Long-term administration of intravenous Trappsol® Cyclo™ (HP-ß-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.

Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-ß-cyclodextrin (HP-ß-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-ß-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. Methods: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-ß-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-ß-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2-39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-ß-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-ß-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor α [TNFα]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). Results: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-ß-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-ß-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. Interpretation: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol® Cyclo™ (HP-ß-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol® Cyclo™ IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol® Cyclo™ as a disease-modifying treatment in this patient population.

Intravenous 2-hydroxypropyl-ß-cyclodextrin (Trappsol® Cyclo™) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial.

BACKGROUND: Niemann-Pick Disease Type C1 (NPC1) is a disorder of intracellular cholesterol and lipid trafficking that leads to the accumulation of cholesterol and lipids in the late endosomal/lysosomal compartment, resulting in systemic manifestations (including hepatosplenomegaly and lung infiltration) and neurodegeneration. Preclinical studies have demonstrated that systemically administered 2-hydroxypropyl-ß-cyclodextrin (HPßCD; Trappsol® Cyclo™) restores cholesterol metabolism and homeostasis in peripheral organs and tissues and in the central nervous system (CNS). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of HPßCD in peripheral tissues and the CNS in adult subjects with NPC1. METHODS: A Phase 1, randomized, double-blind, parallel group study enrolled 13 subjects with NPC1 who received either 1500 mg/kg or 2500 mg/kg HPßCD intravenously every 2 weeks for a total of 7 doses (14 weeks). Subjects were 18 years or older, with a confirmed diagnosis of NPC1 and evidence of systemic involvement on clinical assessment. Pharmacokinetic evaluations in plasma and cerebrospinal fluid (CSF) were performed at the first and seventh infusions. Pharmacodynamic assessments included biomarkers of systemic cholesterol synthesis (serum lathosterol) and degradation (serum 4ß-hydroxycholesterol), secondary sphingomyelin storage (plasma lysosphingomyelin-509, now more accurately referred to as N-palmitoyl-O-phosphocholineserine [PPCS]), and CNS-specific biomarkers of neurodegeneration (CSF total Tau) and cholesterol metabolism (serum 24(S)-hydroxycholesterol [24(S)-HC]). Safety monitoring included assessments of liver and kidney function, infusion related adverse events, and hearing evaluations. RESULTS: Ten subjects completed the study, with 6 at the 1500 mg/kg dose and 4 at the 2500 mg/kg dose. One subject withdrew following the first infusion after experiencing hypersensitivity pneumonitis, and 2 subjects withdrew after meeting a stopping rule related to hearing loss. Overall, HPßCD had an acceptable safety profile. The observed pharmacokinetic profile of HPßCD was similar following the first and seventh infusions, with a plasma half-life of 2 h, a maximum concentration reached at 6 to 8 h, and no evidence of accumulation. Serum biomarkers of cholesterol metabolism showed reduced synthesis and increased degradation. Compared to Baseline, filipin staining of liver tissue showed significant reductions of trapped unesterified cholesterol at both dose levels at Week 14. Plasma PPCS levels were also reduced. HPßCD was detected at low concentrations in the CSF (maximum, 33 µM) at both dose levels and persisted longer in CSF than in plasma. Total Tau levels in CSF decreased in most subjects. Serum levels of 24(S)-HC, a cholesterol metabolite from the CNS that is exported across the blood-brain barrier and into the circulation, decreased after both the first and seventh doses. Hence, pharmacodynamic assessments in both peripheral and CNS-related tissue show target engagement. While not the aim of the study, subjects reported favorable impacts on their quality of life. CONCLUSIONS: The plasma pharmacokinetics and pharmacodynamics of HPßCD administered at two intravenous dose levels to subjects with NPC1 were comparable to those observed in preclinical models. HPßCD cleared cholesterol from the liver and improved peripheral biomarkers of cholesterol homeostasis. At low CSF concentrations, HPßCD appeared to be pharmacologically active in the CNS based on the increased efflux of 24(S)-HC and reduction in CSF total Tau, a biomarker of CNS neurodegeneration. These data support the initiation of longer-term clinical trials to evaluate the safety and efficacy of intravenous HPßCD in subjects with NPC1. (ClinicalTrials.gov numbers: present trial, NCT02939547; open-label extension of the present trial, NCT03893071; global pivotal trial, NCT04860960).

