Liver Transplantation for Primary Sclerosing Cholangitis (PSC) With or Without Inflammatory Bowel Disease (IBD)-A European Society of Organ Transplantation (ESOT) Consensus Statement.

Primary sclerosing cholangitis (PSC) is the classical hepatobiliary manifestation of inflammatory bowel disease (IBD) and a lead indication for liver transplantation (LT) in the western world. In this article, we present a Consensus Statement on LT practice, developed by a dedicated Guidelines' Taskforce of the European Society of Organ Transplantation (ESOT). The overarching goal is to provide practical guidance on commonly debated topics, including indications and timing of LT, management of bile duct stenosis in patients on the transplant waiting list, technical aspects of transplantation, immunosuppressive strategies post-transplant, timing and extension of intestinal resection and futility criteria for re-transplantation.

The optimal timing of hepatitis C therapy in liver transplant-eligible patients: Cost-effectiveness analysis of new opportunities.

Different strategies of DAAs treatment are currently possible both pre- and postliver transplantation (LT). Clinical and economic consequences of these strategies still need to be adequately investigated; this study aims at assessing their cost-effectiveness. A decision analytical model was created to simulate the progression of HCV-infected patients listed for decompensated cirrhosis (DCC) or for hepatocellular carcinoma (HCC). Three DAAs treatment strategies were compared: (i) a 12-week course of DAAs prior to transplantation (PRE-LT), (ii) a 4-week course of DAAs starting at the time of transplantation (PERI-LT) and (iii) a 12-week course of DAAs administered at disease recurrence (POST-LT). The population was substratified according to HCC presence and, in those without HCC, according to the MELD score at listing. Data on DAAs effectiveness were estimated using a cohort of patients still followed by 11 transplant centres of the European Liver and Intestine Transplant Association and by data available in the literature. In this study, PRE-LT treatment strategy was dominant for DCC patients with MELD<16 and cost-effective for those with MELD16-20, while POST-LT strategy emerged as cost-effective for DCC patients with MELD>20 and for those with HCC. Sensitivity analyses confirmed PRE-LT as the cost-effective strategy for patients with MELD≤20. In conclusion, PRE-LT treatment is cost-effective for patients with MELD≤20 without HCC, while treatments after LT are cost-effective in cirrhotic patients with MELD>20 and in those with HCC. It is worth reminding, though, that the final choice of a specific regimen at the patient level will have to be personalized based on clinical, social and transplant-related factors.

Long-term outcomes of direct acting antivirals in post-transplant advanced hepatitis C virus recurrence and fibrosing cholestatic hepatitis.

Long-term functional outcomes of sofosbuvir-based antiviral treatment were evaluated in a cohort study involving 16 Italian centres within the international compassionate use programme for post-transplant hepatitis C virus (HCV) recurrence. Seventy-three patients with cirrhosis (n=52) or fibrosing cholestatic hepatitis (FCH, n=21) received 24-week sofosbuvir with ribavirin±pegylated interferon or interferon-free sofosbuvir-based regimen with daclatasvir/simeprevir+ribavirin. The patients were observed for a median time of 103 (82-112) weeks. Twelve of 73 (16.4%) died (10 non-FCH, 2 FCH) and two underwent re-LT. Sustained virological response was achieved in 46 of 66 (69.7%): 31 of 47 (66%) non-FCH and 15 of 19 (79%) FCH patients. All relapsers were successfully retreated. Comparing the data of baseline with last follow-up, MELD and Child-Turcotte-Pugh scores improved both in non-FCH (15.3±6.5 vs 10.5±3.8, P<.0001 and 8.4±2.1 vs 5.7±1.3, P<.0001, respectively) and FCH (17.3±5.9 vs 10.1±2.8, P=.001 and 8.2±1.6 vs 5.5±1, P=.001, respectively). Short-treatment mortality was higher in patients with baseline MELD≥25 than in those with MELD<25 (42.9% vs 4.8%, P=.011). Long-term mortality was 53.3% among patients with baseline MELD≥20 and 7.5% among those with MELD<20 (P<.0001). Among deceased patients 75% were Child-Turcotte-Pugh class C at baseline, while among survivors 83.9% were class A or B (P<.0001). Direct acting antivirals-based treatments for severe post-transplant hepatitis C recurrence, comprising fibrosing cholestatic hepatitis, significantly improve liver function, even without viral clearance and permit an excellent long-term survival. The setting of severe HCV recurrence may require the identification of "too-sick-to-treat patients" to avoid futile treatments.

A Multistep, Consensus-Based Approach to Organ Allocation in Liver Transplantation: Toward a "Blended Principle Model".

