therapeutic strategy in severe alcoholic hepatitis - … · therapeutic strategy in severe...

Therapeutic Strategy in Severe

Alcoholic Hepatitis: Present to future development of New

molecules

Philippe Mathurin

Service Maladies de l’Appareil Digestif

Inserm U995

Hôpital Claude Huriez

Lille

France

Assessment of Disease

severity

At admission

During treatment

Acknowledgements

• Vijay Shah, Philippe Mathurin and Patrick

Kamath for use of material

Infection

SEVERE ALCOHOLIC HEPATITIS: COURSE

Organ Failure

SIRS

Death

DF and MELD predict AH mortality

DF

Dunn et al; Hepatology 2005;41:353-58

20%

www.mayoclinic.org/gi-rst/mayomodel7.html

MELD

• INR is more reproducible than PT

• Easily available calculators

• Cut point can be based on toxicity of proposed treatment.

• May be used to categorize mild, moderate and severe AH.

Lower but still

important

risk of death in

patients

with DF<32…

• Extensively validated

• DF >32 predicts high mortality

• 4.6 (PT – Control) + Bilirubin

• Especially useful to determine

need for steroid treatment: in

patients with severe AH

Glasgow Alcoholic Hepatitis score

Forrest, E H et al. Gut 2005;54:1174-1179

•A value between

5 and 12 is

obtained

1 2 3

Age < 50 50 -

WBC (109/l) < 15 15 -

Urea (mmol/l) < 5 5 -

PT ratio/ INR < 1.5 1.5 – 2.0 > 2.0

Bilirubin (mol/l) < 125 125 - 250 > 250

•GAHS score 9 predicts

a poor outcome

ABIC Model

Mathurin P et al, Hepatology 2003

Dynamic Models to Determine Response to

Therapy

• No bilirubin decrease by

1 week (EBR): Steroid

non-responder -

discontinue

Days

25 %

50 %

75 %

100 %

Patients with EBR, 82.8 ± 3.3%

Patients without EBR, 23 ± 5.8%

100 days50 days 150 days 180 days

25 %

50 %

75 %

100 %

85±2.5%Lille score < 0.45

Lille score ≥ 0.45 25±3.8%

p<0.00001

Lille model: a tool for new strategiesEvaluation of Lille model on overall patients (n=438)

http://www.lillemodel.com

Louvet A et al, Hepatology 2007

50 days 100 days 150 days 180 days

Surrogate markers Evolution of Severity of scores vs Lille Score

Louvet A, Hepatology 2007

Lille model: a tool for new strategiesEvaluation of Lille model on overall patients (n=438)

Combining Data from Liver Disease Scoring Systems outcome as a continuum in probabilities of death

Louvet A, Gastroenterology 2015

For example, predicted 6-month mortality

- complete responders with MELD scores of 15−45 (Lille score 0.16)

was 8.5% to 49.7%, compared with 16.4%–75.2% for non-

responders (Lille score 0.45).

- According to the joint-effect model, for 2 patients with the same

baseline MELD score of 21, the patient with a Lille score of 0.45 had

a 1.9-fold higher risk of death than the patient with a Lille score of

0.16 (23.7% vs 12.5%)

Present Therapeutic strategy

Corticosteroids improve survival of patients with

severe Alcoholic HepatitisIndividual Data Analysis Of The Last 5 RCTS (Mendenhall, Carithers, Ramond, Cabre*, Philipps*) 221 allocated to Corticosteroids and 197 to controlled groups

p=0.0005

P Mathurin, J O’Grady, RL Carithers Jr, Philipps et al. Gut 2011

1.00

Corticosteroids

Surv

ival (%

)

0.00

0.25

0.50

0.75

0 8 12 20 28

Patients treated in the corticosteroid group (n=221)

Patients treated in the non-corticosteroid group (n=197)

65.73.4%

79.972.8%

4 16 24221 213 204 188 165217 193 180

197 176 166 143 124191 153 136

days

28-Day Mortality

OR = 0,72 (0,52-1,01)p = 0,056

0

10

15

20

Prednisolone

No

Pentoxifylline

25

5

OR = 1,07 (0,77-1,49)p = 0,686

YesNoYes

Mo

rtal

ity

(%)