Lower Likelihood of Post-transplant Graft Failure, Death, and Retransplantation in the Era of Direct-Acting Antivirals.

BACKGROUND: Direct-acting antivirals (DAAs) are expected to improve outcomes for patients with hepatitis C virus (HCV) infection after liver transplantation (LT). We aim to evaluate trends in post-LT outcomes with availability of DAAs. METHODS: We retrospectively evaluated US adults transplanted from January 1, 2002, to March 31, 2018, using the United Network for Organ Sharing Registry, stratified by pre-DAA (January 1, 2002- to December 31, 2013) vs. post-DAA (January 1, 2014-, to March 31, 2018) eras. Adjusted multivariate Cox regression analyses and competing risk models evaluated likelihood of graft failure, death, and retransplantation (re-LT). RESULTS: Among 97,147 patients, 30.2% had HCV infection and 19.4% had hepatocellular carcinoma (HCC). Of all patients, 31.9% experienced graft failure, 27.1% died after LT, and 4.7% underwent re-LT. The post-DAA era experienced lower likelihood of graft failure (hazard ratio [HR] = 0.69, p < 0.001). Although patients with HCV infection (HR = 1.18, p < 0.001) and HCC (HR = 1.11, p < 0.001) had higher likelihood of graft failure in the pre-DAA era, no differences were seen in the post-DAA era. Although patients with HCV infection (HR = 1.20, p < 0.001) and HCC (HR = 1.17, p < 0.001) had higher likelihood of death after LT in the pre-DAA era, no differences were seen in the post-DAA era. The post-DAA era had lower likelihood of post-LT death when stratified by non-HCC (HR = 0.70, p < 0.001) and HCC cohorts (HR = 0.67, p < 0.001) or by non-HCV (HR = 0.73, p < 0.001) and HCV (HR = 0.58, p < 0.001) cohorts. CONCLUSION: Although patients with HCV infection and HCC had higher risk of post-LT graft failure and death in the pre-DAA era, the disparity disappeared in the post-DAA era independently of each other. This likely reflects impact of DAAs on improving post-LT outcomes among patients with HCV infection and improved selection of patients with HCC for LT after 2014.

A Comprehensive Analysis of Liver Transplantation Outcomes Among Ethnic Minorities in the United States.

GOALS: The aim of this study was to perform a comprehensive assessment of liver transplant (LT) outcomes among US adults with a specific focus on understanding race/ethnicity-specific disparities. BACKGROUND: Despite improvements in the liver allocation and LT-related care, disparities in LT outcomes persist. STUDY: Using data from the 2005 to 2016 United Networks for Organ Sharing LT registry, we evaluated waitlist survival, probability of receiving LT, and post-LT survival among US adults stratified by race/ethnicity and liver disease etiology. Kaplan-Meier methods evaluated unadjusted waitlist and post-LT outcomes, and multivariate regression models evaluated adjusted waitlist and post-LT outcomes. RESULTS: Among 88,542 listed for LT patients (41.3% hepatitis C virus, 25.3% alcoholic liver disease, 22.3% nonalcoholic steatohepatitis, 11.1% hepatitis C virus/alcoholic liver disease), significant race/ethnicity-specific disparities were observed. Compared with non-Hispanic whites, Hispanics had a significantly lower risk of waitlist death [hazard ratio (HR)=0.84, 95% confidence interval (CI): 0.79-0.90, P<0.001]. Compared with non-Hispanic whites, significantly lower likelihood of receiving LT was observed in African Americans (HR=0.94, 95% CI: 0.91-0.98, P<0.001), Hispanics (HR=0.70, 95% CI: 0.68-0.73, P<0.001) and Asians (HR=0.74, 95% CI: 0.69-0.80, P<0.001). Compared with non-Hispanic whites, African Americans had a significantly higher risk of 5-year post-LT death (HR=1.31, 95% CI: 1.23-1.39, P<0.001). CONCLUSION: Among US adults awaiting LT, significant race/ethnicity-specific disparities in LT outcomes were observed. Despite evaluating an era after implementation of the Model for End-Stage Liver Disease, ethnic minorities continue to demonstrate a lower probability of receiving LT, and significantly higher risk of death post-LT in African Americans.

