This program is supported by educational grants from · 1 million 0 million 10% Reduction 65% Reduction 2 million 1,8 million 1,6 million 1,4 million 1,2 million 1 million 0,8 million

This program is supported

by educational grants from

Dova Pharmaceuticals, Inc.,

Mallinckrodt Pharmaceuticals,

and Salix Pharmaceuticals

Disclosures

All faculty and staff involved in the planning or presentation of continuing education activities

provided by the Annenberg Center for Health Sciences at Eisenhower (ACHS) are required

to disclose to the audience any real or apparent commercial financial affiliations related to

the content of the presentation or enduring material. Full disclosure of all commercial

relationships must be made in writing to the audience prior to the activity. Staff at the

Annenberg Center for Health Sciences at Eisenhower and the Chronic Liver Disease

Foundation (CLDF) have no relationships to disclose.

Planning Committee Member

Lisa D. Pedicone, PhD – Nothing to disclose.

Faculty

All faculty disclosures can be found in your meeting guide.

4

Breaking News in Chronic Liver Disease

Kimberly Brown, MD, FAST,

FAASLD, AGAF

Acute Hepatitis C on the Rise

CDC (2013-2016): Estimated HCV Prevalence Among Adults in the United States

• HCV antibody positive (including past

and current infection)

– Number: 4.1 million (95% CI 3.4-4.9)

– Prevalence: 1.7% (95% CI 1.4-2.0)

• HCV RNA positive

(including current infection)

– Number: 2.4 million (95% CI 2.0-2.8)

– Prevalence: 1.0% (95% CI 0.8-1.1) 0

1

2

3

4

5

Nu

mb

er

(in

mil

lio

ns)

73%

3.5

Number (in millions) With HCV Infection

NHANES NHANES adjusted

HCV Ab Positive

HCV RNA Positive

HCV Ab Positive

HCV RNA Positive

2003-2010 2013-2016

2.7

57%

2.4

2.1

Estimated adult US population in 12/2016: 245 million.

Datasets analyzed: National Health and Nutrition Examination Survey (noninstitutionalized civilian population).

Combination of literature reviews and population size estimation approaches (incarcerated people, unsheltered homeless people, active-duty

military personnel, and nursing home residents).

Hofmeister MG, et al. Hepatology. 2019 Mar;69(3):1020-1031. doi: 10.1002/hep.30297. Epub 2018 Nov 6. 7

Changing Trends in Acute HCV in the US (2001-2016)

• New acute HCV infection in 2016

– Reported cases (n=2967)

– Estimated (n=41,200, adjusted for under-

ascertainment and under-reporting)

• 3.5-fold increase in new cases since 2010

– Reflects new infections associated with

rising rates of injection-drug use

• Most newly acquired acute HCV infections

occurred among young, white, PWIDs,

who live in non-urban areas (i.e.,

Appalachian, Midwestern, and New

England states)

Acute HCV Rate in US 2001-2016

CDC. Surveillance for viral hepatitis - United States, 2016. https://www.cdc.gov/hepatitis/statistics/2016surveillance/index.htm

0

0.5

1

1.5

2

2.5

3

2001 2004 2007 2010 2013 2016

Rate

(p

er

100,0

00 p

op

ula

tio

n)

Year

0-19 yrs

20-29 yrs

30-39 yrs

40-49 yrs

50-59 yrs

> 60 yrs

8

Populations at Risk

1960s Up to 300,000 cases

of acute HCV per year; risk of

exposure via blood

transfusion up to 33%

30-70% prevalence

Baby Boomers (born 1945-1965) People Who Inject

Drugs (PWID)

1992 Widespread

introduction

of HCV antibody

testing

1970s Volunteer donor system

reduces risk of exposure

via blood transfusion

1989 HCV

discovered

Alter HJ. Nat Med. 2000;6:1082-1086. 9

CDC report identified >220

counties vulnerable to outbreaks of

HIV and HCV among people who

inject drugs

Risk Factors – Unemployment rates

– Overdose deaths

– Prescription opioid sales

Counties Vulnerable to Outbreaks of HIV and Hepatitis C

Geographic Areas Most at Risk for HCV

Van Handel MM. J Acquir Immune Defic Syndr. 2016;73:323. 10

WHO Goal:

Global Elimination of Viral Hepatitis

Global Health Sector Strategy:

Eliminate Viral Hepatitis as a Major Public Health Threat by 2030

30%

Reduction

90%

Reduction

NEW INFECTIONS

DEATHSHEPATITIS B + C HEPATITIS B + C

2015 2020 2025 2030 2015 2020 2025 2030

10 million

9 million

8 million

7 million

6 million

5 million

4 million

3 million

2 million

1 million

0 million

10%

Reduction 65%

Reduction

2 million

1,8 million

1,6 million

1,4 million

1,2 million

1 million

0,8 million

0,6 million

0,4 million

0,2 million

0 million

Reduction in new infections by 90% Reduction in deaths by 65%

Programmatic Targets

90% of people

infected are

diagnosed

80% of people

diagnosed are

treated

90% coverage of BD

and B3 doses

(PAHO: 95%)

100% of blood

products are safe

90% of injections in

health facilities

are safe

Impact Targets

12

HCV No Longer a Disease Limited to Baby Boomers H

CV

Cases (

nu

mb

er)

2005

0

50

100

150

200

250

300

350

400Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

2012

0

50

100

150

200Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

2015

0

50

100

150

200Male

Female

20 30 0 10 60 70 40 50 80 90

Age (years)

Data for New York State (excluding NYC).

https://www.health.ny.gov/statistics/diseases/communicable/index.htm. 13

https://www.health.ny.gov/statistics/diseases/communicable/index.htm

Claims data for HCV Ab screening from a single large commercial payer (CPT and ICD-9 codes):

Screened (n=1,056,583); not screened (n=1,243,581).

Factors that increased the odds of getting screened: female gender, Medicare, presence of comorbidities.

Mehta D, et al. J Hepatol. 2018;68(suppl S1):S177. Abstract THU-113.

Effectiveness of HCV Screening in the US (2010-2016)

• In the US, to meet the 2030 diagnosis

targets, this means diagnosing at least

– 110,000 cases/year until 2020

– 89,000 cases/year between 2020-2024

– >70,000 cases/year between 2025-

2030

• At the current screening rate, 92% of

US states are not on target to meet

WHO screening goals of HCV

elimination by 2030

14

Timeline to Achieve WHO Screening Target for HCV Elimination

Reach WHO Target by: 2030 2040 2050 Beyond 2050

Negative

Positive

Test for

Quantitative HCV RNA

Refer to specialist for Disease

Staging and Management Plan

Positive

Negative Retest in

6 months

STOP

Genotyping testing

also recommended

Screening Test for Anti-HCV

HCV Screening Is Straightforward: Algorithm for Screening/Diagnosis

Modified from http://www.cdc.gov/hepatitis/HCV/PDFs/hcv_flow.pdf.

