of portal pressure: correlation with LSM if HVPG < 10 mmHg4

1 Fraquelli M et al. Gut 2007; 2 Coco B et al J Viral Hepatitis 2007; 3 Arena U et al Hepatology 2008;4 Ganne-Carri N et al. Hepatology 2008; 4 Vizzuti Hepatology 2007

Cirrhosis: complications

Esophageal Varices Bleeding F1 +/- red signs F2 +/- red signs F3 +/- red signs

Ascites Mild Moderate Severe Refractory Complicated

Hepatorenal syndrome Spontaneous Bacterial

Peritonitis

Hepatic Encephalopathy Grade 1 Grade 2 Grade 3

Hepatic Failure Prolonged PT (higher INR) Low Albumin High Bilirubin

Hepatocellular Carcinoma

Clinical/Biochemical Indicator

1 point 2 points 3 points

Serum bilirubin (mg/dL)

< 2 2 - 3 > 3

Serum albumin (g/dL)

> 3.5 2.8 3.5 < 2.8

Prothrombine time (s > control)

< 4 4 - 6 > 6

Encephalopathy (grade)

none 1 or 2 3 or 4

Ascites absent slight moderate

Points are summed, and the total score is classified according to severity as follows:

GROUP A (mild) = 5 6 points GROUP B (moderate) = 7 9 points GROUP C (severe) = 10 15 points

Child-Pugh classification and scoring of liver diseases

Verbeeck RK. Eur J Clin Pharmacol 2008; 64: 1147-1161

MELD SCORE

MELDScore = 10 * ((0.957 * ln(Creatinine)) + (0.378 * ln(Bilirubin)) + (1.12 * ln(INR))) + 6.43

Median survival Compensated cirrhosis: > 12 years

Decompensated cirrhosis: ~ 2 years

Natural history and prognostic indicators for survival in Cirrhotic Patients

Markedly longer survival in patients with compensated cirrhosis vs those with decompensated cirrhosis

1 year risk

DAmico G, et al. J Hepatology. 2006;44:217-231

ESLD: assessment

Diagnosis of cirrhosis Physical exam Blood tests Diagnostic algorythms ( APRI, FIB-4) US & Elastometry If discordant data Liver Biopsy

Staging of cirrhosis & Prognosis Blood Tests + physical exam + EGDS

Child Pugh score (HE Ascites INR, Bilirubin, Albumin) MELD Score ( INR, creatininae, Bilirubin) Varices -/+ bleeding -/+ Ascites -/+

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Treatment of complications of cirrhosis Compl. AASLD GUIDELINE EASL GUIDELINE

Ascites

http://www.aasld.org/sites/default/files/guideline_documents/adultascitesenhanced.p

df

http://www.easl.eu/medias/cpg/issue4/Report.pdf

Varices and Bleeding

http://www.aasld.org/sites/default/files/guideline_documents/GastroVaricesand2009H

emorrhage.pdf

TIPS

http://www.aasld.org/sites/default/files/guideline_documents/TIPS%20Update%20Nov

%202009.pdf

Hepatic Encephal.

http://www.easl.eu/medias/cpg/issue10/Report.pdf

Interactions between drugs commonly used in cirrhotics and antiretrovirals

Drug Carvedilole Propanolole Torasemide Sorafenib

NRT

I

ATV

DRV

FPV

LPV

NV

P

EFV

RPV

ETV

MR

C

DO

LU

EV/C

OB

I

RA

L

No interaction Lactulose, Furosemide, Vasopressin, Somatostatin, Norfloxacine, Ofloxacine, Ceftriaxone Rifaximine, Neomycine

Potential interaction may require dose monitoring, alteration of drug dosage or timing of admistration

www.hiv-druginteractions.org

CO

BI +

A

TV/D

RV

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Impaired synthesis of albumin edema, ascites reduced plasma binding of drugs

CIRRHOSIS results in several pathophysiologic changes in the liver that may influence pharmacokinetics Histologically it consists of a diffuse process characterized by fibrosis and a conversion of normal organ architecture into structurally abnormal nodules

1. Reduction in liver blood flow 2. Intra- and extra-hepatic

portal-systemic shunting 3. Reduction in the number and

function of hepatocytes 4. Capillarization of the

sinusoids

Loss of fenestration, thickening of the cytoplasm, and development of an organized basement membrane is called capillarization.