Race/Ethnicity-specific Disparities in In-Hospital Mortality and Hospital Charges Among Inflammatory Bowel Disease-related Hospitalizations in the United States.

GOAL: The goal of this study was to evaluate disparities in hospital outcomes among inflammatory bowel disease (IBD) related hospitalizations in the United States with a focus on ethnicity-specific disparities. BACKGROUND: IBD-related hospitalizations contribute to significant morbidity and health care economic burden. METHODS: IBD-related hospitalizations (identified with ICD-9) among US adults were evaluated using 2007 to 2013 Nationwide Inpatient Sample. In-hospital mortality between groups was evaluated using χ and multivariate logistic regression models, stratified by Crohn's disease (CD) and ulcerative colitis (UC). Inflation-adjusted total hospitalization charges were evaluated using Student t test and multivariate linear regression. RESULTS: Among 224,500 IBD-related hospitalizations (77.8% CD, 22.2% UC), overall in-hospital mortality was low (0.99% CD, 0.78% UC). Although Hispanic UC patients had a trend towards higher odds of in-hospital mortality compared with non-Hispanic whites (OR, 1.54; 95% CI, 0.95-2.51; P=0.08), no ethnicity-specific disparities were observed in CD. From 2007 to 2013, mean inflation-adjusted hospitalization charges increased from $29,632 to $41,484, P<0.01 in CD and from $31,449 to $43,128 in UC, P<0.01. On multivariate regression, hospitalization charges in Hispanic CD patients were $9302 higher (95% CI, 7910-10,694; P<0.01) and in Asian CD patients were $7665 higher (95% CI, 4859-10,451; P<0.001) than non-Hispanic whites. Compared with non-Hispanic white UC patients, Hispanics had $6910 (95% CI, $4623-$9197) higher charges and African Americans had $3551 lower charges (95% CI, -$5002 to -$2101). CONCLUSIONS: Although most IBD hospitalizations in the United States were among non-Hispanic whites, Hispanic patients with IBD had a trend towards higher in-hospital mortality and contributed to significantly higher hospitalization charges.

Updated Assessment of Colorectal Cancer Incidence in the U.S. by Age, Sex, and Race/Ethnicity.

BACKGROUND: Whether recent updates to colon cancer screening guidelines benefit men and women or all race/ethnic groups equally is not clear. AIMS: The aim of this study is to evaluate age-, sex-, and race/ethnicity-specific trends in CRC incidence and disease burden among adults. METHODS: Using 2000-2014 surveillance, epidemiology, and end results database, annual CRC incidence (per 100,000 persons/year) among U.S. adults was categorized by age (using 10-year age intervals) and stratified by sex and race/ethnicity. Comparison of incidence between groups utilized the z-statistic with p < 0.05 indicating statistical significance. RESULTS: Overall, CRC incidence was the highest among patients aged ≥ 80 years (330.8 per 100,000 persons/year), which was significantly higher in men versus women (377.2 vs. 304.3 per 100,000 persons/year, p < 0.001). CRC incidence in younger individuals was 22.8 per 100,000 persons/year (age 40-49) and 6.8 per 100,000 persons/year (age 30-39). CRC incidence was significantly higher in African Americans compared to non-Hispanic whites. From 2000 to 2014, CRC incidence declined in all age groups over age 60, remained stable in age 50-59, and demonstrated proportional increases in among age 20-49 years. While CRC incidence in all race/ethnic groups aged ≥ 60 years declined, Hispanics aged 50-59 increased 21.9%, but remained stable in other race/ethnic groups. Race/ethnicity-specific disparities in CRC incidence in patients aged 20-49 were also observed. CONCLUSIONS: While CRC incidence has declined among U.S. adults aged ≥ 60, increasing incidence among patients aged < 50 is concerning. Identifying risk factors among "average-risk" patients is needed to better implement targeted screening of individuals not currently meeting CRC screening criteria.

Expanded access with intravenous hydroxypropyl-ß-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis.

