Behind CHANCE: Bringing change to the liver transplantation landscape The team lead by Prof. Alberto Farias at Hospital das Clínicas da Universidade de São Paulo – the largest healthcare center in Latin America and the most active liver transplantation center in Brazil – recruited the 500th patient in the CHANCE study one year ago, and has continued to be ahead of patient recruitment helping us reach the 1000th patient milestone.

At our 6th CHANCE Investigator Meeting in Boston, MA, USA, we caught up with Prof. Farias who shared his view on the findings of the study and their wider implications. As part of our campaign to recruit patient no. 1000, Prof. Farias received free registration to attend the American Association for the Study of Liver Diseases (AASLD) annual meeting, The Liver Meeting® (TLM 2023). We took this opportunity to ask him about his insights from the conference and emerging topics in the field of hepatology.

Prof. Alberto Farias (left) with Cristina Sánchez-Garrido (right), Head of the Data Management Center at EF CLIF, at TLM 2023 in Boston, MA, USA. Picture: © Cristina Sánchez-Garrido.

What are the major challenges in liver transplantation today?

The demand for organs far outstrips the donation rates in liver transplantation. The costs are high, and there are significant regional disparities, leading to delayed referral and inequity in access to transplant programs and post-operative care. The burden of liver diseases includes the need for transplantation for very sick patients at risk of high short-term mortality, such as acute-on-chronic liver failure (ACLF), which remains a major cause of death while on the waitlist. Liver transplantation is the only curative treatment for patients with ACLF. However, its applicability is challenging due to the timely selection of candidates, high short-term risks, and the limited accuracy of the model for end-stage liver disease (MELD) score in predicting mortality related to multiple organ failures. Furthermore, organ allocation policies and regulations vary across the world, with marked regional differences. In addition, current criteria do not take into account variations in mortality related to racial and genetic ancestry, as recently demonstrated in the ACLARA study. Despite these drawbacks, ACLF, and particularly ACLF-3, should not be considered a contraindication for liver transplantation. Recent studies have demonstrated that ACLF patients have good post-transplant survival rates. However, ACLF-3 patients were shown to have greater use of hospital resources and a longer hospital stay. Clearly, there is room for more studies and granular data. In the era of precision medicine, it is hoped that new markers may help improve the criteria for patient selection.

Based on results derived from our interim analysis, how are the findings of the CHANCE study expected to impact care of patients with severe acute-on-chronic liver failure (ACLF)?

The worldwide experience of liver transplantation for ACLF patients is growing. Nevertheless, published data are heterogeneous, and some experts consider the benefits of transplanting with three or more failing organs (ACLF-3) controversial. However, most evidence comes from retrospective studies with selection bias, including the lack of analysis of outcomes for non-transplanted ACLF patients and the reasons for delisting. From this perspective, the definition of transplant futility remains elusive, with large prospective international collaborative studies urgently warranted.

The CHANCE study might offer new insights into the role of transplantation for ACLF patients, providing good-quality data on issues such as: (1) Improving the survival of patients with ACLF-3 through liver transplantation and identifying the limits of its effectiveness or futility; (2) critically analyzing current allocation systems and exploring possible strategies to implement ACLF criteria for prioritization; (3) investigating disparities and barriers to equitable access to liver transplantation for ACLF-3 patients; and (4) assessing the role of additional prognostic markers such as frailty.

As part of our campaign to recruit patient no. 1000, you received free registration to attend The Liver Meeting 2023 (TLM 2023) – the annual meeting of the American Association for the Study of Liver Diseases (AASLD). What are your key takeaways from TLM 2023?

In addition to providing a good opportunity to network with clinicians, surgeons, and scientists, the 2023 edition of The Liver Meeting featured discussions on ACLF during the post-graduate course, regular sessions, and in several posters. The most relevant topics were related to viewing cirrhosis as an immune deficiency state, opening opportunities for translational research, as well as improving the outcomes of ACLF patients through liver transplantation. Discussions focused on clinical pre-operative management strategies included the need for future studies on the role of dynamic volume status assessment tools such as point-of-care ultrasound (POCUS), timing of renal replacement therapy, and lung protective strategies. Pragmatic case selection for transplantation, whether center-driven or guided centrally, was discussed to overcome the very limited time window to offer liver transplantation for patients with multiple organ failures. Future challenges include the need for international cross-collaborations between research groups to foster the establishment of widely accepted criteria for transplantation.

The CHANCE study is promoted by EF CLIF.

About the CHANCE study

CHANCE is a multicenter, global, observational study designed to assess the benefit of liver transplantation in patients with acute-on-chronic liver failure (ACLF) grade 2 or grade 3. This study counts with the support of the International Liver Transplantation Society (ILTS) and the European Liver and Intestine Transplant Association (ELITA) to recruit 2000 patients in 80 centers in 27 countries around the world. The primary objective of the CHANCE study is to compare 1-year graft and patient survival rates after liver transplantation in patients with ACLF grade 2 or grade 3 at the time of liver transplantation with patients with decompensation of cirrhosis without ACLF-2 or 3 and transplant-free survival of patients with ACLF-2 or 3 not listed for liver transplantation. The international nature of this study will allow for deep assessments of the potential impact of different precipitating factors of ACLF (e.g., alcohol vs. Hepatitis B virus flare), different types of liver transplantation (deceased donor vs. living donor liver transplantation) and different regional and national allocation systems on transplant outcomes. Beside these clinical objectives, the CHANCE study aims to build a repository of biological samples to explore new biomarkers to predict prognosis on the waiting list and after liver transplantation, and mechanisms of liver and extrahepatic organ recovery.

ClinicalTrials.gov Identifier: NCT04613921