T. Marianelli

Liver Match, a prospective observational cohort study on liver transplantation in Italy: Study design and current practice of donor-recipient matching

BACKGROUND The Liver Match is an observational cohort study that prospectively enrolled liver transplantations performed at 20 out of 21 Italian Transplant Centres between June 2007 and May 2009. Aim of the study is to investigate the impact of donor/recipient matching on outcomes. In this report we describe the study methodology and provide a cross-sectional description of donor and recipient characteristics and of graft allocation. METHODS Adult primary transplants performed with deceased heart-beating donors were included. Relevant information on donors and recipients, organ procurement and allocation were prospectively entered in an ad hoc database within the National Transplant Centre web-based Network. Data were blindly analysed by an independent Biostatistical Board. RESULTS The study enrolled 1530 donor/recipient matches. Median donor age was 56 years. Female donors (n = 681, median 58, range 12-92 years) were older than males (n = 849, median 53, range 2-97 years, p < 0.0001). Donors older than 60 years were 42.2%, including 4.2% octogenarians. Brain death was due to non-traumatic causes in 1126 (73.6%) cases. Half of the donor population was overweight, 10.1% was obese and 7.6% diabetic. Hepatitis B core antibody (HBcAb) was present in 245 (16.0%) donors. The median Donor Risk Index (DRI) was 1.57 (>1.7 in 35.8%). The median cold ischaemia time was 7.3h (≥ 10 in 10.6%). Median age of recipients was 54 years, and 77.7% were males. Hepatocellular carcinoma (HCC) was the most frequent indication overall (44.4%), being a coindication in roughly 1/3 of cases, followed by viral cirrhosis without HCC (28.2%) and alcoholic cirrhosis without HCC (10.2%). Hepatitis C virus infection (with or without HCC) was the most frequent etiologic factor (45.9% of the whole population and 71.4% of viral-related cirrhosis), yet hepatitis B virus infection accounted for 28.6% of viral-related cirrhosis, and HBcAb positivity was found in 49.7% of recipients. The median Model for End Stage Liver Disease (MELD) at transplant was 12 in patients with HCC and 18 in those without. Multivariate analysis showed a slight but significant inverse association between DRI and MELD at transplant. CONCLUSIONS The deceased donor population in Italy has a high-risk profile compared to other countries, mainly due to older donor age. Almost half of the grafts are transplanted in recipients with HCC. Higher risk donors tend to be preferentially allocated to recipients with HCC, who are usually less ill and older. No other relevant allocation strategy is currently adopted at national level.

Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: Evidence from the Liver Match cohort study

BACKGROUND & AIMS The appropriate allocation of grafts from HBcAb positive donors in liver transplantation is crucial, yet a consensus is still lacking. METHODS We evaluated this issue within Liver Match, a prospective observational Italian study. Data from 1437 consecutive, first transplants performed in 2007-2009 using grafts from deceased heart beating donors were analyzed (median follow-up: 1040 days). Of these, 219 (15.2%) were HBcAb positive. Sixty-six HBcAb positive grafts were allocated to HBsAg positive and 153 to HBsAg negative recipients. RESULTS 329 graft losses occurred (22.9%): 66 (30.1%) among 219 recipients of HBcAb positive grafts, and 263 (21.6%) among 1218 recipients of HBcAb negative grafts. Graft survival was lower in recipients of HBcAb positive compared to HBcAb negative donors, with unadjusted 3-year graft survival of 0.69 (s.e. 0.032) and 0.77 (0.013), respectively (log-rank, p=0.0047). After stratifying for recipient HBsAg status, this difference was only observed among HBsAg negative recipients (log rank, p=0.0007), 3-year graft survival being excellent (0.88, s.e. 0.020) among HBsAg positive recipients, regardless of the HBcAb donor status (log rank, p=0.4478). Graft loss due to de novo HBV hepatitis occurred only in one patient. At Cox regression, hazard ratios for graft loss were: MELD (1.30 per 10 units, p=0.0002), donor HBcAb positivity (1.56, p=0.0015), recipient HBsAg positivity (0.43, p <0.0001), portal vein thrombosis (1.99, p=0.0156), and DRI (1.41 per unit, p=0.0325). CONCLUSIONS HBcAb positive donor grafts have better outcomes when transplanted into HBsAg positive than HBsAg negative recipients. These findings suggest that donor HBcAb positivity requires more stringent allocation strategies.