BACKGROUND: Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPßPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPßCD has been administered to NPC patients with approved INDs globally since 2009. RESULTS: Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPßCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPßCD following on average 13 months of IV HPßCD. Several patients transitioned to an alternate HPßCD. Moderately affected NPC patients treated with HPßCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. CONCLUSIONS: These expanded access data support the safety and potential benefit of systemic IV administration of HPßCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPßCD in NPC patients.

The Impact of Ethnic Subgroups on Tumor Stage at Diagnosis, Treatment Received, and Long-Term Survival Among Asian Adults With Hepatocellular Carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) outcomes among Asians may differ by the Asian ethnic subgroup. We aim to evaluate the impact of the Asian ethnic subgroup on HCC tumor stage, treatment received, and overall survival among US adults. METHODS: Using the 2004-2012 Surveillance, Epidemiology, and End Results U.S. cancer registry, we retrospectively evaluated disparities in HCC tumor stage at diagnosis, HCC treatment received, and overall survival among Asian adults, stratified by Asian ethnic subgroups. Multivariate regression models evaluated the independent impact of Asian ethnic subgroups on the HCC tumor stage at diagnosis, treatment received, and overall long-term survival. RESULTS: Among 8160 Asians with HCC, Southeast Asian (SEA) patients accounted for 26% of all HCC, followed by Chinese (CH) (22%), and Filipinos (FP) (14.0%) patients. Japanese (JP) patients were significantly older than those of the other subgroups (mean 71.1, SD 10.8, P < 0.01). When evaluating HCC stage, FP patients were less likely to have localized HCC and less likely to have HCC within the Milan criteria than CH HCC patients. When evaluating HCC treatment, pacific islanders (PI), FP and SEA patients were significantly less likely to any receive HCC treatment than CH patients. Overall five-year HCC survival was highest among CH HCC patients (33.1%) and lowest among FP (19.9%) and JP patients (22.0%). CONCLUSION: Among Asians with HCC in the US, significant disparities among Asian ethnic subgroups exist. More advanced disease was seen among FP patients, less HCC treatment was seen among FP and SEA patients, and significantly higher mortality was seen among FP, SEA, and JP patients with HCC.

Assessing the safety of beta-blocker therapy in cirrhosis patients with ascites: A meta-analysis.

BACKGROUND & AIMS: Beta-blocker therapy is effective at reducing risks of variceal bleeding. However, beta-blockers may detrimentally exacerbate the underlying haemodynamic changes in cirrhosis. A systematic review and meta-analysis was performed to evaluate impact of beta-blockers on all-cause mortality among cirrhosis patients with ascites. METHODS: A literature search identified studies that evaluated beta-blocker vs no beta-blocker therapy in cirrhosis patients with ascites. The primary outcome was all-cause mortality with subcohort analysis of patients with refractory or severe ascites. Quality of observational studies was assessed with Newcastle-Ottawa Scale and overall certainty of the evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Eight observational studies, representing 3627 cirrhosis patients with ascites (1630 treated with beta-blockers and 1997 not treated), were included. Pooled all-cause mortality was 38.6% in beta-blocker group vs 42.2% in no beta-blocker group (RR 0.93, 95% CI 0.77-1.13, χ2  = 54.03, I2  = 87%). Subcohort analysis of cirrhosis patients with refractory or severe ascites demonstrated 33.3% mortality in beta-blocker group vs 32.1% in no beta-blocker group (RR 0.99, 95% CI 0.70-1.40, χ2  = 32.99, and I2  = 82%). Three studies were good quality and five studies were fair quality. GRADE rating was 'very low' certainty of evidence, given concern for bias and inconsistency stemming from significant heterogeneity. CONCLUSION: No significant increase in all-cause mortality was observed in cirrhosis patients with ascites treated with beta-blockers. However, given the low certainty of the evidence, high quality prospective studies are needed.

Low Rates of Retention Into Hepatocellular Carcinoma (HCC) Surveillance Program After Initial HCC Screening.

