Therapeutic Strategy in Severe Alcoholic Hepatitis: Present to future development of New

Transcription

1 Therapeutic Strategy in Severe Alcoholic Hepatitis: Present to future development of New Philippe Mathurin Service Maladies de l Appareil Digestif Inserm U995 Hôpital Claude Huriez Lille France molecules

2 Assessment of Disease severity At admission During treatment

3 Acknowledgements Vijay Shah, Philippe Mathurin and Patrick Kamath for use of material

4 SEVERE ALCOHOLIC HEPATITIS: COURSE Infection SIRS Organ Failure Death

5 DF and MELD predict AH mortality DF 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 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 20% Dunn et al; Hepatology 2005;41:353-58

6 Glasgow Alcoholic Hepatitis score Age < WBC (10 9 /l) < Urea (mmol/l) < PT ratio/ INR < > 2.0 A value between 5 and 12 is obtained Bilirubin ( mol/l) < > 250 GAHS score 9 predicts a poor outcome Forrest, E H et al. Gut 2005;54:

7 ABIC Model

8 Dynamic Models to Determine Response to Therapy 100 % No bilirubin decrease by 1 week (EBR): Steroid non-responder - discontinue 75 % 50 % 25 % Patients with EBR, 82.8 ± 3.3% Patients without EBR, 23 ± 5.8% 50 days 100 days 150 days 180 days Days Mathurin P et al, Hepatology 2003

9 Lille model: a tool for new strategies Evaluation of Lille model on overall patients (n=438) 100 % 75 % Lille score < ±2.5% 50 % p< % Lille score ±3.8% 50 days 100 days 150 days 180 days Louvet A et al, Hepatology 2007

10 Surrogate markers Evolution of Severity of scores vs Lille Score Louvet A, Hepatology 2007

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

12 Combining Data from Liver Disease Scoring Systems outcome as a continuum in probabilities of death For example, predicted 6-month mortality - complete responders with MELD scores of (Lille score 0.16) was 8.5% to 49.7%, compared with 16.4% 75.2% for nonresponders (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%) Louvet A, Gastroenterology 2015

13 Present Therapeutic strategy

14 Survival (%) Corticosteroids improve survival of patients with severe Alcoholic Hepatitis Individual Data Analysis Of The Last 5 RCTS (Mendenhall, Carithers, Ramond, Cabre*, Philipps*) 221 allocated to Corticosteroids and 197 to controlled groups % p= % Patients treated in the corticosteroid group (n=221) Patients treated in the non-corticosteroid group (n=197) Corticosteroids days P Mathurin, J O Grady, RL Carithers Jr, Philipps et al. Gut 2011

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16 Mortality (%) Pentoxifylline vs Corticosteroids 28-Day Mortality OR = 0,72 (0,52-1,01) p = 0,056 OR = 1,07 (0,77-1,49) p = 0, Yes No Yes No Prednisolone Pentoxifylline Thursz NEJM 2015

17 Pentoxifylline vs Corticosteroids Independent Prognostic Factors Multivariate Analysis Variable Odds ratio (95% CI) p-value Prednisolone vs no ( ) prednisolone Prothrombin ratio ( ) Bilirubin ( ) Age ( ) <0.001 White Blood Cells ( ) Urea ( ) Creatinine ( ) Hepatic Encephalopathy ( ) <0.001 Thursz NEJM 2015

18 Corticosteroids as a first therapeutic option in the treatment of alcoholic hepatitis End of the controversy on the short-term benefit?

19 Meta-Analysis of therapeutic options

20 Meta-Analysis of therapeutic options NAC alone vs Placebo: No effect

21 Meta-Analysis of therapeutic options Pentoxifylline vs Placebo: No effect in direct meta-analysis

22 Meta-Analysis of therapeutic options Corticosteroids vs Placebo: Improvement in short-term mortality

23 Meta-Analysis of therapeutic options Corticosteroids + NAC : The best therapeutic regimen?

24 Meta-Analysis of therapeutic options No significant effect on Medium-Term mortality

25 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 Controlled treatment p= % 70% 60% 50% 40% 30% 20% 10% 0% % of response (Lille score< 0.45) 67,4% 54,1% Corticosteroids Controlled Treatment

26 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 p=0.04 Pentoxifylline

27 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 Pentoxifylline p=0.6 N o pentoxifylline

28 Combinative therapies Where are we?

29 Cumulative incidence of hepatorenal syndrome (%) CorpentoxHAA study 25 PTX-C: pentoxifylline + prednisolone Plac-C: placebo + prednisolone % 15.3% (n=21) Steroids + pentoxifylline n=133 p=0.07 AH biopsy proven p=0.007 Madddrey 32 Jaundice < months 3.05% 8.4% (n=11) n=270 Steroids + Placebo 0 n= End point = 6 month-survival 270 patients included 200 Fig. 3: Cumulative incidence of hepatorenal syndrome in the two groups. Mathurin P et al, JAMA 2013 Time (days)

30 N-acetylcysteine and corticosteroids : The near future? Nguyen-Khac E,New Engl J Med 2011

31 How to improve management?

32 Complete responders Partial responders Null responders Lille score [35-70 th percentile] Lille score 0.56 [ 70th percentile] Lille score 0.16 [ 35 th percentile] P Mathurin, Gut 2011

33 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 Prednisolone Infection before steroids Infection after steroids (2 months) A Louvet, Gastroenterology 2009