Ghany MG, et al. Hepatology. 2011;54(4):1433-1444. 15

HCV Continuum of Care Among PWIDs: Philadelphia Department of Health

• Random sample of newly reported

HCV antibody positive persons

(n=29,820; 2013-2017)

– Interviewed and disclosed being a

PWID (n=2390)

• Measurable gaps exist in the HCV

continuum of care for PWIDs,

especially those ≤35 years of age

– Among those HCV RNA positive

• Only 25% and 8% of PWIDs >35

and ≤35 years of age, respectively,

were treated

• Need for enhanced navigation

to services

0

20

40

60

80

100

Pati

en

ts (

%)

81% 85%

90%

75%

HCV Continuum of Care Among

HCV Ab-Positive PWIDs

Years of age

>35 (n=1151)

≤35 (n=1239)

Ever Tested for HCV RNA

HCV RNA Positive

Initiated HCV Care

Treated

66%

25%

41%

8%

Addish E, et al. Hepatology. 2018;68:929A-930A. Abstract 1632. 16

Important New Treatment for

Primary Biliary Cholangitis

PBC is characterized by destruction of the interlobular and septal bile ducts

that may lead to cirrhosis

Immune

response

Bile duct

damage

Environment

Genetics

Primary Biliary Cholangitis (PBC) Is a Chronic, Progressive Autoimmune Disease

• Factors possibly associated with onset

and perpetuation of bile-duct injury in PBC

Poupon R. J Hepatol. 2010;52(5):745-758; Selmi C, et al. Lancet. 2011;377(9777):1600-1609;

Carey EJ, et al. Lancet. 2015;386(10003):1565-1575. 18

Farnesoid X Receptor Signaling

Bile Acids

(Primary ligands

for FXR)

↓ Bile Acid

Synthesis

and

Uptake

↑ Gene

Expression (BSEP, MDR3, MRP

2/3/4, OST α/β)

↓ Gene

Expression (CYP7A1, NTCP,

OATP)

FXR

(Hepatocytes, biliary

epithelium, small

bowel enterocytes,

renal tubular cells,

adrenal cells,

adipocytes, beta

cells)

Binding

Direct

Effects

Indirect

Effects

↑ Bile Acid

Efflux

Abbreviations: BSEP, bile salt export pump; FXR, farnesoid X receptor; MRP 2/3/4, multidrug resistant protein 2/3/4;

NTCP, sodium/taurocholate cotransporting polypeptide; OATP, organic anion transporting polypeptide; OST α/β, organic soluble transporter α/β.

Neuschwander-Tetri BA. Curr Gastroenterol Rep. 2012;14:55-62. 19

Obeticholic Acid (OCA): Approved FXR Agonist for PBC

• PBC: OCA is associated with statistically significant, clinically

meaningful improvements

– Biochemical criteria correlated with clinical benefit (alkaline

phosphatase and bilirubin)

– Markers of inflammation (C-reactive protein) and apoptosis (CK18)

• Nonalcoholic steatohepatitis (NASH): Phase 3 topline results

released February 19th

– OCA showed statistically significant improvement in liver fibrosis without

worsening of NASH at 18 months

– Very active research area; however, OCA is expected to be the first FDA

approved drug for NASH 20

Long Term Side Effects Reduced with

New Treatment for Hepatitis B

*Nonresponders included pts with HBV rebound or genotypic resistance, primary nonresponse, NE due to early event (death, LT, LTFU).

Jang JW, et al. Hepatology. 2015;61:1809-1820.

HBV Therapy Reduces Risk of Disease Progression

• Patients with HBV and first-onset complications of decompensated cirrhosis treated

predominantly with lamivudine or entecavir

• Antiviral therapy improved transplant-free survival over mean follow-up of 49 mos

(P = .0098 vs untreated)

Treated, responder (n = 245)

Treated, nonresponder* (n = 178)

Untreated (n = 284)

Bonferroni-adjusted P < .0003 LT-F

ree

Su

rviv

al (%

)

Mos 0 84 12 24 36 48 60 72

100

80

60

40

20

0

22

The Evolution of HBV Therapy

1998 2002 2005 2006

1992 2008 2016

Lamivudine Entecavir Telbivudine Tenofovir

Alafenamide

IFN-α Adefovir PegIFN-α Tenofovir Disoproxil Fumarate

23

Guidelines: What to Start as Initial HBV Therapy

Treatment Preferred Notes

Entecavir Yes High potency, high genetic barrier to resistance

TAF Yes High potency, high genetic barrier to resistance

TDF Yes High potency, high genetic barrier to resistance

PegIFN

Should only be considered as initial therapy

for pts with mild/moderate CHB or

selected pts with compensated cirrhosis

(no portal hypertension)

Less safe in pts with cirrhosis, contraindicated in

pts with decompensated cirrhosis

Adefovir No Low genetic barrier to resistance

Lamivudine No Low genetic barrier to resistance

Telbivudine No Low genetic barrier to resistance

ETV, TDF, TAF have very favorable safety and resistance profiles

TAF= Tenofovir alafenamide

TDF= Tenofovir disoproxil fumarate

Terrault NA, et al. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. 24

Chronic Hepatitis B: Newest Therapy (Tenofovir AF)

• Higher levels of TFV-diphosphate

in target cells at lower doses than

tenofovir DF

• Tenofovir AF has a lesser effect on

the proximal

renal tubule

• 90% lower TFV levels in plasma

minimizes renal

and bone effects while maintaining

high potency for suppressing HBV

HBV TARGET CELL PLASMA

TAF 25 mg TFV HBV

TDF 300 mg

TFV

TFV

TFV

GI Tract

25 TFV= Tenofovir

TAF TDF

HBeAg loss, n/N (%) 135/565 (24) 39/175 (22)

HBeAg seroconversion, n/N (%) 105/565 (19) 23/175 (13)

HBsAg loss, n/N (%) 9/857 (1) 3/251 (1)

HBsAg seroconversion, n/N (%) 7/857 (1) 1/251 (<1)

No resistance to TAF and TDF was detected through Week 144

p =0.71 87 85

20

40

60

80

100

TAF TDF

74 71

0

20

40

60

80

100

TAF TDF

p=0.59

Study 108 and 110 Pooled Analysis: TAF vs TDF at 144 Weeks

HBeAg-Negative HBeAg-Positive

HB

V D

NA

<29 IU

/mL

, %

248/285 63/74 428/581 127/178

Chan. AASLD 2018. Abstracts 0381 and 0386. 26

HBeAg-Negative

71

59

0

20

40

60

80

100

188/

264

Pati

en

ts,

%

43/

73

TDF TAF

P=0.052

64

53

0

20

40

60

80

100

362/

567

Pati

en

ts,

%

91/

172

TDF TAF

P=0.01

There were higher rates of ALT normalization by AASLD 2018 criteria in

patients on TAF compared to TDF

HBeAg-Positive

ALT Normalization at Week 144

AASLD 2018 criteria ULN: males ≤ 35 U/L, females ≤ 25 U/L.

Chan. AASLD 2018. Abstract 0381.

Study 108 and 110 Pooled Analysis: TAF vs TDF at 144 Weeks

27

Change in Renal Parameters Over 144 Weeks

There were significantly smaller decreases in eGFRCG and smaller changes in proximal

tubular markers with TAF compared to TDF at Week 144

Med

ian

Ch

an

ge F

rom

Baseli

ne,

mL

/min

(Q

1, Q

3)

TAF TDF

−1.2

−6.0

p<0.001

Week

144 120 96 72 48 24 0 -20

-10

0

10

-5

0

50

100

150

200

250

β2-Microglobulin:Cr

54.2

102.7

23.1

120.7

Med

ian

% C

han

ge F

rom

Baseli

ne (

Q1, Q

3)

p<0.001* p<0.001*

Change in eGFRCG

388.5

Retinol-Binding

Protein:Cr

*From 2-sided Wilcoxon rank-sum test.

Chan. AASLD 2018. Abstract 0381. 28

There were significantly less declines in hip BMD in patients on TAF compared to TDF

Changes in Bone Mineral Density (BMD) in Patients Over 144 Weeks

Hip TAF TDF

Week

-0.41

-2.49

144 120 96 72 48 24 0 -8

-6

-4

-2

0

2

4 M

ea

n c

han

ge f

rom

baseli

ne,

% (

SD

)

p<0.001*

*From analysis of variance model including treatment as fixed effect. †From Cochran-Mantel-Haenszel test for ordinal data (row mean scores differ statistic was used).

