Porcine-derived pancreatic enzyme replacement therapy may be linked to chronic hepatitis E virus infection in cystic fibrosis lung transplant recipients.

OBJECTIVES: In high-income countries hepatitis E virus (HEV) is an uncommonly diagnosed porcine-derived zoonoses. After identifying disproportionate chronic HEV infections in persons with cystic fibrosis (pwCF) postlung transplant, we sought to understand its epidemiology and potential drivers. DESIGN: All pwCF post-transplant attending our regional CF centre were screened for HEV. HEV prevalence was compared against non-transplanted pwCF and with all persons screened for suspected HEV infection from 2016 to 2022 in Alberta, Canada. Those with chronic HEV infection underwent genomic sequencing and phylogenetic analysis. Owing to their swine derivation, independently sourced pancreatic enzyme replacement therapy (PERT) capsules were screened for HEV. RESULTS: HEV seropositivity was similar between transplanted and non-transplanted pwCF (6/29 (21%) vs 16/83 (19%); p=0.89). Relative to all other Albertans investigated for HEV as a cause of hepatitis (n=115/1079, 10.7%), pwCF had a twofold higher seropositivity relative risk and this was four times higher than the Canadian average. Only three chronic HEV infection cases were identified in all of Alberta, all in CF lung transplant recipients (n=3/29, 10.3%). Phylogenetics confirmed cases were unrelated porcine-derived HEV genotype 3a. Ninety-one per cent of pwCF were taking PERT (median 8760 capsules/person/year). HEV RNA was detected by RT-qPCR in 44% (47/107) of PERT capsules, and sequences clustered with chronic HEV cases. CONCLUSION: PwCF had disproportionate rates of HEV seropositivity, regardless of transplant status. Chronic HEV infection was evident only in CF transplant recipients. HEV may represent a significant risk for pwCF, particularly post-transplant. Studies to assess HEV incidence and prevalence in pwCF, and potential role of PERT are required.

Spending on nucleos(t)ide analogues for hepatitis B in medicaid beneficiaries: 2012-2021.

INTRODUCTION AND OBJECTIVES: Treatment of chronic hepatitis B (CHB) with nucelos(t)ide analogues (NA) can improve outcomes, but NA treatment is expensive for insurance plans. MATERIALS AND METHODS: The Centers for Medicare & Medicaid Services database was assessed from 2012 to 2021 to assess the use of NA for CHB in patients on Medicaid. Data extracted included the number of claims, units, and costs of each agent stratified by originator and generic. RESULTS: Over the study period, 1.9 billion USD was spent on NA, with spending peaking in 2016 at $289 million US, which has subsequently decreased. Lower expenditures since 2016 have been associated with increased use of generics. The use of generic tenofovir or entecavir led to savings of $669 million US over the study period. CONCLUSIONS: Increased generic use has significantly reduced expenditures for NA drugs; policy shifts towards generic drug use may help with sustainability.

A randomized-controlled trial of SOF/VEL/VOX with or without ribavirin for retreatment of chronic hepatitis C.

BACKGROUND & AIMS: The combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) is recommended for the retreatment of patients with HCV infection in whom previous direct-acting antiviral (DAA) treatment failed. However, whether ribavirin further increases the therapeutic efficacy of SOF/VEL/VOX retreatment remains unclear. We aimed to test this hypothesis in a randomized-controlled trial. METHODS: We randomly assigned 315 patients with DAA treatment failure from five Egyptian sites into two groups. Group A (n = 158) received SOF/VEL/VOX for 12 weeks, and group B (n = 157) received SOF/VEL/VOX + weight-based ribavirin for 12 weeks. Therapeutic efficacy was defined as SVR12 (sustained virologic response 12 weeks after treatment end). Safety and tolerability were evaluated by monitoring treatment-related adverse events (AEs) and laboratory abnormalities. RESULTS: Males comprised 53.9% of group A and 57.1% of group B (p = 0.58); mean ages were 51.8 and 47.3 years in group A and B, respectively. Seventeen patients in each group were lost to follow-up. SVR12 rates were 87.3% (138/158) by intention-to-treat analysis and 97.8% (138/141) by per-protocol analysis in group A; and 87.9% (138/157) and 98.5% (138/140), respectively, in group B (p = n.s. for intention-to-treat and per-protocol analyses). Both regimens were well-tolerated, with no deaths and only one serious AE (anemia) in group B, which required ribavirin discontinuation. Fifty-five patients in group A vs. 77 in group B experienced any AE (p = 0.002). CONCLUSION: This randomized-controlled trial showed equal, high efficacy of both regimens for the retreatment of previous DAA failures, although ribavirin was associated with more AEs. Therefore SOF/VEL/VOX monotherapy should be the preferred retreatment strategy. CLINCIALTRIALS. GOV NUMBER: NCT04695769. IMPACT AND IMPLICATIONS: HCV treatment guidelines recommend retreatment of direct-acting antiviral (DAA) treatment failures with the combination of sofosbuvir, velpatasvir and voxilaprevir (SOF/VEL/VOX) for 12 weeks. However, whether ribavirin exerts an additional/synergistic effect remains unclear. The present study confirmed that SOF/VEL/VOX without ribavirin is the best regimen for retreatment of DAA treatment failures, and thus will help guide clinicians caring for patients who are not cured with a first course of DAA therapy.