Raltegravir in HIV+ Patients With End-Stage Liver Disease: LIVERAL-ANRS 148 Study

Substudy 1 (N=10) Despite an increased RAL exposure, RAL was well tolerated, and no patient had to stop RAL because of AEs

Substudy 2 (N=4) No PK was observed between cyclosporine, mycophenolic acid, and RAL.

Barau C. Clinical Infectious Diseases 2014; 59: 117784

Management of ESLD

ESLD Definition and classification ESLD in HIV: a special population Treatment of complications of cirrhosis Antiviral treatment in ESLD

HIV HBV HCV

Study 0108: Safety of TDF vs FTC/TDF vs ETV in CHB Pts With Decomp Cirrhosis

HBV-infected pts with decompensated liver

disease* (N = 112)

TDF 300 mg (n = 45)

ETV 0.5 mg or 1 mg (n = 22)

FTC/TDF 200/300 mg (n = 45)

Liaw YF, et al. Hepatology. 2011;53:62-72.

Wk 48: interim analysis Wk 168

*Patients with < 2 log10 copies/mL decrease in HBV DNA at Wk 8, with virologic breakthrough ( 1 log10 copies/mL increase from nadir on 2 consecutive determinations or consecutive HBV DNA 400 copies/mL after being < 400 copies/mL), or with HBV DNA levels > 400 copies/mL at or after 24 wks of treatment could begin open-label FTC/TDF; these patients considered failures in efficacy analysis.

Randomized, double-blind phase II study

Study 0108: Efficacy Results at Wk 48

Liaw YF, et al. Hepatology. 2011;53:62-72.

Efficacy Result TDF (n = 45)

FTC/TDF (n = 45)

ETV (n = 22)

HBV DNA < 400 copies/mL, % 70.5 87.8 72.7 Median change in MELD score from baseline (IQR)

-2.0 (-12 to 3)

-2.0 (-18 to 4)

-2.0 (-10 to 1)

CTP score 2 point decrease, % 25.9 48.0 41.7 CTP score 2 point increase, % 0 2.6 0 Median change in serum ALT from baseline, U/L -7.0 -16.5 -25.5

HBeAg loss, % 21.4 26.7 0 HBeAg seroconversion, % 21.4 13.3 0

Improved CTP and MELD Scores in Decomp CHB Patients Treated With

ETV

Shim JH, et al. J Hepatol. 2010;52:176-182.

Chan

ge in

CTP

Sco

re T

hrou

gh

12 M

os 8

6

4

2 8.1 1.7

P < .001

10

12

6.6 2.4

At 12 Mos

At Pretreatment

Chan

ge in

MEL

D Sc

ore

Thro

ugh

12 M

os 16

12

10

2 11.1 3.8

P < .001 18

20

8.8 2.3

At 12 Mos

At Pretreatment

14

8

Deaths due to HCC or liver decompensation after P/R treatment in 440 patients with HCV cirrhosis

Di Marco et al, Gastroenterology, submitted

Grafico1

3SVR/no EV (67 pts)

146

2.415

2123

0%

HCC

LD

3%

14%

2,4%

21%

6%

15%

23%

Foglio1

HCCLDSerie 3

SVR/no EV (67 pts)32

no SVR/no EV (151 pts)1462

SVR/EV (41 pts)2.4153

no SVR/EV (185 pts)21235

Per ridimensionare l'intervallo di dati del grafico, trascinare l'angolo inferiore destro dell'intervallo.

Decompensated Cirrhosis

Ombitasvir/Paritaprevir/Ritonavir + Dasabuvir ( RBV)

Sofosbuvir + Simeprevir ( RBV)

Sofosbuvir + Daclatasvir ( RBV)

Ombitasvir/Paritaprevir/Ritonavir ( RBV)

PegIFN + RBV + sofosbuvir

PegIFN + RBV + simeprevir

Sofosbuvir + RBV

Sofosbuvir/Ledipasvir ( RBV)

IFN-free regimens

IFN-containing regimens

GT

1

1, 4

All

4

1, 4

2, 3

1, 4, 5, 6

All

SVR12 in Compensated and decompensated cirrhosis HCV GT

Ref Treatment Schedule

N with SVR 12 /total (%)

