Cost-effectiveness of noninvasive liver fibrosis tests for treatment decisions in patients with chronic hepatitis B in the UK: systematic review and economic evaluation.

We compared the cost-effectiveness of various noninvasive tests (NITs) in patients with chronic hepatitis B and elevated transaminases and/or viral load who would normally undergo liver biopsy to inform treatment decisions. We searched various databases until April 2012. We conducted a systematic review and meta-analysis to calculate the diagnostic accuracy of various NITs using a bivariate random-effects model. We constructed a probabilistic decision analytical model to estimate health care costs and outcomes quality-adjusted-life-years (QALYs) using data from the meta-analysis, literature, and national UK data. We compared the cost-effectiveness of four decision-making strategies: testing with NITs and treating patients with fibrosis stage ≥F2, testing with liver biopsy and treating patients with ≥F2, treat none (watchful waiting) and treat all irrespective of fibrosis. Treating all patients without prior fibrosis assessment had an incremental cost-effectiveness ratio (ICER) of £28,137 per additional QALY gained for HBeAg-negative patients. For HBeAg-positive patients, using Fibroscan was the most cost-effective option with an ICER of £23,345. The base case results remained robust in the majority of sensitivity analyses, but were sensitive to changes in the ≥ F2 prevalence and the benefit of treatment in patients with F0-F1. For HBeAg-negative patients, strategies excluding NITs were the most cost-effective: treating all patients regardless of fibrosis level if the high cost-effectiveness threshold of £30,000 is accepted; watchful waiting if not. For HBeAg-positive patients, using Fibroscan to identify and treat those with ≥F2 was the most cost-effective option.

Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis.

We hypothesized that current trough concentrations of tacrolimus after liver transplantation are set too high, considering that clinical consequences of rejection are not severe while side effects are increased.We systematically reviewed 64 studies (32 randomized controlled trials and 32 observational studies) to determine how lower tacrolimus trough concentrations than currently recommended affect acute rejection rates and renal impairment. Among randomized trials the mean of tacrolimus trough concentration during the first month was positively correlated with renal impairment within 1 year (r = 0.73; p = 0.003), but not with acute rejection, either defined using protocol biopsies (r = -0.37; p = 0.32) or not (r = 0.11; p = 0.49). A meta-analysis of randomized trials directly comparing tacrolimus trough concentrations (five trials for acute rejection [n = 957] and two trials for renal impairment [n = 712]) showed that "reduced tacrolimus" trough concentrations (<10 ng/mL) within the first month after liver transplantation were associated with less renal impairment at 1 year (RR = 0.51 [0.38-0.69]), with no significant influence on acute rejection (RR = 0.92 [0.65-1.31]) compared to "conventional tacrolimus" trough levels (>10 ng/mL). Lower trough concentrations of tacrolimus (6-10 ng/mL during the first month) would be more appropriate after liver transplantation. Regulatory authorities and the pharmaceutical industry should allow changes of regulatory drug information.

Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Early postoperative mortality in liver transplant recipients involving indications other than hepatocellular carcinoma. A retrospective cohort study.

AIMS: To analyze the perioperative differences in a consecutive cohort of liver transplant recipients (LTRs) classified according to the indication of transplantation, and assess their impact upon early mortality 90 days after transplantation. DESIGN: A retrospective cohort study was carried out. SCOPE: A single university hospital. PATIENTS: A total of 892 consecutive adult LTRs were included from January 1995 to December 2017. Recipients with acute liver failure, retransplantation or with grafts from non-brain death donors were excluded. Two cohorts were analyzed according to transplant indication: hepatocellular carcinoma (HCC-LTR) versus non-carcinoma (non-HCC-LTR). MAIN VARIABLES OF INTEREST: Recipient early mortality was the primary endpoint. The pretransplant recipient and donor characteristics, surgical time data and postoperative complications were analyzed as independent predictors. RESULTS: The crude early postoperative mortality rate related to transplant indication was 13.3% in non-HCC-LTR and 6.6% in HCC-LTR (non-adjusted HR=2.12, 95%CI=1.25-3.60; p=0.005). Comparison of the perioperative features between the cohorts revealed multiple differences. Multivariate analysis showed postoperative shock (HR=2.02, 95%CI=1.26-3.24; p=0.003), early graft vascular complications (HR=4.01, 95%CI=2.45-6.56; p<0.001) and multiorgan dysfunction syndrome (HR=18.09, 95%CI=10.70-30.58; p<0.001) to be independent predictors of mortality. There were no differences in early mortality related to transplant indication (adjusted HR=1.60, 95%CI=0.93-2.76; p=0.086). CONCLUSIONS: The crude early postoperative mortality rate in non-HCC-LTR was higher than in HCC-LTR, due to a greater incidence of postoperative complications with an impact upon mortality (shock at admission to intensive care and the development of multiorgan dysfunction syndrome).