Factors Associated With Geographic Disparities in Gastrointestinal Cancer Mortality in the United States.

BACKGROUND & AIMS: Significant geographic variability in gastrointestinal (GI) cancer-related death has been reported in the United States. We aimed to evaluate both modifiable and nonmodifiable factors associated with intercounty differences in mortality due to GI cancer. METHODS: Data from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research platform were used to calculate county-level mortality from esophageal, gastric, pancreatic, and colorectal cancers. Multivariable linear regression models were fit to adjust for county-level covariables, considering both patient (eg, sex, race, obesity, diabetes, alcohol, and smoking) and structural factors (eg, specialist density, poverty, insurance prevalence, and colon cancer screening prevalence). Intercounty variability in GI cancer-related mortality explained by these covariables was expressed as the multivariable model R2. RESULTS: There were significant geographic disparities in GI cancer-related county-level mortality across the US from 2010-2019 with the ratio of mortality between 90th and 10th percentile counties ranging from 1.5 (pancreatic) to 2.1 (gastric cancer). Counties with the highest 5% mortality rates for gastric, pancreatic, and colorectal cancer were primarily in the Southeastern United States. Multivariable models explained 43%, 61%, 14%, and 39% of the intercounty variability in mortality rates for esophageal, gastric, pancreatic, and colorectal cancer, respectively. Cigarette smoking and rural residence (independent of specialist density) were most strongly associated with GI cancer-related mortality. CONCLUSIONS: Both patient and structural factors contribute to significant geographic differences in mortality from GI cancers. Our findings support continued public health efforts to reduce smoking use and improve care for rural patients, which may contribute to a reduction in disparities in GI cancer-related death.

Epidemiologic Burden and Treatment of Chronic Symptomatic Functional Bowel Disorders in the United States: A Nationwide Analysis.

BACKGROUND & AIMS: Functional bowel disorders (FBDs) are the most common gastrointestinal problems managed by physicians. We aimed to assess the burden of chronic symptomatic FBDs on ambulatory care delivery in the United States and evaluate patterns of treatment. METHODS: Data from the National Ambulatory Medical Care Survey were used to estimate annual rates and associated costs of ambulatory visits for symptomatic irritable bowel syndrome, chronic functional abdominal pain, constipation, or diarrhea. The weighted proportion of visits associated with pharmacologic and nonpharmacologic (stress/mental health, exercise, diet counseling) interventions were calculated, and predictors of treatment strategy were evaluated in multivariable multinomial logistic regression. RESULTS: From 2007-2015, approximately 36.9 million (95% CI, 31.4-42.4) weighted visits in patients of non-federally employed physicians for chronic symptomatic FBDs were sampled. There was an annual weighted average of 2.7 million (95% CI, 2.3-3.2) visits for symptomatic irritable bowel syndrome/chronic abdominal pain, 1.0 million (95% CI, 0.8-1.2) visits for chronic constipation, and 0.7 million (95% CI, 0.5-0.8) visits for chronic diarrhea. Pharmacologic therapies were prescribed in 49.7% (95% CI, 44.7-54.8) of visits compared to nonpharmacologic interventions in 19.8% (95% CI, 16.0-24.2) of visits (P < .001). Combination treatment strategies were more likely to be implemented by primary care physicians and in patients with depression or obesity. The direct annual cost of ambulatory clinic visits alone for chronic symptomatic FBDs is approximately US$358 million (95% CI, 233-482 million). CONCLUSIONS: The management of chronic symptomatic FBDs is associated with considerable health care resource use and cost. There may be an opportunity to improve comprehensive FBD management because fewer than 1 in 5 ambulatory visits include nonpharmacologic treatment strategies.

Impact of the COVID-19 Pandemic on Hospitalizations for Alcoholic Hepatitis or Cirrhosis in Alberta, Canada.

