Elsevier

Journal of Hepatology

Volume 45, Issue 1, July 2006, Pages 127-143
Journal of Hepatology

EASL Meeting Report
Report of the Monothematic EASL Conference on Liver Transplantation for Viral Hepatitis: (Paris, France, January 12–14, 2006)

https://doi.org/10.1016/j.jhep.2006.05.001Get rights and content

Introduction

This EASL monothematic conference aimed to review in a 2-day meeting the most recent aspects of liver transplantation for viral hepatitis. Experts from Europe and overseas exchanged their views and expertise on the different aspects of liver transplantation and viral hepatitis, and presented the most updated information available at the time of the conference which was held in Paris, France, January 12-14, 2006.

Massimo Levrero, Department of Internal Medicine and Laboratory of Gene Expression, Fondazione A. Cesalpino, University of Rome La Sapienza, Rome, Italy.

The outcome of HBV infection is the result of complicated viral–host interactions that involve different actors, including the immune system, viral mechanisms, the liver microenvironment and the host anti-viral responses. For instance, HBV tolerance appears as the result of an “immune defect”, with a reduced T-cell-dependent Th1 response. HBV is the prototype of the hepadnavirus family, sharing a distinctive strategy for replication. HBV replication occurs in the cytoplasm within viral capsids (core particles), where a terminally redundant RNA replication intermediate is converted, by the virally encoded RNA-dependent and DNA-dependent reverse transcriptase/polymerase, into a specific open circular (OC) duplex DNA without amplification. Transcription in the nucleus of the 1.1 genome-sized pre-genome RNA from the cccDNA is the critical step for genome amplification and ultimately determines the rate of HBV replication. A continued productive HBV infection requires a persistent population of transcriptionally active cccDNA molecules to ensure a stable source of pre-genome RNA for replication and the templates for mRNA synthesis and viral proteins production. HBV cccDNA has proven to be relatively insensitive to the therapeutic regimens based upon the use of antiviral drugs currently used to suppress HBV replication in chronically infected patients and the persistence of viral cccDNA is the basis for the rapid recurrence of HBV replication upon discontinuation of treatment. Recent studies have shown that cccDNA do decline after 48 weeks of treatment with adefovir dipivoxil or lamivudine plus pegylated interferon (from 1 to 2 logs) but it can be inferred, based upon a mathematical modelling, that it would take more than 14 years to completely clear a HBV-chronically infected human liver of intracellular cccDNA.

Nuclear cccDNA molecules have been shown to be organized into a chromatin-like structure as a viral minichromosome that has been shown to consist of both histone and non-histone proteins, including the virally encoded core protein, the cellular acetyltransferases PCAF and CBP and the histone deacetylase 1 (HDAC1). It has been shown that HBV replication is regulated by the acetylation status of the cccDNA-bound H3/H4 histones. Accordingly, class I histone deacetylases inhibitors induced an evident increase of both cccDNA-bound acetylated H4 and HBV replication. Interestingly, histones hypoacetylation and HDAC1 recruitment onto the cccDNA in liver tissue correlates with low HBV viremia in hepatitis B patients. A similar epigenetic regulation of HBV transcription/replication cycle might be involved in the strong suppression of viral replication and gene expression that characterize the “occult” HBV infection, i.e., the presence of both integrated and episomal HBV genomes in the liver of HBsAg negative individuals with or without circulating antibodies to HBsAg (anti-HBs) and/or hepatitis B core antigen (anti-HBc). In the Mediterranean basin, about one-third of the patients with chronic hepatitis C carry such a cryptic infection, which is associated with advanced disease, cirrhosis and an increased risk to develop HCC. The mechanisms through which occult HBV infection may produce or contribute to liver damage are at present poorly defined. Recent studies on both humans and woodchucks convalescent from acute HBV and WHV infections have shown that the lifelong persistence of small amounts of replicating viruses induces a very mild liver necroinflammation that may last for life. Such “occult” HBV infection may become clinically relevant in the cases of immunosuppressed patients.

Anna S.F. Lok, University of Michigan, Ann Arbor, MI, USA.