Pretransplant predictors of early mortality in adult recipients of liver transplantation in the MELD-Na Era. / Predictores pretrasplante de mortalidad precoz en receptores adultos de trasplante hepático en la era MELD-Na.

AIMS: To identify pretransplant predictors of early mortality (90 days after transplantation) and evaluate their discriminating capacity in adult liver transplant recipients (LTR). DESIGN: An observational, retrospective, nested cases-controls study from a consecutive cohort of LTRs was carried out. SETTING: University hospital. PATIENTS: All consecutive LTR between January 2003 and December 2016 were eligible for inclusion. Patients with acute liver failure, previous graft dysfunction, simultaneous multiple organ transplantation, non-heart beating donors, and those needing urgent retransplantation during the study period were excluded. The analysis comprised 471 patients. MAIN VARIABLES OF INTEREST: Pretransplant characteristics were the main variables of interest. The LTR were grouped according to the dependent variable (early mortality). Multivariate logistic regression analysis was conducted to identify predictors of early mortality. The discriminating capacity of the models obtained was evaluated by comparing ROC curves (models versus MELD-Na). RESULTS: The MELD-Na score (OR = 1.069, 95% CI = 1.014-1.127), age > 60 years (OR = 2.479, 95% CI = 1.226-5.015), and LTR height < 163cm (OR = 4.092, 95% CI = 2.115-7.917) were identified as independent predictors of early mortality. The cause of transplantation (hepatocellular carcinoma or decompensated cirrhosis) was identified as a confounding factor. CONCLUSIONS: In LTR due to decompensated cirrhosis, the MELD-Na score, age > 60 years, and height < 163cm are independent predictors of early mortality. These factors provide a better classification model than the MELD-Na score for early post-transplant mortality.

Use of Peritoneovenous Shunt for the Management of Refractory Ascites.

BACKGROUND: Guidelines for the management of refractory ascites (RA) recommend transjugular intrahepatic portosystemic shunting (TIPS), diuretics, and paracentesis as the main strategies, discouraging use of surgical peritoneovenous shunts (PVSs). However, PVSs, including both Denver (DS) or saphenoperitoneal (SPS) modalities, may still have indications. Herein we report our experience with PVSs in the context of modern surgical and anesthetic management. METHODS: In our unit, PVSs are offered to patients with ascites refractory to diuretics in which TIPS are contraindicated. Heart function and spontaneous bacterial peritonitis must be assessed before surgical indication. RESULTS: Seven procedures were performed on 5 patients (6-DS, 1-SPS) in 2013. Their mean age was 61 (range, 54-68) years. In 3 patients, the indication was RA without options for liver transplant; 2 patients were on the waiting list for liver transplantation, which were performed to improve renal function and quality of life (QOL). The median hospital stay was 6.5 (range, 3-12) days. All patients were alive after 12 months. One patient died 2 years after the first DS and another later died due to liver insufficiency with patency of the DS. The ascites was well-controlled in 4 of 5 patients at up to 48 months of follow-up. Decreases in diuretics doses, proper weight maintenance, and a dramatic improvement in QOL (measured by a modified Ascites Symptom Inventory-7 [ASI-7] test) were observed after the procedures. CONCLUSION: PVSs are useful for the treatment of patients with RA who develop resistance to common therapies, leading to a major improvement in QOL. These surgical procedures should be included in the armamentarium of experienced liver surgeons.

Rescue of Discarded Grafts for Liver Transplantation by Ex Vivo Subnormothermic and Normothermic Oxygenated Machine Perfusion: First Experience in Spain.

BACKGROUND: Ex vivo machine perfusion (MP) has been reported as a possibly method to rescue discarded organs. The main aim of this study was to report an initial experience in Spain using MP for the rescue of severely marginal discarded liver grafts, and to, secondarily, define markers of viability to test the potential applicability of these devices for the real increase in the organ donor pool. METHODS: The study began in January 2016. Discarded grafts were included in a research protocol that consisted of standard retrieval followed by 10 hours of cold ischemia. Next, either normothermic (NMP) or controlled subnormothermic (subNMP) rewarming was chosen randomly. Continuous measurements of portal-arterial pressure and resistance were screened. Lactate, pH, and bicarbonate were measured every 30 minutes. The perfusion period was 6 hours, after which the graft was discarded and evaluated as potentially usable, but never implanted. Biopsies of the donor and at 2, 4, and 6 hours after ex vivo MP were obtained. RESULTS: A total of 4 grafts were included in the protocol. The first 2 grafts were perfused by NMP and grafts 3 and 4 by subNMP. The second and third grafts showed a clear trend toward optimal recovery and may have been used. Lactate dropped to levels below 2.5 mmol/L with stable arterial and portal pressure and resistance. Clear biliary output started during MP. Biopsies showed an improvement of liver architecture with reduced inflammation at the end of the perfusion. CONCLUSION: This preliminary experience has demonstrated the potential of MP devices for the rescue of severely marginal liver grafts. Lactate and biliary output were useful for viability testing of the grafts. The utility of NMP or subNMP protocols requires further research.