Chan. AASLD 2018. Abstract 0381. 29

> 3%

≤ 3%

≤ 3%

≤ 3%

≤ 3%

> 3%

P<0.001†

0

20

40

60

80

100

TAF TDF

Pati

en

ts,

%

Improvement Decline

> 3%

> 3%

E/C/F/TAF vs E/C/F/TDF in HIV Infection: Wk 144 Renal and Bone Outcomes

• Randomized phase III trials conducted

in treatment-naive HIV-infected pts

with eGFR ≥ 50 mL/min

Renal Events Leading to

Discontinuation, n

E/C/F/TAF (n = 866)

E/C/F/TDF (n = 867)

Proximal renal tubulopathy 0 4

Cr elevation or

eGFR decrease 0 3

Renal failure 0 2

Nephropathy 0 1

Proteinuria 0 1

Bladder spasm 0 1

Total 0 12

Change in Spine and Hip BMD Through Wk 144*

2

0

-2

-4 Mean

% C

han

ge

(95

% C

I)

-1.3 -1.0 -0.9

-2.8 -3.0

∆ 2.0

E/C/F/TAF E/C/F/TDF

P < .001 for all

Spine

0 48 96 144 Wk n =

n = 845 850

797 816

795 790

744 745

702 686

2

0

-2

-4 Mean

% C

han

ge

(95

% C

I)

-0.7 -0.6 -0.8

-2.9 -3.3 -3.4

∆ 2.6 Hip

0 48 96 144 Wk n =

n = 836 848

789 815

791 784

735 742

690 683

E, elvitegravir; C, cobicistat; F, emtricitabine; TAF, tenofovir alafenamide.

*P values calculated using analysis of variance model including treatment as a fixed effect.

Arribas JR, et al. CROI 2017. Abstract 453. 30

Clinical Case Forum I: Current and

Emerging Management Approaches for the

Cirrhotic Patient with Thrombocytopenia

Sammy Saab, MD, MPH, AGAF,

FACG, FAASLD

History of Present Illness – June 2018

MEDICATIONS LABS PROGRESS

NOTES

OTHER HISTORY

& PE

47 year old male with

decompensated alcohol-

related cirrhosis

• 47 year old gentleman with decompensated alcohol-

related cirrhosis returns to clinic after being recently

admitted and banded for bleeding esophageal varices.

– Pertinent admission labs:

• HB 5.2, PLT 32, INR 1.4, TB 1.2

– Required 6 bands.

– Transfused PRBCs and Platelets

• Follow up outpatient endoscopy with additional

banding recommended.

32



related cirrhosis

Patient Case


NOTES

OTHER HISTORY

& PE

• Family History

– No family history of liver disease.

• Social History:

– No history of injectable drugs. Stopped

drinking alcohol about 3 years ago. Not

currently working.

33



related cirrhosis

Past Medical History


NOTES

OTHER HISTORY

& PE

• PMH:

– Alcohol related cirrhosis

– Diabetes

– No hypercoagulable state

• PSH:

– Noncontributory

34

HISTORY

& PE



related cirrhosis

Past Medical History

LABS PROGRESS

NOTES

OTHER

• Medications:

– Propranolol

– Diabetes

• Allergies:

– None

35

MEDICATIONS



related cirrhosis

Physical Examination


NOTES

OTHER HISTORY

& PE

• 98.7 temp; 65 heart rate, 110/65.

• General: Overweight.

• Neurology: A&O x 4. No asterixis.

• Neck: Supple. Oral cavity not examined.

• Heart: Regular rate and rhythm. No murmurs, rubs, or gallops.

• Lungs: Clear to auscultation. No wheezes, rhonchi, or rales.

• Skin: Spider angiomas and palmar erythema. No caput medusa. No

fluid wave.

• Abdomen: Overweight. Splenomegaly. Normoactive bowel sounds.

• Extremity: No edema.

36



related cirrhosis

HISTORY

& PE

Outpatient Labs

MEDICATIONS PROGRESS

NOTES

OTHER

WBC 2.7 INR 1.2

HB 10.9 Na 137

PLT 37 CR 1.1

ALB 3.8 MELD 11

TB 1.4

AST 52

ALT 48

AP 119

STUDIES

37

Laboratory

Thrombocytopenia in CLD

• Thrombocytopenia is a common problem in patients with

cirrhosis (platelets <100,000)

– Estimated to affect up to 70% of CLD patients

– Extent worsens with severity of portal hypertension and disease

– Patients may be ineligible for elective surgical or diagnostic

procedures due to risk of bleeding

– Increases risk of mortality

– Increases risk of poor clinical outcomes

Mitchell O, et al. Hepatic Medicine: Evidence and Research. 2016;8:39-50; Maan, et al. Drugs. 2015;75(17):1981-92;

Giannini EG. Aliment Pharmacol Ther. 2006;23:1055-65. 38

Etiologies of Thrombocytopenia in Chronic Liver Disease

• Splenic sequestration secondary to

portal hypertension

• Direct bone marrow suppression secondary

to viruses, alcohol, iron, or drugs

• Increased destruction secondary

to anti-platelet antibodies, shear stress,

infection, or increased fibrinolysis

• Decreased production of thrombopoietin

(TPO) by the liver

Mitchell O, et al. Hepatic Medicine: Evidence and Research. 2016;8:39-50; Maan, et al. Drugs. 2015;75(17):1981-92;

Afdhal N et al. Journal of Hepatology. 2008;48:1000-1007. 39



related cirrhosis

HISTORY

& PE

Radiology

MEDICATIONS PROGRESS

NOTES

OTHER

STUDIES

40

• Abdominal ultrasound

– Nodular liver

– No hepatocellular carcinoma

– No ascites

– Portal vein patent

HISTORY

& PE



related cirrhosis

History of Present Illness – July 2018

MEDICATIONS LABS OTHER

• Patient referred to outpatient

EGD with banding.

• Because of thrombocytopenia,

platelet transfusion also ordered.

41

PROGRESS

NOTES

Platelet Transfusions: Benefits and Considerations

Benefits:

• Prevent the risk of bleeding:

– Thrombocytopenic patients

– Patients with

platelet dysfunction

• Control bleeding in patients with

active bleed

Considerations:

• Risk of infections

• Hemolytic/Febrile

non-hemolytic/Allergic/

Anaphylactic Reactions

• Refractoriness

(immune vs nonimmune)

• Storage logistics

• Patient scheduling logistics

• Limited shelf life

• Cost

• Supply vs demand

42

HISTORY

& PE



related cirrhosis

History of Present Illness – July 2018


• Patient returns for follow up

• Said he will never undergo endoscopy again

– Developed platelet transfusion reaction with fever

and rigor

• Discussed risks of recurrent esophageal

variceal bleeding

43

PROGRESS

NOTES

Current Landscape in Patients with Thrombocytopenia and CLD

• Patients require 1-3 procedures annually

• Different procedures are associated with different risks of bleeding

– Procedures are required to clinically manage patients with CLD

– Thrombocytopenia can lead to serious uncontrolled bleeding in these

patients negatively impacting clinical care

• Prolonged hospitalizations

• Serious complications

• Poor clinical outcomes

• Historically, the only treatment option was platelet transfusion

Szczepiorkowski ZM and Dunbar NM. Hematology Am Soc Hematol Educ Program. 2013;2013:638-44;

