Long-term trends in chronic hepatitis B virus infection associated liver transplantation outcomes in the United States.

With effective antiviral therapies, rates of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) and decompensated liver disease requiring liver transplantation (LT) are expected to decrease. We aim to evaluate overall trends in LT waitlist registrations, waitlist survival and likelihood of receiving LT among chronic HBV patients in the United States. Using the United Network for Organ Sharing database, we retrospectively evaluated adults (age≥18) with chronic HBV (with and without HCC) listed for LT from 1992 to 1996 (Era 1) vs 1997 to 2004 (Era 2) vs 2005-2015 (Era 3). Multivariate Cox-regression models evaluated probability of waitlist survival and receiving LT. Overall, 6797 chronic HBV adults were listed for LT. While the total number of HBV patients listed for LT remained stable, the proportion of HBV patients with HCC increased from 5.4% in Era 1 to 39.0% in Era 3. Compared to Era 1, waitlist mortality was higher in Era 2 (HR: 4.55, P<.001) and Era 3 (HR: 3.63, P<.001). However, in the most recent era, waitlist mortality significantly improved (compared to 2005-2007: 2008-2011: HR: 0.74, P=.05, 95% CI: 0.55-0.99; 2012-2015: HR: 0.53, P<.001, 95% CI: 0.38-0.75). Probability of receiving LT was also lower with latter time periods (compared to 2005-2007: 2008-2011: HR: 0.77, P<.001 95% CI: 0.68-0.86; 2012-2015: HR: 0.61, P<.001, 95% CI: 0.54-0.69). Although the number of HBV patients requiring LT remained stable, the proportion of HBV patients with HCC continues to rise. The decrease in waitlist mortality and lower likelihood of LT among HBV patients may reflect the effectiveness of antiviral therapies in delaying disease progression in the current era.

The impact of viral hepatitis-related hepatocellular carcinoma to post-transplant outcomes.

Hepatocellular carcinoma (HCC) is the most common complication of HCV infection leading to liver transplantation. We evaluated the impact of aetiology of liver disease on patient and graft survival following liver transplantation for HCC. From the Scientific Registry of Transplant Recipients (2002-2011), all adults who underwent liver transplantation for HCC were retrospectively included. Aetiology of liver disease was grouped into HCV, HBV, HCV-HBV co-infection and nonviral liver disease. Of 8,733 liver transplant recipients with HCC, 5507 had HCV, 631 had HBV, 163 were co-infected, and 2432 had nonviral causes of liver disease. In follow-up (48 ± 32 months), 8.2% had graft failure and 29.5% died. The mean rates of graft failure were 9.5%, 4.7%, 6.1% and 6.4% in HCV, HBV, HCV-HBV co-infection and nonviral liver disease, respectively (P < 0.0001). Post-transplant mortality rate in patients with HBV was 20.2%, HCV 31.0%, HCV-HBV 28.5% and nonviral 28.5% (P < 0.0001). This difference was significant starting one year post-transplant and became even more prominent later in follow-up. Five-year post-transplant survival was 64.7% in HCV, 77.7% in HBV, 71.0% in HCV-HBV and 69.1% in nonviral HCC (P < 0.0001). A diagnosis of HCV in patients with HCC was also independently associated with an increased risk of both graft failure (adjusted hazard ratio = 1.84 (1.46-2.33), P < 0.0001) and mortality (1.35 (1.21-1.50), P < 0.0001) in multivariate analysis. Patients with HCV-related HCC are at higher risk of adverse post-transplant outcomes. These patients should be considered for preemptive interferon-free antiviral therapy prior to or immediately following liver transplantation.

Simultaneous liver-kidney transplantation summit: current state and future directions.

Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver-kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed.

Major challenges limiting liver transplantation in the United States.

Liver transplantation is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver transplantation in the United States grew 3.7-fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: (1) the need for an expanded number of useable donor organs, (2) the need for improved therapies to treat recurrent hepatitis C after transplantation and (3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma.

