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