Lin Y and Foltz LM. BCMJ. 2005;47(5):245-248. 44

Thrombopoietin Receptor Agonists

• Mimics effects of

thrombopoietin (TPO) to

increase platelet production

• Binds to a different region of

the TPO receptor and does not

block native TPO

• Predictable PK/PD profile

45

TPO agonist

PRE-RANDOMIZATION FOLLOW-UPRANDOMIZATION(2:1 avatrombopag:placebo)

mean Baseline PC<40 x 109/L

mean Baseline PC40 to <50 x 109/L

Screening PeriodDay -14 to -1

BASELINE

DAY 1

TREATMENT

DAY 2-5

PROCEDURE*

DAY 10-13

7 DAYS POST

PROCEDUREDAY 35

6 TISIV5 TISIV4 TISIV3 TISIV2 TISIV1 TISIV

Low BaselinePlatelet Count Cohort

High BaselinePlatelet Count Cohort

5-8 days afterlast dose ofstudy drug

30 days afterlast dose ofstudy drug

60 mg AVATROMBOPAGqd x 5 Days

40 mg AVATROMBOPAGqd x 5 Days

PLACEBO

PLACEBO

R2:1

R2:1

Avatrombopag Phase 3 Study Design ADAPT-1 & ADAPT-2 (N=435)

*Platelet transfusions were not mandatory

AASLD 2017 46

Study Endpoints

• Primary Endpoint:

– Proportion of patients who do not require a platelet transfusion or any

rescue procedure for bleeding after randomization and up to 7 days

following a scheduled procedure

• Secondary Endpoints:

– Proportion of patients achieving target platelet count of ≥ 50 × 109/L on

Procedure Day

– Change in platelet count from Baseline to Procedure Day

– Safety

47

22.9%

65.6%

38.2%

88.1%

0%

20%

40%

60%

80%

100%

p<0.0001 p<0.0001

RESULTS: Patients Who Did Not Require Platelet

Transfusion or Rescue Procedure for Bleeding

48

Pati

en

ts (

%)

Low Baseline Platelet

Count Cohort

<40 x 109/L

High Baseline Platelet

Count Cohort

40 to <50 x 109/L

4.2%

68.9%

20.6%

88.1%

0%

20%

40%

60%

80%

100%

p<0.0001 p<0.0001

Low Baseline Platelet

Count Cohort

<40 x 109/L

High Baseline Platelet

Count Cohort

40 to <50 x 109/L

Adapt 1 (231 patients) Adapt 2 (204 patients)

Terrault N et al. Abstract 217. AASLD 2017.

Mean Platelet Counts by Treatment Group and Visit Day

Low Baseline Platelet Count Cohort:

HighBaseline Platelet Count Cohort:

60 mg AvatrombopagPlacebo

40 mg AvatrombopagPlacebo

0 5 10 15 20 25 30 35

90

80

70

60

50

40

30

Me

an

Pla

tele

t C

ou

nt

x 1

09/L

DaysDosing

Visit 2

Day 1

Visit 3

Day 4

Visit 4

Day 10

Visit 5

Day 17

Visit 6

Day 35

Baseline Procedure Day49

Combined ADAPT-1 & ADAPT-2 Safety

Combined Safety Data

Low Baseline Platelet Count Cohort

<40 x 109/L

High Baseline Platelet Count Cohort

40 to <50 x 109/L

Placebo

(n=91)

%

Avatrombopag

60 mg

(n=159)

%

Placebo

(n=65)

%

Avatrombopag

40 mg

(n=115)

%

TEAEs, n (%) 53 (58.2) 89 (56.0) 33 (50.8) 59 (51.3)

Pyrexia (fever) 8 (8.8) 18 (11.3) 6 (9.2) 9 (7.8)

Abdominal pain 6 (6.6) 10 (6.3) 4 (6.2) 8 (7.0)

Nausea 7 (7.7) 10 (6.3) 4 (6.2) 8 (7.0)

Headache 7 (7.7) 7 (4.4) 3 (4.6) 8 (7.0)

Diarrhea 4 (4.4) 7 (4.4) 2 (3.1) 3 (2.6)

Fatigue 4 (4.4) 7 (4.4) 1 (1.5) 3 (2.6)

Portal vein thrombosis 0 1 (0.6) 0 0

50 Terrault, Norah et al. Gastroenterology. Volume 155, Issue 3, 705 – 718.

Lusutrombopag Study Design

• Phase 3, multinational, randomized, double-blind, placebo-controlled study

– Conducted at 138 study sites in 22 countries

• Platelet transfusion was required by the protocol if a patient’s post treatment pre-procedural

platelet count was below 50 x 109/L

US/CT/MRI on portal vein US/CT/MRI on portal vein

ICF

108

pts LUSU (3 mg/day)

Invasive

Procedure Follow-up

107

pts PBO Day 9 to 14 Day 35

Screening (0 - 4 weeks) Treatment period* (up to 7 days) Post-treatment period (28 days)

Rando

miz

atio

n

*If a patient met the stopping criterion on Day 5, 6 and 7 (platelet count ≥ 50 x 109/L with an increase of ≥ 20 x 109/L from baseline),

no additional dose of study drug was administered.

CT, computed tomography; ICF, informed consent form; LUSU, lusutrombopag; MRI, magnetic resonance imaging; PBO, placebo; US, ultrasonography.

Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561. 51

Endpoints

• Primary endpoint:

– Proportion of patients who required no platelet transfusion prior to the primary

invasive procedure and no rescue therapy for bleeding from randomization

through 7 days after the primary elective procedure

• Key secondary endpoints (prespecified in the SAP):

– Proportion of patients who required no platelet transfusion during

the study

– Proportion of responders: patients who achieved a platelet count ≥50 x 109/L with

an increase of ≥20 x 109/L from baseline at any time during the study

– Number of days during which the platelet count was ≥50 x 109/L

SAP, statistical analysis plan.


Lusutrombopag

29

64.8

0

10

20

30

40

50

60

70

No platelet transfusions or rescue therapy (%)

Placebo Lusu

13

64.8

0

10

20

30

40

50

60

70

Platelet > 50K and increased > 20K (%)

Placebo Lusu

Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561.

Pa

tie

nt

%

53

0

20

40

60

80

100

120

1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35

LUSU (n=74)

PBO (n=73)

Mean

Pla

tele

t C

ou

nt

(x 1

09/L

) ±S

D

Study Drug

Administration

Invasive

Procedure

Platelet Response (ITT Population)

LUSU: platelet count in patients who did not receive platelet transfusion.

PBO: platelet count in patients who received platelet transfusion.

Peck-Radosavljevic, M et al. Hepatology. Feb 2019. https://doi.org/10.1002/hep.30561.

Day

54

Lusutrombopag

Lusutrombopag Placebo

TEAE 47.7 % 48.6%

SAE 6.5% 6.5%

Bleeding related

TEAE 3 6

PVT 1 2

TEAE: Treatment Emergent Adverse Events

SAE: Serious Adverse Events


HISTORY

& PE



related cirrhosis

History of Present Illness – July 2018 (cont.)


• Discussed TPO receptor agonists as an alternative to

platelet transfusion.

• Searched Package Insert for drug interactions and signature

adverse events.

• Undergoes repeat EGD with banding. Platelet count doubles

measured immediately prior to procedure.

– 34 to 67

• Patient tolerated TPO receptor agonist and endoscopy.

• Additional EGD with banding recommended.

56

PROGRESS

NOTES

HISTORY

& PE



related cirrhosis

History of Present Illness – August 2018


• Undergoes 3rd repeat EGD with banding.

