ADDITIONAL SUPPORTIVE THERAPY (BIOLOGICAL VERSUS NON BIOLOGICAL DEVICES)

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1 18th AISF Pre-Meeting Course Update on the Management of Acute Liver Failure Aula Magna, Università di Roma Sapienza Rome, February 17th, 2016 ADDITIONAL SUPPORTIVE THERAPY (BIOLOGICAL VERSUS NON BIOLOGICAL DEVICES) Antonio Gasbarrini, Francesca Ponziani Internal Medicine, Gastroenterology and Liver Diseases Gemelli Hospital Catholic University of Rome

2 Acute/Acute on Chronic liver failure: morbidity and mortality ALF ACLF Bernal W et al. J Hepatol 2015 Arroyo V et al. J Hepatol 2015

3 GENERAL management SPECIFIC management ICU Organ function monitoring OLTx Extracorporeal support systems G-CSF/Stem cells

4 GENERAL management SPECIFIC management ICU Organ function monitoring OLTx Extracorporeal support systems G-CSF/Stem cells Organs shortage Patients often not eligible (age, concomitant/previous diseases, multi-organ failure, sepsis, psycho-social reasons..)

5 GENERAL management SPECIFIC management ICU Organ function monitoring OLTx Extracorporeal support systems G-CSF/Stem cells Engraftment in the liver? Long-term efficacy? Malignant transformation? Unwanted differentiation?

6 GENERAL management SPECIFIC management ICU Organ function monitoring OLTx Extracorporeal support systems G-CSF/Stem cells

7 Why an extracorporeal liver support system? The liver is a largely dormant organ: only % hepatocytes goes under mitosis division at any given time During severe liver injury or a surgical process there is a massive hepatocytes proliferation, leading to recuperation of functional liver mass within 2 weeks even after the loss of up to 2/3 of the liver There is no satisfactory treatment for Acute Liver Failure other than keeping patients stable! Starzl TE. Ciba Found Symp Fausto N. Liver regeneration Diehl AM. J Gastroenterol Hepatol Michalopoulos GK.Science. 1997

8 ARTIFICIAL LIVER SUPPORT SYSTEMS Extracorporeal systems able to support/replace liver function Bridge to: Spontaneous Recovery (ALF) Recompensation (AoC-LF) OLTx

9 ARTIFICIAL LIVER SUPPORT SYSTEMS Goals To provide detoxification and synthetic function during liver failure To remove or reduce the production of proinflammatory cytokines to correct the systemic inflammatory response of liver failure To stimulate the regeneration of the injured liver and increase the likelihood of spontaneous recovery Nyberg SL Liver Transplanttion 2012

10 ARTIFICIAL LIVER SUPPORT SYSTEMS Ideal characteristics Detoxification Metabolic function Synthetic function Biocompatible Safe Simple to use Inexpensive

11 ARTIFICIAL LIVER SUPPORT SYSTEMS Cells-free systems Bioartificial systems Detoxification Overall liver function replacement

12 ARTIFICIAL LIVER SUPPORT SYSTEMS Cells-free systems Detoxification

13 The ideal system: toxins removal Water-soluble toxins (free) Water based human body Diffusion Non water-soluble toxins (protein bound) Binding site related distribution Filtration (unselective) Dialysis Balance of water-soluble substances Albumin Dialysis Balance of protein bound substances Plasma exchange (unselective) Extracorporeal Liver Support

14 ALSS- Artificial Liver Support Systems Hemodialysis Hemofiltration Hemoperfusion BioLogic-DT Plasma-Aferesis Plasma-Exchange Total Body Washout PF-Liver dialysis MARS FPSA-Prometheus SPAD Borra et al Int J Art Org 2002

15 ALSS- Artificial Liver Support Systems Hemodialysis Hemofiltration Hemoperfusion BioLogic-DT Plasma-Aferesis Plasma-Exchange Total Body Washout PF-Liver dialysis MARS FPSA-Prometheus SPAD Borra et al Int J Art Org 2002