Thursz NEJM 2015

Pentoxifylline vs Corticosteroids

Independent Prognostic Factors

Multivariate Analysis

Variable Odds ratio (95% CI) p-value

Prednisolone vs no

prednisolone

0.609 (0.409 – 0.090) 0.015

Prothrombin ratio 1.381 (1.129 – 1.691) 0.002

Bilirubin 1.002 (1.001 – 1.003) 0.003

Age 1.050 (1.029 – 1.071) <0.001

White Blood Cells 1.030 (1.002 – 1.060) 0.037

Urea 1.065 (1.015 – 1.118) 0.037

Creatinine 1.564 (1.048 – 2.332) 0.028

Hepatic Encephalopathy 3.073 (2.050 – 4.605) <0.001

Thursz NEJM 2015

Pentoxifylline vs Corticosteroids

Corticosteroids as a first therapeutic option

in the treatment of alcoholic hepatitis

End of the controversy on the short-term benefit?

Meta-Analysis of therapeutic options

Meta-Analysis of therapeutic optionsNAC alone vs Placebo: No effect

Meta-Analysis of therapeutic optionsPentoxifylline vs Placebo:

No effect in direct meta-analysis

Meta-Analysis of therapeutic optionsCorticosteroids vs Placebo:

Improvement in short-term mortality

Meta-Analysis of therapeutic optionsCorticosteroids + NAC :

The best therapeutic regimen?

Meta-Analysis of therapeutic optionsNo significant effect on Medium-Term mortality

Corticosteroids

Controlled treatment

p=0.002

67,4%

54,1%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Corticosteroids Controlled Treatment

% of response (Lille score< 0.45)

Corticosteroids are the only remaining pharmacological option for severe alcoholic

hepatitis: a meta-analysis of individual data on 1974 patients. Mark Thursz, Alexandre Louvet, Dong Joon Kim, Julien Labreuche, Stephen Atkinson, Sandeep Sidhu, John O’Grady, RL Carithers

Marie-José Ramond, Charles Mendenhall, Willis C Maddrey, Tim Morgan, Alain Duhamel, Philippe Mathurin

Corticosteroids

Pentoxifylline

p=0.04




p=0.6Pentoxifylline

N o pentoxifylline




Combinative therapies

Where are we?

CorpentoxHAA study

Steroids + pentoxifylline

n=133

Steroids + Placebo

n=137

End point = 6 month-survival

270 patients included

AH biopsy proven

Madddrey ≥ 32

Jaundice < 3 months

n=270

Mathurin P et al, JAMA 2013

0

6.3

12.5

18.8

25

0 50 100 150 200

Cum

ula

tive incid

ence o

f hepato

renal syndro

me (

%)

PTX-C: pentoxifylline + prednisolone

Plac-C: placebo + prednisolone

p=0.07

8.4% (n=11)

15.3% (n=21)

Fig. 3: Cumulative incidence of hepatorenal syndrome in the two groups.

Time (days)

3.05%

11.7%

p=0.007

N-acetylcysteine and corticosteroids : The near future ?

Nguyen-Khac E,New Engl J Med 2011

How to improve management?

Complete respondersLille score ≤0.16 [≤35th percentile]

Partial responders

Lille score 0.16-0.56 [35-70th percentile]

P Mathurin, Gut 2011

Null responders Lille score ≥0.56 [≥ 70th percentile]

Prednisolone

Infection before steroids Infection after steroids (2 months)

A Louvet, Gastroenterology 2009

Infection in severe alcoholic hepatitis

treated with steroids: Early response to therapy is the key factor

25 % already infected at admission 25 % being infected upon steroids

0.00

0.25

0.50

0.75

1.00

0 15 30 45 60

Time in days

Surv

ival

Patients with development of infection

after initiation of corticosteroids

Patients without development of infection

p<0.00001

Figure 2: 2-month survival according to the development

of infection after corticosteroids

46.46.9%

77.53.2%

0.00

0.25

0.50

0.75

1.00

0 15 30 45 60

Time in days

Surv

ival

Patients with development of infection

after initiation of corticosteroids

Patients without development of infection

p<0.00001

Figure 2: 2-month survival according to the development

of infection after corticosteroids

46.46.9%

77.53.2%

Infection and severe alcoholic hepatitis

Median time infection

14 days after steroids

0

0.25

0.50

0.75

1

0 15 30 45 60

Time (days)