Platelet count doubles again.

– Platelet increases from 31 to 59

• Additional EGD recommended in 3 months.

57

PROGRESS

NOTES

Conclusions

• Patients with cirrhosis often need multiple invasive procedures

• Thrombocytopenia is common in patients with cirrhosis

• Severe thrombocytopenia places patients at risk of bleeding with

invasive procedures

• Use of platelet transfusion to mitigate the risk is cumbersome and

can be associated with adverse events

• The use of TPO agonists significantly increases platelet counts and

can avoid the need for platelet transfusion

58

Clinical Case Forum II: Current and Emerging

Management Approaches for the Patient with

Hepatorenal Syndrome

R. Todd Frederick, MD

Acute Kidney Injury (AKI) in Cirrhosis

• Traditional criteria (IAC criteria)1

– 50% increase in SCr

over baseline

– Cut-off value of SCr: 1.5 mg/dL

• New definition of AKI2

– in SCr ≥0.3 mg/dL within 48

hours or SCr ≥50% from

baseline that is known or

presumed to have occurred

within the prior 7 days

1. Angeli P, et al. J Hepatol. 2015;62:968-974; 2. J Hepatol. 2018;69:406-460.

Stage AKI1 Criteria

Stage 1 Increase in SCr ≥0.3 mg/dL or an increase

in SCr ≥1.5-fold to 2-fold from baseline

Stage 2 Increase in SCr >2- to 3-fold from baseline

Stage 3

Increase of SCr >3-fold from baseline or

SCr ≥4.0 mg/dL with an acute increase ≥0.3

mg/dL or initiation of renal replacement

therapy

60

HRS-1 AKI-HRS

HRS-2 CKD-HRS

AKI in Cirrhosis: Differential Diagnosis

• Prerenal

– Hypovolemia: diuretics, GI bleeding, diarrhea

– Hepatorenal syndrome

• Acute tubular necrosis: shock, nephrotoxic drugs, other

• Nephrotoxicity: NSAIDs, Iodinated contrast, other

• Intrinsic renal disease (glomerulonephritis, interstitial nephritis)

• Obstructive

• Miscellaneous, unknown

61 Graupera I, et al. Clin Liver Dis. 2013;2:128-131.

AKI and Cirrhosis

• AKI diagnosed with AKIN criteria associated with increased mortality

in patients with cirrhosis1

• Progression through stages strongly correlates with

increased mortality2

• However, serum creatinine cutoff of 1.5 mg/dL is still prognostic3

– Identifies patients at increased risk of mortality

• New AKI-HRS criteria enable earlier treatment (by 4 days) at lower

creatinine (1 mg/dL lower)4

– Baseline serum creatinine is a predictor of response to therapy

1. Piano S, et al. Hepatology. 2013;57:753-762; 2. Belcher JM, et al. Hepatology. 2013;57:753-762;

3. Fagundes C, et al. J Hepatol. 2013;59:474-481; 4. Wong F. et al. Journal Hepatology 2019;70(1)Supp. 62

Prospective Studies in Nonselected Hospitalized Patients

Fagundes C et al. J Hepatol. 59(3), 474-481; Piano S et al. J Hepatol. 59(3), 482-489.

Pro

ba

bil

ty o

f s

urv

iva

l (%

)

100

75

50

25

00 30 60 90

p <0.0001

88% No-AKI

84% AKI-1#

68% AKI-1*

42% AKI-2

31% AKI-3

Days

No AKIN Stage 1 Stage 2 Stage 3

AKIN

Mo

rta

lity

(%

)

100

80

60

40

20

0

p <0.0001

p <0.0001

n.s.

n.s.

p <0.001

p <0.01

sCR <1.5 mg/dlsCR ≥1.5 mg/dl

No AKI (n = 198 191 182 172

AKI-1 (n = 44) 41 39 37

AKI-1 (n = 66) 57 48 40

AKI-2 (n = 30) 18 11 11

AKI-3 (n = 37) 18 12 10

63

HISTORY

& PE

Patient Case


NOTES

60-Year Old Woman

with Decompensated Cirrhosis

• Alcoholic liver disease

• Listed for liver transplant

• History of ascites, HE, esophageal varices with

prior bleeding

• Labs 12 weeks ago in clinic: Na 136, Cr 1.1, bilirubin

1.8, INR 1.3, MELD 13

• Admitted to the hospital with worsening confusion

64


NOTES HISTORY

& PE

Patient Case (cont.)

• Worsening ascites over the past 3 months despite

sodium restriction and alcohol abstinence

• Diuretics recently increased to furosemide 80 mg daily,

spironolactone 200 mg daily

• Now requiring therapeutic paracentesis every 2 weeks

(last 5 days ago)

• Takes lactulose and rifaximin for HE

• Takes propranolol for prophylaxis of EVH

60-Year Old Woman


65

60-Year Old Woman



NOTES HISTORY

& PE


• On admission she is awake but disoriented with + asterixis

• Initial BP 102/54, HR 78, T 100.2, RR 18, SpO2 95% on

ambient air

• Exam shows a distended abdomen with erythema, warmth,

and severe tenderness at previous paracentesis site

• Labs now: Cr 1.7, INR 2, Bili 4.5, Na 131, Ascites WBC 345

(46% PMNs, ANC 159), Blood Cx pending; MELD-Na 28

• Oliguric and UA shows: Na <10, no protein or RBC, Cx pend

66

60-Year Old Woman



NOTES HISTORY

& PE


• On admission she is awake but disoriented with + asterixis

• Initial BP 102/54, HR 78, T 100.2, RR 18, SpO2 95% on

ambient air

• Exam shows a distended abdomen with erythema, warmth,

and severe tenderness at previous paracentesis site

• Labs now: Cr 1.7, INR 2, Bili 4.5, Na 131, Ascites WBC 345

(46% PMNs, ANC 159), Blood Cx pending; MELD-Na 28

• Oliguric and UA shows: Na <10, no protein or RBC, Cx pend

• AKI (AKIN Grade 1)

• HE (Grade 2)

• Abdominal wall cellulitis

• Acute decompensation of cirrhosis

67


NOTES HISTORY

& PE


• Doppler US of abdomen shows moderate ascites, no liver

masses, no hydronephrosis, no flow in portal vein visible

• Repeat BP is 88/52, HR 108

• Started on IV vancomycin and piperacillin/tazobactam

• IV albumin infused (1 gm/kg)

• Furosemide, spironolactone, and propranolol are discontinued

• Lactulose and rifaximin are continued 60-Year Old Woman


68

Patient Case (cont.): Urine Output

69

-2000

-1500

-1000

-500

0

500

1000

1500

2000

Volume Intake/Output

output intake

1 2 3 4 5

Vo

lum

e m

L

Time, Days

IV Albumin

Hepatorenal Syndrome International Ascites Club – Diagnostic Criteria

• Diagnosis of cirrhosis and ascites (portal hypertension)

• Meet AKI criteria

• No response after 2 days with withdrawal of diuretics and volume

expansion with albumin (0.5-1 g/kg/day with max of 100 g/day)

• Absence of shock and recent use of nephrotoxic drugs

• No parenchymal kidney disease

– No proteinuria > 500 mg/day, no microhematuria (> 50 RBC) and/or

abnormal renal ultrasound (“medical renal disease”)

70 EASL website. Hepatorenal Syndrome.

Pathophysiology AKI-HRS

• Portal Hypertension

• Decreased effective arterial

volume (splanchnic)

• Endogenous vasoconstrictors

• Superimposed inflammatory

response (infection, other)