Posttransplantation hepatitis B prophylaxis with combination oral nucleoside and nucleotide analog therapy.

Liver transplant recipients are at risk of developing recurrent hepatitis B after liver transplantation for hepatitis B virus (HBV)-related liver disease. We evaluated the efficacy of a new hepatitis B prophylaxis regimen involving conversion from at least 12 months of HBIg with lamivudine to combination therapy with an oral nucleoside and nucleotide analog. Between June 2008 and May 2010, a total of 61 liver transplant recipients were converted to a combination of a nucleoside and nucleotide analog. The mean (±standard deviation) follow-up time after conversion was 15.0 (±6.1) months. Recurrent HBV occurred in two (3.3%) patients at 3.1 and 16.6 months after HBIg cessation. The overall person time incidence rate for HBV recurrence after HBIg cessation was 2.7 cases per 100 person-years. The estimate of HBV recurrence was 1.7% at 1 year after HBIg cessation. HBIg cessation a minimum of 12 months after liver transplantation with subsequent combination therapy with a nucleoside and nucleotide analog provides effective prophylaxis against recurrent HBV infection. The clinical implications of HBsAg detection without clinical, biochemical or molecular manifestations of recurrent hepatitis B require further study.

Apparent remission of a solitary metastatic pulmonary lesion in a liver transplant recipient treated with sorafenib.

Hepatocellular carcinoma (HCC) remains a significant disease worldwide and its incidence is expected to increase. In selected patients, liver transplantation offers a 5-year patient survival between 48% and 75%. However, HCC recurrence occurs in approximately 20% of transplant recipients. No therapy has proven efficacious in decreasing the risk of recurrence after transplantation. Sorafenib, a multitargeted tyrosine kinase inhibitor, has been shown to improve survival in patients with advanced HCC that have no history of liver transplantation. We report complete remission of HCC in a 54-year-old man who developed biopsy-proven lung metastasis after liver transplantation treated with sorafenib.

Feasibility of completing an accelerated vaccine series for homeless adults.

Homeless adults are at high risk for hepatitis B virus (HBV) infection. In addition to culturally sensitive programmes designed to enhance vaccination compliance, accelerated HBV vaccination (three doses over 21 days) have also been suggested to improve compliance among high-risk groups. In this paper, we examined predictors of completers of two of three doses of a HAV/HBV vaccine series, normally delivered over a 6-month period, to simulate compliance with an accelerated series, dosed over 4 weeks. A convenience sample of 865 homeless adults was randomized into a nurse case-managed approach (NCMIT) vs standard programmes with (SIT) and without tracking (SI). Each group was assessed for completion of two of the three dose HAV/HBV vaccine series as well as the full three dose vaccine series. Sixty-eight percent of the NCMIT participants completed the three dose vaccination series at 6 months compared to 61% of SIT participants and 54% of SI participants. Eighty-one percent of the NCMIT participants completed two of the vaccinations compared to 78% of SIT participants and 73% of SI participants. The NCMIT approach resulted in greater numbers of completers of two of three doses and of the full three dose vaccine series. Predictors of completers of two doses and the full three dose vaccine series are provided. A greater number of homeless persons completed two doses across the three groups compared to the three dose vaccine series. The use of nurse case-management and tracking, coupled with an accelerated HAV/HBV vaccination schedule, may optimize vaccination compliance in homeless adults.

Development of Focal Segmental Glomerulosclerosis and Thrombotic Microangiopathy in a Liver Transplant Patient on Sorafenib for Hepatocellular Carcinoma: A Case Report.