Surv

ival

p=0.99

Patients not infected before initiation of steroids

Patients infected and treated with antibiotics

before initiation of steroids

Figure 1: Survival impact of infection diagnosed before initiation of

corticosteroids

70.9±6.1%

71.6±3.4%

0

0.25

0.50

0.75

1

0 15 30 45 60

Time (days)

Surv

ival

p=0.99

Patients not infected before initiation of steroids

Patients infected and treated with antibiotics

before initiation of steroids

Figure 1: Survival impact of infection diagnosed before initiation of

corticosteroids

70.9±6.1%

71.6±3.4%


Corticosteroids started

7 days after diagnosis of infection

After control of infection

0

5

10

15

20

25

30

35

40

45

Responders

Non-responders

42.5 %

11.1 %

p<0.000001

% o

f in

fections u

pon s

tero

ids

Infection and response to therapy

Ascitis 1.75 (0.78-3.9) 0.2

Encephalopathy 1.2 (0.6-2.2) 0.6

Maddrey 1.9 (0.99-1.01) 0.6

Infection 1.2 (0.6-2.3) 0.5

MELD 1.1 (1.02-1.22) 0.006

Lille model 17.3 (5.4-54.9) <0.00001

Multivariate analysis


Prednisolone is Associated with

Higher Rates of Infection

0.000

0.001

0.002

0.003

0.004

0.005

0.006

7 14 21 28 90

Nu

mb

er

of

infe

ctio

ns/

pe

rso

n/d

ay

Incidence rate of infections reported as SAEs

Placebo

Prednisolone

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

7 14 21 28 90

Incidence rate of all reported infections

Placebo

Prednisolone

Time after treatment start date (days) Time after treatment start date (days)

Prednisolone significantly associated with infections reported as SAEs

(p=0.005, OR 2.24, [95% CI 1.27 – 3.94])

Prednisolone is significantly associated with infections reported after 7 days of treatment

(p=0.014, OR 1.47, [95%CI 1.08 – 1.98])

Sites of infection

SBP/BACTERAEMIA

20%

RESPIRATORY32%

URINARYTRACT

INFECTION18%

OTHER9%

UNKNOWN21%

Baselineinfec onsinSTOPAH,bysite

SBP/BACTERAEMIA

26%

RESPIRATORY37%

URINARYTRACTINFECTION10%

OTHER12%

UNKNOWN15%

Incidentinfec onsinSTOPAH,bysite

•Pattern of infection significantly different (p=0.027)

Patients = 127, Infections = 133

Culture positive = 39%

Patients = 309, Infections = 403

Culture positive = 48%

Atkinson EASL 2016

Impact of Baseline Infection

• No difference in baseline infection between treatment arms

• No statistically significant association between baseline infection and mortality or incident infection irrespective of prednisolone usage

Mortality Infection-free survival

No baseline infection

Baseline infection

No baseline infection

Baseline infection

Time from treatment start date (days)

Impact of incident infection upon survival

No incident infection

Incident infection

87 ± 2.6 days

98 ± 1.5 daysvs.

p=0.00035

p<0.000001 p=0.001

Atkinson EASL 2016

Association between Incident Infection

and Prognostic Scores

28-day infection 120-day infection

Scoring system OR (95% CI) P OR (95% CI) P

mDF 1.009 (1.004 – 1.014) 0.00038 1.007 (1.003 – 1.01) 0.002

MELD 1.06 (1.04 – 1.09) <0.00001 1.05 (1.03 – 1.08) <0.0001

GAHS 1.24 (1.10 – 1.41) 0.001 1.21 (1.08 – 1.36) 0.001

Lille 2.20 (1.35 – 3.57) 0.002 2.30 (1.44 – 3.66) 0.001

Lille (w/o day 7) 1.85 (1.00 – 3.41) 0.049 2.00 (1.15 – 3.47) 0.014

Atkinson EASL 2016

Not infected Infected0

10

20

30

40

50

bD

NA

(p

g/m

l w

ho

le b

loo

d)

All patients

p=0.01

Elevated bDNA is associated with the

development of infection by day 7

No infection by D7 Infection by D70

20

40

60

80

bDN

A (p

g/m

l who

le b

lood

)

Patients treated without prednisolone

p=0.97

Not infected by D7 Infection by D70

20

40

60

80bD

NA

(pg/

ml w

hole

blo

od)