16 Plasma-Exchange/Aferesis 2 or 3 l of plasma per session usually replaced Fresh frozen plasma Albumin

17 Plasma-Exchange Plasma exchange: a procedure used to treat various diseases through the bulk removal of plasma After plasma separation, the blood cells are returned to the person undergoing treatment, while the plasma is removed and discarded and the patient receives fresh frozen plasma (advantage: replacement of clotting factors) or albumin The procedure takes about 2 hours In ALF or ACLF, PE is performed to remove bilirubin, bile acids and ammonia from the blood

18 Plasma-Apheresis In traditional plasma-apheresis, patient s plasma is not discarded but treated and then returned to the patient An exchange resin can be added to the system to eliminate specific toxic substances (this is the case of bilirubin adsorption columns)

19 Plasma-Exchange in ALF/AoCLF 9 patients with ALF and Grade IV HE received daily PE until recovery or death. 7 (77%) showed an improvement in coma grade and 5 (55%) survived. Plasmapheresis significantly decreased serum bilirubin, aspartate aminotransferase and plasma ammonia concentrations Freeman JG et al. Int J Artif Organs patient who suffered from sclerosing cholangitis has maintained a near-normal life for almost five years by 170 plasma treatments Takahashi T et al. Dig Dis Sci patients with fulminant hepatic failure, all in stage 3 or 4 HE. 5 patients (46%) survived, 4/6 non-survivors showed a temporary improvement in cerebral function. The 6 nonsurvivors maintained a stable condition Kondrup J Int J Artif Organs patients with ALF and 9 with decompensated cirrhosis; 15/23 survivors, recovered or received LT Clemmsen JO et al. Hepatology 1999 Positive hemodynamic effects in ALF but not in ACLF (removal of humoralfactors?) Clemmesen JO et al. Eur J Gastroenterol Hepatol 1997 Significant decrease in hepatic encephalopathy and IL-18 levels in 4 patients with ALF Nakae Ther Apher Dial pts with FHF; 10/40 survived without transplantation. Overall survival was 54%. Akdogan M. et al. J Clin Apher 2006 Significant improvement in hepatic encephalopathy stage, serum prothrombin time, aminotransferases, and total bilirubin levels after PE. 10/31 survived. Bektas M et al. J Clin Gastroenterol

20 RCT, 182 pts with ALF SMT: 90 pts SMT + HVP for 3 days: 92 pts 15% of ideal body weight (8 12 L per day per procedure)

21 High volume PE (HVP) Overall LT-free hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (HR 0.56; 95% CI, ; p=0.0083). Larsen FS et al. J Hepatology 2016

22 High volume PE (HVP) HVP prior to LT did not improve post LT survival. The survival of those patients who were not listed for transplantation was significantly higher in SMT + HVP group Larsen FS et al. J Hepatology 2016

23 High volume PE (HVP) Larsen Fs et al. J Hepatology 2016

24 High volume PE (HVP) RENAL PRESERVATION: Fewer patients in the HVP group required renal replacement therapy from day 1 7 compared to the control group (47% vs. 68%, p<0.0045) despite similar creatinine at enrolment. Plasma creatinine unchanged in the HVP group but increased in the SMT group (p<0.0001). HAEMODYNAMIC IMPROVEMENT: Mean arterial pressure increased in the HVP group compared to the control group alongside a significant decrease in vasopressor requirement Larsen Fs et al. J Hepatology 2016

25 Hepatocyte death in ALF triggers release of Damaged Associated Molecular Peptides (DAMPs) that activate innate immune cells in the liver and the circulation, and leads to tissue inflammation and SIRS HVP leads to a reduction of circulatory DAMPs and to an attenuation of the pro-inflammatory response, reducing tissue damage Larsen Fs et al. J Hepatology 2016

26 The ideal system: toxins removal Water-soluble toxins (free) Water based human body Diffusion Non water-soluble toxins (protein bound) Binding site related distribution Filtration (unselective) Dialysis Balance of water-soluble substances Albumin Dialysis Balance of protein bound substances Plasma exchange (unselective) Extracorporeal Liver Support

27 ALSS- Artificial Liver Support Systems Hemodialysis Hemofiltration Hemoperfusion BioLogic-DT Plasma-Aferesis Plasma-Exchange Total Body Washout PF-Liver dialysis MARS FPSA-Prometheus SPAD Borra et al Int J Art Org 2002