The goal of treatment for patients with compensated HBV-cirrhosis is to prevent decompensation and hepatocellular carcinoma (HCC) and to reverse cirrhosis. For patients with decompensated cirrhosis, the main goal is to improve liver function, thereby obviating the need for liver transplant. Moreover, for patients who require liver transplantation, another aim of treatment is to decrease the risk of HBV recurrence post-transplant. In all these situations, the key is to maintain viral suppression and reduction in hepatic necroinflammation. Available treatments of hepatitis B include standard interferon (IFN) alfa, pegylated IFN alfa, lamivudine, adefovir, and entecavir.

IFN is not recommended for patients with decompensated cirrhosis because of the risk of hepatitis flares and infectious complications. However, clinical trials of IFN showed that patients with clinically and biochemically compensated cirrhosis and adequate cell counts have a similar side effect profile as those without cirrhosis and the risk of hepatic decompensation is not increased. Long-term follow-up studies reported that patients with a sustained response to IFN have a lower risk of hepatic decompensation compared to those who did not respond. A beneficial effect of IFN on HCC development has been reported in some Asian studies but not in European or US studies.

Lamivudine suppresses HBV replication, normalizes ALT levels and reduces hepatic necroinflammation in patients with chronic hepatitis B. It is well tolerated in patients with cirrhosis including those with decompensation. A beneficial effect of antiviral therapy on the clinical outcome of patients with HBV-cirrhosis was demonstrated by the Asian trial in which lamivudine was found to significantly reduce the rate of disease progression, 7.8% vs. 18% (p = 0.001) and HCC development, 3.9% vs. 7.4% (p = 0.047) [1]. Lamivudine has also been shown to stabilize or improve liver function in patients with decompensated cirrhosis thereby obviating or delaying the need for liver transplant. However, clinical improvement is slow and may take up to 6 months [2]. Moreover, HCC can still occur even in patients with clinical improvement. For patients who are not transplant candidates, lamivudine can be a life-saving treatment, but a major concern is the risk of viral resistance, and the beneficial impact on clinical outcome is reduced in the case of viral resistance. Prospective studies to evaluate the efficacy of adefovir and entecavir in preventing or reversing adverse clinical outcomes in patients with HBV-cirrhosis have not been reported, but, based on data from lamivudine studies, it is anticipated that similar benefit can be observed. The major advantage of adefovir and entecavir is a lower rate of drug resistance (0% at 1 year, 29% at 5 years for adefovir). Entecavir is more potent but its long-term safety remains to be established. Antiviral efficacy of adefovir is variable and long-term use may be associated with a low risk of nephrotoxicity. Adefovir has been shown to be well tolerated and effective in suppressing lamivudine-resistant HBV in patients with decompensated cirrhosis with resultant clinical improvement [3]. Adefovir resistance is uncommon in patients who continued to receive lamivudine. The optimal antiviral strategy seems to be an association of different nucleos(t)ides analogues, in order to minimize the risk of viral resistance, viral breakthrough, and liver disease decompensation. Nevertheless, the best association is not known yet.

Daniel Shouval, Liver Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

HBV-induced liver disease represents 10% of the indications for liver transplantation in Europe and this has been very stable over the past 10 years. The timing of liver transplantation in the case of HBV infection depends on both the clinical and virological status of the patients. Therefore, a clinical score, involving these two different aspects of HBV liver disease, seems to be highly relevant [2]. In addition, rather than a score value at listing (MELD or others), the variation of this score during the waiting period seems to be the most relevant for the decision of transplantation.

