Decompensated cirrhosis: targeted training of acute medical teams to improve quality of care in first 24 hours.

BACKGROUND: A quality improvement project in a secondary care centre was initiated to investigate and evaluate the impact of staff education and the use of the British Society of Gastroenterology/British Association for the Study of the Liver cirrhosis care bundle in improving care of patients admitted to hospital with decompensated liver cirrhosis. METHOD: A staff training programme was implemented, involving around 30 health professionals consisting of consultants, junior doctors, physician associates and nurses from the acute medical unit. A review of electronic documentation and analysis of key clinical parameters, pre- and post-intervention, was carried out. RESULTS: The data show that the intervention has led to an improvement in patient management and clinical outcomes. CONCLUSION: This project illustrates that collaboration between hepatology and medical teams, with emphasis on education and training, benefits patients who present to hospital with decompensated liver cirrhosis.

JNJ-4178 (AL-335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus-Infected Patients Without Cirrhosis: OMEGA-1.

The combination of three direct-acting antiviral agents (AL-335, odalasvir, and simeprevir: JNJ-4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)-1-infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA-1. This multicenter, randomized, open-label study (NCT02765490) enrolled treatment-naïve and interferon (±ribavirin) treatment-experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL-335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8-week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a-infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment-related serious AEs. All randomized patients completed treatment. Conclusion: In HCV-infected patients, 6 and 8 weeks of treatment with JNJ-4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

A 3-year follow-up study after treatment with simeprevir in combination with pegylated interferon-α and ribavirin for chronic hepatitis C virus infection.

BACKGROUND: Simeprevir is approved with pegylated interferon and ribavirin (PR) for chronic hepatitis C virus (HCV) genotype (GT) 1 and GT4 infection in the USA and the European Union. METHODS: This 3-year follow-up study assessed the durability of sustained virologic response (SVR) (undetectable HCV RNA 12 or 24 weeks after treatment end), and evaluated the persistence of treatment-emergent NS3/4A protease inhibitor resistance in patients not achieving SVR following treatment with simeprevir plus PR in the parent study. The maintenance of SVR after the last post-therapy follow-up visit of the parent study (LPVPS) was assessed using HCV RNA measurements. The persistence of treatment-emergent NS3 amino acid substitutions in patients with no SVR at LPVPS was assessed using population sequencing. No study medications were administered. RESULTS: Overall, 249 patients were enrolled (200 with SVR at LPVPS; 49 with no SVR at LPVPS); 40 patients discontinued prematurely (18 with SVR; 22 with no SVR). All 200 enrolled patients who achieved SVR in the parent study maintained SVR until the last available visit in this study (median follow-up time: 35.8 months). The treatment-emergent NS3 amino acid substitutions detected at time of failure in the parent study in 43/49 enrolled patients were no longer detected in 37/43 (86.0%) at the end of this study (median follow-up time: 179.9 weeks [41.3 months]). CONCLUSION: This 3-year follow-up study provides evidence for the long-term durability of SVR (100%) after successful treatment with simeprevir plus PR. Treatment-emergent NS3 amino acid substitutions became undetectable in the majority of patients. TRIAL REGISTRATION: NCT01349465; ClinicalTrials.gov .

Simeprevir with peginterferon α-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study.

BACKGROUND: This Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients. METHODS: Patients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir. Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12). RESULTS: Phase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies. CONCLUSIONS: The majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted. TRIAL REGISTRATION: NCT01323244 . (date of registration: March 24, 2011).

Early occurrence of new-onset diabetes after transplantation is related to type of liver graft and warm ischaemic injury.

BACKGROUND & AIMS: We studied new-onset diabetes after transplantation (NODAT) in liver transplantation with grafts donated after brain death (DBD) or circulatory death (DCD), focusing on the early post-transplant period. METHODS: A total of 430 non-diabetic primary liver transplant recipients [DCD, n = 90 (21%)] were followed up for 30 months (range 5-69). NODAT was defined as the composite endpoint of one of following: (i) Two non-fasting plasma glucose levels > 11.1 mmol/L ≥ 30 days apart, (ii) oral hypoglycaemic drugs ≥ 30 days consecutively (iii) insulin therapy ≥ 30 days and (iv) HbA1c ≥ 48 mmol/L. Resolution of NODAT was defined as cessation of treatment or hyperglycaemia. RESULTS: Total of 81/430 (19%) patients developed NODAT. Incidence and resolution of NODAT over time showed significantly different patterns between DCD and DBD liver graft recipients; early occurrence, high peak incidence and early resolution were seen in DCD. In multivariate logistic regression including age, ethnicity, HCV, tacrolimus level and pulsed steroids, only DCD was independently associated with NODAT at day 15 post-transplant (OR 6.5, 95% CI 2.3-18.4, P < 0.001), whereas age and pulsed steroids were significant factors between 30-90 days. Combined in multivariate Cox regression model for NODAT-free survival, graft type, age and pulsed steroids were each independent predictor for decreased NODAT-free survival in the first 90-postoperative days. CONCLUSION: Early peak of NODAT in DCD graft recipients is a novel finding, occurring independently from known risk factors. Donor warm ischaemia and impact on insulin sensitivity should be further studied and could perhaps be associated with graft function.

