therapeutic strategy in severe alcoholic hepatitis - … · therapeutic strategy in severe...
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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
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Assessment of Disease
severity
At admission
During treatment
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Acknowledgements
• Vijay Shah, Philippe Mathurin and Patrick
Kamath for use of material
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Infection
SEVERE ALCOHOLIC HEPATITIS: COURSE
Organ Failure
SIRS
Death
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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
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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
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ABIC Model
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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
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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
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Surrogate markers Evolution of Severity of scores vs Lille Score
Louvet A, Hepatology 2007
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Lille model: a tool for new strategiesEvaluation of Lille model on overall patients (n=438)
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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%)
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Present Therapeutic strategy
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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
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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
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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
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Corticosteroids as a first therapeutic option
in the treatment of alcoholic hepatitis
End of the controversy on the short-term benefit?
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Meta-Analysis of therapeutic options
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Meta-Analysis of therapeutic optionsNAC alone vs Placebo: No effect
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Meta-Analysis of therapeutic optionsPentoxifylline vs Placebo:
No effect in direct meta-analysis
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Meta-Analysis of therapeutic optionsCorticosteroids vs Placebo:
Improvement in short-term mortality
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Meta-Analysis of therapeutic optionsCorticosteroids + NAC :
The best therapeutic regimen?
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Meta-Analysis of therapeutic optionsNo significant effect on Medium-Term mortality
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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
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Corticosteroids
Pentoxifylline
p=0.04
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
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p=0.6Pentoxifylline
N o pentoxifylline
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
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Combinative therapies
Where are we?
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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
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N-acetylcysteine and corticosteroids : The near future ?
Nguyen-Khac E,New Engl J Med 2011
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How to improve management?
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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]
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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
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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%
A Louvet, Gastroenterology 2009
Corticosteroids started
7 days after diagnosis of infection
After control of infection
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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
A Louvet, Gastroenterology 2009
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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])
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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
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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)
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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
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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
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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
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Bacterial DNA – Stratified Approach
0 20 40 60 800
50
100
Time on study
Perc
en
t su
rviv
al
hibDNA
Not prednisolone
Prednisolone
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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
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Insights in future plan of
development
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Main drivers of outcome differ
between short and long-term
in severe alcoholic hepatitis:
a prospective study
Hepatology 2017
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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)
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Drivers of mortality at short and long-terma prospective study
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Drivers of mortality at short-term
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Drivers of mortality at long-term
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Drivers of mortality at short and long-terma prospective study
❖ 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
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Drivers of mortality at short and long-terma prospective study
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
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Time-Frame for testing
molecules: We need to look outside the liver field
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SHORT-TERM OUTCOME
Tissue Repair Is The Issue and endpoint
Saver JL , NEJM 2015
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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
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LONG-TERM OUTCOME
Patient Behavior Is The Issue
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LONG-TERM OUTCOME
Exposure of therapy preventing the
expected events: a prerequisite
UKPDS 38, BJM 1998
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RR Holman, NEJM 2008
LONG-TERM OUTCOME
Exposure of therapy preventing the
expected events: a prerequisite
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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
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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
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NEAR FUTURE
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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
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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
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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
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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
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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