Pre-workshop Education Course Evaluation of End...

Massimo Puoti

Dept of Infectious Diseases

ASST

Grande Ospedale Metropolitano Niguarda

Milano

Pre-workshop Education Course

Evaluation of End-stage Liver Disease

12th Co-infection Workshop 20162 Jun 2016 - 3 Jun 2016

Berlin, Germany

Disclosures

Massimo Puoti acted

• in a consultancy capacity for Abbvie, BMS, BoehringerIngelheim, Janssen, GSK, ViiV, Gilead Sciences, MSD

• as a speaker at company-sponsored events for Abbvie, BMS, Boehringer Ingelheim, Janssen, Gilead Sciences, GSK, ViiV, Roche, Roche Diagnostics, MSD, Beckman,

During this lecture data on not licensed products and on off labeluse of licensed products will be discussed

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.

ESLD: definition

• End-stage liver disease (ESLD) is the final decompensationphase in the liver trajectory.

• It is characterized by episodic, acute exacerbations, oftenrequiring hospitalization.

• Life-threatening complications, such as varicealhemorrhage or hepatoma, combine with multiple debilitating symptoms, including ascites, extreme fatigue, pruritus, and cachexia.

• Patients may also experience cognitive decline, rangingfrom mild chronic impairment to severe hepaticencephalopathy and coma.

• Many suffer from psychological distress and depression.

Boyd K et al Hepatology 2012

Diagnosis of Cirrhosis:

the pieces of the puzzle

Blood Tests & US

Fibroscan

Physical examBiopsy

Progression of Cirrhosis

Compensated Advanced ChronicLiver Disease

Liver Stiffness:< 10 not not probable

10-15 suggestive>15 highly suggestive

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-linkingAcellular scar

Nodule size

Insoluble scar & small nodules

Scars & large nodules

HVPG: > 5 > 10 > 12 > 12

Clinical: none noneVarices formation

Ascites

(without VH)

VH

(+ ascites)

Stage:Early stage cirrhosis

Compensated (stage 1)


Decompensated (stage 3)

Decomp(stage 4)

Stages according to D’Amico 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

Evaluation of End Stage Liver Disease

• Diagnosis of Cirrhosis

– HCVRNA + - TE + Blood Tests + US

Increased intrahepatic resitance is the initial mechanism leading toPortal hypertension in Cirrhosis

Fibrous tissue

Regenerative Nodules

Vasoconstriction

Microthrombi?

PORTAL HYPERTENSION

Increased Resistance

Varices

HVPG

HVPG (hepatic vein-portal pressuregradient), measuredby an interventionalradiologist = difference betweenthe free hepatic veinpressure and the wedged hepatic veinpressure

Prognosis in Cirrhosis:HVPG

PROGNOSTIC VALUE OF HVPG IN LIVER CIRRHOSIS

Measurement Significance

1-5 mmHg Normal

6-10 mmHg Preclinical sinusoidal portal hypertension

> 10 mmHg Clinically significant portal hypertension

> 12 mmHg Increased risk for rupture of varices

> 16 mmHg Increased risk of Mortality

> 20 mmHg Treatment failure and mortality in acute variceal bleeding

Hepatic Venous Pressure Gradient as a predictor of decompensation in Cirrhosis

Ripoll et al Gastroenterology 2007

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-Carriè N et al. Hepatology 2008; 4 Vizzuti Hepatology 2007

Liver stiffness as a predictorof HVPG levels and of CSPH

The Portal Hypertesive state is enhanced becausean increase in portal venous inflow

Fibrous tissue


Vasoconstriction

Microthrombi?

PORTAL HYPERTENSION


Varices

Splancnic vasodilation Increased blood flow

Effective Hypovolemia

Activation NeurohumoralSystem

Sodium & Water retentionHypervolemia

Increased Cardiac Output

Metavir F4

Ishak S 5-6

Metavir F4

Ishak S 6

Metavir F4

Ishak S 6

Metavir F4

Ishak S 6




Nodule size



HVPG: > 5 > 10 > 12 > 12


Ascites

(without VH)

VH

(+ ascites)





Decomp(stage 4)






Not Clinically Significant Portal Hypertension (HVPG <10 mmHg) Liver Stiffness < 20KPa & PLT > 150.000No US signs of portal hypeertension No Need EGDS repeat Blood Tests & TE at laest yearly

Clinically Significant Portal Hypertension (CSPH) Liver Stiffness > 20 Kpa &/or PLT < 150000 need for EGDS