Since Italian liver allocation policy was last revised (in 2012), relevant critical issues and conceptual advances have emerged, calling for significant improvements. We report the results of a national consensus conference process, promoted by the Italian College of Liver Transplant Surgeons (for the Italian Society for Organ Transplantation) and the Italian Association for the Study of the Liver, to review the best indicators for orienting organ allocation policies based on principles of urgency, utility, and transplant benefit in the light of current scientific evidence. MELD exceptions and hepatocellular carcinoma were analyzed to construct a transplantation priority algorithm, given the inequity of a purely MELD-based system for governing organ allocation. Working groups of transplant surgeons and hepatologists prepared a list of statements for each topic, scoring their quality of evidence and strength of recommendation using the Centers for Disease Control grading system. A jury of Italian transplant surgeons, hepatologists, intensivists, infectious disease specialists, epidemiologists, representatives of patients' associations and organ-sharing organizations, transplant coordinators, and ethicists voted on and validated the proposed statements. After carefully reviewing the statements, a critical proposal for revising Italy's current liver allocation policy was prepared jointly by transplant surgeons and hepatologists.

Cost-Effectiveness of New Direct-Acting Antivirals to Prevent Post-Liver Transplant Recurrent Hepatitis.

Preliminary studies on HCV-cirrhotics listed for transplant suggest that sofosbuvir in combination with ribavirin is very effective in promoting viral clearance and preventing disease recurrence. Unfortunately, the high cost of such treatment (€46 500 per 12 weeks of treatment) makes its cost-effectiveness questionable. A semi-Markov model was developed to assess the cost-effectiveness of sofosbuvir/ribavirin treatment in cirrhotic patients without HCC (HCV-CIRRH) and with HCC (HCV-HCC) listed for transplant. In the base-case analysis, the incremental cost-effectiveness ratio for 24 weeks of sofosbuvir/ribavirin was €44 875 per quality-adjusted life-year gained in HCV-CIRRH and €60 380 in HCV-HCC patients. Both results were above the willingness to pay threshold of €37 000 per quality-adjusted life-year. Our data also show that in order to remain cost-effective (with a 24-week treatment), any novel interferon-free treatment endowed with ideal efficacy should cost less than €67 224 or €95 712 in HCV-cirrhotics with and without HCC, respectively. The results shows that sofosbuvir/ribavirin therapy, given to patients listed for transplant, is not cost-effective at current prices despite being very effective, and new, more effective treatments will have little economic margins to remain cost-effective. New interferon-free combinations have the potential to revolutionize the treatment and prognosis of HCV-positive patients listed for transplant; however, without sustainable prices, this revolution is unlikely to happen.

Management of treatment-naïve chronic hepatitis C genotype 1 patients: a cost-effectiveness analysis of treatment options.

New and more promising therapies for chronic hepatitis C (CHC) genotype 1 (G1) naive patients have recently been approved in the United States and Europe, and several more regimens are expected to become available within the next several years. While this scenario unfolds, it is necessary to develop a rational method to allocate current treatment in CHC G1 patients. We performed a cost-effectiveness analysis of boceprevir (BOC)- and telaprevir (TVR)-based triple therapy according to different patients' selection strategies. A semi-Markov model of CHC natural history and progression towards end-stage liver disease was built. We considered 3 selection strategies based on METAVIR fibrosis stage: (i) treat all patients with F1-F4 fibrosis, (ii) only F2-F4 and (iii) only F3-F4. For each strategy, TVR interleukin-28B-guided (IL28B-guided) and BOC rapid virologic response-guided (RVR-guided) therapies were applied. The model assessed the costs and outcomes, using a lifetime and 5-year time horizon, and adopting the Italian National Health System perspective. The incremental cost-effectiveness ratio (ICER) for F1-F4 strategy relative to F3-F4 was €5132 per quality-adjusted life years gained, across TVR IL-28B-guided therapy, and €7042 in the BOC RVR-guided therapy. Conversely, in the 5-year scenario, the ICER for F1-F4 strategy relative to F3-F4 was €1 818 679 (TVR IL28B-guided) and €1 866 437 (BOC RVR-guided) per end-stage liver disease or death (ESLD-D) avoided. In view of anticipated improvement in the efficacy of future regimens, selective treatment of only patients with advanced fibrosis and cirrhosis with TVR or BOC could represent the most cost-effective strategy to optimize resource utilization.

Long-term maintenance of sustained virological response in liver transplant recipients treated for recurrent hepatitis C.