• Reduced cardiac reserve

(cirrhotic cardiomyopathy)

• Overwhelmed renal

compensatory mechanisms

• Abrupt decline in GFR

71 Ginès P, et al. Nat Rev Dis Primers. 2018;4:23.

Initial Management

• Early identification

• Assess and treat bacterial infection

– Blood, urine, ascitic fluid culture

• Avoid large-volume paracentesis

• Stop β-blockers

• Stop nephrotoxic medications: NSAIDs, diuretics

• Volume expansion

Tapper EB, et al. Am J Med. 2016;129:461-467. 72

Patient Case (cont.): Renal Function

0

0.5

1

1.5

2

2.5

3

3.5

1 2 3 4 5

Octreotide/Midodrine S

eru

m C

rea

tin

ine m

g/d

l

Time, Days

Albumin

AKI-HRS Confirmed

73

Albumin


0

0.5

1

1.5

2

2.5

3

3.5

1 2 3 4 5

Octreotide/Midodrine S

eru

m C

rea

tin

ine m

g/d

l

Time, Days

Albumin

74

Albumin


• Progressive renal failure despite albumin, midodrine and

octreotide; creatinine rises to 4.3mg/dL

• Oliguria worsens and anasarca and hypoxemia develop

• Hypotension worsens

• Moved to the ICU and started on norepinephrine infusion

• Urgent activation for liver transplantation

• Discussions regarding renal replacement therapy

75


0

1

2

3

4

5

6

1 2 3 4 5 6 7 8 9

Octreotide/Midodrine

Norepinephrine

Se

rum

Cre

ati

nin

e m

g/d

l

Time, Days 76

Pharmacologic Therapy for HRS

IV Albumin

• 0.5-1gm/kg (max 100gm/d) for resuscitation; then

• 25 to 50 g/day

Plus

Vasoconstrictors

• Midodrine (+/- octreotide)

• Norepinephrine

• Terlipressin

77 Ginès P, et al. Nat Rev Dis Primers. 2018;4:23

**Midodrine Plus Octreotide: Dosing

Midodrine: initially 7.5 mg oral 3 times daily

• Titrate to maximum of 12.5 mg 3 times daily

Octreotide: 100 µg SC 3 times daily

• Maximum dose 200 µg SC 3 times daily

• Titrate to achieve increase of MAP by 15 mmHg

78 Runyon BA. Hepatology. 2013;57:1651-1653.

**Note this is off-label treatment for HRS but

recommended by AASLD Practice Guidelines

Comparative Efficacy of Midodrine and Norepinephrine:

Systematic Review and Network Meta-Analysis

Short-Term Mortality Reversal of HRS

OR (95% CI) Quality of Evidence OR (95% CI) Quality of Evidence

Efficacy vs Placebo

Midodrine + octreotide 0.61 (0.19, 1.93) Low (network) 0.44 (0.06, 3.23) Low (network)

Noradrenaline 0.75 (0.32, 1.76) Low (network) 4.17 (1.37, 12.50) Low (network)

Efficacy vs Midodrine + Octreotide

Noradrenaline 1.50 (0.60, 3.78) Low (network) 10.00 (1.49, 50.00) Low (network)

79 Facciorusso A, et al. Lancet Gastroenterol Hepatol. 2017;2:94-102.

Terlipressin and Albumin

• Vasopressin analogue

• Prodrug with longer

half-life

• Selective V1a > V1b or

V2 activity

• Splanchnic and portal

vasoconstriction

• Requires IV Albumin

for HRS treatment

Solà E, et al. Curr Opin Organ Transplant. 2013;18:265-270.

Diagnosis of HRS

Terlipressin bolus IV 1 mg every 4-6 hours or

continuous IV infusion (2 to 12 mg/day)

0 3 6 9 12 15 Days

Albumin IV

1 g/kg Albumin 20 to 40 g/day

Increase terlipressin dose if creatinine

does not decrease by 25% on day 3

80

Improvement in Renal Function: TERLI vs MID/OCT

Cavallin M, et al. Hepatology. 2015;62:567-574.

70.4

28.6

55.6

4.8

0

10

20

30

40

50

60

70

80

90

100

Terlipressin Midodrine + Octreotide

Resp

on

se t

o T

reatm

en

t, %

Complete/partial response Complete response

P=0.01

P <0.001

81

Su

rviv

al

Time (days)

P< 0.0011,0

0,8

0,6

0,4

0,2

0,0

0 30 60 90

Group TERLI

Su

rviv

al

Time (days)

P = N.S.1,0

0,8

0,6

0,4

0,2

0,0

0 30 60 90

Group MID/OCT

TERLI vs MID/OCT: 90-Day Survival

Fig. 4. Cumulative 3-month survival in patients who were randomized to terlipressin plus albumin (TERLI group) or to midodrine and

octreotide plus albumin (MID/OCT group) according to the response: solid line represents responders; dotted line represents nonresponders.

Abbreviation: N.S., nonsignificant.

Cavallin M, et al. Hepatology. 2015;62:567-574.

Probability of 90-Day, Transplant-Free Survival

According to Response to Treatment

82

Systematic Review with Meta-Analysis: Vasoactive Drugs for the Reversal of HRS Type 1

Gifford FJ, et al. Aliment Pharmaceutical Ther. 2017;45:593-603. 83

Safety: Terlipressin and Albumin

Adverse Cardiovascular Effects Terli+Alb

n (%)

Albumin

n (%)

Arrhythmias 2 (9) 0

Circulatory overload 7 (30) 4 (17)

Suspected intestinal ischemia 3 (13) 0

Arterial hypertension 1 (4) 0

Myocardial infarction 1 (4) 0

Martin-Liahi, et al. Gastroenterology. 2008;134:1352-1359.

EASL website. Hepatorenal Syndrome.

Not statistically significantly different

84

Survival: Terlipressin and Albumin – ACLF

• Cumulative mortality at 90-

days according to ACLF grade

in responders and

nonresponders to terlipressin

and albumin

– Baseline SCr and ACLF

grade independently

associated with response

– Patient age, WBC, ACLF

grade, and no response

to treatment associated

with mortality

85 Piano S, et al. Clin Gastroenterol Hepatol. 16(11), 1792-1800.

A

Cu

mu

lati

ve i

ncid

en

ce o

f d

ea

th

Days

0 30 60 90

1.0

0.8

0.6

0.4

0.2

0.0

P = .001

Responders

ACLF III

ACLF II

ACLF I

B

Cu

mu

lati

ve i

ncid

en

ce o

f d

ea

th

Days

0 30 60 90

1.0

0.8

0.6

0.4

0.2

0.0

P < .001

Nonresponders

ACLF III

ACLF II

ACLF I

Patients at risk

ACLF I

ACLF II

ACLF III

106

43

7

90

36

5

81

27

3

70

21

2

68

47

20

44

24

4

33

19

3

18

14

3

RCT (Open Label): Terlipressin vs Norepinephrine in Patients with ACLF and HRS-AKI

• Continuous IV infusion of terlipressin (2 to 12 mg/day) vs. norepinephrine (0.5 to 3 mg/hour)

• Terlipressin reduced need for RRT

• Terlipressin improved survival

Response Rate, n/N (%)

Norepinephrine Terlipressin P Value

Day 4 7/60 (11.7%) 16/60 (26.7%) 0.03

Day 7 12/60 (20%) 25/60 (41.7%) 0.01

Reversal of

HRS-AKI

(Day 14)