GOALS: To evaluate rates and predictors of retention into hepatocellular carcinoma (HCC) surveillance beyond initial screening among underserved cirrhosis patients. BACKGROUND: Although initial HCC screening among cirrhosis patients remains low, few studies have evaluated retention to HCC surveillance beyond initial screening. METHODS: We retrospectively evaluated all consecutive adults with cirrhosis from 2014 to 2017 at a single underserved safety net hospital system to determine rates of HCC surveillance at 6 months and at 1 year beyond initial screening. Rates of HCC surveillance was stratified by sex, race/ethnicity, and etiology of liver disease. Multivariate Cox proportional hazards models evaluated predictors of retention into HCC surveillance. RESULTS: Among 235 cirrhosis patients [hepatitis C virus: 35.7%, hepatitis B virus (HBV): 15.7%, alcoholic cirrhosis: 36.2%, nonalcoholic steatohepatitis (NASH): 8.1%], mean age of cirrhosis diagnosis was 54.2±8.9 years. Overall, 74.8% received initial screening within 1 year of cirrhosis diagnosis. Among those who completed initial screening, 47.6% [95% confidence interval (CI), 41.4-54.2) received second surveillance within 1 year. On multivariate analyses, patients with NASH and HBV were significantly more likely to receive second HCC surveillance compared with hepatitis C virus, HBV (hazard ratio, 2.32; 95% CI, 1.18-4.56; P=0.014) and NASH (hazard ratio, 2.49; 95% CI, 1.22-5.11; P=0.012). No sex or race-specific/ethnicity-specific differences in HCC surveillance retention were observed. CONCLUSIONS: Although overall rates of initial HCC screening among cirrhosis patients is nearly 75%, retention into continued HCC surveillance is poor, with less than half of patients undergoing subsequent HCC surveillance. Cirrhosis patients with HBV and NASH were more likely to be retained into HCC surveillance.

Low Rates of Linkage and Retention Into Care Among Patients With Chronic HBV Infection.

Successful linkage and retention of newly diagnosed hepatitis B virus (HBV) patients is critical for disease monitoring. Existing studies have demonstrated significant gaps in the HBV care continuum among U.S. veterans1 and have mostly focused on adherence to laboratory testing or initial linkage. However, retention is especially important, given that decisions to start antiviral therapies are often not made until subsequent evaluation, and studies report high rates of becoming treatment-eligible among patients who were not eligible at initial evaluation.2 Given the existing system and socioeconomic barriers in access to care, understanding contributors to gaps and delays in HBV linkage and retention among safety-net populations is critical. We aim to evaluate prevalence and predictors of linkage and retention among HBV patients at an urban safety-net hospital.

Improved liver transplant waitlist mortality and lower risk of disease progression among chronic hepatitis C patients awaiting liver transplantation after the introduction of direct-acting antiviral therapies in the United States.

Direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection achieve high cure rates, reducing HCV-related disease progression to cirrhosis and hepatocellular carcinoma. We aim to evaluate the impact of DAAs on US liver transplant (LT) waitlist outcomes. We retrospectively evaluated US adults (age ≥18) with and without chronic HCV listed for LT before and after the widespread use of sofosbuvir, allowing a 6-month period after approval (Era 1: 1/1/2002-5/31/2014 vs Era 2: 6/1/2014-12/31/2016) using the United Network for Organ Sharing registry. Overall, LT waitlist survival and likelihood of receiving LT were evaluated with multivariate Cox regression models. From 2002 to 2016, 158 045 patients were listed for LT. While the number of patients listed for HCV has been decreasing since 2012, the proportion of HCV patients with concurrent HCC is increasing by 3.33% per year (R2 : 0.99, P < 0.001 by simple linear regression). While there was no difference in likelihood of LT between HCV and non-HCV patients, those listed in Era 2 had lower likelihood of LT (HR: 0.91, P < 0.001), more pronounced in the HCV cohort (HR: 0.83, P < 0.001) compared to the non-HCV cohort (HR: 0.93, P < 0.001). Compared to non-HCV patients, higher waitlist mortality was seen in HCV patients in Era 1 (HR: 1.08, P < 0.001) but not in Era 2 (HR: 1.02, P = 0.75). Since the introduction of DAAs for HCV treatment, number of patients with HCV listed for LT has declined. In the post-DAA era, HCV patients on the LT waitlist had improved waitlist mortality.

High Prevalence of Cirrhosis at Initial Presentation Among Safety-Net Adults with Chronic Hepatitis B Virus Infection.

