Gavin Wright

King's College London

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Rajiv Jalan

The Royal Free Hospital

Nathan Davies

University College London

Vanessa Stadlbauer

Medical University of Graz

Rajeshwar P. Mookerjee

University College London

Debbie L. Shawcross

King's College London

Shilpa Chokshi

Foundation for Liver Research

Banwari Agarwal

The Royal Free Hospital

Natalie Zemon Davis

Princeton University

Vicente Arroyo

European Foundation for the Study of Chronic Liver Failure

Stephen Hodges

UiT The Arctic University of Norway

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University College London

143

European Foundation for the Study of Chronic Liver Failure

The Royal Free Hospital

University of Michigan–Ann Arbor

Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas

King's College London

Instituto de Salud Carlos III

King's College Hospital

Cambridge University Press

University of California, Davis

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P076 A multi-centre, randomized controlled study, to evaluate the safety and performance of the DIALIVE liver dialysis device in patients with acute on chronic liver failure (ACLF) versus standard of care (SOC) (ALIVER Consortium)

Banwari Agarwal Faouzi Saliba Dana Tomescu Rafael Bañares Daniel Martín

Background and Aims

Treatment of ACLF is an unmet need. DIALIVE is a novel liver dialysis device that replaces dysfunctional albumin and removes PAMPs and DAMPs. This RCT tests the hypothesis that DIALIVE improves the prognosis of ACLF patients. Primary endpoint was safety, and other endpoints included clinical and pathophysiologic effects and device performance.

Method

EUH2020 funded the RCT. Patients population had ACLF Grades 1–3a, and the main endpoints were evaluated at Day 10. For the patient to be evaluable, they had 3–5 DIALIVE sessions. No specific hypothesis was to be statistically assessed. 2-populations were defined: Safety: Patients having at least 1 DIALIVE treatment. Modified-safety (MS): Evaluable patients. A post-hoc inferential Mixed Models for Repeated Measurements analysis was performed to evaluate the differences between groups at Days 5 and 10. Log-rank and Wald tests were performed to assess ACLF resolution.

Results

Study: 32-ACLF patients with alcoholic cirrhosis were randomised either to DIALIVE (N=17; 13M; age: 49 (12.4); CLIF-OFs: 10.3 (1.6); CLIF-C ACLFs: 48.6 (7.3)) or SOC (n=15; 13M; age: 49.1 (10.2); CLIF-OFs: 9.9 (1.2); CLIF-C ACLFs: 47 (6.5)). 30 patients (15 in each arm) comprised the MS set. DIALIVE was administered for a median of 3 sessions (range 1–5) in first 3-days (range 1–6) for a median of 8 hours (7–12) each day. Safety: 5 of 17 patients died in the DIALIVE group; 4 of 15 in SOC group. SAEs were seen in 64.7% in DIALIVE and 53.3% in the SOC group. Efficacy: CLIF-OF score: Significant improvement in the Liver (p=0.045) and Brain (p<0.001) subscores in DIALIVE; and deterioration of Lung subscore (p=0.002) in the SOC group (Day 10). This resulted in a significant overall treatment effect in CLIF-OFs (p=0.043). ACLF Grade: Significantly more cases reached ACLF 0 (33.3% vs 66.7%) favoring DIALIVE (logrank p=0.0357) and a 2.8x faster time to ACLF 0 (Wald test p=0.059) (figure 1). CLIF-C ACLF score: Difference of means (standard error) between DIALIVE and SOC at Day 10 was -5.4 (2.9) in favour of the DIALIVE group (p=0.064). MELD score: Significantly lower in DIALIVE at both Days 5 (p=0.049) and 10 (p=0.028) vs SOC.

Conclusions

DIALIVE is safe and significantly increases proportion of patients resolving ACLF and reduces time to resolution. The data justify late phase clinical trials.

Clinical endpoint

10.1136/gutjnl-2021-basl.84

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Citations (5)

Haemostasis is patients with acute kidney injury due to acute liver failure

Banwari Agarwal Alex Gatt Anne Riddell Gavin Wright Pratima Chowdary

Acute kidney failure

Source

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Evaluation of coagulation abnormalities in acute liver failure

Journal of Hepatology (2012)

Banwari Agarwal Gavin Wright Alex Gatt Anne Riddell Vishwaraj Vemala

Thromboelastography

Prothrombin time

Concomitant

Clotting factor

Coagulation testing

10.1016/j.jhep.2012.06.020

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Citations (172)

Liver Injury in COVID-19: A Direct Hit or Collateral Damage?

