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.

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.

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.

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.

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.

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.

The impact of type 2 diabetes and obesity on the long-term outcomes of more than 85 000 liver transplant recipients in the US.

BACKGROUND: Type 2 diabetes is known to negatively impact the outcome of chronic liver disease. AIM: To evaluate the impact of diabetes on the outcomes of liver transplants (LT). METHODS: Study cohort included adults (>18 years) who received LT in the US between 1994 and 2013 (The Scientific Registry of Transplant Recipients). Pre- and post-transplant diabetes was recorded in patients with mortality follow-up. RESULTS: We included 85 194 liver transplant recipients. Of those, 11.2% had history of pre-transplant diabetes. The most common indications for liver transplant were hepatitis C (36.4%), alcohol-related liver disease (20.6%), primary liver malignancy of unspecified aetiology (14.7%), cryptogenic cirrhosis (8.0%), hepatitis B (4.6%) and non-alcoholic steatohepatitis (3.9%). A total of 96.5% transplants were from deceased donors, and 7.9% donors had history of diabetes. During an average 6.5 years of follow-up, 31.3% recipients died and 8.8% had a graft failure. In multivariate survival analysis [at least 5 years of cohort follow-up (N = 35 870)], after adjustment for age, ethnicity, insurance type, history of chronic diseases, HCV infection and noncompliance, independent predictors of recipient mortality included the presence of pre-transplant diabetes [adjusted hazard ratio (95%CI) = 1.21 (1.12-1.30)] and developing diabetes post-transplant [1.06 (1.02-1.11)]. Donor's history of diabetes was also independently associated with higher mortality [1.10 (1.02-1.19)]. Furthermore, donor's history of diabetes was also associated with an increased the risk of liver graft failure [1.35 (1.24-1.47)]. CONCLUSIONS: Presence of type 2 diabetes pre- and post-transplant, as well as presence of type 2 diabetes in the donors, are all associated with an increased risk of adverse post-transplant outcomes.

Cost-effectiveness analysis of sofosbuvir plus peginterferon/ribavirin in the treatment of chronic hepatitis C virus genotype 1 infection.

BACKGROUND: Sofosbuvir, an oral NS5B nucleotide polymerase inhibitor, is indicated for the treatment of patients infected with hepatitis C virus (HCV). AIM: To evaluate the long-term health economic outcomes of sofosbuvir + pegylated interferon alfa/ribavirin (pegIFN/RBV) compared with current treatments in patients infected with HCV genotype 1 in the US. METHODS: A decision-analytic Markov model was developed to estimate health outcomes, number needed to treat and short-term and long-term economic outcomes, including incremental cost-effectiveness ratios and cost per sustained virological response (SVR), for several sofosbuvir-comparator regimen pairings for a cohort of 10 000 patients. It considered three patient cohorts: treatment-naïve, treatment-experienced and treatment-naïve human immunodeficiency virus (HIV) co-infected. Subgroup analyses were conducted for treatment-naïve patients with and without cirrhosis. RESULTS: Reductions in the incidence of new cases of liver-disease complications with sofosbuvir + pegIFN/RBV compared with pegIFN/RBV, boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV were 64-82%, 50-68%, 43-58% and 33-56%, respectively. Sofosbuvir + pegIFN/RBV was typically associated with the lowest 1-year cost per SVR. When considering the lifetime incremental cost per quality-adjusted life-year gained, sofosbuvir + pegIFN/RBV was the most cost-effective treatment option assessed. Sofosbuvir + pegIFN/RBV generally dominated (less costly and more effective than) boceprevir + pegIFN/RBV, telaprevir + pegIFN/RBV and simeprevir + pegIFN/RBV. CONCLUSION: Sofosbuvir + pegIFN/RBV yields more favourable future health and economic outcomes than current treatment regimens for patients across all levels of treatment experience and cirrhosis stage, as well as for individuals with or without HIV co-infection.

The impact of hepatitis C burden: an evidence-based approach.