BACKGROUND AND AIMS: Delays in diagnosis of chronic hepatitis B virus infection (HBV) may be more common among underserved safety-net populations, contributing to more advanced disease at presentation. We aim to evaluate rates of and predictors of cirrhosis and cirrhosis-related complications among adults with chronic HBV. METHODS: We retrospectively evaluated consecutive chronic HBV adults from gastroenterology clinics from July 2014 to May 2016 at a community-based safety-net hospital. Prevalence of cirrhosis or cirrhosis-related complications (ascites, variceal bleeding, hepatic encephalopathy (HE), hepatocellular carcinoma (HCC)) at initial presentation was stratified by sex and race/ethnicity. Predictors of cirrhosis or cirrhosis-related complications at presentation were evaluated with multivariate logistic regression. RESULTS: Among 329 chronic HBV patients (mean age 49.1 years, 55.3% male, 66.5% Asian, 18.6% HBeAg positive) 27.7% had cirrhosis at presentation, 4.3% ascites, 3.7% variceal bleeding, 4.9% HE, and 4.0% HCC. Compared to women, men were more likely to have cirrhosis (34.6% vs. 19.1%, P < 0.01) and variceal bleeding (5.6% vs. 1.4%, P < 0.05) at presentation. On multivariate regression, older age at presentation (OR, 1.04; 95% CI, 1.01-1.07; P = 0.003) and positive HBeAg (OR, 2.57; 95% CI, 1.20-5.51; P = 0.015) were associated with higher odds of cirrhosis at presentation, whereas men had a non-significant trend toward higher odds of cirrhosis (OR, 1.88; 95% CI, 0.99-3.58; P = 0.055). CONCLUSION: Among adults with chronic HBV at an ethnically diverse safety-net hospital system, nearly 30% of patients had cirrhosis at initial presentation, with the greatest risk seen among patients of male sex, older age, and with positive HBeAg.

Advanced Hepatocellular Carcinoma Tumor Stage at Diagnosis in the 1945-1965 Birth Cohort Reflects Poor Use of Hepatocellular Carcinoma Screening.

Individuals from the 1945-1965 birth cohort account for the majority of hepatocellular carcinoma (HCC) cases in the United States. Understanding trends in HCC among this birth cohort is vital given the increasing burden of chronic liver disease among this group. We retrospectively evaluated trends and disparities in HCC tumor stage at the time of diagnosis among the 1945-1965 birth cohort in the United States using the Surveillance, Epidemiology, and End Results (SEER) cancer registry. Tumor stage at the time of HCC diagnosis was assessed using Milan criteria and SEER HCC staging systems. Among 38,045 patients with HCC within the 1945-1965 birth cohort (81.6% male, 50.1% non-Hispanic white, 16.2% African American, 12.6% Asian, 19.8% Hispanic), 66.2% had Medicare or commercial insurance, 27.2% had Medicaid, and 6.6% were uninsured. During the period 2004-2006 to 2013-2014, the number of patients with HCC from the 1945-1965 birth cohort increased by 58.7% (5.9% increase per year). While the proportion of patients with HCC within the Milan criteria increased with time (36.4% in 2003-2006 to 46.3% in 2013-2014; P < 0.01), less than half were within the Milan criteria. On multivariate analysis within the Milan criteria, men were 12% less likely to have HCC compared to women, and African Americans were 27% less likely to have HCC compared to non-Hispanic whites (odds ratio, 0.73; 95% confidence interval, 0.68-0.78; P < 0.01). Conclusion: From 2004 to 2014, the burden of newly diagnosed HCC among the 1945-1965 birth cohort increased by 5.9% per year. While improvements in earlier staged HCC at diagnosis were observed, the majority of patients with HCC among the 1945-1965 birth cohort were beyond the Milan criteria at diagnosis; this may reflect poor utilization or suboptimal performance of HCC screening tests.

Clostridium difficile co-infection in inflammatory bowel disease is associated with significantly increased in-hospital mortality.