28 Albumin: the Emergency Transporter Binding sites

29 Patient s plasma (primary circuit) Toxins binded to albumin albumin Free plasma toxins binding sites at membrane Albumin dialysate (secondary circuit)

30 MARS (Molecular Adsorbent Recirculating System) I CIRCUIT Not permeable to albumin DIALYSIS CIRCUIT 20% albumin II CIRCUIT ANION FILTER Maiwall R et al. Hepatol Int 2014

31 SPAD (Single Pass Albumin Dialysis) I CIRCUIT Not permeable to albumin DIALYSIS CIRCUIT WITH ALBUMIN direct purification of the patient s own albumin fraction after plasma separation Maiwall R et al. Hepatol Int 2014

32 FPSA-Prometheus (Fractionated Plasma Separation and Adsorption) Permeable to albumin I CIRCUIT II CIRCUIT DIALYSIS CIRCUIT Maiwall R et al. Hepatol Int 2014

33 MARS-SPAD-PROMETHEUS Clinical indications Drug toxicity Acute liver failure (ALF) PNF or DNF Major liver surgery Multi Organ Failure (MOF) Acute on Cronic Liver Failure (ACLF) Chronic cholestatic hepatopaty

34 How to assess efficacy of Specific Artificial Liver Support Biochemical Profile Pruritus Hepatic encephalopathy Hemodynamics Renal function Liver function Quality of Life Safety Survival

35 How to assess efficacy of Specific Artificial Liver Support Biochemical Profile Pruritus Hepatic encephalopathy Hemodynamics Renal function Liver function Quality of Life Safety Survival

36 Efficacy of specific Artificial Liver Support Toxins removal: Bilirubin Bile acids Ammonia Creatinine Pruritus: Effective (case reports/small series) Parés et al, Am J Gastroenter 2004 Heemann et al, Hepatology 2002 Hassanein et al, Hepatology 2008 Mitzner et al, Liver Transpl 2000 Rifai et al, Scand J Gastroenterol 2006 Preliminary Studies HE: Clinically improved Ammonia reduction Renal function: Uremia reduction Creatinine reduction Increased urinary volume Cytokines: Incostant results Haemodynamics: Usually improved Krisper et al, J Hepatol 2005 Klammt et al, Liver Transpl 2008 Stadlbauer et al, Crit Care 2006 Di Campli et al, Transpl Proc 2005 Novelli G et al, Transpl Proc 2009

37 Hemodynamics - MARS Change in mean arterial pressure MAP change from baseline in % + 20,0% + 10,0% Baseline - 10,0% MARS therapy p<0.05 SMT + MARS SMT - 20,0% Hospital days Heemann et al., Hepatology 2002

38 Hemodynamics - MARS Systemic Vascular Resistance Index (dyn. s/cm 3 /m 2 ) Increased SVRI from 757 ( ) to 884 ( ) dyn s/cm 3 /m 2 ; p< Before After Schmidt et al. Liver Transpl 2001

39 Biochemical Profile Cytokines 18 AoCLF conscutive pts: Pre-Post MARS cytokines levels All patients with AOCLF Survivors Nonsurvivors Pre-MARS Post-MARS Pre-MARS Post-MARS Pre-MARS Post-MARS Ammonia (mmol/l) * ^ TNF-a (pg/ml) ^ ^ IL-1b (pg/ml) * * IL-6 (pg/ml) * ^ IL-10 (pg/ml) ^ Pre-MARS compared to Post-MARS: ^p<0.01; *p< 0.05 Survivors compared to Nonsurvivors: p<0.01; #p< 0.05 Di Campli et al, Transpl Proc 2005

40 Pruritus - Prometheus 7 AoCLF Pts: severe pruritus Pts with initial higher bile acids levels have sustained response Individual course EoT, 1 week, 4 weeks Rifai et al, Scand J Gastroenterol 2006

