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19th

International Liver Support Meeting Rostock

Detoxification and endotoxin removal combined in AoCLF – the ALIVER-EU study

Liver failure can occur either on the background of a normal liver; acute liver failure (ALF), or in patients with existing liver disease; acute-on-chronic liver failure (ACLF). ACLF, the definition, severity stratification into grades 0, 1, 2 and 3 on the basis of progression to extrahepatic organ dysfunction/failure, the associated prognoses, and a unifying pathophysiological basis underpinning development of this unique syndrome, characterised by dysregulated hepatic and systemic inflammation irrespective of the nature of  precipitating event has been elegantly captured in the seminal work by the CLIF consortium, paving the way for the clinicians and researchers to use this as a toll for a more objective and measurable determination of prognosis of this illness [1]. The condition is widespread, affecting about 30% of all hospitalised cirrhotic patients; frequently young patients (mean age 52 years) with half of them not aware of their underlying cirrhosis, and has a 28-day mortality of about 30%. 

Liver transplantation is the only definitive treatment but is limited by organ availability; a recent analysis of the Eurotransplant data of over 16,000 patients listed for liver transplantation in Europe, 27.8% died while on the waiting list for transplantation. Consequently, there is a clear need to find interventions which can be used as a ‘holding measure’ by replacing the functions of the failing liver in order to permit spontaneous recovery as the liver’s powerful regenerative potential obviates the need for transplantation in some ALF or support hepatic function during an acute deterioration of chronic liver disease in ACLF until spontaneous recovery from the episode of decompensation or to bridge to transplantation. Liver dialysis, akin to kidney dialysis for patients with end stage kidney disease, offers one such potential alternative but development of an ideal liver dialysis device (LDD) has thus far eluded the medical community.

The currently available non-biological Liver Dialysis Devices (LDDs) are largely based on the principal of removal of protein bound and water soluble substances (blood purification) by albumin dialysis, by plasma separation and filtration or by therapeutic plasma exchange. Recent clinical trials of MARS® and Prometheus, devices based on the principles of albumin dialysis, in patients with ACLF failed to demonstrate a survival benefit compared to standard medical treatment. In these trials the oxidized fractions of human mercaptalbumin (HMA, non-oxidized), human nonmercaptalbumin-1 (HNA1, reversibly oxidized) and human nonmercaptalbumin- 2 (HNA2, irreversibly oxidized), were markedly increased. Both MARS® and Prometheus treatments resulted in a shift of HNA1 to HMA while HNA2 was not significantly affected. 

DIALIVE targets the ACLF spiral with a combination of 1) albumin exchange (removal of damaged albumin and replacement with fresh albumin) and 2) endotoxin removal, using SepTex™ filter with a high cut-off membrane and oXiris® filter with an endotoxin-specific adsorber respectively, the filters connected in series (Fig1). Two pre-clinical stuides in porcine models of acetaminophen induced acute liver failure demonstrated that DIALIVE was easy to set up, safe and biocompatible, and increased the survival of the pigs treated with the device compared with untreated controls [2].

The Horizon 2020 EU Grant brought together the collective wealth of expertise and knowledge of consortium members to test DIALIVE LDD in a first-in-human trial, the safety and performance component of the study already underway with 2 patients enrolled thus far; 1 each in the DIALIVE and SOC arms. The first DIALIVE patient was treated at the Royal Free Hospital, which provided real-time insight in to the technical and safety features of the device, as well as performance measures. The patient has completed 28 days of study period and is doing well.

References:
1. Moreau, R., et al., Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology, 2013. 144(7): 1426-37

2. Karla C L Lee et al. Extracorporeal liver-assist device to exchange albumin and remove endotoxin in acute liver failure: Results of a pivotal pre-clinical study. J Hepatol. 2015; 63 (3): 634-42

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