It is well known that the presence of HBeAg and the detection of a high viral load (usually >105 copies/ml) pre-transplantation is associated with an increased risk of graft HBV re-infection [4], [5], [6]. Consequently, a consensus gradually emerged that suppression of viral load prior to transplantation should be an important independent goal. The development of the new nucleos(t)ide analogues has revolutionized the treatment of HBV. This also includes patients with end-stage HBV cirrhosis pending or already listed for liver transplantation. These well-tolerated anti-viral agents such as lamivudine and adefovir were shown to have a rapid and potent anti-viral effect. Thus, administration of lamivudine to HBV decompensated patients with a viral load >105 copies/ml is associated with successful suppression of viral load in 60–90% of patients prior to transplantation. However, severity of liver disease (as manifested by elevated bilirubin and serum creatinine levels as well as viral load) at time of treatment initiation is an important factor in predicting success of anti-viral therapy and delaying time of transplantation. Thus, clinicians who prescribe lamivudine to decompensated patients must differentiate between the anti-viral response, which often is rapid and impressive, and clinical improvement, which may take 6 months and longer to achieve. Regardless if both goals are achieved, suppression of viral load <105 copies/ml and preferably to 102-103 copies/ml remains an independent goal since a low viral load, pre-transplantation, reduces the risk of post-transplantation HBV re-infection [4], [7]. Pre-transplant administration of lamivudine is not always effective and 20–25% of treated patients will not survive until transplantation. A major reason for lamivudine failure is the emergence of the YMDD mutant with an incidence of ∼20% in the first year of treatment. Thus, lamivudine recipients must be monitored closely by quantitative HBV-DNA assays every 1–3 months and switched to another analogue, which is effective against YMDD mutants. It is likely that the new anti-viral agents such as adevofir, entecavir or tenofovir, which are effective against YMDD mutants, will enhance the options for successful pre-transplant therapy. The importance of combination as opposed to sequential therapy in prevention of breakthrough must also be clarified in the near future. Suppression of viral load and improvement of synthetic liver functions may lead to removal of transplant candidates from the waiting list. Indeed the estimated 3-year survival in lamivudine recipients who survived 6 months of therapy with improved liver functions was 88% on continued treatment [2]. In conclusion, the impressive results in reversal of decompensation must be balanced on an individual basis against the risk of emerging breakthrough mutants as well as development of hepatocellular carcinoma and losing or delaying the option of liver transplantation. Thus, patients with HBV infection and discussion of liver transplantation should be referred to a transplant centre before the choice of anti-viral treatment.

Christian Trautwein, Medizinische Klinik III, University Hospital RWTH Aachen, Germany.

The risk of HBV reinfection directly correlates with the viral load before OLT. If re-infection does occur in most cases, the course of the disease is enhanced compared to the situation before OLT. The progression of HBV-related liver disease is accelerated starting 2 months after OLT and may result in re-transplantation or death of the patients. In the absence of treatment, prognosis after liver transplantation is significantly poorer in the case of HBV infection. Factors associated with HBV recurrence are the status of viral replication at the time of transplantation and the type of liver disease (cirrhosis, fulminant hepatitis, HDV co-infection). When HBV-reinfection does occur, enhanced HBV replication is found, compared to the situation before OLT. Several molecular mechanisms are involved to explain increased HBV replication in these patients. 1. There is a glucocorticoid-responsive element in the HBV genome and glucocorticoids stimulate HBV-dependent transcription [8]. 2. Immunosuppression after OLT suppresses the virus-specific immune response. After OLT more frequently wild-type HBV is re-selected and this can result in a better replication fitness of the virus. 3. Mutations selected in the HBV preS region can result in a cytotoxic HBV strain, which is associated with fibrosing cholestatic hepatitis [9], [10]. After OLT, the selection of cytotoxic HBV strains leads to a new histological picture that can be observed in the course of HBV-related liver disease and was described as fibrosing cholestatic hepatitis. These patients present with jaundice rapidly progressing to hepatic failure. Liver histology is characterised by cholestasis with an inflammatory infiltrate and fibrosis. Hepatocytes show a very prominent staining for HBsAg in the cytoplasm and it is thought that a direct cytopathic effect of viral proteins is the pathophysiological clue for this disease entity. After these observations were made in the early 1990s, new approaches were developed in order to block HBV-reinfection after OLT and these efforts resulted in effective prophylactic regimens.

Didier Samuel, Centre HépatoBiliaire, Unité INSERM 785, Université Paris Sud, Hôpital Paul Brousse, 94800 Villejuif, France.