BACKGROUND: Infection with the hepatitis C virus (HCV) has been considered a major cause of mortality, morbidity and resource utilisation in the US. In addition, HCV is the main cause of hepatocellular cancer (HCC) in the US. Recent developments in the diagnosis and treatment of HCV, including new recommendations pertaining to screening for HCV by the Centers for Disease Control and Prevention and newer treatment regimens with high efficacy, short duration and the potential for interferon-free therapies, have energised the health care practitioners regarding HCV management. AIM: To assess the full impact of HCV burden on clinical, economic and patient-reported outcomes. METHODS: An expert panel was convened to assess the full impact of HCV burden on a number of important outcomes using an evidence-based approach predicated on Grading of Recommendations Assessment, Development and Evaluation methodology. The literature was summarised, graded using an evidence-based approach and presented during the workshop. Workshop presentations were intended to review recent, relevant evidence-based literature and provide graded summary statements pertaining to HCV burden on topics including the relationships between HCV and the development of important outcomes. RESULTS: The associations of HCV with cirrhosis, HCC, liver-related mortality, type 2 diabetes mellitus, rheumatological diseases and quality of life impairments are supported by strong evidence. Also, there is strong evidence that sustained viral eradication of HCV can improve important outcomes such as mortality and quality of life. CONCLUSIONS: The current evidence suggests that HCV has been associated with tremendous clinical, economic and quality of life burden.

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.

Gonadotrophin-releasing hormone neurons in a photoperiodic songbird express fos and egr-1 protein after a single long day.

Birds use a variety of environmental cues, such as day length, temperature and social interactions, to time reproductive efforts. For most seasonally breeding birds, day length is the most important cue and takes precedence over all others. Experimental manipulation of day length has shown that, in a number of galliformes and passeriformes, exposure to a single long day induces a rise in plasma luteinising hormone (LH). The mechanisms underlying this response are only beginning to be understood. In Japanese quail and Zonotrichia sparrows, one long day causes striking up-regulation of the protein products of immediate early genes (IEGs) in the mediobasal hypothalamus, near gonadotrophin-releasing hormone (GnRH) axons and terminals. Photoperiodic induction of the same proteins in the GnRH somata themselves, however, has not been described in these species. In the present study, we used immunohistochemistry to assay the induction of two IEGs, Fos and Egr-1, in the GnRH somata of male and female white-throated sparrows (Zonotrichia albicollis) exposed to a single long day. We found that immunoreactivity for both proteins increased in a subset of the GnRH neurones of the septo-preoptic area by the morning after the long day. Photo-induced expression of Egr-1 or Fos protein in GnRH neurones was limited to a population of cells in the medial preoptic area. Males showed significantly greater induction of both proteins in this population of GnRH neurones than did females, which is consistent with the hypothesis that males may be more sensitive to photic cues. Overall, the results obtained suggest that photostimulation stimulates new protein synthesis in GnRH neurones on a relatively rapid time scale. Further research is required to determine whether the GnRH somata are themselves integrating photic cues, or whether they are responding rapidly to an increased demand for GnRH synthesis.

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.

Prospective validation of the short form liver disease quality of life instrument.

BACKGROUND: Despite the realization that health-related quality of life (HRQOL) is an important outcome in patients with liver disease, there is scarcity of disease-targeted HRQOL measures that have undergone prospective evaluation. AIM: To validate prospectively the short form of liver disease quality of life instrument (the SF-LDQOL) in patients with advanced liver disease. METHODS: The SF-LDQOL includes 36 disease-targeted items representing nine domains: symptoms of liver disease, effects of liver disease, memory/concentration, sleep, hopelessness, distress, loneliness, stigma of liver disease and sexual problems. We administered the SF-LDQOL to 156 advanced liver disease patients at baseline and at 6-month follow-up. We estimated internal consistency reliability for multi-item scales, item discrimination across scale and evaluated construct validity by estimating the associations of SF-LDQOL scores with SF-36 scores, symptom severity and disability days. To evaluate the SF-LDQOL's responsiveness, we compared HRQOL changes for patients who received with those who did not receive liver transplantation (LT). RESULTS: The internal consistency reliability coefficients were > or = 0.70 for seven of nine scales in baseline and for all scales in follow-up administration. The SF-LDQOL correlated highly with SF-36 scores, symptom severity, disability days and global health. Patients undergoing LT reported improved HRQOL compared with patients without LT and the responsiveness indices were excellent. CONCLUSIONS: This study provides support for the reliability and validity of the SF-LDQOL in patients with advanced chronic liver disease. This instrument may be useful in everyday clinical practice and in future clinical trials.