The role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) in the management of variceal hemorrhage.

BACKGROUND: Variceal bleeding in cirrhosis represents a lethal complication of their disease. In the last 20 years, management of AVH has improved greatly with reduction in mortality from 43% in 1980 to 15% in 2000. AIM: Advances in endoscopic therapy, pharmacologic agents including vasoconstrictor therapy and antibiotics have played a large part in improving outcomes, but the role of Transjugular Intrahepatic Portosystemic Stent-Shunt (TIPSS) remains controversial, which this review will cover. METHODS: MEDLINE search for the following terms was performed to July 2011: variceal hemorrhage, portal hypertension, cirrhosis, transjugular intrahepatic portosystemic stent-shunt (TIPSS), PTFE, covered stents. Where possible randomized controlled studies were used for this review, although uncontrolled studies were also included if they made a significant contribution to the literature. RESULTS: Literature used for the present study was selected from a total of 252 publications and abstracts from meetings. RESULTS: TIPSS has been used as a salvage therapy after initial medical and endoscopic therapy for the bleed given its high success rate in arresting uncontrolled variceal bleeding. The recent trial by Garcia- Pagan et al. suggested beneficial effects of an earlier covered TIPSS in those at high risk of treatment failure (Childs C and those who are Childs B with active bleeding). CONCLUSIONS: TIPSS can reduce failure to control bleeding and rebleeding as well as mortality with no increase in the risk of hepatic encephalopathy.This needs to be confirmed in further trials. However, it is clear that prevention of rebleeding is the key to improved outcomes following a variceal bleed.

Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics.

It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 profiling, we find that mitochondria of many adult somatic tissues, including brain, heart, and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

Reticulocyte count and hemoglobin concentration predict survival in candidates for liver transplantation.

BACKGROUND: Prognostic scores are used to assess the likelihood of mortality in cirrhosis and the necessity of liver transplantation. These models are imperfect and refinement would allow more accurate prognostication and selection of patients for transplant. This study investigated association of red cell parameters and mortality in liver transplant candidates. METHODS: Data from patients with cirrhosis assessed for transplantation from 2008 to 2010 at Queen Elizabeth Hospital Birmingham, UK were reviewed retrospectively. Kaplan-Meier analysis and Cox regression models were used to generate indices predicting mortality. Accuracy of existing and updated models was tested by calculation of c-statistics. Results were validated in a cohort of patients assessed for liver transplant in Jena, Germany. RESULTS: Data were collected from 386 patients in the study cohort. Median follow-up was 15 months (0-45). During follow-up, 151 patients (39%) were transplanted, 138 (36%) died, and 97 (25%) survived without transplant. Abnormal reticulocyte count (P<0.001, c-statistic 0.623) and hemoglobin concentration (P<0.001, c-statistic 0.609) predicted mortality in Cox regression analysis. Abnormal reticulocyte count was also found to predict mortality in competing risk analysis. Refining the Model for End-Stage Liver Disease (MELD) to incorporate reticulocyte count and hemoglobin concentration (MELD-red) improved predictive power from 0.701 to 0.731 (c-statistics). This was confirmed in an independent validation cohort of 157 patients with c-statistics of 0.787 and 0.816, respectively, for MELD and MELD-red. CONCLUSIONS: Abnormal red cell indices, in particular increased reticulocyte count and decreased hemoglobin concentration, are associated with increased risk of death in liver transplant candidates. Refining MELD to incorporate these indices improves prediction of mortality.

A case-control study of transjugular intrahepatic portosystemic stent shunts for patients admitted to intensive care following variceal bleeding.