41 MARS in drug toxicity 1. REMOVAL OF ALBUMIN BOUND DRUGS IN ALBUMIN DIALYSIS (MARS) - A NEW LIVER SUPPORT SYSTEM J.Majcher-Peszynska et al, J Hepatol 2000 Removal of benzodiazepine-like substances from blood of patients in hepatic coma or in iatrogenic or suicidal poisoning with benzodiazepines 2. DRUGS IN LIVER DISEASE AND DURING ALBUMIN DIALYSIS- MARS J.Majcher-Peszynska et al, Z Gastroenterol 2001 Toxicity from drugs accumulation may be avoided with MARS therapy 3. TREATMENT OF PHENYTOIN (PHT) TOXICITY BY THE MOLECULAR ADSORBENT RECIRCULATING SYSTEM (MARS) Sen S et al, Epilepsia 2003 MARS is effective in PHT removal, clinical improvement, reduction of oxidative stress II A : FDA approval

42 Efficacy of Artificial Liver Support Biochemical Profile Pruritus Hepatic encephalopathy Hemodynamics Renal function Liver function Quality of Life Safety Survival

43 Survival: MARS + SMT vs. SMT 4 RCT selected: 2 ACLF 2 ALF P=0.33 NS 67 pz: 36 (53.7%) MARS+SMT 31 (46.3%) SMT Subgroup analysis: ACLF P=0.35 NS ALF P=0.23 NS Khuroo et al. Liver Transplantation 2004

44 MARS vs. SMT: reduction in mortality NS Vaid A et al, ASAIO J 2012

45 Efficacy of specific Artificial Liver Support RCT Survival Studies

46 Efficacy of specific Artificial Liver Support RCT Survival Studies RCT pts with ACLF enrolled at varied timepoints PROMETEUS+SMT (n 77) SMT (n 68) Up to 11 sessions RCT pts with ACLF enrolled h after presentation MARS (n 95) SMT (n 94) Up to 10 sessions

47 Biochemical Profile MARS (RELIEF trial) Banares R et al. Hepatology 2013

48 Biochemical Profile Prometheus (HELIOS trial) Kribben A et al. Gastroenterology 2012

49 MARS: survival (RELIEF trial) MARS therapy + SMT SMT alone ITT p=0.79 PP p=0.88 Banares et al. Hepatology 2013

50 PROMETEUS: survival (HELIOS trial) Kribben A et al. Gastroenterology 2012

51 MARS for post-lt hepatic dysfunction

52 MARS for post-lt hepatic dysfunction Vaid A et al, ASAIO J 2012

53 MARS for post-lt hepatic dysfunction Our experience: 25 pts UCSC (primary nonfunction, 7 patients; graft dysfunction, 18 patients) All patients tolerated MARS treatment, with no adverse event Decrease in serum bilirubin (P 0.05), bile acids (P 0.05), serum creatinine, ammonia levels and pruritus Improvement of HE, renal and synthetic liver function were observed in 14 of 18 patients with graft dysfunction, but not among those with primary nonfunction. Gaspari R et al, Transpl Proceedings 2009

54 Efficacy of specific Artificial Liver Support Biochemical Profile Pruritus Hepatic encephalopathy Hemodynamics Renal function Liver function Quality of Life Safety Survival

55 ALSS Safety In several studies no comments about safety In two studies no AEs were reported Montejo González JC, et al. Hepatogastroenterology 2009 Schmidt LE et al.liver Transpl 2003 Two studies reported thrombocytopenia Mitzner SR et al. Liver Transpl 2000 Laleman W et al. Crit Care2006 Serious AEs in 9/39 pts: hemodynamic instability, thrombocytopenia, AKI none resulting in death. Also high incidence of catheter-related events Hassanein TI et al. Hepatology 2007 Skin rash Qin G et al. Medicine 2014 One study reported 17 AEs in 12 patients (bleeding, coagulopathy, anemia, and catheter-related sepsis), with only one death when compared with six deaths among 12 patients undergoing standard medical therapy Heemann U et al. Hepatology 2002