Patients treated with prednisolone

p=0.004

Bacterial DNA – Stratified Approach

0 20 40 60 800

50

100

Time on study

Perc

en

t su

rviv

al

hibDNA

Not prednisolone

Prednisolone

Acute Kidney Injury

AKI network [AKIN] criteria

creatinine at least 0.3 mg/dL (or a 50% increase) from

baseline within 48 H

Altamirano J, Clin Gastroenterol Hepatol 2012

Insights in future plan of

development

Main drivers of outcome differ

between short and long-term

in severe alcoholic hepatitis:

a prospective study

Hepatology 2017

Drivers of mortality at short and long-terma prospective study

464 patients with severe AH admitted to Lille liver unit

Short-term Outcome = 6 months

Alive Patients at 6 months

Long-term Outcome = 62 [25-102] months)

Total of 10413 patients-months were compiled

Total of 1581 alcohol consumption

(corresponding to 2554 patients-months)

Drivers of mortality at short-term

Drivers of mortality at long-term


❖ Using responders and alcohol consumption <30 g/d as a reference

❖ HR of death = 2.15 for non-responders and alcohol <30 g/d

❖ HR of death = 4.12 for responders and alcohol ≥30 g/d,

❖ HR of death = 8.34 for non-responders and ≥ 30 g/day


6-MONTH PERIOD OR 3-MONTH PERIODOPTIMAL PERIOD FOR STUDIES TESTING DRUG

PREVENTING LIVER INJURY

AFTER 6 MONTHS OR 3-MONTHS AVOID STUDIES TESTING DRUG PREVENTING

LIVER INJURY

Time-Frame for testing

molecules: We need to look outside the liver field

SHORT-TERM OUTCOME

Tissue Repair Is The Issue and endpoint

Saver JL , NEJM 2015

SHORT-TERM OUTCOME

Tissue Repair Is The Issue and endpoint

No data in terms of long-term mortality as stent-

retriever thrombectomy is not designed to influence

drivers of long-term recurrence or mortality

LONG-TERM OUTCOME

Patient Behavior Is The Issue

LONG-TERM OUTCOME

Exposure of therapy preventing the

expected events: a prerequisite

UKPDS 38, BJM 1998

RR Holman, NEJM 2008

LONG-TERM OUTCOME

Exposure of therapy preventing the

expected events: a prerequisite

Phase I study:

Key points:

1. Time of exposure and low competitive risk of mortality

2. Identification of therapeutic pathways involved in liver injury

3. Better classification of disease profile

Combining Data from Liver Disease Scoring Systems an intesting approach to select patients

Louvet A, Gastroenterology 2015

Optimal candidates Phase I studies

Suboptimal candidates Phase I studies

NEAR FUTURE

French Randomized controlled trial Antibiocor HAA study

Prednisolone + placebo

Prednisolone +Augmentin®

[Amoxycilline1g x 3/j + 125 mg x 3/j Clavunalic Acid]

End point = 2 month-survival

Statistical Hypothesis 83% vs 67% [α Risk= 5%; β Risk : 20% (n= 280 patients)

Last update 145 patients have been included

AH biopsy proven; Jaundice < 3 months

Madddrey ≥ 32; MELD ≥21

Phase II Controlled trial from Gilead

Inhibition of apoptosis using GS-4997 (ASK1 inhibitor)

Prednisolone + placebo

Prednisolone +GS 4997

Primary Objective = evaluate the safety and tolerability of GS-4997

Secondary Objectives = improvement of liver function, 28-day survival

AH biopsy proven or possible AH (NIAA consortium definition)

≥ 32 Madddrey <60

Conclusion

Cortisteroids improve short-term survival of patients with severe AH

(Maddrey criteria 32)

Pentoxyfilline is not efficient

Combination of these 2 molecules is not effective

Progress have been made in the management of patients with

severe AH treated with steroids

Conclusion

Corticosteroids should be interrupted in null-responders after 7 days of

therapy

Development of an infection during steroids treatment is linked to the

response of treatment evaluated by the Lille model

In terms of survival, only response to treatment is useful for prediction of the

evolution whereas infection rather seems to be a consequence of it

Conclusion

Combinative therapy NAC + corticosteroids is and interesting approach

Progress have been made to reach consensus of experts for study design

Study design will be an important issue

Network of collaboration between basic resarchers and clinicicans are

warranted

therapeutic strategy in severe alcoholic hepatitis - … · therapeutic strategy in severe...

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