Without Varices surveillanceWith Varices

Small folllow upLarge treatment





No CSPH

CSPH

Without Varices

With Varices



1%*

3%*

* 5 years mortality

Baveno VI conference on Portal Hypertension:Surveillance of Oesophageal Varices

ScreeningEndoscopy Results

Liver Disease Stage

Ongoing Liver damage

Follow up EGDS intervals

Treatment

Negative No CSPH/CSPH w/o Varices

Yes 2 years None

Negative No CSPH/ CSPH w/o Varices

No 3 years None

Small Varices CSPH with varices

Yes 1 year None

Small Varices CSPH with varices

No & no cofactors

2 years None

Medium or Large Varices

CSPH with Varices

Any 1 year NSBB or Carvediolol or

EBL

CSPH: Clinically Significant Portal Hypertension. NSBB: Non Specific Beta Blockers EBL Endoscopic Band Ligation

Reducing portal pressure by treating Eeiologyand reducing Increased Resistance and by reducing portal flow

Fibrous tissue


Vasoconstriction

Microthrombi?

PORTAL HYPERTENSION


Varices

Splancnic vasodilation Increased blood flow

Effective Hypovolemia

Activation NeurohumoralSystem

Sodium & Water retentionHypervolemia

Increased Cardiac Output

NSBB or Carvediole

Etiological Treatment

1 block

2 block

Histological outcome during long-term Entecavir treatment

• 57 patients with CHB, at least 3 years of Entecavir therapy and paired liver biopsy (median interval bw biopsies: 6yr)

• Histological improvement (2-point ↘ in the HAI and no worsening of the fibrosis score) was observed in 96% of patients,

• 88% of patients improved Ishak score of fibrosis, including all patients with advanced fibrosis or cirrhosis at baseline (100%)

The majority of patients with chronic hep B who were treated with entecavir achieved regression of fibrosis or cirrhosis

Chang TT, et al. Hepatology 2010; 52:886-93

Adapted from Chang TT, et al. Hepatology 2010; 52:886-93

0

10

20

30

40

50

60

Baseline Week 48 Long-term

Nu

mb

er

of

pat

ien

ts

B

0

10

20

30

40

50

60

Baseline Week 48 Long-term

Nu

mb

er

of

pat

ien

ts

A

Knodell HAI

10-14

7-9

4-6

0-3

Missing

Ishak Fibrosis Score

6

5

4

3

2

1

0

Missing

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

4

0

2

0

1

0

3

0

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

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 9672

Arm 1

n=25

Arm 2

n=25

HVPG Assessment

RBV 1000–1200 mg

Arm 1n=25

Arm 2n=25

All With Paired HVPG n=37

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

Mean age, y (range) 55 (43–69) 56 (44–69) 55 (44–69)

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

SVR12SOF + 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

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 varices may decrease in size

a a a



• Diagnosis of Portal Hypertension and Esophageal Varices

– US

– HVPG ( restricted to small subgroups)

– EGDS

• F1 (small) +/-red signs

• F2 (medium) +/-Red Signs

• F3(large) +/-Red Signs

Metavir F4

Ishak S 5-6

Metavir F4

Ishak S 6

Metavir F4

Ishak S 6

Metavir F4

Ishak S 6




Nodule size



HVPG: > 5 > 10 > 12 > 12


Ascites

(without VH)

VH

(+ ascites)





Decomp(stage 4)






DecompensatedCirrhosis

Variceal Haemorrage

One Non Bleeding Complications AscitesHepatic Encephalpathy

Two Complications

20%*

30%*

88%*

* 5 years mortality

Cirrhosis: Diagnosis of complicationsAscites

• Identification: US and Physical exam

• Evaluation: Paracentesis ( First Episode or Suspect of Spontaneous Bacterial Peritonitis)

• Classification– Not Complicated

• Mild ( Volume & Diuretic Response)

• Moderate (Volume & Diuretic Response)

Cirrhosis: Diagnosis of complicationsHepatic Encephalopathy

• DEFINITION OF HE IN CIRRHOSIS Hepatic encephalopathy is a braindysfunction caused by liver insufficiency; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging fromsubclinical alterations to coma.

• According to its time course, HE is subdivided into– Episodic HE

– Recurrent HE denotes bouts of HE that occur with a time interval of 6 monthsor less.

– Persistent HE denotes a pattern of behavioral alterations that are alwayspresent and interspersed with relapses of overt HE.