A Bayesian methodology to improve prediction of early graft loss after liver transplantation derived from the Liver Match study

BACKGROUND To generate a robust predictive model of Early (3 months) Graft Loss after liver transplantation, we used a Bayesian approach to combine evidence from a prospective European cohort (Liver-Match) and the United Network for Organ Sharing registry. METHODS Liver-Match included 1480 consecutive primary liver transplants performed from 2007 to 2009 and the United Network for Organ Sharing a time-matched series of 9740 transplants. There were 173 and 706 Early Graft Loss, respectively. Multivariate analysis identified as significant predictors of Early Graft Loss: donor age, donation after cardiac death, cold ischaemia time, donor body mass index and height, recipient creatinine, bilirubin, disease aetiology, prior upper abdominal surgery and portal thrombosis. RESULTS A Bayesian Cox model was fitted to Liver-Match data using the United Network for Organ Sharing findings as prior information, allowing to generate an Early Graft Loss-Donor Risk Index and an Early Graft Loss-Recipient Risk Index. A Donor-Recipient Allocation Model, obtained by adding Early Graft Loss-Donor Risk Index to Early Graft Loss-Recipient Risk Index, was then validated in a distinct United Network for Organ Sharing (year 2010) cohort including 2964 transplants. Donor-Recipient Allocation Model updating using the independent Turin Transplant Centre dataset, allowed to predict Early Graft Loss with good accuracy (c-statistic: 0.76). CONCLUSION Donor-Recipient Allocation Model allows a reliable donor and recipient-based Early Graft Loss prediction. The Bayesian approach permits to adapt the original Donor-Recipient Allocation Model by incorporating evidence from other cohorts, resulting in significantly improved predictive capability.

Recipient female gender is a risk factor for graft loss after liver transplantation for chronic hepatitis C: Evidence from the prospective Liver Match cohort.

BACKGROUND Female gender has been reported to be a risk factor for graft loss after liver transplantation for hepatitis C virus (HCV)-related cirrhosis but evidence is limited to retrospective studies. AIMS To investigate the impact of recipient gender and donor/recipient gender mismatch on graft outcome. METHODS We performed a survival analysis of a cohort of 1530 first adult transplants enrolled consecutively in Italy between 2007 and 2009 and followed prospectively. After excluding possible confounding factors (fulminant hepatitis, human immunodeficiency virus co-infection, non-viremic anti-HCV positive subjects), a total of 1394 transplant recipients (604 HCV-positive and 790 HCV-negative) were included. RESULTS Five-year graft survival was significantly reduced in HCV-positive patients (64% vs 76%, p=0.0002); Cox analysis identified recipient female gender (HR=1.44, 95% CI 1.03-2.00, p=0.0319), Mayo clinic End stage Liver Disease score (every 10 units, HR=1.25, 95% CI 1.03-1.50; p=0.022), portal thrombosis (HR=2.40, 95% CI 1.20-4.79, p=0.0134) and donor age (every 10 years, HR=1.14, 95% CI 1.05-1.24, p=0.0024) as independent determinants of graft loss. All additional mortality observed among female recipients was attributable to severe HCV recurrence. CONCLUSIONS This study unequivocally shows that recipient female gender unfavourably affects the outcome of HCV-infected liver grafts.

Cost-effectiveness of pretransplant sofosbuvir for preventing recurrent hepatitis C virus infection after liver transplantation.