34 Survival Survival Infection and severe alcoholic hepatitis Corticosteroids started 7 days after diagnosis of infection After control of infection Median time infection 14 days after steroids ±3.4% p= ±6.1% % p< Patients not infected before initiation of steroids Patients infected and treated with antibiotics before initiation of steroids Patients without development of infection Patients with development of infection after initiation of corticosteroids % Time (days) Time in days Figure 1: Survival impact of infection diagnosed before initiation of corticosteroids Figure 2: 2-month survival according to the development of infection after corticosteroids A Louvet, Gastroenterology 2009

35 % of infections upon steroids Infection and response to therapy 45 Multivariate analysis 40 Ascitis % ( ) Responders Encephalopathy ( ) p< Non-responders Maddrey 1.9 ( ) Infection ( ) MELD % ( ) Lille 0 model 17.3 ( ) < A Louvet, Gastroenterology 2009

36 Number of infections/person/day Prednisolone is Associated with Higher Rates of Infection Incidence rate of infections reported as SAEs Placebo Prednisolone 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 ]) Prednisolone is significantly associated with infections reported after 7 days of treatment (p=0.014, OR 1.47, [95%CI ])

37 Sites of infection Baseline infec ons in STOPAH, by site Patients = 127, Infections = 133 Incident infec ons in STOPAH, by site Patients = 309, Infections = 403 OTHER 9% UNKNOWN 21% URINARY TRACT INFECTION 18% SBP/ BACTERAEMIA 20% RESPIRATORY 32% OTHER 12% URINARY TRACT INFECTION 10% UNKNOWN 15% SBP/ BACTERAEMIA 26% RESPIRATORY 37% Culture positive = 39% Culture positive = 48% Pattern of infection significantly different (p=0.027) Atkinson EASL 2016

38 Impact of Baseline Infection Mortality Infection-free survival No baseline infection Baseline infection No baseline infection Baseline infection Time from treatment start date (days) No difference in baseline infection between treatment arms No statistically significant association between baseline infection and mortality or incident infection irrespective of prednisolone usage

39 Impact of incident infection upon survival 98 ± 1.5 days vs. 87 ± 2.6 days p= p< p=0.001 No incident infection Incident infection Atkinson EASL 2016

40 Association between Incident Infection and Prognostic Scores 28-day infection 120-day infection Scoring system OR (95% CI) P OR (95% CI) P mdf ( ) ( ) MELD 1.06 ( ) < ( ) < GAHS 1.24 ( ) ( ) Lille 2.20 ( ) ( ) Lille (w/o day 7) 1.85 ( ) ( ) Atkinson EASL 2016

41 bdna (pg/ml whole blood) bdna (pg/ml whole blood) bdna (pg/ml whole blood) Elevated bdna is associated with the development of infection by day 7 80 Patients treated without prednisolone 60 p= All patients p= No infection by D7 Infection by D Patients treated with prednisolone p= Not infected Infected Not infected by D7 Infection by D7

42 Percent survival Bacterial DNA Stratified Approach hi bdna 100 Not prednisolone Prednisolone Time on study

43 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

44 Insights in future plan of development

45 Main drivers of outcome differ between short and long-term in severe alcoholic hepatitis: a prospective study Hepatology 2017

46 Drivers of mortality at short and long-term a prospective study 464 patients with severe AH admitted to Lille liver unit Alive Patients at 6 months Short-term Outcome = 6 months Long-term Outcome = 62 [25-102] months) Total of patients-months were compiled Total of 1581 alcohol consumption (corresponding to 2554 patients-months)

47 Drivers of mortality at short and long-term a prospective study

48 Drivers of mortality at short-term

49 Drivers of mortality at long-term

50 Drivers of mortality at short and long-term a 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

51 Drivers of mortality at short and long-term a prospective study 6-MONTH PERIOD OR 3-MONTH PERIOD OPTIMAL PERIOD FOR STUDIES TESTING DRUG PREVENTING LIVER INJURY AFTER 6 MONTHS OR 3-MONTHS AVOID STUDIES TESTING DRUG PREVENTING LIVER INJURY

52 Time-Frame for testing molecules: We need to look outside the liver field

53 SHORT-TERM OUTCOME Tissue Repair Is The Issue and endpoint Saver JL, NEJM 2015

54 SHORT-TERM OUTCOME Tissue Repair Is The Issue and endpoint No data in terms of long-term mortality as stentretriever thrombectomy is not designed to influence drivers of long-term recurrence or mortality

55 LONG-TERM OUTCOME Patient Behavior Is The Issue

56 LONG-TERM OUTCOME Exposure of therapy preventing the expected events: a prerequisite UKPDS 38, BJM 1998

57 LONG-TERM OUTCOME Exposure of therapy preventing the expected events: a prerequisite RR Holman, NEJM 2008

58 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

59 Combining Data from Liver Disease Scoring Systems an intesting approach to select patients Optimal candidates Phase I studies Suboptimal candidates Phase I studies Louvet A, Gastroenterology 2015

60 NEAR FUTURE

61 French Randomized controlled trial Antibiocor HAA study AH biopsy proven; Jaundice < 3 months Madddrey 32; MELD 21 Prednisolone + placebo Prednisolone +Augmentin [Amoxycilline1g x 3/j 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

62 Phase II Controlled trial from Gilead Inhibition of apoptosis using GS-4997 (ASK1 inhibitor) AH biopsy proven or possible AH (NIAA consortium definition) 32 Madddrey <60 Prednisolone + placebo Prednisolone +GS 4997 Primary Objective = evaluate the safety and tolerability of GS-4997 Secondary Objectives = improvement of liver function, 28-day survival

63 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

64 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

65 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