BACKGROUND: The recurrence of hepatitis C viral infection is common after liver transplant, and achieving a sustained virological response to antiviral treatment is desirable for reducing the risk of graft loss and improving patients' survival. AIM: To investigate the long-term maintenance of sustained virological response in liver transplant recipients with hepatitis C recurrence. METHODS: 436 Liver transplant recipients (74.1% genotype 1) who underwent combined antiviral therapy for hepatitis C recurrence were retrospectively evaluated. RESULTS: The overall sustained virological response rate was 40% (173/436 patients), and the mean follow-up after liver transplantation was 11±3.5 years (range, 5-24). Patients with a sustained virological response demonstrated a 5-year survival rate of 97% and a 10-year survival rate of 93%; all but 6 (3%) patients remained hepatitis C virus RNA-negative during follow-up. Genotype non-1 (p=0.007), treatment duration >80% of the scheduled period (p=0.027), and early virological response (p=0.002), were associated with the maintenance of sustained virological response as indicated by univariate analysis. Early virological response was the only independent predictor of sustained virological response maintenance (p=0.008). CONCLUSIONS: Sustained virological response achieved after combined antiviral treatment is maintained in liver transplant patients with recurrent hepatitis C and is associated with an excellent 5-year survival.

Examining patients' preferences for participation in clinical decision-making: the experience in a Latin American chronic obstructive pulmonary disease and cancer outpatient population.

BACKGROUND AND AIMS: It is generally accepted that patients prefer to be told the truth by their physicians; however, the practice of partial truth-telling is frequent with an existing 'norm of nondisclosure.' Our primary objective was to determine what patients wanted to be told about their illness, and whether there might be differences between patients with either cancer or advanced chronic obstructive pulmonary disease (COPD). A second objective was to determine how these patients envisioned their participation, or lack thereof, in the treatment decision-making process. METHODS: Subjects were eligible for this prospective study if they were attending the oncology or pulmonary outpatient consultation services at the British Hospital or the Sanatorio Güemes Private Hospital in Buenos Aires, Argentina between June 2009 and May 2010. RESULTS: Ninety-nine patients were recruited. Forty-four had a diagnosis of COPD, and 55 patients had cancer. Seventeen of the patients expected their health to improve in the future, but a significantly higher proportion of patients with malignant disorders expected to get better in the near future as compared with those with COPD (98.2% vs 62.8%, P < 0.001). Most study participants expressed a desire to receive all the information available about their condition. A majority of the participants expressed a preference for making treatment decisions in collaboration with their physician (40.4%) CONCLUSIONS: While they considered the role of their families relevant and wanted information to be shared so that family members might participate in decision-making, they did not want their families to have a right to withhold information, make final decisions.

Hypoxic liver perfusion with mitomycin-C for treating multifocal metastases and unresectable primary tumours: a single-centre series of 42 patients.

PURPOSE: The purpose of our study was to retrospectively evaluate the feasibility, toxicity and impact on overall (OS) and disease-free (DFS) survival of intra-arterial liver perfusion with mitomycin-C (MMC) [hypoxic liver perfusion with MMC (HLPM)] in patients with multifocal liver metastases or with unresectable primary liver tumours. MATERIALS AND METHODS: Forty-two patients underwent 56 intra-arterial liver infusions with MMC between June 2001 and May 2009. The patients presented specific characteristics, i.e. they were all refractory to locoregional (LR) and/or systemic treatments. HLPM consists of selective catheterisation of the common hepatic artery, permanent occlusion of the gastroduodenal artery at its origin using metal coils, an inflated balloon catheter placement at the origin of the proper hepatic artery to block blood flow and induce hypoxia for around 10 min, MMC infusion and vascular-bed occlusion through injection of an absorbable haemostatic agent. During the procedure, the patients received anaesthesiological monitoring. Biochemical and morphological responses were evaluated, as were haematological, hepatic and systemic toxicity. RESULTS: Patients were hospitalised for 10 days on average (range 7-15). Side effects were liver toxicity in all cases, acute pancreatitis in one case and liver failure in one case. Computed tomography performed at 30 days documented a partial response (PR) in 29%, stable disease (SD) in 45% and progressive disease (PD) in 26% of patients. The response lasted 4 months on average (range 3-6). Mean overall survival (OS) was 20 months for all patients, reaching 30 months in those with colorectal carcinoma. CONCLUSIONS: The procedure is feasible, and treatmentrelated toxicity and mortality rates are acceptable. It may be considered a palliative treatment option in patients with advanced liver disease in centres with adequately experienced medical teams.

Right hemiliver transplant: results from living and cadaveric donors.