• According to the existence of precipitating factors, HE is subdividedinto– Nonprecipitated or

– Precipitated, and the precipitating factors should be specified. Precipitatingfactors can be identified in nearly all bouts of episodic HE type C and should beactively sought and treated when found

Hepatic Encephalopathy: precipitating factors

Cirrhosis: Diagnosis of complicationsHepatic Encephalopathy: Grading




• Diagnosis and Clasification of Complications– Non complicated Ascites:

• Identification: US, History & Physical examination

• Evaluation

– Paracentesis ( 1° Episode or Suspect of PBS)

• Grading ( volume + Diuretic response)

– Hepatic Encephalopathy

• Identification : Neuropsychological tests only in special circumstances toifdentify covert forms

• Grading: according to Physical examination and Histiry

• Classification: Time course & precipitating factors




Further Decompensation

Death

Worsening Vasodilation

Systemic Inflammation

Infection/Microbial translocation

AntibioticsEnoxaparinAlbumin




Further Decompensation

Death

Recurrent VH

Complicated AscitesPBSRefractoryHyponatremiaHepatorenal Syndrome

Type I Type II

Hepatic FailureProlonged INRLow AlbuminaHigh Bilirubin (Jaumìndice)

Complications of AscitesRefractory Ascites and SBP

• REFRACTORY ASCITES is defined as fluid overload that– is unresponsive to sodium-restricted diet and highdose diuretic treatment

(400 mg per day of spironolactone and 160 mg per day furosemide), or– recurs rapidly after

• Failure of diuretic therapy may be manifested by– minimal to no weight loss together with inadequate (<78 mmol per day)

urinary sodium excretion despite diuretics, or – development of clinically significant complications of diuretics, e.g.,

encephalopathy, serum creatinine greater than 2.0 mg/dL, serum sodium lessthan 120 mmol/L, or serum potassium greater than 6.0 mmol/

• SPONTANEOUS BACTERIAL PERITONITIS dx made in the presence of an elevated ascitic fluid absolute polymorphonuclear leukocyte (PMN) count (i.e., ≥250 cells/mm3 [0.25 x 109/L]) without an evident intra-abdominal, surgically treatable source of infection

Complications of Ascites:Hepato Renal Syndrome

• Diagnostic Criteria– cirrhosis with ascites;

– serum creatinine greater than 1.5 mg/dL;

– no improvement of serum creatinine (decrease to a level of 1.5 mg/dL or less) after at least twodays with diuretic withdrawal and volume expansion with albumin (The recommended dose ofalbumin is 1 g/kg of body weight per day up to a maximum of 100 g/ d);

– absence of shock;

– no current or recent treatment with nephrotoxic drugs;

– absence of parenchymal kidney disease as indicated by proteinuria >500 mg/day, microhematuria(>50 red blood cells per high power field), and/or abnormal renal ultrasonography.

• Type I is characterized by rapidly progressive reduction in renal function as definedby a doubling of the initial serum creatinine to a level greater that 2.5 mg/dL or a 50% reduction of the initial 24-hour creatinine clearance to a level lower that 20 mL per minute in less than 2 weeks.

• Type II does not have a rapidly progressive course and is a commonly associatedwith death in patients who do not die of other complications of cirrhosis

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

Sofosbuvir and Velpatasvir forHCV

in Patients withDecompensated Cirrhosis.Changes in CPT and MELD

Scoresfrom Baseline.

Long-Term Effect of Antiviral Therapy on DiseaseCourse After Decompensation in Patients With

Hepatitis B Virus–Related Cirrhosis

Jang et al Hepatology 2015

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 compensatedcirrhosis vs those with decompensated cirrhosis

1 year risk

D’Amico G, et al. J Hepatology. 2006;44:217-231

Concomitant alterations

• Malnutrition & Sarcopenia (Impact on prognosis after Liver transplantation)

– Global assessment of nutritional status by Physicalexamination and blood tests

• Royal Free Hospital-Global Assessment (RFH-GA) tool

– Physical examination

• In some cases L3-psoas muscle index (L3-PMI) on CT




• Diagnosis and Clasification of Complications

– Non complicated Ascites:

– Hepatic Encephalopathy

• Assessment of complications of Ascites

– PMN cell counts and ascitic fluid culture if PBS is suspected

– Assessment of Response to and safety of Diuretics ( Body weight, Creatinine Electrolyte)

• Assessment of Liver Function with CTP and MELD scores

– INR

– Albumina

– Creatinine

– Bilirubin

• Assessment of Nutritional status and Sarcopenia

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