Optimizing the management of patients with BCLC stage-B hepatocellular carcinoma: Modern surgical resection as a feasible alternative to transarterial chemoemolization.

OBJECTIVE: To analyse the impact of liver resection (LR) in patients with Hepatocellular Carcinoma (HCC) within the Barcelona-Clinic-Liver-Cancer (BCLC)-B stage. METHODS: Analysis of patients with BCLC-B HCC treated with LR or transarterial chemoembolization (TACE) between 2007 and 2012 in our hospital. Survival/recurrence analyses were performed by log-rank tests and Cox multivariate models. Further analyses were specifically obtained for the HCC subclassification (B1-2-3-4) proposed recently. RESULTS: Eighty patients were treated (44-TACE/36-LR). Number of nodules was [1.8(1.1)], being multinodular in 50% of cases. Although resected patients had a higher hospital stay than those who underwent TACE (14 ± 13 vs 7 ± 6; P = 0.004), the rate and severity of complications was lower measured by Dindo-Clavien scale (P < 0.05). Overall survival was 40% with a median follow-up of 29.5 months (0.07-96.9). Five-years survival rates were 62.9%, 28.1% and 15.4%, respectively (P = 0.004) for B1, B2 and B3-4 stages. Cox model showed that only total bilirubin [OR = 2.055(1.23-3.44)] and BCLC subclassification B3-4 [OR = 2.439(1.04-5.7)] and B2 [OR = 2.79(1.35-5.77)] vs B1 were independent predictors of 5-years-survival. In B1 patients, surgical approach led a significant decrease in 5-years recurrence-rate (25% vs 60%; P = 0.018). In the surgical subgroup analysis, better results were observed if well/moderate differentiation combined with no microvascular-invasion (VI) in 5-years-survival (84.6%; P = 0.001) and -recurrence (23.1%; P = 0.041), respectively. These survival and recurrence trends were remarkable in B1 stages. CONCLUSIONS: Management of Intermediate BCLC-B HCC stage should be more complex and include updated criteria regarding B-stage subclassifications, VI and tumour differentiation. Modern surgical resection would offer improved survival benefit with acceptable safety in selected BCLC-B stage patients.

Biochemical criteria at 1 year are not robust indicators of response to ursodeoxycholic acid in early primary biliary cirrhosis: results from a 29-year cohort study.

BACKGROUND: In primary biliary cirrhosis (PBC), biochemical criteria at 1 year are considered surrogates of response to ursodeoxycholic acid (UDCA). However, due to the slow natural history of PBC, evaluation at 1 year may be suboptimal to assess the therapeutic response, particularly in early disease. AIM: To determine whether evaluation of biochemical criteria at 1 year is a reliable surrogate of UDCA response in early PBC. METHODS: We analysed the prospectively collected data of 215 patients (untreated = 129; UDCA-treated = 86) with early PBC (normal baseline bilirubin/albumin) and a median follow-up of 8 years (range: 1-29.1). The 1-year attainment rates of the Barcelona, Paris-I, Paris-II and Toronto definitions, and their predictive relevance for a poor outcome (death, transplantation, complications of cirrhosis), were assessed either as a result of UDCA or no treatment. Independent associations with attaining each UDCA response definition were identified by multivariate analysis. RESULTS: Untreated patients displayed 1-year biochemical features compatible with 'treatment response' at rates (Barcelona: 36.4%, Paris-I: 66.7%, Toronto: 59.7%, Paris-II: 40.3%) similar to those obtained under UDCA. Depending on the definition, baseline ALP≤3xULN (OR: 4.80-35.90), AST≤2xULN (OR: 5.63-9.34) and early histological stage (OR: 3.67-3.87) were the stronger predictors for attaining the criteria. UDCA treatment was associated with attaining Barcelona (OR = 2.16) and Paris-II (OR = 2.84), but not Paris-I, and not Toronto definition when excluding late histological cases. Paris-I criteria were significantly predictive of long-term outcomes (HR = 2.83) in untreated patients. CONCLUSIONS: In early PBC, biochemical criteria at 1 year reflect severity of the disease rather than the therapeutic response to UDCA.