CTP Class A CTP Class B CTP Class C

1 & 4

Poordad EASL 2015

SOFO + DAC + RBV 12 w 11/12 (92%) 30/32 (94%) 9/16 (56%)

Bourliere AASLD 2014 Flamm AASLD 2014 Manns EASl 2015

SOFO + LEDI + R 12 w 305/322 (95%) 48/56 (86%)

36/43 (84%)

SOFO + LEDI + RBV 24 w 188/191 (98%) 48/52 (92%)

32/40 (80%)

Foster EASL 2015

SOFO + LEDI + RBV 12 w 141 /164 (86%)

SOFO + DAC + R 12 w 37/45 ( 82%)

ALL

SOFO + DAC + R12 w 11/12 (92%) 76/93 (82%)

SOFO + LEDI+ R 12 w 305/322 (95%) 225/263 (85%)

SOFO + LEDI + R 24 w 188/191 (98%) 80/92 (87%)

3 Foster EASL 2015

SOFO + LEDI + R 12 w 36/59 ( 61%)

SOFO + DAC + R 12 w 80/114 (70%)

Liver Function Change from Baseline to Follow-Up Week 4

42 Manns, EASL, 2015, GO2

MELD Score Change Change in CTP Class

Majority of patients showed improvements in MELD and CTP scores

*Missing FU-4: n=24

Pre/Post-Transplant (CTP B and C, n=136*) Baseline CTP

A (56) n=73

B (79) n=100

C (1012) n=54

Follow-up Week 4 CTP

A (56) 67 (96) 31 (35) 2 (5)

B (79) 3 (4) 57 (65) 20 (48)

C (1012) 0 0 20 (48)

-10

-8

-6

-4

-2

0

2

4

n=95

(-17)

Chan

ge in

MEL

D Sc

ore

(-11)

(+8)

SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients

no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12

n=22

n=18

HVPG: 5-12 mm Hg

HVPG > 12 mm Hg

X X HCV clearance

X HCV clearance

Effect of SOF+RBV on Hepatic Venous Pressure Gradient SOF+RBV in Compensated and Decompensated Cirrhotics with Portal Hypertension

SOF + RBV

Observation

Week 0 24 48 96 72

Arm 1 n=25

Arm 2 n=25

HVPG Assessment

RBV 10001200 mg

Arm 1 n=25

Arm 2 n=25

All With Paired HVPG n=37

Male, n (%) 18 (72) 20 (80) 28 (76)

Mean age, y (range) 55 (4369) 56 (4469) 55 (4469)

HCV GT 1, n (%) 19 (76) 15 (60) 25 (68)

HCV GT 2, 3, 4, n (%) 2 (8), 2 (8), 2 (8) 1 (4), 8 (32), 1 (4) 2 (5), 8 (22), 2 (5)

Prior HCV treatment 17 (68) 23 (92) 28 (76)

SVR12

SVR12 SOF + RBV

Afdhal, EASL, 2015, LP13

HVPG = hepatic venous pressure gradient

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

HVPG

Cha

nge

(%) n=2

a

30

20 10

0

-10 -20

-30

-40 -50

-60 -70

-80 HV

PG C

hang

e (%

)

Patients with >20% decrease (8/33)

Baseline MELD Score

Number of patients

(%) Albumin >

35 g/L Albumin <

35 g/L

Age 65

Harmed- SAE/MELD worse by 2 9 (32%) 14 (33%)

Helped MELD improved by 2 4 (14%) 6 (14%)

TOTAL 28 43

Risk:Benefit of anti HCV Tx in pts with decompensated cirrhosis observed during 12 w of Tx + 4-12 w FU

NHS England EAP: SOF+NS5ARBV for 12 Weeks

Foster G et al EASL 2015

Management of end stage liver disesae

Key Messages ESLD main cause of death in PLHIV Reduced survival and quality of life Classified by Varices, ascitis status, CTP and MELD best

predictor in the short term Treatment of complication guidelines Accelerated course in HIV Treatment of HIV is mandatory but pK of antiretrovirals may be

changed TDM? Treatment of HBV improvement Treatment of HCV:

Lower rate of eradication but still > 80% HCV eradication may be futile : point of no return ? strategic role in management

of HCV ESLD should be established