Transplant patients are at risk for hemodynamic injury and glomerular diseases such as focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA). Calcineurin inhibitors (CNI) can cause various patterns of acute kidney injury (AKI) in transplant patients and their effects must be differentiated from kidney injury due to other agents. Transplant populations are also at risk for atypical infections and malignancies. These conditions and the agents that are used to treat them can then induce their own set of glomerular diseases. We report a patient with hepatitis C who had received an orthotopic liver transplant and then developed recurrent hepatocellular carcinoma, which was treated with the oral tyrosine kinase inhibitor (TKI) sorafenib. In a manner temporally related to the initiation of the TKI, progressive AKI and high-grade rising proteinuria were noted. A biopsy disclosed FSGS and concomitant TMA. Despite the discontinuation of the TKI and high-dose steroid treatment, the patient developed end-stage renal disease and was initiated on hemodialysis. After determining the TKI as the probable culprit, as opposed to CNIs, the patient successfully received a living related renal transplant. CNIs are used to maintain renal and hepatic allografts without the development of hematuria, significant proteinuria, or significant impairment of renal function. It is noted that the pathologic phenotype observed in this case is only the second reported case of concomitant TMA and FSGS in a sorafenib-treated patient.

TIPS versus paracentesis for cirrhotic patients with refractory ascites.

BACKGROUND: Refractory ascites (ie, ascites that cannot be mobilized despite sodium restriction and diuretic treatment) occurs in 10 per cent of patients with cirrhosis. It is associated with substantial morbidity and mortality with a one-year survival rate of less than 50 per cent. Few therapeutic options currently exist for the management of refractory ascites. OBJECTIVES: To compare transjugular intrahepatic portosystemic stent-shunts (TIPS) versus paracentesis for the treatment of refractory ascites in patients with cirrhosis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2006), the Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 4, 2005), MEDLINE (1950 to January 2006), EMBASE (1980 to January 2006), CINAHL (1982 to August 2004), and Science Citation Index Expanded (1945 to January 2006). SELECTION CRITERIA: We included randomised clinical trials comparing TIPS and paracentesis with or without volume expanders for cirrhotic patients with refractory ascites. DATA COLLECTION AND ANALYSIS: We evaluated the methodological quality of the randomised clinical trials by the generation of the allocation section, allocation concealment, and follow-up. Two authors independently extracted data from each trial. We contacted trial authors for additional information. Dichotomous outcomes were reported as odds ratio (OR) with 95% confidence interval (CI). MAIN RESULTS: Five randomised clinical trials, including 330 patients, met the inclusion criteria. The majority of trials had adequate allocation concealment, but only one employed blinded outcome assessment. Mortality at 30-days (OR 1.00, 95% CI 0.10 to 10.06, P = 1.0) and 24-months (OR 1.29, 95% CI 0.65 to 2.56, P = 0.5) did not differ significantly between TIPS and paracentesis. Transjugular intrahepatic portosystemic stent-shunts significantly reduced the re-accumulation of ascites at 3-months (OR 0.07, 95% CI 0.03 to 0.18, P < 0.01) and 12-months (OR 0.14, 95% CI 0.06 to 0.28, P < 0.01). Hepatic encephalopathy occurred significantly more often in the TIPS group (OR 2.24, 95% CI 1.39 to 3.6, P < 0.01), but gastrointestinal bleeding, infection, and acute renal failure did not differ significantly between the two groups. AUTHORS' CONCLUSIONS: The meta-analysis supports that TIPS was more effective at removing ascites as compared with paracentesis without a significant difference in mortality, gastrointestinal bleeding, infection, and acute renal failure. However, TIPS patients develop hepatic encephalopathy significantly more often.

Disconnected by design: analytic approach in treatment networks having no common comparator.

In a network meta-analysis, comparators of interest are ideally connected either directly or via one or more common comparators. However, in some therapeutic areas, the evidence base can produce networks that are disconnected, in which there is neither direct evidence nor an indirect route for comparing certain treatments within the network. Disconnected networks may occur when there is no accepted standard of care, when there has been a major paradigm shift in treatment, when use of a standard of care or placebo is debated, when a product receives orphan drug designation, or when there is a large number of available treatments and many accepted standards of care. These networks pose a challenge to decision makers and clinicians who want to estimate the relative efficacy and safety of newly available agents against alternatives. A currently recommended approach is to insert a distribution for the unknown treatment effect(s) into a network meta-analysis model of treatment effect. In this paper, we describe this approach along with two alternative Bayesian models that can accommodate disconnected networks. Additionally, we present a theoretical framework to guide the choice between modeling approaches. This paper presents researchers with the tools and framework for selecting appropriate models for indirect comparison of treatment efficacies when challenged with a disconnected framework. Copyright © 2016 John Wiley & Sons, Ltd.