The spontaneous risk for HBV reinfection after transplantation is around 80%. Thus 20% of patients have a spontaneous disappearance of HBsAg, which was more frequent in patients transplanted for acute liver failure [4]. From a historical point of view, the first therapeutic breakthrough was the long-term administration of high doses of anti-HBs Ig (HBIG) that reduces drastically the rate of HBV recurrence. In the Paul Brousse series of 284 patients, the overall 10-year HBV recurrence rate was 27%, which was higher in patients with viral B cirrhosis (50%) than in those with fulminant hepatitis (0%) or with viral B-Delta cirrhosis (15%) [11]. Moreover, it was significantly higher in patients with viral B cirrhosis who were serum HBV-DNA positive before transplantation than in those who were HBV-DNA negative (80% vs. 27%). The advent of nucleos(t)ide analogues was the second breakthrough. Lamivudine alone without HBIG administration has been given as a prophylaxis. The medium-term results showed that HBsAg remained positive in the serum of a significant percentage of patients and that HBV DNA reactivation due to viral breakthrough was increasing with time to 40% at 3–4 years post-transplant [12]. Results of adefovir monotherapy post-transplantation are not yet available. The third breakthrough was the combination of HBIG with nucleos(t)ide analogue, which is able to reduce the recurrence risk to less than 10%, even in patients at high risk of HBV recurrence [6], [13]. The result of these progresses during the past 15 years was that patients receiving adequate immunoprophylaxis have a similar 10-year survival rate to that of patients transplanted for other liver diseases [14]. Nevertheless, the excellent results of combined post-transplant prophylaxis and the high cost of HBIG have put in front the role of HBIG in these prophylaxis strategies. It has been suggested that the dose of HBIG in combination therapy can be reduced, and that IM HBIG can safely replace IV HBIG. There are ongoing studies on the possibility of discontinuation of HBIG after several weeks or months, with the introduction of HBV vaccine, or maintenance of nucleos(t)ide analogues. The future will probably see the emergence of a “à la carte” HBV prophylaxis taking into account the individual risk of HBV recurrence and the advantages and drawbacks of HBIG and/or antiviral therapy (Fig. 1).

Norah Terrault, University of California, San Francisco, USA.

Hepatitis B immune globulin (HBIG) was the first therapy to show efficacy in preventing HBV reinfection in liver transplant recipients. The exact mechanism of action of HBIG is unknown, but it has been suggested that HBIG can bind circulating virus and prevent binding to receptors on hepatocytes, and that, in vitro, anti-HBs IgG can enter hepatocytes and bind HBsAg, and therefore prevent secretion of HBsAg and HBV virions from cells.

HBIG was used as prophylactic monotherapy until the mid-1990s, but with the availability of lamivudine and other safe and effective nucleos(t)ide analogues, the standard of practice quickly shifted to combination prophylaxis using oral antivirals (lamivudine, adefovir and entecavir) in combination with HBIG. The combination of HBIG and oral antivirals is attractive since these drugs have different mechanisms of action and different drug resistance patterns [6]. Indeed, though not compared head-to-head in randomized controlled trials, the outcomes achieved with HBIG in combination with antivirals appear superior to those achievable with HBIG or lamivudine monotherapies. Studies of the efficacy of combination prophylaxis using other antivirals (adefovir or entecavir) and HBIG have not been published but the efficacy of these agents would be expected to be at least comparable to those achieved with lamivudine and HBIG. Thus, HBIG is a central part of prophylaxis for LT patients and combination therapy using HBIG plus antivirals is the “standard” to which new prophylactic strategies will be compared.

Prior studies have shown that failure of HBIG prophylaxis during the early post-LT period was due to insufficient dosing of HBIG, and was more frequent in patients with high HBV replication. Anti-HBs titers associated with efficient prevention of re-infection were established during the HBIG monotherapy era and recently revisited in the combination therapy era. In patients on HBIG and concurrent lamivudine therapy, HBsAg neutralization was achieved with anti-HBs >300 IU/L during week 1 and >200 IU/L during weeks 2–12. However, the HBIG requirements during weeks 1–12 were higher in those patients who had HBV DNA levels >105 copies/mL at the time of transplantation [15]. With the increasing availability of effective antivirals to suppression HBV DNA pre-LT, lower doses of HBIG may be needed in the early post-LT period.

The main limitations of HBIG as part of a long-term prophylactic strategy are its high cost, the need for parenteral administration, and the low risk for blood-borne infections. The emergence of mutations involving the “a” determinant of the HBV surface protein causing resistance to HBIG is a recognized complication of prolonged HBIG monotherapy but appears to be rare with combination therapy. The cost and safety issues have prompted studies of alternative anti-HBs agents and alternative treatment protocols using lower doses and shorter duration of HBIG. Alternative forms of antibody therapy studied include high-titer anti-HBs from plasma donors (economical but clinical experience limited), monoclonal antibodies (cost may still be issue, but presumably supply and safety not a concern), and vaccination (economical but antibody responses inconsistent). Lower dose protocols, including those using intramuscular HBIG, report efficacy rates of ⩾90% in the first 1–2 years of follow-up, and are highly cost-effective [16]. Similarly, protocols using combination HBIG plus lamivudine for the first 1–6 months post-LT and then discontinuing HBIG report a low failure rate ∼10% after 1–2 years follow-up [17], [18].