BACKGROUND & AIMS: Coronavirus disease 2019 (COVID-19) pandemic lockdown and restrictions had significant disruption to patient care. We aimed to evaluate the impact of COVID-19 restrictions on hospitalizations of patients with alcoholic and nonalcoholic cirrhosis as well as alcoholic hepatitis (AH) in Alberta, Canada. METHODS: We used validated International Classification of Diseases (ICD-9 and ICD-10) coding algorithms to identify liver-related hospitalizations for nonalcoholic cirrhosis, alcoholic cirrhosis, and AH in the province of Alberta between March 2018 and September 2020. We used the provincial inpatient discharge and laboratory databases to identify our cohorts. We used elevated alanine aminotransferase or aspartate aminotransferase, elevated international normalized ratio, or bilirubin to identify AH patients. We compared COVID-19 restrictions (April-September 2020) with prior study periods. Joinpoint regression was used to evaluate the temporal trends among the 3 cohorts. RESULTS: We identified 2916 hospitalizations for nonalcoholic cirrhosis, 2318 hospitalizations for alcoholic cirrhosis, and 1408 AH hospitalizations during our study time. The in-hospital mortality rate was stable in relation to the pandemic for alcoholic cirrhosis and AH. However, nonalcoholic cirrhosis patients had lower in-hospital mortality rate after March 2020 (8.5% vs 11.5%; P = .033). There was a significant increase in average monthly admissions in the AH cohort (22.1/10,000 admissions during the pandemic vs 11.6/10,000 admissions before March 2020; P < .001). CONCLUSIONS: Before and during COVID-19 monthly admission rates were stable for nonalcoholic and alcoholic cirrhosis; however, there was a significant increase in AH admissions. Because alcohol sales surged during the pandemic, future impact on alcoholic liver disease could be detrimental.

Trends in the Economic Burden of Chronic Liver Diseases and Cirrhosis in the United States: 1996-2016.

INTRODUCTION: The management of chronic liver diseases (CLDs) and cirrhosis is associated with substantial healthcare costs. We aimed to estimate trends in national healthcare spending for patients with CLDs or cirrhosis between 1996 and 2016 in the United States. METHODS: National-level healthcare expenditure data developed by the Institute for Health Metrics and Evaluations for the Disease Expenditure Project and prevalence of CLDs and cirrhosis derived from the Global Burden of Diseases Study were used to estimate temporal trends in inflation-adjusted US healthcare spending, stratified by setting of care (ambulatory, inpatient, emergency department, and nursing care). Joinpoint regression was used to evaluate temporal trends, expressed as annual percent change (APC) with 95% confidence intervals (CIs). Drivers of change in spending for ambulatory and inpatient services were also evaluated. RESULTS: Total expenditures in 2016 were $32.5 billion (95% CI, $27.0-$40.4 billion). Over 65% of spending was for inpatient or emergency department care. From 1996 to 2016, there was a 4.3%/year (95% CI, 2.8%-5.8%) increase in overall healthcare spending for patients with CLDs or cirrhosis, driven by a 17.8%/year (95% CI, 14.5%-21.6%) increase in price and intensity of hospital-based services. Total healthcare spending per patient with CLDs or cirrhosis began decreasing after 2008 (APC -1.7% [95% CI, -2.1% to -1.2%]), primarily because of reductions in ambulatory care spending (APC -9.1% [95% CI, -10.7% to -7.5%] after 2011). DISCUSSION: Healthcare expenditures for CLDs or cirrhosis are substantial in the United States, driven disproportionately by acute care in-hospital spending.

Sexual Dysfunction and Sex Hormone Abnormalities in Patients With Cirrhosis: Review of Pathogenesis and Management.

Healthy sexual function is important to maintain a good quality of life but is frequently impaired in patients with cirrhosis. The degree of sexual dysfunction appears to be linked with the degree of hepatic dysfunction. In men, sexual dysfunction can be related to the hyperestrogenism of portal hypertension and/or to decreased testosterone resulting from testicular dysfunction. In women, suppression of the hypothalamic-pituitary-gonadal axis appears to be a principal contributor, with no significant effect of portal hypertension. There is also a huge psychological barrier to break through as there is a component of depression in many patients with cirrhosis. Sexual dysfunction is often underdiagnosed in the cohort with cirrhosis. Management of sexual disorders in patients with cirrhosis can be challenging as they are often multifactorial. A multidisciplinary approach is key in managing these patients. We review the current literature on the pathogenesis of sexual dysfunction in patients with cirrhosis and propose a stepwise algorithm to better manage these patients.

The cirrhosis care Alberta (CCAB) protocol: implementing an evidence-based best practice order set for the management of liver cirrhosis - a hybrid type I effectiveness-implementation trial.

