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.

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.

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.

The role of transplantation in small hepatocellular carcinoma complicating cirrhosis of the liver.

Of 176 hepatic transplants performed from 1986 to December 1992, 27 patients had small hepatocellular carcinoma (< or = 5 centimeters) complicating cirrhosis of the liver. All patients were asymptomatic for the hepatic malignancy and the diagnosis was established in each instance preoperatively by means of serial sonographic scans and alpha-fetoprotein levels. Cirrhosis was classified as Child's A in eight instances, as Child's B in 16 and Child C's in three. The cause was alcoholic in three patients, posthepatitic in 21 patients (eight hepatitis B virus [HBV] positive and 13 hepatitis C virus [HCV] positive) and undetermined in three. The in-hospital mortality rate was 11 percent (three of 27). Additionally, five patients died at different intervals after transplantation: only two died of neoplastic recurrence at 12 and 32 months, respectively (7.4 percent rate). Actuarial survival rates were 82 percent at one year and 71 percent at three years, with a mean follow-up period of 32 months (range six to 78 months). Morbidity related to the procedure was a relevant problem: 21 percent of the patients had prompt resumption of normal life while 37 percent required repeated hospitalization and 42 percent required strict control on an outpatient basis. The most frequent problem was HBV or HCV reinfection of the grafted liver, which occurred in 42 percent. Based on this experience, transplantation of the liver has shown an excellent oncologic accuracy for small hepatocellular carcinoma in cirrhosis of the liver, thus representing the most rational surgical procedure for patients with Child's B and Child's C cirrhosis classification. The relevant mortality and morbidity rates, strictly related to this procedure, suggest other options as more appropriate in those with Child A cirrhosis at this time.

Immunophenotyping of mononuclear cell infiltrates associated with renal disease.

Twenty-eight frozen renal biopsy specimens with a marked mononuclear cell interstitial infiltrate (MCI) were analyzed with monoclonal antibodies and a biotin-avidin peroxidase technique to define the surface phenotype distribution of the infiltrating cells. Twelve cases were diagnosed as tubulointerstitial nephritis of acute and chronic presentation, of unknown cause in 5 cases or secondary to multiple myeloma or drug reactions. Sixteen cases occurred in primary and secondary glomerulonephritis, 3 cases being associated with lymphoproliferative disorders. The results showed a remarkable heterogeneity of the MCI composition, even in cases with similar clinical and pathological findings. Namely, the T cells accounted for the majority of the infiltrating cells in most cases but a variable predominance of the T cell subsets Leu3 and Leu2 was observed. B cells and monocytes were also prominent in some cases. Such differences in the MCI composition may indicate the activation of different mechanisms of tissue damage, or a different phase of the renal disease. In the three cases of glomerulonephritis associated with lymphoproliferative disorders, the malignant origin of the MCI was demonstrated in one case, while in the remaining cases it was excluded.

The role of donor and recipient factors in initial renal graft non-function.

ATN is a deleterious problem in the outcome of kidney transplantation. This complication is usually related to multiple factors including donor parameters, surgical technique, ischemic time, and recipient variables. In order to develop prophylactic measures, out of 430 kidney transplants performed in our Department, a series of 90 consecutive cadaveric renal allografts has been considered in this study. The overall incidence of IGNF was 23/90 (25.5%). Kidneys from MOD revealed a lower rate of IGNF (7/35 = 20%) when compared with organs from SOD (16/55 = 29%, P = NS). No difference was noted when kidneys were removed together with heart and/or liver and/or pancreas. Out of the donor factors, only CID was significant (17 +/- 9 hours in IGNF v 11 +/- 10 hours in patients with IGF, P = less than .05). Analysis of data concerning the fate of paired kidneys revealed two cases of IGNF in both kidneys from the same donor v 14 cases of IGNF in only one of the two paired grafts (P = NS). We conclude that: 1. Donor factors are clearly associated with a minority of IGNF. 2. The introduction of multiorgan procurement programs does not complicate early function. 3. Recipient factors (immunological events and intraoperative fluid management) provides important additive effects on initial graft nonfunction.

Thromboendarterectomy (TEA) in the recipient as a major risk of arterial complication after kidney transplantation.

The authors analyze a series of 383 kidney transplantation pointing out the role of recipient's vessels atherosclerosis in the determination of vascular complication of the kidney graft. Three groups were considered. The first included 55 patients which required TEA for severe atherosclerotic lesion of the anastomosed vessels. The second group included 305 patients who didn't required TEA; the third group was of 20 patients who received a graft with multiple arteries which required more than one anastomosis. A significative higher rate of arterial complications was evident in the first group (p less than 0.001). Within this group the end to end arterial anastomosis was more frequently associated to thrombosis or stenosis than the end to side one (p less than 0.05). Kidney with multiple vessels also presented with an higher rate of complications (p less than 0.05).