OBJECTIVE: Inflammatory bowel disease (IBD) patients with Clostridium difficile co-infection (CDCI) have an increased risk of morbidity and mortality. We aim to evaluate the impact of CDCI on in-hospital outcomes among adults with IBD hospitalized in the USA. PATIENTS AND METHODS: Using the 2007-2013 Nationwide Inpatient Sample, hospitalizations among US adults with Crohn's disease (CD), ulcerative colitis (UC) and CDCI were identified using ICD-9 coding. Hospital charges, hospital length of stay (LOS), and in-hospital mortality was stratified by CD and UC and compared using χ-testing and Student's t-test. Predictors of hospital charges, LOS, and in-hospital mortality were evaluated with multivariate regression models and were adjusted for age, sex, race/ethnicity, year, insurance status, hospital characteristics, and CDCI. RESULTS: Among 224 500 IBD hospitalizations (174 629 CD and 49 871 UC), overall prevalence of CDCI was 1.22% in CD and 3.41% in UC. On multivariate linear regression, CDCI was associated with longer LOS among CD [coefficient: 5.30, 95% confidence interval (CI): 4.61-5.99, P<0.001] and UC (coefficient 4.08, 95% CI: 3.54-4.62, P<0.001). Higher hospital charges associated with CDCI were seen among CD (coefficient: $35 720, 95% CI: $30 041-$41 399, P<0.001) and UC (coefficient: $26 009, 95% CI: $20 970-$31 046, P<0.001). On multivariate logistic regression, CDCI was associated with greater risk of in-hospital mortality (CD: odds ratio: 2.74, 95% CI: 1.94-3.87, P<0.001; UC: OR: 5.50, 95% CI: 3.83-7.89, P<0.001). CONCLUSION: Among US adults with CD and UC related hospitalizations, CDCI is associated with significantly greater in-hospital mortality and greater healthcare utilization.

Low serum high density lipoprotein is associated with the greatest risk of metabolic syndrome among U.S. adults.

AIMS: Better understanding risk factors for metabolic syndrome (MetS) will allow early targeted intervention to mitigate long term risk. We aim to determine the disparate impact of each individual MetS component on overall risk of developing MetS, stratified by sex, race/ethnicity, and age. METHODS: Using data from the 2003-2014 National Health and Nutrition Examination Survey (NHANES), MetS prevalence among adults (age ≥18) was stratified by sex, race/ethnicity, age, and by individual MetS components (e.g. hypertension (HTN), diabetes mellitus (DM), waist circumference, serum high density lipoprotein (HDL), serum triglycerides (TG). Mutlivariate logistic regression models were used to evaluate the disparate impact of each risk factor on MetS risk. RESULTS: Overall MetS prevalence was 33.3%, with the highest prevalence among older individuals, among women, and among Hispanics. When stratified by each individual component of MetS, low serum HDL was the strongest predictor of MetS risk overall and among both men and women, among all race/ethnic groups, and among all age groups (overall: OR 20.1, 95% CI 18.6-21.7). While presence of DM also increased an individual's risk of MetS, DM was the weakest predictor of MetS. CONCLUSIONS: Among U.S. adults, low serum HDL carries the strongest risk in predicting development of MetS. This effect was seen among men and women, among all race/ethnic groups, and among all age groups, highlighting the importance of low serum HDL as a marker of MetS risk.

African-Americans with Cirrhosis Are Less Likely to Receive Endoscopic Variceal Screening Within One Year of Cirrhosis Diagnosis.

BACKGROUND: Esophageal variceal hemorrhage is a complication of cirrhosis that carries high mortality, and can be reduced with timely endoscopic variceal screening and treatment. AIM: We aim to evaluate overall rates of and disparities in receipt of endoscopic variceal screening among an ethnically diverse urban safety-net hospital. METHODS: All consecutive adults with cirrhosis (7/1/2014 to 12/31/2015) were retrospectively evaluated to determine the rates of receiving esophageal variceal screening within 6 months and within 1 year after cirrhosis diagnosis. Race-/ethnicity-specific differences in rates of variceal screening were compared using chi-square testing and multivariate regression methods. RESULTS: Among 157 patients (65% male, 33.8% Hispanic, 22.3% African-American, 44.6% alcoholic liver disease, 29.9% chronic HCV), 56.8% received variceal screening within 6 months and 65.8% received screening within 1 year. Compared to non-Hispanic whites with cirrhosis, African-Americans (52.2 vs. 76.2%, p < 0.05), Asians (57.1 vs. 76.2%, p < 0.05), and Hispanics (43.9 vs. 76.2%, p < 0.05) were all significantly less likely to receive endoscopic variceal screening within 6 months after cirrhosis diagnosis. On multivariate analysis, African-Americans with cirrhosis were 66% less likely to receive variceal screening compared to non-Hispanic whites (HR 0.34, 95% CI 0.15-0.77, p < 0.01). CONCLUSION: Among adults with cirrhosis at a community-based safety-net hospital system, overall first-time variceal screening remains suboptimal. African-Americans were the least likely to receive timely variceal screening. These findings are particularly concerning given the significant barriers that ethnic minorities and safety-net populations already face in timely access to medical care.