Long-term outcomes of lung transplant recipients with hepatitis C infection: a retrospective study of the U.S. transplant registry.

BACKGROUND: Chronic hepatitis C patients in need of a lung transplant are often considered ineligible due to their infection. AIM: To assess the association of hepatitis C virus (HCV) infection with long-term outcomes of lung transplants. METHODS: From the Scientific Registry of Transplant Recipients (1995-2011), we selected all adults with and without HCV infection who underwent lung transplantation. RESULTS: A total of 17 762 lung transplant recipients were included (55.5% bilateral). Of those, 319 (1.83%) had positive HCV serology. The HCV-positive recipients were 1.6 years younger, less Caucasian and more African-American, and had a significantly higher rate of co-infection with hepatitis B virus (all P < 0.001). Post-transplant patients were discharged alive at similar rates regardless of HCV status: 88.4% in HCV+ vs. 90.3% in HCV- (P = 0.25). The mortality rates were also similar at 1 and 2 years after transplantation (20.7% in HCV+ vs. 19.2% in HCV- and 31.6% in HCV+ vs. 28.9% in HCV-, respectively; both P > 0.05), but at post-transplant year 3 year, mortality rate in HCV+ became significantly higher (42.5% vs. 36.4%, P = 0.04) and remained higher for the duration of the follow-up (mean 9.1 years, max 18.4 years). In multivariate survival analysis, after adjustment for confounders, being HCV+ was associated with higher mortality: adjusted hazard ratio 1.24 (1.04-1.46), P = 0.01. No association of HCV infection with time to graft loss was found (P = 0.92). CONCLUSIONS: Chronic HCV infection is associated with a moderate increase in post-lung transplant mortality. Treatment of HCV in lung transplant recipients may, therefore, result in improvement of post-transplant outcomes.

Cost-effectiveness of all-oral ledipasvir/sofosbuvir regimens in patients with chronic hepatitis C virus genotype 1 infection.

BACKGROUND: An all-oral, pegylated interferon (pegIFN)-free and ribavirin (RBV)-free single-tablet of ledipasvir (LDV) and sofosbuvir (SOF) is now approved for the treatment of patients infected with hepatitis C virus (HCV) genotype 1. AIM: To estimate the health economic outcomes for LDV/SOF compared with current treatments in US patients infected with HCV genotype 1. METHODS: A hybrid decision-tree and Markov state-transition model was developed. For a cohort of 10,000 patients, the model captured outcomes for several pairings of LDV/SOF with comparators, including long-term health outcomes, number need to treat, life-years gained, quality-adjusted life-years (QALYS) gained, incremental cost-effectiveness ratios and costs per sustained virologic response (SVR). Patients with different levels of treatment experience and different cirrhosis stages were included. RESULTS: LDV/SOF decreased the number of advanced liver disease cases by 0-93% compared with current regimens or no treatment in treatment-naïve patients. In treatment-experienced [pegIFN plus ribavirin (PR) or protease inhibitor (PI) + PR] patients, treatment with LDV/SOF decreased the incidence of advanced liver disease complications in most of the cases analysed, except SOF + SMV. For all patient sub-cohorts, LDV/SOF was associated with the lowest 1-year costs per SVR and, with regard to lifetime incremental costs per QALY gained, was either dominant or the most cost-effective treatment. Overall, treatment initiation at earlier stages of liver fibrosis resulted in improved health economic outcomes. CONCLUSION: LDV/SOF is associated with more favourable short- and long-term health economic outcomes compared with current therapies for patients across all levels of treatment experience and cirrhosis stages.

The association of hepatitis C virus infection and post-liver transplant diabetes: data from 17 000 HCV-infected transplant recipients.