BACKGROUND: Liver cirrhosis is a leading cause of morbidity, premature mortality and acute care utilization in patients with digestive disease. In the province of Alberta, hospital readmission rates for patients with cirrhosis are estimated at 44% at 90 days. For hospitalized patients, multiple care gaps exist, the most notable stemming from i) the lack of a structured approach to best practice care for cirrhosis complications, ii) the lack of a structured approach to broader health needs and iii) suboptimal preparation for transition of care into the community. Cirrhosis Care Alberta (CCAB) is a 4-year multi-component pragmatic trial which aims to address these gaps. The proposed intervention is initiated at the time of hospitalization through implementation of a clinical information system embedded electronic order set for delivering evidence-based best practices under real-world conditions. The overarching objective of the CCAB trial is to demonstrate effectiveness and implementation feasibility for use of the order set in routine patient care within eight hospital sites in Alberta. METHODS: A mixed methods hybrid type I effectiveness-implementation design will be used to evaluate the effectiveness of the order set intervention. The primary outcome is a reduction in 90-day cumulative length of stay. Implementation outcomes such as reach, adoption, fidelity and maintenance will also be evaluated alongside other patient and service outcomes such as readmission rates, quality of care and cost-effectiveness. This theory-based trial will be guided by Normalization Process Theory, Consolidated Framework on Implementation Research (CFIR) and the Reach-Effectiveness-Adoption-Implementation-Maintenance (RE-AIM) Framework. DISCUSSION: The CCAB project is unique in its breadth, both in the comprehensiveness of the multi-component order set and also for the breadth of its roll-out. Lessons learned will ultimately inform the feasibility and effectiveness of this approach in "real-world" conditions as well as adoption and adaptation of these best practices within the rest of Alberta, other provinces in Canada, and beyond. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04149223, November 4, 2019.

Nationwide estimates and risk factors of hospital readmission in patients with cirrhosis in the United States.

BACKGROUND: The burden of cirrhosis on the healthcare system is substantial and growing. Our objectives were to estimate the readmission rates and hospitalization costs as well as to identify risk factors for 90-day readmission in patients with cirrhosis. METHODS: We conducted a weighted analysis of the 2014 Nationwide Readmission Database to identify adult patients with cirrhosis-related complications in the United States and assessed readmission rates at 30, 60 and 90 days post-index hospitalization. Predictors of 90-day readmissions were identified using weighted regression models adjusting for patient and hospital characteristics; the national estimate of hospitalization costs was also calculated. RESULTS: Of the 58 954 patients admitted with cirrhosis-related complications in 2014, 14 910 (25%) were readmitted within 90 days because of cirrhosis-related complications. The main causes of readmission were ascites (56%), hepatic encephalopathy (47%) and bleeding oesophageal varices (9%). Independent predictors of 90-day readmissions were male sex (adjusted OR [aOR]: 1.08, 95% CI, 1.04-1.13), age <60 (aOR: 1.27, 95% CI, 1.22-1.32), privately insured (aOR: 0.74, 95% CI, 0.70-0.77), having ≥3 comorbid conditions (aOR: 1.27, 95% CI, 1.14-1.42) and being discharged against medical advice (aOR: 1.41, 95% CI, 1.25-1.59). The weighted cumulative national cost estimate of the index admission was $1.8 billion, compared to $0.5 billion for readmission. CONCLUSIONS: A quarter of patients admitted with cirrhosis-related complications were readmitted within 90 days, representing a significant economic burden related to readmission of this population. Interventions and resource allocations to reduce readmission rates among cirrhotic patients is critical.

Cost Effectiveness of Early Insertion of Transjugular Intrahepatic Portosystemic Shunts for Recurrent Ascites.

BACKGROUND & AIMS: Treatment options for recurrent ascites resulting from decompensated cirrhosis include serial large-volume paracentesis and albumin infusion (LVP+A) or insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Insertion of TIPSs with covered stents during early stages of ascites (early TIPS, defined as 2 LVPs within the past 3 weeks and <6 LVPs in the prior 3 months) significantly improves chances of survival and reduces complications of cirrhosis compared with LVP+A. However, it is not clear if TIPS insertion is cost effective in these patients. METHODS: We developed a Markov model using the payer perspective for a hypothetical cohort of patients with cirrhosis with recurrent ascites receiving early TIPSs or LVP+A using data from publications and national databases collected from 2012 to 2018. Projected outcomes included quality-adjusted life-year (QALY), costs (2017 US dollars), and incremental cost-effectiveness ratios (ICERs; $/QALY). Sensitivity analyses (1-way, 2-way, and probabilistic) were conducted. ICERs less than $100,000 per QALY were considered cost effective. RESULTS: In base-case analysis, early insertion of TIPS had a higher cost ($22,770) than LVP+A ($19,180), but also increased QALY (0.73 for early TIPSs and 0.65 for LVP+A), resulting in an ICER of $46,310/QALY. Results were sensitive to cost of uncomplicated TIPS insertion and transplant, need for LVP+A, probability of transplant, and decompensated QALY. In probabilistic sensitivity analysis, TIPS insertion was the optimal strategy in 59.1% of simulations. CONCLUSIONS: Based on Markov model analysis, early placement of TIPSs appears to be a cost-effective strategy for management of specific patients with cirrhosis and recurrent ascites. TIPS placement should be considered early and as a first-line treatment option for select patients.