10/60 (16.7%) 24/60 (40%) 0.004

p=0.001 at Day 28

Time in Days

Intention to Treat Analysis

0

0.0

0.2

0.4

0.6

0.8

1.0

5 10 15 20 25 30

GroupsTerlipression

Noradrenaline

1-censored

2-censored

86 Arora V, et al. Hepatology. 2019; 0:1-11.

Renal Function Predicts Post-LT Outcomes

Survival in Days

00.4

0.5

0.6

0.7

0.8

0.9

1.0

1000 2000 3000 4000 5000

1

2

3

4

1=CCr>70

3=CCr20-39.9

2=CCr40-69.9

4=CCr<20

• UNOS Database

• GFR < 40 predicted

worse graft and

patient survival post

liver transplant

87 Nair, et al. Hepatology. 2002.

Treatment of HRS Pre-LT

p=0.15

0

0

0.2

0.4

0.6

0.8

1.0

1 2 3 Years

Patients at risk

HRS-treated

No-HRS 27

9 9 9 9

27 24 23

• Successful reversal of

HRS may improve post-

LT outcomes

88 Restuccia, et al. J Hepatology. 2004;40:140-146.

Hepatorenal Syndrome

• Devastating complication of cirrhosis and ACLF

• Early recognition essential to improve outcomes; new diagnostic

criteria offer promise

• Currently available treatment in the US has limited efficacy

• Terlipressin may be superior to other vasoconstrictors in reversing HRS

• In suitable patients, liver transplantation is the best treatment option

• Improving renal function reduces short-term mortality and need for RRT and

may improve post-liver transplant outcomes

89

Clinical Case Forum III:

Current Management Approaches for the

Patient with Hepatic Encephalopathy

Steven L. Flamm, MD, FAASLD


NOTES

OTHER

Patient Case

56-yr-old woman

admitted for OHE for the

first time

HPI

• History of NASH and noted

cirrhosis based on abdominal US

about 4 years ago

• Noted melena one day prior to and

hematemesis on the day of

admission

• Her husband noted that she

became confused on the way to

the Emergency Unit and became

unresponsive at the hospital

Social History

• Used to drink heavily as an

bartender when she

was young

• Quit drinking and smoking for

the last 12 years

• Lives with husband

91

HISTORY

& PE

56-yr-old woman


first time


NOTES

OTHER


PE

• Confused, disoriented

• Anemic, but not icteric

• Positive flapping, tremor

• No ascites, not tender

• Trace edema

• Stool tarry and hemoccult (+)

BP 108/54 mm Hg

PR 116/min

RR 16/min

BMI 35 kg/m2

92

HISTORY

& PE

56-yr-old woman


first time

HISTORY

& PE LABS PROGRESS

NOTES

OTHER


• Lisinopril

• Metformin

• Simvastatin

• Baby aspirin

93

MEDICATIONS

56-yr-old woman


first time

MEDICATIONS HISTORY


PROGRESS

NOTES

OTHER

H/H 8.9/28

Platelets 79,000

INR 1.5

Ammonia

level 108

BUN 30

Creatinine 1.4

Na 132

K 3.2

Albumin 3.1

AST/ALT 45/32

Bilirubin 1.2

Alk phos 122

MELD 19

94

LABS

Patient Case

How do you classify this

patient’s HE?

What is the role of

ammonia testing?

95

Normal “Covert” HE I II III IV

“Overt” HE Stages

Categorization is often arbitrary and

varies between raters

Clinical

Diagnosis

Worsening cognitive dysfunction

coma

Characterization of HE Stages

Bajaj JS, et al. Hepatology. 2009;50:2014-2021. 96

Role of Ammonia Testing in HE

• “Increased blood ammonia alone does not add any

diagnostic, staging, or prognostic value for HE in patients

with CLD. A normal value calls for diagnostic

reevaluation (GRADE II-3, A, 1)”

97 Vilstrup H, et al. Hepatology. 2014;60:715-35.

US Hospital Discharges Due to Cirrhosis Are Increasing

403,665 411,029 436,901 444,883 459,496 498,181

526,096 576,573

0

100000

200000

300000

400000

500000

600000

700000

2004 2005 2006 2007 2008 2009 2010 2011

10% increase

*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses.

HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD.

http://hcupnet.ahrq.gov. Accessed January 2014. 98

Resource Utilization for Patients Hospitalized with Hepatic Encephalopathy, 2005-2009

0

10000

20000

30000

40000

50000

60000

70000

2005 2006 2007 2008 2009

Health Care Resource Utilization in Patients Discharged

with HE Diagnosis

Avera

ge c

harg

e,

2009 U

SD

P<0.001

0

0.4

0.8

1.2

1.6

2

2.4

2005 2006 2007 2008 2009

Number of procedures

P<0.001

Average hospitalization charges

Nu

mb

er

of

pro

ced

ure

s

Stepanova M, et al. Clin Gastroenterol Hepatol. 2012;10(9):1034-1041. 99

Patient Case

How do you manage

this patient?

100

Specific Approach to Overt HE Treatment

• Four-pronged approach to management of HE

(GRADE II-2, A, 1):

– Initiation of care for patients with altered consciousness

– Alternative causes of AMS should be sought and treated

• e.g. diabetic ketoacidosis, drugs (benzodiazepines, neuroleptics, opioids),

neuroinfections, electrolyte disorders, intracranial bleeding and stroke1

– Identification of precipitating factors and their correction

– Commencement of empirical HE treatment

Vilstrup H, et al. Hepatology. 2014;60:715-35. 101

Current Therapy Options for HE

Agent Drug Class Indication

Lactulose1 Poorly absorbed disaccharide

• Decrease blood ammonia concentration

• Prevention and treatment of

portal-systemic encephalopathy

Rifaximin2 Non-aminoglycoside semi-

synthetic, nonsystemic antibiotic

Reduction in risk of OHE recurrence in

patients ≥18 years of age

Neomycin3 Aminoglycoside antibiotic Not to be used, renal and ototoxic risk

Metronidazole1 Synthetic antiprotozoal and

antibacterial agent Not approved for HE

Vancomycin1 Aminoglycoside antibiotic Not approved for HE

1. USNLM. DailyMed. Available at https://dailymed.nlm.nih.gov/dailymed. Accessed March 22, 2018; 2. Xifaxan (rifaximin) [prescribing information].

Valeant Pharmaceuticals North America LLC; Bridgewater, NJ; 2018; 3. Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. 102

https://dailymed.nlm.nih.gov/dailymed

Rifaximin Randomized, Controlled Trial:

Time to First Breakthrough HE Episode Primary Endpoint

0

100

80

60

40

20

028 56 84 112 140 168

Pro

po

rtio

n o

f P

ati

en

ts W

ith

ou

t

Bre

akth

rou

gh

HE

(%

) Rifaximin*

(77.9%)

Placebo*

(54.1%)

Hazard ratio with rifaximin, 0.42 (95% Cl, 0.28–0.64) P<0.001

Days Since Randomization

*Rifaximin 550 mg or placebo twice daily. 91% of patients in both arms received concomitant lactulose.