BACKGROUND: Hepatitis C virus (HCV) is associated with metabolic manifestations including insulin resistance and diabetes through various mechanisms. Whether HCV infection is associated with an increased risk of post-transplant diabetes in liver transplant recipients is unclear. AIM: To assess the association of HCV infection with post-transplant diabetes. METHODS: All liver transplant recipients infected with hepatitis C (exposed) and hepatitis B (HBV) (controls) with post-transplant follow-up from the Scientific Registry of Transplant Recipients (2003-2012) were included. RESULTS: A total of 17 121 HCV patients and 1450 HBV controls were included in this observational study. Subjects with HCV were more likely to be overweight and obese at transplant, but the rate of pre-transplant diabetes of 13.7% was similar to HBV (P > 0.05). Post-transplant, 32.5% of HCV patients and 27.5% of HBV patients had diabetes (P < 0.0001). This difference was observed starting as early as 6 months post-transplant: 22.5% HCV and 18.9% HBV (P = 0.0043). With longer follow-up, both the cumulative and incidental risks of developing post-transplant diabetes were consistently higher in HCV patients. In particular, by 5 years post-transplant, both the relative risk of having diabetes [1.18 (1.08-1.29), P = 0.0002] and the hazard ratio for time to developing diabetes [1.27 (1.15-1.41), P < 0.0001] were significantly higher in HCV patients compared to HBV patients. In multivariate analysis, after adjustment for confounders including the use of immunosuppressants, hepatitis C infection was independently associated with developing post-transplant diabetes: aHR = 1.55 (1.34-1.79), P < 0.0001. CONCLUSION: Hepatitis C infection is associated with a higher risk of post-transplant diabetes that persists up to 5 years post-transplant.

Ascites and the acquired immunodeficiency syndrome. Report of 54 cases.

We identified 54 patients with AIDS and ascites seen over a 4.5-year period at a university hospital. This retrospective study is the largest reported series of patients with AIDS and ascites. Patients with AIDS who are evaluated for ascites should be stratified by the CD4 + cell count and the presence or absence of portal hypertension based upon the serum-ascites albumin gradient and clinical presentation. Awareness of possible surgery-related causes of ascites is crucial, as these patients may not manifest the usual signs and symptoms of peritonitis or abdominal catastrophes seen in immunocompetent hosts. Patients with evidence of portal hypertension due to hepatic cirrhosis and an elevated ascitic neutrophil count should be suspected to be infected with common bacterial pathogens associated with peritonitis unless the CD4 + cell count is below 50 cells/mm3. When the CD4 + cell count declines below this threshold, infections due to Mycobacterium avium complex, cytomegalovirus, and other opportunistic infections should be considered.

True and false aneurysms of the left ventricle following myocardial infarction.

Anterolateral myocardial infarction resulted in the formation of both true and false aneurysms in a 75 year old man in whom severe congestive heart failure subsequently developed as the false aneurysm became progressively larger. Left ventriculography detected and quantified both aneurysms, and demonstrated reasonable function of the remaining volume-overloaded left ventricle. Resection of both aneurysms was accomplished with marked relief of symptoms. The literature on false aneurysm is reviewed, and the dilemma posed by the need to recognize false aneurysms before they become symptomatic or rupture is discussed.

Liver transplantation. Selection, listing criteria, and preoperative management.

Although only the expansion of the donor pool will have a major impact on the survival of patients with decompensated cirrhosis awaiting OLT, anticipation of complications such as SBP may improve the likelihood of a patient surviving until OLT, and may ameliorate some of the major causes of morbidity of cirrhosis, such as osteoporosis. Close communication between the treating physicians and the transplant center is crucial to ensure that the patients' UNOS status can be appropriately adjusted if additional complications of cirrhosis, such as intractable ascites, have occurred.

Serum alanine aminotransferase in hepatitis c screening of patients on hemodialysis.