A Pilot Program Integrating Hepatitis B Virus (HBV) Screening into an Outpatient Endoscopy Unit Improves HBV Screening Among an Ethnically Diverse Safety-Net Hospital.

BACKGROUND: Safety-net hospitals are enriched in ethnic minorities and provide opportunities for high-impact hepatitis B virus (HBV) screening. AIM: We aim to evaluate the impact of a pilot program integrating HBV screening into outpatient endoscopy among urban safety-net populations. METHODS: From July 2015 to May 2017, consecutive adults undergoing outpatient endoscopy were prospectively assessed for HBV screening eligibility using US Preventative Services Task Force guidelines. Rates of prior HBV screening were assessed, and those eligible but not screened were offered HBV testing. Multivariate logistic regression models evaluated predictors of test acceptance among eligible patients. RESULTS: Among 1557 patients (47.1% male, 69.4% foreign born), 65.1% were eligible for HBV screening, among which 24.5% received prior screening. In our pilot screening program in the endoscopy unit, 91.4% (n = 855) of eligible patients accepted HBV testing. However, only 55.3% (n = 415) of those that accepted actually completed HBV testing. While there was a trend toward higher rates of test acceptance among African-Americans compared to non-Hispanic whites (OR 3.31, 95% CI 0.96-11.38, p = 0.06), no other sex-specific or race/ethnicity-specific disparities in HBV test acceptance were observed. Among those who completed HBV testing, we identified 10 new patients with chronic HBV (2.4% prevalence). Only 24.5% of eligible patients received prior HBV screening among our cohort. CONCLUSIONS: Our pilot program integrating HBV screening into outpatient endoscopy successfully tested an additional 415 patients, improving overall HBV screening from 24.5 to 75.6%. Integrating HBV testing into non-traditional settings has potential to bridge the gap in HBV screening among safety-net systems.

Sub-optimal Testing and Awareness of HCV and HBV Among High Risk Individuals at an Underserved Safety-Net Hospital.

Sub-optimal screening for chronic hepatitis C virus (HCV) and chronic hepatitis B virus (HBV) among high risk groups delays diagnosis and treatment. We aimed to evaluate overall rates of HCV and HBV screening and patient knowledge of their testing result. Adults age ≥18 years undergoing elective outpatient endoscopy at a large, urban safety-net hospital from July 2015 to July 2016 were prospectively evaluated to determine rates of HCV and HBV testing, the results of those completed tests, and patient knowledge of test results among high risk individuals (as determined by U.S. Preventative Services Task Force). Among 1125 patients (52.3% male, 70.4% foreign-born), 66.5% were high risk for chronic HCV; only 30.9% received prior testing. 14.7% had positive chronic HCV infection. Patients born in the 1945-1965 cohort were more likely to have received prior HCV testing compared to those born outside of this cohort (32.7 vs. 16.9%, p = 0.01). Among patients who received HCV screening, 29.3% were aware of test results. Overall, 61.6% were high risk for chronic HBV; only 25.1% received prior testing. 4.1% were positive for chronic HBV. Compared to Caucasians, Asians (19.0 vs. 44.4%, p < 0.001) and Hispanics (20.0 vs. 44.4%, p < 0.001) were less likely to have previous HBV testing. Among patients who received prior HBV screening, 18.4% were aware of test results. Less than one-third of high risk patients received HCV and HBV screening among an ethnically diverse safety-net population. Equally low rates of patient knowledge of testing results were observed.