There are reports of pretransplant sofosbuvir (SOF) plus ribavirin being effective in preventing recurrent hepatitis C virus (HCV) infection after liver transplantation (LT). The aim of this study was to assess the cost‐effectiveness of this strategy in the area served by the North Italy Transplant program. We retrospectively assessed the impact of HCV infection on post‐LT survival in 2376 consecutive adult patients (MELD ≤ 25, unknown genotype, period 2004–2009) and the prevalence costs of conventional standard of care (SOC) antiviral therapy (pegylated interferon plus ribavirin) after LT. A Markov model was developed to compare two strategies: 12–24 weeks of SOF+ ribavirin for pre‐LT anti‐HCV treatment versus on‐demand post‐LT SOC antiviral therapy. Among the 1794 patients undergoing LT, 860 (48%) were HCV+ and 50% of them were given SOC therapy after LT (mean cost of drugs and adverse effect management = 14 421€ per patient). HCV etiology had a strong impact on post‐LT survival (hazard ratio = 1.59, 95% CI = 1.22–2.09, P = 0.0007). After Monte Carlo simulation, pre‐LT SOF therapy showed a median survival benefit of 1.5 quality‐adjusted life years and an Incremental cost‐effectiveness ratio (ICER) of 30 663€/QALY, proving cost‐effective in our particular Italian scenario. The costs of SOF therapy, sustained viral response rate 12 weeks after LT, and recipients age were the main ICER predictors at multivariate analysis. This study proposes a dynamic model based on real‐life data from northern Italy for adjusting the costs of pre‐LT direct‐acting antiviral therapies to the actual sustained virological response reached after LT.

International comparison of liver transplant programmes: differences in indications, donor and recipient selection and outcome between Italy and UK

Comparing liver transplant (LT) programmes internationally can improve outcomes by stimulating cross‐national learning. Yet, comparison of crude outcomes, by using registry data, is limited by missing data, not allowing proper risk‐adjustment for donor‐ and recipient‐related factors. The objective of this study was to compare two European LT programmes based on high‐quality national longitudinal databases prospectively collected in Italy and UK respectively.

93 THE USE OF MYCHOPHENOLATE MOFETIL IS A MAJOR DETERMINANT OF ONE YEAR GRAFT SURVIVAL AFTER LIVER TRANSPLANTATION: RESULTS FROM THE LIVER MATCH PROSPECTIVE STUDY

93 THE USE OF MYCHOPHENOLATE MOFETIL IS A MAJOR DETERMINANT OF ONE YEAR GRAFT SURVIVAL AFTER LIVER TRANSPLANTATION: RESULTS FROM THE LIVER MATCH PROSPECTIVE STUDY M. Angelico, T. Marianelli, L. Caccamo, A. Gasbarrini, C. Gavrila, A. Ricci, A. Nardi, on behalf of Liver Match Investigators: AISF and CNT Governing Boards, Directors of Liver Transplant Programs and AISF Fellowship Recipients. Hepatology & Liver Transplantation, Tor Vergata University, Rome, Liver Transplantation, Milan University, Milan, Gastroenterology, Catholic University, Biomathematics, Tor Vergata University, Biostatistics, National Transplant Center, Rome, Italy E-mail: angelico@med.uniroma2.it

455 PREDICTORS OF ONE-YEAR GRAFT SURVIVAL AFTER LIVER TRANSPLANTATION GREATLY DIFFER BETWEEN RECIPIENTS WITH AND WITHOUT HCV INFECTION: INSIGHTS FROM THE LIVER MATCH PROSPECTIVE STUDY

455 PREDICTORS OF ONE-YEAR GRAFT SURVIVAL AFTER LIVER TRANSPLANTATION GREATLY DIFFER BETWEEN RECIPIENTS WITH AND WITHOUT HCV INFECTION: INSIGHTS FROM THE LIVER MATCH PROSPECTIVE STUDY M. Angelico, T. Marianelli, S. Fagiuoli, G. Grazi, S. Ginanni Corradini, M. Rossi, A. Nardi, on behalf of Liver Match Investigators: AISF and CNT Governing Boards, Directors of Liver Transplant Programs and AISF Fellowship Recipients. Hepatology & Liver Transplantation, Tor Vergata University, Rome, Gastroenterology, Ospedali Riuniti di Bergamo, Bergamo, Liver Transplantation, Bologna University, Bologna, Gastroenterology, Liver Transplantation, La Sapienza University, Biomathematics, Tor Vergata University, Rome, Italy E-mail: angelico@med.uniroma2.it