56 Shen Y et al. Medicine 2016 ALSS Safety

57 PROMETEUS Safety (HELIOS trial) NS Kribben A et al. Gastroenterology 2012

58 PROMETEUS Safety Senturk E et al. J Clin Apheresis 2010

59 MARS Safety (RELIEF trial) NS Hemoglobin and Platelets Banares R et al. Hepatology 2013

60 MARS/PROMETHEUS Very stressful procedure Session duration: 6 to 8 hours, up to 10 sessions!!! Vaid A et al, ASAIO J 2012

61 BIO-ARTIFICIAL liver (BAL) support systems Overall liver function

62 Kumar A et al. JECT. 2011

63 Primary porcine hepatocytes PROS Physiological similarities to the human liver CONS May induce immunogenic reactions, often retain their differentiated functions for only a short period, risk oftransfer of viral pathogens Hepatoblastoma cell line (HepG2) Readily available, importantly produces human proteins, longer operating time in comparison to the devices that use primary hepatocytes HepG2 are tumor-derived cells, which may not perform fully differentiated metabolic functions, risk of spontaneous mutations or changes in gene expression Human-derived stem cells % of liver mass is needed to sustain life, which accounts for g of normal liver, which is equivalent to 1x x10 10 liver cells (normal cell count is 1x10 11 ) Kumar A et al. JECT. 2011

64 BAL: Hepat Assist - ELAD Very complex systems A) plasmapheresis device, B) pump, C) plasma reservoir, D) charcoal column, E) oxygenerator, F) bioartificial liver (hollow fibre cartridge), G) porcine hepatocytes, H) plasma and I) hollow fibre ELAD uses immortalized human liver cells seeded cellulose acetate based hollow fiber bioreactor Kobayashi et al. J Artif Organs 2003

65 Bio ALSS - Efficacy Kumar A et al. JECT. 2011

66 Bio ALSS - Efficacy 171 pts (RCT: ALF and PNF after LT) BAL BAL P=0.1 controls P=0.09 controls ALF+PNF ALF only Demetriou A et al. Ann Surg 2004

67 Shi X-L et al. Cell Research 2016 hiheps previously converted mouse and human fibroblasts into functional hepatocytes

68 Shi X-L et al. Cell Research 2016

69 SUMMARY

70 POTENTIAL CLINICAL INDICATIONS FOR AN ARTIFICIAL LIVER DEVICE Drug toxicity Acute liver failure (ALF) PNF or DNF Major liver surgery Multi Organ Failure (MOF) Acute on Cronic Liver Failure (ACLF) Chronic severe cholestasis

71 2016 SUMMARY ALSS Differences in term of efficacy as regards to biochemical profile, clinical improvement, safety, survival Expertise Cost Main limitations

72 High Volume Plasma-Exchange HVPE continues to be used to remove toxins, mainly for its availability and for the transient correction of coagulopathy Due to the simplicity of the procedure and to the limited costs, also considering the recent data demonstrating a favorable impact on survival, PE could be considered is an acceptable bridge to pts recovery in ALF The cost of PE varies considerably; the cost for a session is approximately 439 euros (+ the cost of hospital stay) NOMENCLATORE TARIFFARIO LAZIO n.99 del 06/12/2010

73 SUMMARY High cost of MARS-PROMETHEUS! Single 7-h session of MARS (= to PROMETEUS): approximately serum albumin (20 %): MARS treatment kit: Disposables for dialysis machine: 125 Brown K. Liver Dialysis: Molecular Adsorbent Recirculating System (MARS) BME 281 Second Presentation, November 27,2012

74 Open issues Efficacy: gain in survival when LT is not feasible. Useful in restricted clinical settings such as severe hepatic encephalopathy, hepatorenal syndrome and cholestatic liver disease Experience: to be used only by expert liver teams Safety: important warnings about safety with some devices: anticoagulant-related bleeding, anemia (MARS) and thrombocytopenia (MARS and PROMETEUS)

75 SUMMARY The role of BAL support systems Over 30 different BAL systems have been reported for treatment of ALF since the first report by Matsumura in of these systems have been reported in clinical trials However, at present, none of the BAL systems have received FDA approval also for SAFETY ISSUE!!

76 Developing an effective liver support system able to improve pts survival is difficult, due to the complexity of liver (gut) functions that should be ideally replaced