Liver transplantation in patients with CirrHosis and severe Acute-on-Chronic Liver Failure (ACLF): iNdications and outComEs (CHANCE)

Patients with acute decompensation of cirrhosis are a heterogeneous clinical
group associated with different prognoses which need to be stratified to define
appropriate management. The term *Acute-on-Chronic Liver Failure (ACLF)*
characterizes a subgroup of patients with chronic liver diseases which develop
organ failure(s) leading to very poor short-term outcome. Several tools for
estimating outcomes of patients with ACLF have been developed.
The management of ACLF per se is mainly supportive with intensive monitoring
and supports of failing organs. Clinical deterioration despite maximal
supportive management is associated with very poor outcomes and leads
physicians to consider potential salvage liver transplantation (LT).
This option remains highly controversial. LT in sicker recipients is
unquestionably associated with an improved survival benefit but could result in
less acceptable longer-term survival rates after LT. Due to the scarcity of
deceased liver donors, we need a strategy of rationing where the success of
deceased-donor LT (DDLT) will be maximized.
A Patients listed with ACLF-3 has a high probability to die on the waiting list
(WL) or be removed from the WL. Thus, we must define predictive factors of
death or removal from the WL for patients with severe ACLF based on prospective
data to try to design better rule for organ allocation for this group of
patients. This especially in the context of scarcity of liver donors, the
potential benefit of LT in ACLF patients must also be balanced against the need
for rationing of limited resources.
Prospective data from large multicenter international studies are urgently
needed, aiming to resolve objectively this controversial ethical issue that
results either in wasting scarce organ resources or in precluding severely sick
patient*s access to life-saving treatment.

This CHANCE study aims to develop new biomarkers to predict the prognosis on
the waiting list and after LT for patients with decompensated cirrhosis with or
without ACLF-2 or 3, to investigate the impact of LT on systemic disturbances
(inflammation, leukocyte dysfunction, metabolic alterations, dysbiosis)
observed in ACLF and to explore the mechanisms of liver and extrahepatic organ
recovery after LT in patients with ACLF-2 or 3 and determinants of this
recovery.

1. Primary objective: Survival results of LT in patients with severe ACLF

To compare 1-year graft and patient survival rates after LT in patients
with ACLF-2 or 3 at the time of LT with patients with decompensated
cirrhosis without ACLF 2-3 and transplant-free survival of patients
with ACLF-2 or 3 not listed for LT.

2. Secondary objectives

1) To define the factors in decision-making process for listing patients
with severe ACLF; in particular to assess the proportion of patients
with ACLF-2 or 3 referred to transplant team who are listed or
not and reasons of not listing.
2) To analyze the clinical course of patients listed with ACLF-2 or 3 on
the waiting list compared with those of patients listed with
decompensated cirrhosis without ACLF-2 or 3.
3) To define independent predictive factors of death/delisting on the
waiting list for patients listed with ACLF-2 or 3 and develop a new
prognostic model based on ACLF criteria to predict mortality
on the waiting list and to improve the allocation of organs.
4) To compare the characteristics of accepted grafts for patients listed
with ACLF-2 or 3 with those of patients listed with decompensated
cirrhosis without ACLF-2 or 3 and their impact on post-LT
outcomes.
5) To explore independent predictive factors of death after LT for
patients transplanted with ACLF-2 or 3 to design futility criteria for LT.
6) To compare post-LT survival rates of patients with ACLF-2 or 3 at
listing and patients without ACLF at listing who develop ACLF-2 or 3 on
the waiting list.
7) To compare post-LT quality of life (QoL) for patients listed with
ACLF-2 or 3 with those of patients listed with decompensated cirrhosis
without ACLF-2 or 3.
8) To assess the resources utilization of care and LT procedure in
patients listed with ACLF-2 or 3 (in intention-to-treat and per protocol)
compared with patients listed with decompensated cirrhosis
without ACLF-2 or 3.

3. Exploratory objectives

1) To develop new biomarkers to predict the prognosis on the waiting list
and after LT for patients with decompensated cirrhosis with or
without ACLF-2 or 3.
2) To investigate the impact of LT on systemic disturbances (inflammation,
leukocyte dysfunction, metabolic alterations) observed in ACLF.
3) To explore the mechanisms of liver and extrahepatic organ recovery
after LT in patients with ACLF-2 or 3 and determinants of this
recovery.
*

Prospective non-interventional observational study

The current study does not pose any significant risk to the patients and the
only burden is collection of blood, urine, liver tissue and saliva.
The study has no direct benefit for the included subjects. The results of this
study may result in a substantial improvement in knowledge about pathogenesis,
prognosis and treatment.