In all studies of prophylaxis in the transplant setting, the risk of HBV re-infection has been related largely to the level of HBV replication at time of transplantation [7]. Thus, the available data suggest treatment strategies should differ for patients with and without HBV replication before transplantation. Most experts recommend combination therapy of HBIG and antivirals for “replicators” or those with drug-resistant HBV infection. For “non-replicators”, discontinuation of HBIG after a defined period of time may be an option. However, the decision to stop HBIG must be tempered by the recognition that studies evaluating HBIG discontinuation in patients on combination therapy are limited to a few years of follow-up, and the risk of HBV recurrence may increase with time off HBIG. Additionally, there is evidence of HBV-DNA in serum, liver or peripheral blood mononuclear cells in HBsAg negative transplanted patients on HBIG or combination prophylaxis, suggesting that a persistent reservoir for re-infection exists in many patients [11]. Thus, a safer long-term prophylactic strategy may be to replace HBIG with a second antiviral agent or possibly by HBV vaccination.

In summary, HBIG combined with antiviral drugs is a highly effective form of prophylaxis in HBV-infected transplant recipients and this combination therapy remains the “standard”. Cost and the inconvenience of parenteral administration are the main limitations of HBIG prompting consideration of alternative agents and protocols. Replication status is the primary determinant of prophylaxis failure and as such should be the primary factor influencing current and future combination protocols.

Alfredo Marzano, Department of Gastro-Hepatology San Giovanni Battista Ospedale, Torino, Italy.

The use of nucleos(t)ide analogues after transplantation has increased with time and is dependent upon recipient and liver graft parameters. In HBsAg-positive recipients, indefinite hepatitis B immunoglobulin (HBIg) immunoprophylaxis is required, and the adjunct of a nucleos(t)ide analogue is conditioned by pre-LT virological status. The cut-off between “replicators” and “non-replicators” is around 105 copies/ml [7]: (1) In pre-LT active carriers (HBV DNA > 105 copies/ml), nucleos(t)ide analogues are introduced in order to decrease viral load prior to LT. After surgery, combined prophylaxis with nucleos(t)ide analogues (lamivudine in lamivudine-sensitive patients, or lamivudine and/or adefovir in YMDD carriers) and HBIg led to less than 10% HBV recurrence. In this setting, the use of nucleos(t)ide analogues is essential and their withdrawal is not recommended in such patients; (2) in pre-LT inactive carriers (HBV DNA < 105 copies/ml), combined prophylaxis with nucleos(t)ide analogues is also useful because this strategy is associated with very low risk of recurrence post-LT. If attempted, HBIg withdrawal should be considered at least 1–2 years after LT, and must be carefully monitored in patients treated with both lamivudine and adefovir. The perspective of long-term prophylaxis with two analogues is promising, but requires comparative trials in the near future; (3) in inactive carriers with undetectable viremia, pre-LT requires HBIg prophylaxis alone without an analogue.

Peter Neuhaus, Department of General, Visceral, and Transplantation Surgery Hospital La Charité CampusVirchow , Berlin, Germany.

The efficacious combination of HBIg and nucleos(t)ide analogues has long-term disadvantages in terms of cost, side effects and inconvenience for the patient. Thus, other strategies such as active HBV vaccination have been investigated. Studies have shown that conventional HBV vaccination of cirrhotic patients awaiting liver graft and of transplanted patients is disappointing due to relatively weak production of protective anti-HBs antibodies in these patients, who have an impaired immune system response related to the disease or to immunosuppressive agents. Therefore, alternative strategies of vaccination have been developed to overcome non-responsiveness: additional vaccine doses, double-dose vaccination, addition of pre-S-epitopes to HBsAg vaccine, DNA vaccines, use of more immunogenic adjuvants or immune-stimulating agents (e.g., GM-CSF).