Bass NM, et al. N Engl J Med. 2010;362:1071-1081. 103

58% relative reduction in the risk of a breakthrough episode

0

0

20

40

60

80

100

28 56 84 112 140 168

Hazard ratio with rifaximin, 0.50 (95% Cl, 0.29-0.87)

P=.01

Placebo

(77.4%)

(86.4%)

Rifaximin

Days Since Randomization

0

Hazard ratio with rifaximin, 0.50 (95% Cl, 0.29-0.87)

P=.01

Placebo

(77.4%)

(86.4%)

Rifaximin

Rifaximin Randomized, Controlled Trial:

Time to First HE-Related Hospitalization (Secondary Endpoint)

Bass NM, et al. N Engl J Med. 2010;362(12):1071-81. 104

50% relative reduction in the risk of HE-related hospitalization

56-yr-old woman


first time

LABS MEDICATIONS HISTORY


OTHER

Hospital Course

• She has an EGD with variceal banding and bleeding stopped

• Mental status improved with lactulose but dosage has to be

reduced due to significant diarrhea and rifaximin was added

3 days before discharge

– Her husband was instructed to follow up in one week

after discharge

105

PROGRESS

NOTES

Prevention of Overt HE (OHE)

• Lactulose is recommended for prevention of recurrent episodes of HE after

the initial episode (GRADE II-1, A, 1)

• Rifaximin as an add-on to lactulose is recommended for prevention of

recurrent episodes of HE after the second episode (GRADE I, A, 1)

• Routine prophylactic therapy (lactulose or rifaximin) is not recommended for

the prevention of post-TIPS HE (GRADE III, B, 1)

• Under circumstances where the precipitating factors have been well

controlled (i.e., infections and VB) or liver function or nutritional status

improved, prophylactic therapy may be discontinued (GRADE III, C, 2)

106 AASLD Practice Guideline. 2014.


What is the social burden

of HE?

107

56 46

16 15 11 10 7 5

0

20

40

60

80

100

Stoppedsaving

In debt Noeducation

Late on bills No food Moved out Bankrupt Evicted

HE Impacts Family Daily Functioning

Impact of Cirrhosis-Related Expenses on Daily Activities

of Affected Families Within Past 3 Years

Pati

en

ts r

esp

on

din

g y

es,

%

Bajaj JS, et al. Am J Gastroenterol. 2011;106(9):1646-1653. 108

Caregiver Burden Increases with HE Severity

Mean (±SE) Caregiver Scores in the Objective Burden

Domain of the Caregiver Burden Inventory

10

8

6

4

2

0

-2

-4Unimpaired (n=7) Minimal HE (n=6) Overt HE (n=18)

CB

I O

bje

cti

ve

Bu

rde

n

*

1.8(1.3)

Montagnese S, et al. Metab Brain Dis. 2012;27(4):567-572. 109

56-yr-old woman


first time



OTHER

Hospital Course

• She was re-admitted 9 days later due to recurrent grade III

encephalopathy without melena

• She is taking lactulose only since unable to obtain rifaximin

after discharge due to high co-pay

– She has not seen her PCP yet

110

PROGRESS

NOTES

Hospital Readmissions Among Patients with Decompensated Cirrhosis Are Common

• Retrospective study of 402 patients from an

academic transplant center

– Follow-up time censored at death, elective

admissions such as transplant or post-

procedure observation, or the date of last clinic

note; median follow-up was 203 days

– Included cirrhotic patients hospitalized for

ascites, SBP, renal failure, hepatic

encephalopathy, or variceal hemorrhage

• Median time to readmission was 67 days

• Median number of readmissions was

2 (range 0-40); overall rate was 3

hospitalizations/person-year

111

14%

37%

69%

0

10

20

30

40

50

60

70

80

Within 1 wk Within 1 mo Overall

Pati

en

ts,

%

Hospital Readmissions

Volk ML, et al. Am J Gastroenterol. 2012;107(2):247-252.

All-Cause and HE-Related Re-Hospitalization for Patients with Hepatic Encephalopathy

N=8,125 alive

at discharge

27.4

49.7

56.4

17.6

33.7 39.5

0

10

20

30

40

50

60

30 days 180 days 1 year

Pati

en

ts (

%)

All-cause HE-related

Neff GW, et al. Poster presented at AASLD Annual Liver Meeting 2013. November 2, 2013. Abstract No. 374. 112

Unadjusted and Adjusted Odds Ratios for 30-Day Readmissions

by Condition for Complications of Liver Disease

Unadjusted OR

(95% Cl)

Model 1 OR

(95% Cl)

Model 2 OR

(95% Cl)

Ascites 1.28 (1.20-1.37) 1.47 (1.37-1.58) 1.78 (1.66-1.90)

Variceal hemorrhage 1.85 (1.71-2.00) 1.69 (1.56-1.83) 1.55 (1.43-1.69)

Hepatic

encephalopathy 2.62 (2.41-2.83) 2.67 (2.46-2.89) 3.23 (2.97-3.52)

Hepatorenal syndrome 2.33 (1.90-2.85) 2.46 (2.00-3.02) 1.41 (1.13-1.77)

Hepatocellular

carcinoma 1.79 (1.61-2.00) 1.64 (1.45-1.84) 1.70 (1.51-1.91)

30-Day Hepatology Readmission

Tapper EB, et al. Clin Gastro Hepatol. 2016;14:1181-1188. 113

Unadjusted and Adjusted Odds Ratios for 90-Day Readmissions

by Condition for Complications of Liver Disease

Unadjusted OR

(95% Cl)

Model 1 OR

(95% Cl)

Model 2 OR

(95% Cl)

Ascites 1.11 (1.05-1.18) 1.31 (1.23-1.39) 1.60 (1.52-1.69)

Variceal hemorrhage 2.03 (1.90-2.16) 1.83 (1.71-1.95) 1.70 (1.60-1.82)

Hepatic

encephalopathy 2.44 (2.28-2.60) 2.53 (2.37-2.70) 3.07 (2.86-3.30)

Hepatorenal syndrome 2.06 (1.75-2.43) 2.31 (1.96-2.73) 1.43 (1.20-1.71)

Hepatocellular

carcinoma 1.98 (1.82-2.15) 1.79 (1.63-1.96) 1.83 (1.67-2.01)

Tapper EB, et al. Clin Gastro Hepatol. 2016;14:1181-1188.

90-Day Hepatology Readmission

114

Reasons for Readmission

Polypharmacy

Psychological

Comorbidities

Frailty

Malnutrition

Home situation

Communication issues

Transplant candidacy

Inpatient care

Goals of care

Discharge instructions

Outpatient care

Multidisciplinary management

Patient Factors

System Factors

Medical Factors

Tapper EB, et al. Clin Gastroenterol Hepatol. 2016;14:1181-1188. 115

The Majority of Overt HE Patients Do Not Receive Proper Management Therapy After Discharge

• Analysis of medical and

hospital claims

– Outpatients who had ≥1 OHE

episodes from 2009 to 2011

during a 3-year period

• >60% of patients did not

receive ongoing prophylactic

therapy to reduce risk of HE

recurrence after discharge

Neff GW, Frederick RT. Hepatology. 2012;56(suppl 1):945A. 116

Reducing 30 Day Readmission by Intervention Phase

• Electronic phase

– Checklist items incorporated

into electronic provider

order system

• Check list phase

– QI checklist prompted

medication review and dosing

Reasons for 30-day Readmission

By Intervention Phase

Electronic n=146

Checklist n=139

Control n=194

Percentage

Study phase

0 100

HE

Infection

GI bleeding

Symptomatic

ascites

Other

Tapper EB, et al. Clin Gastro Hepatol. 2016;14:753-759. 117

56-yr-old woman


first time



OTHER

Discharge

• Follow up visit scheduled with gastroenterologist in 6 days

• 14 days of rifaximin obtained

118

PROGRESS

NOTES

Conclusions

• Hepatic encephalopathy is an economic and social burden

– Increased burden is realized not only by patients but also experienced

by caregivers

• Hepatic encephalopathy is an important cause of hospital

readmission

– To avoid the “revolving door”, treat after discharge

• Lactulose and rifaximin are important for secondary prophylaxis

119

Panel Discussion / Q&A

120

Documents

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