INTRODUCTION: Variceal bleeding has a 6-week mortality of 20%. Recent evidence suggests that early covered transjugular intrahepatic portosystemic stent shunts (TIPSS) can improve outcomes following a variceal bleed in selected patients. We aim to assess the outcomes following the insertion of covered TIPSS in a real-life intensive care setting. MATERIALS AND METHODS: This is a retrospective matched cohort study of all patients referred for TIPSS with variceal bleeding admitted to intensive care (2007-2009). Patients were matched with others admitted to intensive therapy unit following a variceal bleed but did not proceed to TIPSS. All TIPSS procedures were carried out using polytetrafluoroethylene-covered stents. RESULTS: Thirty-eight patients [mean age 55.2 years; mean model for end-stage liver disease (MELD)=14.0; and median follow-up 458 days] were assessed. Nineteen underwent TIPSS and were well matched to the controls. All patients received terlipressin and antibiotics and 86% had active bleeding at endoscopy. Indication for TIPSS was salvage therapy (47%), rebleeding after day 5 (11%) and as secondary prophylaxis (42%). There was 34% all-cause inpatient mortality. The TIPSS group had lower mortality than the non-TIPSS group at 6 weeks (10.5 vs. 47.4%, P<0.05) that persisted at 1 year (21.1 vs. 52.6%, P<0.05). Multivariate analysis indicated MELD [HR 1.131, 95% confidence interval (CI) 1.018-1.257] and TIPSS (HR 0.301, 95% CI 0.091-0.995) as significant predictors of mortality (P<0.05). TIPSS was found to significantly reduce the incidence of failure to control bleeding and rebleeding (HR 0.120, 95% CI 0.015-0.978, P<0.05). CONCLUSION: Patients with recent severe variceal bleeding admitted to intensive care have significantly better outcomes following covered TIPSS insertion. These findings should be validated in randomized-controlled trials.

Mental health disorders and solid-organ transplant recipients.

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ~2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.

Alcohol and substance abuse in solid-organ transplant recipients.

This review focuses on alcohol and substance abuse in the context of solid-organ transplantation. Alcohol and substance abuse are common and may lead to a need for solid-organ transplantation and may also contribute to significant physical and psychologic problems that impact upon the recipient. Damaging levels of alcohol intake can occur in the absence of dependence. Alcohol or substance abuse after transplantation is associated with poor medication compliance and this may increase risk of graft loss. Intravenous drug use is associated with increased risk of infections (especially secondary to opportunistic organisms-bacterial, viral, protozoal, and others-and such infections may be more severe in the immunosuppressed), but there is only anecdotal evidence that such behavior has a worse outcome in transplant recipients. Whereas previous alcohol excess and drug use in kidney recipients are both associated with a small but statistically significantly increased risk of adverse outcomes (hazard ratio, 1.16-1.56), alcohol use within recommended guidelines after transplantation appears safe and possibly beneficial. Robust data are lacking for other organs, but those available suggest that heart transplantation is safe in individuals with a history of alcohol or substance abuse. Health specialists in drug or alcohol addiction should carefully screen all potential transplant candidates for these conditions, and where there is evidence of dependency or abuse, effective psychologic and physical treatment should be offered. Studies have shown that interventions such as psychologic intervention have improved alcohol behavior in the context of liver transplantation. Although there are no comparable studies with other solid-organ recipients, it is reasonable to expect transferable outcomes.

Tobacco smoking and solid organ transplantation.

Smoking, both by donors and by recipients, has a major impact on outcomes after organ transplantation. Recipients of smokers' organs are at greater risk of death (lungs hazard ratio [HR], 1.36; heart HR, 1.8; and liver HR, 1.25), extended intensive care stays, and greater need for ventilation. Kidney function is significantly worse at 1 year after transplantation in recipients of grafts from smokers compared with nonsmokers. Clinicians must balance the use of such higher-risk organs with the consequences on waiting list mortality if the donor pool is reduced further by exclusion of such donors. Smoking by kidney transplant recipients significantly increases the risk of cardiovascular events (29.2% vs. 15.4%), renal fibrosis, rejection, and malignancy (HR, 2.56). Furthermore, liver recipients who smoke have higher rates of hepatic artery thrombosis, biliary complications, and malignancy (13% vs. 2%). Heart recipients with a smoking history have increased risk of developing coronary atherosclerosis (21.2% vs. 12.3%), graft dysfunction, and loss after transplantation. Self-reporting of smoking is commonplace but unreliable, which limits its use as a tool for selection of transplant candidates. Despite effective counseling and pharmacotherapy, recidivism rates after transplantation remain high (10-40%). Transplant services need to be more proactive in educating and implementing effective smoking cessation strategies to reduce rates of recidivism and the posttransplantation complications associated with smoking. The adverse impact of smoking by the recipient supports the requirement for a 6-month period of abstinence in lung recipients and cessation before other solid organs.