Nonetheless, results of double-dose vaccination are difficult to analyze because the response rate in liver transplant patients, defined as anti-HBs antibodies higher than 10 U/l, is achieved in 20–80% of cases, and the only available study using a vaccine containing pre-S1, pre-S2 vaccines, showed only a 7% response rate. Anti-HBs antibodies titer higher than 100 IU/l was observed in less than 20% of the patients [19], [20]. Promising preliminary results were found in studies using new adjuvants such as monophosphoryl lipid A (MPL) and Quillaja saponaria QS 21, which, in healthy adults, produced up to 10-fold-higher anti-HBs titers than standard hepatitis B vaccine. In a transplanted population, a better response rate, varying between 40% and 80%, was also observed but will require confirmation in a larger cohort of patients [21]. In a small cohort, a vaccine using MPL as adjuvant gave a low anti-HBs response. A difference observed among studies is the discontinuation or not of HBIG during vaccination. In the study from Berlin giving the best results of vaccine, the vaccine contains these 2 combined MPL and SQ21 adjuvant and HBIG were maintained during vaccination. The hypothesis is that starting the vaccine before discontinuation of HBIg favours the formation of antigen–antibody complexes. It increases the uptake of these immune-complexes through Fc-receptors of antigen presenting cells (APC), which might enhance immune responses. Thus, results of vaccination are controversial and should be analyzed on large cohorts.

David Mutimer, Queen Elisabeth Hospital, Liver Unit Birmingham, UK.

The current prophylactic strategy which associates HBIg with nucleos(t)ide analogues is efficacious in reducing the risk of HBV recurrence. Nevertheless, HBsAg positivity after liver transplantation may occur due to failure of prophylaxis (HBsAg “escape” mutants, YMDD mutants, resistance to adefovir), donor-acquired infection (de novo infection) or acquired HBV infection (sexual acquisition post-LT).

Therapeutic management should be individualized: withdrawal of HBIg and the start of nucleos(t)ide analogues in HBsAg “escape” mutants, treatment with adefovir for YMDD mutants, and the addition of lamivudine in cases of adefovir resistance [22], [23].

Most post-transplant HBV infections are associated with HBeAg positivity and high serum titers. The clinical outcome is unpredictable and may range from mild hepatitis to severe liver graft failure. Nucleos(t)ide analogues can achieve HBeAg and HBsAg seroconversion and improve liver function. De novo infection should be treated as early as possible after diagnosis with a combination of nucleos(t)ide analogues. Retransplantation for HBV recurrence is mostly historical and there is no current specific contraindication.

Mario Rizzetto, Ospedale Molinette, Torino, Italy.

There has been a drastic decline in HDV infections in developed countries due to the control of HBV infection. The prevalence of Delta coinfection in HBV carriers in Italy declined from 25% in 1981 to 8% in 1997. Indeed, HDV requires obligatory helper functions of HBV, and can be transmitted only after prior HBV infection. Therefore, the efficiency of prophylaxis against HBV recurrence significantly decreases the risk of such recurrence following LT. For example, results of an experience by the group of Turin on 117 HDV carrier transplanted patients given prophylaxis with HBIg did not reveal any clinical recurrent HDV over a mean post-LT follow-up of 34 months, suggesting that current HBV prophylaxis can prevent HDV recurrence. Transient subclinical HDV reinfection (HDV RNA positive by PCR) was observed in only 5% of patients without any clinical consequence. Thus HDV infection does not appear as a current problem with the accurate control of HBV reinfection.

Section snippets

Mechanisms of HCV infection

Jean-Michel Pawlotsky, Virology Unit, Inserm U 635, Hopital Henri Mondor, Créteil, France.

Hepatitis C virus (HCV) is a major public health challenge. In the course of HCV acute infection, about 20–50% of patients eliminate the virus, whereas 50–80% of patients will develop chronic infection leading to cirrhosis and ultimately to hepatocellular carcinoma within a few decades. HCV is a single-stranded ribonucleic acid (RNA) virus that belongs to the Flaviviridae family able to develop strategies

Acknowledgements

We thank Dr. Sebastien Dharancy, Jérome Dumortier, Jean-Charles Duclos-Vallee, and Richard Lorho, for their help in the writing of this manuscript, and the EASL Scientific Organizing Committee for its support.

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    This Conference was organized by the EASL. Authors of the paper were members of the organizing committee. Didier Samuel was the chairman of the conference.

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