Infectious Disorders - Drug Targets (2021)

Balasubramaniyan Vairappan Gavin Wright Douglas Corrigal Thanjavur S Ravikumar

: SARS-CoV-2 is a novel coronavirus that has been identified, in December 2019, in Wuhan, China, and since it has become a worldwide pandemic, it has imposed far-reaching impacts on global human health and socio-economic activity. Worldwide, over 4 million Covid-19 related deaths were reported until September 2021. Recently published case studies have reported that Covid-19 patients develop different degrees of liver dysfunction. Inevitably, in hospitalized Covid-19 patients who develop acute liver derangement, there are a plethora of potential pathogenic causes such as direct-viral, immune-driven, and drug-induced and/or ischaemic liver injury. Patients with advanced chronic liver diseases (e.g., cirrhosis) and/or autoimmune liver disease have a poor immune function and associated poorer outcomes compared to other critically ill cohorts. However, largely any immediate liver derangement tends to be relatively mild, and as such, any de novo liver injury may not be a significant feature of Covid-19. There is an immediate necessity, therefore, to better understand the liver-specific pathophysiology of COVID-19. This review focuses on the up-to-date information regarding Covid-19 and associated indices for liver dysfunction, possible mechanisms, and potential drug targeted therapies in Covid-19 patients with and without liver dysfunction. PubMed database was used to perform an extensive literature search using the keywords liver and SARS-CoV-2, liver and Covid-19, Covid 19 and treatment, etc.

Collateral damage

2019-20 coronavirus outbreak

Liver damage

10.2174/1871526521666210913110500

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Citations (2)

Endotoxin measures in patients’ sample: How valid are the results?

Journal of Hepatology (2007)

Vanessa Stadlbauer Nathan Davies Gavin Wright Rajiv Jalan

Alcoholic Hepatitis

Hepatitis C

10.1016/j.jhep.2007.08.001

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Neutrophil Dysfunction Patterns in Early Cirrhosis could be used to Help Identify Patients with Hepatic Encephalopathy

Journal of Clinical and Experimental Hepatology (2017)

Haw Lu Jane Macnaughtan Rohit Swahney Helen Jones Alba Moratalla

Hepatic Encephalopathy

Liver disease

10.1016/j.jceh.2017.01.083

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Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension

Metabolic Brain Disease (2007)

Gavin Wright Debbie L. Shawcross Steven W.M. Olde Damink Rajiv Jalan

Proinflammatory cytokine

10.1007/s11011-007-9071-4

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Citations (117)

Ammonia reduction with ornithine phenylacetate restores brain eNOS activity via the DDAH-ADMA pathway in bile duct-ligated cirrhotic rats

AJP Gastrointestinal and Liver Physiology (2011)

Balasubramaniyan Vairappan Gavin Wright Vikram Sharma Nathan Davies Yalda Sharifi

Ammonia is central in the pathogenesis of hepatic encephalopathy, which is associated with dysfunction of the nitric oxide (NO) signaling pathway. Ornithine phenylacetate (OP) reduces hyperammonemia and brain water in cirrhotic animals. This study aimed to determine whether endothelial NO synthase activity is altered in the brain of cirrhotic animals, whether this is associated with changes in the endogenous inhibitor, asymmetric-dimethylarginine (ADMA) and its regulating enzyme, dimethylarginine-dimethylaminohydrolase (DDAH-1), and whether these abnormalities are restored by ammonia reduction using OP. Sprague-Dawley rats were studied 4-wk after bile duct ligation (BDL) (n = 16) or sham operation (n = 8) and treated with placebo or OP (0.6 g/kg). Arterial ammonia, brain water, TNF-α, plasma, and brain ADMA were measured using standard techniques. NOS activity was measured radiometrically, and protein expression for NOS enzymes, ADMA, DDAH-1, 4-hydroxynonenol ((4)HNE), and NADPH oxidase (NOX)-1 were measured by Western blotting. BDL significantly increased arterial ammonia (P < 0.0001), brain water (P < 0.05), and brain TNF-α (P < 0.01). These were reduced significantly by OP treatment. The estimated eNOS component of constitutive NOS activity was significantly lower (P < 0.05) in BDL rat, and this was significantly attenuated in OP-treated animals. Brain ADMA levels were significantly higher and brain DDAH-1 significantly lower in BDL compared with sham (P < 0.01) and restored toward normal following treatment with OP. Brain (4)HNE and NOX-1 protein expression were significantly increased in BDL rat brain, which were significantly decreased following OP administration. We show a marked abnormality of NO regulation in cirrhotic rat brains, which can be restored by reduction in ammonia concentration using OP.

Asymmetric dimethylarginine

Hyperammonemia

Hepatic Encephalopathy

Endothelial NOS

10.1152/ajpgi.00097.2011

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Citations (41)

l-Ornithine phenylacetate (OP): A novel treatment for hyperammonemia and hepatic encephalopathy

Medical Hypotheses (2007)

Rajiv Jalan Gavin Wright Nathan Davies Stephen Hodges

Hyperammonemia

Phenylacetate

Hepatic Encephalopathy

10.1016/j.mehy.2006.12.061

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Citations (134)

CSS volume 35 issue 1 Cover and Front matter

Comparative Studies in Society and History (1993)

Raymond Grew Aram A. Yengoyan Leonard Barkan Nicholas B. Dirks Diane Hughes

An abstract is not available for this content so a preview has been provided. As you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

Front cover

Content (measure theory)

10.1017/s0010417500018211

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