It is recommended that patients on hemodialysis (HD) therapy undergo regular screening for hepatitis C virus (HCV) infection by using alanine aminotransferase (ALT) values. However, the utility of using ALT values in this setting is unknown. The aim of this prospective study at the University of California Los Angeles Hepatitis Screening Program is to determine the sensitivity, specificity, and predictive values of an elevated ALT level for the diagnosis of HCV infection in HD patients. We screened 2,440 HD patients from 39 dialysis centers for viral infection by using hepatitis antibody serological testing and ALT values. We found the sensitivity and specificity of a newly elevated ALT level for acute HCV infection to be 83% and 90%, respectively. According to Bayes' theorem, the positive predictive value was 4% and the positive likelihood ratio was 8.74. For chronic HCV infection, the sensitivity of a newly elevated aminotransferase level was 21%, and specificity was 91%. The positive predictive value was 16% (according to Bayes' theorem), and the positive likelihood ratio was 2.47. The negative predictive value of a newly elevated aminotransferase value was 99% for acute HCV infection and 94% for chronic HCV infection. Our results indicate that although a newly elevated aminotransferase level is sensitive and specific for acute HCV infection, its positive predictive value is inadequate. A newly elevated aminotransferase level was neither sensitive nor positively predictive of chronic infection. Therefore, an elevated ALT level is an ineffective method for screening for HCV infection in HD patients.

Hepatitis C screening strategies in hemodialysis patients.

Hepatitis C virus (HCV) infection is common in patients undergoing chronic hemodialysis, with an estimated yearly incidence of 0.2% and prevalence between 8% and 10%. Although a screening strategy based on alanine aminotransferase (ALT) values is currently recommended, this strategy has not been evaluated for cost-effectiveness compared with other potential screening strategies. A comparison therefore was made using a decision-analysis model of a simulated cohort of 5,000 hemodialysis patients followed up for 5 years. Using direct medical costs, three strategies were evaluated, including: (1) ALT values with confirmatory testing (biochemical), (2) serial enzyme-linked immunosorbent and strip immunoblot assay testing (serological), and (3) polymerase chain reaction (viral). Under baseline assumptions, the per-patient cost of screening hemodialysis patients for HCV was $378 for biochemical-based testing, $195 for serological-based testing, and $696 for viral-based testing. Our model was robust when varying the costs of testing, as well as the incidence and prevalence of HCV infection. Results of sensitivity analysis by varying costs, HCV incidence, and HCV prevalence indicated that serological-based screening was less costly than biochemical testing. Biochemical testing was in turn less costly than viral-based screening. Serological-based testing was also more effective in the diagnosis of de novo HCV infection, with a likelihood ratio of 85, in contrast to the likelihood ratio of 44 with biochemical-based testing using viral-based screening as the gold standard. A serological-based screening strategy is less costly and more effective than biochemical-based screening in the diagnosis of de novo HCV infection. Serological-based screening should be considered for HCV screening in hemodialysis populations.

Retention of pacemaker electrode complicated by Serratia marcescens septicemia. Removal with total cardiopulmonary bypass.

A case in which Serratia marcescens septicemia complicated the insertion of a transvernous pacemaker unit is reported. Appropriate antibiotic therapy and removal of the pacemaker electrode are two essential steps to achieve a complete cure in this stimulation. Open cardiotomy with total cardiopulmonary bypass provides a safe approach for withdrawal of an incarcerated electrode and is justified because of the lethal potential of systemic Serratia infections, particularly those superimposed on intracardiac prostheses.

Solitary peripheral pulmonary artery aneurysms. Pathogenesis and surgical treatment.

The case of a solitary peripheral pulmonary artery aneurysm in a patient with congenital heart disease and secondary pulmonary hypertension is presented. The aneurysm appeared following an episode of bacterial endocarditis and was probably mycotic in origin. Resection was prompted by a recent increase in size. A successful aneurysmectomy was performed. Lobectomy was the procedure employed in seven other reported cases treated surgically. A brief review of the literature emphasizes the necessity for resection whenever the diagnosis is made to prevent a fatal outcome due to rupture. A classification of pulmonary artery aneurysms based on their etiology is proposed, together with a possible explanation for the pathogenesis of peripheral aneurysms of nonspecific etiology.