UNLABELLED: Although right hemiliver transplant from living donors (LD) is gaining acceptance as a way to overcome the critical organ shortage, splitting a liver for two adults from cadaveric donor (CD) is still controversial. METHODS: From May 1999 to August 2004 we performed nine right hemiliver transplants using segments 5-6-7-8 from CD and 18 from LD. RESULTS: We compared the two procedures to evaluate both the technical aspects and the patients' outcomes. In the CD group, three recipients died (33%), two of whom were UNOS Status 2A. Patient and graft survivals were 67% (median follow-up: 23 months). Among the LD group, three recipients died (17%) and two were retransplanted; one because of arterial thrombosis and the other as a consequence of small-for-size syndrome. Patient and graft survivals were 83% and 72%, respectively (median follow-up: 8 months). There were five early complications in the CD group (55%) and five (27%) in the LD group. Two patients in the LD group experienced a late stenosis of the biliary anastomosis. DISCUSSION: Data from our early experience show that better results are achieved by right hemiliver transplants from LD; the morbidity and mortality are higher among the CD group. We believe that this finding is probably a consequence of better preoperative donor evaluation, shorter ischemia time, better logistics, and learning curve. Recipient selection is crucial; this kind of graft is at high risk of poor function, technical complications, and infections. Further experience will help to clarify the reliability of right hemiliver transplants from CD.

Combined therapy with interferon and low-dose ribavirin in posttransplantation recurrent hepatitis C: a pragmatic study.

Recurrent hepatitis C is a common problem after liver transplantation that can progress to liver cirrhosis of the graft. Preliminary reports of combination treatment with interferon (IFN) and ribavirin have been promising, but long-term follow-up data are not yet available. We report our experience with 1 year of combination therapy with IFN (3 million units thrice weekly) and low-dose ribavirin (600 mg/d), followed by long-term ribavirin monotherapy in 18 patients with moderate to severe recurrent hepatitis C and a median follow-up of 32 months after the completion of combined therapy. All patients were followed up clinically and histologically at regular intervals. Overall, in an intention-to-treat analysis, 15 patients had normal alanine aminotransferase levels (biochemical end-treatment response [ETR], 83%), and 8 patients were also hepatitis C virus RNA negative in serum (virological ETR, 44%) at the end of combined treatment. At last follow-up after the completion of combined therapy (median, 32 months; range, 18 to 73 months), 13 patients were biochemical responders (biochemical long term-sustained response [LT-SR], 72%), and 5 patients also maintained viral clearance (virological LT-SR, 27%). Comparison of liver biopsy specimens before and after 12 months of combined therapy showed improvement in grading scores of at least two points in the majority of the patients (73%). Notably, a trend toward fibrotic progression was only noted in nonresponders. Regarding side effects, despite the low dose of ribavirn, almost half the patients developed hemolytic anemia requiring dose reductions. In addition, long-term ribavirin monotherapy was not associated with iron accumulation. We conclude that combined therapy with low-dose ribavirin followed by long-term ribavirin monotherapy can be recommended because it favorably modifies the natural history of recurrent hepatitis C in most patients and possibly halts histological disease progression without causing iron accumulation.

Influence of immunogenetic background on the outcome of recurrent hepatitis C after liver transplantation.

In immunocompetent patients, specific human leukocyte antigen (HLA) class II alleles have been associated with the severity of hepatitis C virus (HCV)-related disease, in particular, HLA-DRB1*11 has been found to exert a protective effect. The authors have analyzed the role of HLA class I and II alleles in determining the frequency, timing, and progression of histologically proven recurrent hepatitis C in 89 patients who underwent a liver transplant for HCV-related cirrhosis. In addition, the influence of HLA mismatch between donor and recipient, HCV genotype, and use of steroid pulses was also evaluated. Median patient follow up was 35 months (range 4-119). HLA-DRB1 typing was performed by genomic analysis in all cases. Liver biopsies were obtained routinely and at least at yearly intervals. Histologically proven recurrent hepatitis was observed in 46 patients (52%), 10 patients progressing to stage 5-6 fibrosis in most cases within 2 years after transplant. By univariate analysis, 3 variables, HLA-B14, HLA-DRB1*04, and HLA-DRB1 donor/recipient mismatch, showed a significant effect on time to recurrent hepatitis C disease. These parameters were included in a multivariate regression model along with HCV genotype, treatment with steroid pulses and DRB1*11. HLA-B14, HLA-DRB1*04, and HLA-DRB1 donor/recipient mismatch were confirmed to provide a significant and independent contribution to the risk of hepatitic disease recurrence. As for the severity of the disease, none of the 10 patients with stage 5-6 hepatitis carried the HLA-DRB1*11 allele, in line with what was observed in nontransplant subjects. Our results suggest that in posttransplant recurrent hepatitis C, immunogenetic factors are relevant in determining HCV infection outcome.