Long-Term Follow-up and Quantitative Hepatitis B Surface Antigen Monitoring in North American Chronic HBV Carriers.

INTRODUCTION: Quantitative hepatitis B surface antigen (qHBsAg) combined with HBV DNA may be useful for predicting chronic hepatitis B (CHB) activity and nucleoside analogue (NA) response. MATERIAL AND METHODS: In this retrospective cohort study we evaluated qHBsAg levels according to CHB disease phase and among patients on treatment. Random effect logistic regression analysis was used to analyze qHBsAg change with time in the NA-treated cohort. RESULTS: 545 CHB carriers [56% M, median age 48 y (IQR 38-59), 73% Asian] had qHBsAg testing. In the untreated group (44%), 8% were classified as immune tolerant, 10% immune clearance, 40% inactive, and 43% had HBeAg- CHB and the median HBsAg levels were 4.6 (IQR 3.4-4.9), 4.0 (IQR 3.4-4.5), 2.9 (IQR 1.4-3.8), and 3.2 log IU/mL (IQR 2.6-4.0), respectively; p < 0.001. In the NA-treated group (28% entecavir, 68% tenofovir, 4% lamivudine), no significant change in qHBsAg levels occured with time. However, 19% of patients on long-term NA had sustained qHBsAg < 2 log10 IU/mL. CONCLUSION: qHBsAg titers were associated with CHB phase and remained stable in those on long-term NA. A significant number of treated patients had low-level qHBsAg, of which some may be eligible for treatment discontinuation without risk of flare.

Embolization of portosystemic shunts for treatment of medically refractory hepatic encephalopathy.

Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003-2015). Patient data collected included the type of HE, medications, Model for End-Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1-4 months), and longer-term (6-12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty-five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1-4 and 6-12 months, respectively. The majority (67%; 8/12) were free from HE-related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723-731 2016 AASLD.

Cost-effectiveness of quantitative hepatitis B virus surface antigen testing in pregnancy in predicting vertical transmission risk.

BACKGROUND & AIMS: Vertical transmission of hepatitis B virus (HBV) can occur despite immunoprophylaxis in mothers with high HBV DNA levels (>5-7 log10 IU/ml). Quantitative hepatitis B surface antigen (qHBsAg) testing could be used as a surrogate marker to identify high viral load carriers, but there is limited data in pregnancy. We conducted a prospective observational study to determine the cost-effectiveness and utility of qHBsAg as a valid surrogate marker of HBV DNA. METHODS: Pregnant patients with chronic hepatitis B were recruited from a tertiary referral centre. HBV DNA levels and qHBsAg were assessed in the second to third trimester. Statistical analysis was performed by Spearman's rank correlation and student's t-test. The cost-effectiveness of qHBsAg as compared to HBV DNA testing was calculated. RESULTS: Ninety nine women with 103 pregnancies, median age 32 years, 65% Asian, 23% African and 12% other [Hispanic, Caucasian] were enrolled. Overall, 23% (23/99) were HBV e Ag (HBeAg)-positive. A significant correlation between qHBsAg and HBV DNA levels was noted in HBeAg-positive patients (r = 0.79, P < 0.05) but not in HBeAg-negative patients (r = 0.17, P = 0.06). In receiver operating characteristic analysis, the optimal qHBsAg cut-off values for predicting maternal viraemia associated with immunoprophylaxis failure (i.e., HBV DNA ≥7 log10 IU/ml) was 4.3 log10 IU/ml (accuracy 98.7%, sensitivity 94.7%, specificity 94.4%) (95% CI, 97-100%, P < 0.05). Use of HBV DNA as compared to qHBsAg costs approximately $20 000 more per infection prevented. CONCLUSION: In resource poor regions, qHBsAg could be used as a more cost-effective marker for high maternal viraemia, and indicate when anti-HBV nucleos/tide analogue therapy should be used to prevent HBV immunoprophylaxis failure.