Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

Sowing "seeds of trust": How trust in normothermic regional perfusion is built in a continuum of care.

Normothermic regional perfusion (NRP) is a promising technology to improve organ transplantation outcomes by reversing ischemic injury caused by controlled donation after circulatory determination of death. However, it has not yet been implemented in Canada due to ethical questions. These issues must be resolved to preserve public trust in organ donation and transplantation. This qualitative, constructivist grounded theory study sought to understand how those most impacted by NRP perceived the ethical implications. We interviewed 29 participants across stakeholder groups of donor families, organ recipients, donation and transplantation system leaders, and care providers. The interview protocol included a short presentation about the purpose of NRP and procedures in abdomen versus chest and abdomen NRP, followed by questions probing potential violations of the dead donor rule and concerns regarding brain reperfusion. The results present a grounded theory placing NRP within a trust-building continuum of care for the donor, their family, and organ recipients. Stakeholders consistently described both forms of NRP as an ethical intervention, but their rationales were predicated on assumptions that neurologic criteria for death had been met following circulatory death determination. Empirical validation of these assumptions will help ground the implementation of NRP in a trust-preserving way.

Association between public health policies on alcohol and worldwide cancer, liver disease and cardiovascular disease outcomes.

BACKGROUND & AIMS: The long-term impact of alcohol-related public health policies (PHPs) on disease burden is unclear. We aimed to assess the association between alcohol-related PHPs and alcohol-related health consequences. METHODS: We conducted an ecological multi-national study including 169 countries. We collected data on alcohol-related PHPs from the WHO Global Information System of Alcohol and Health 2010. Data on alcohol-related health consequences between 2010-2019 were obtained from the Global Burden of Disease database. We classified PHPs into five items, including criteria for low, moderate, and strong PHP establishment. We estimated an alcohol preparedness index (API) using multiple correspondence analysis (0 lowest and 100 highest establishment). We estimated an incidence rate ratio (IRR) for outcomes according to API using adjusted multilevel generalized linear models with a Poisson family distribution. RESULTS: The median API in the 169 countries was 54 [IQR 34.9-76.8]. The API was inversely associated with alcohol use disorder (AUD) prevalence (IRR 0.13; 95% CI 0.03-0.60; p = 0.010), alcohol-associated liver disease (ALD) mortality (IRR 0.14; 95% CI 0.03-0.79; p = 0.025), mortality due to neoplasms (IRR 0.09; 95% CI 0.02-0.40; p = 0.002), alcohol-attributable hepatocellular carcinoma (HCC) (IRR 0.13; 95% CI 0.02-0.65; p = 0.014), and cardiovascular diseases (IRR 0.09; 95% CI 0.02-0.41; p = 0.002). The highest associations were observed in the Americas, Africa, and Europe. These associations became stronger over time, and AUD prevalence was significantly lower after 2 years, while ALD mortality and alcohol-attributable HCC incidence decreased after 4 and 8 years from baseline API assessment, respectively (p <0.05). CONCLUSIONS: The API is a valuable instrument to quantify the robustness of alcohol-related PHP establishment. Lower AUD prevalence and lower mortality related to ALD, neoplasms, alcohol-attributable HCC, and cardiovascular diseases were observed in countries with a higher API. Our results encourage the development and strengthening of alcohol-related policies worldwide. IMPACT AND IMPLICATIONS: We first developed an alcohol preparedness index, an instrument to assess the existence of alcohol-related public policies for each country. We then evaluated the long-term association of the country's alcohol preparedness index in 2010 with the burden of chronic liver disease, hepatocellular carcinoma, other neoplasms, and cardiovascular disease. The strengthening of alcohol-related public health policies could impact long-term mortality rates from cardiovascular disease, neoplasms, and liver disease. These conditions are the main contributors to the global burden of disease related to alcohol use. Over time, this association has not only persisted but also grown stronger. Our results expand the preliminary evidence regarding the importance of public health policies in controlling alcohol-related health consequences.

Patient-centered care: Key elements applicable to chronic liver disease.

Chronic liver disease (CLD) is a progressive illness with high symptom burden and functional and cognitive impairment, often with comorbid mental and substance use disorders. These factors lead to significant deterioration in quality of life, with immense burden on patients, caregivers, and healthcare. The current healthcare system in the United States does not adequately meet the needs of patients with CLD or control costs given the episodic, reactive, and fee-for-service structure. There is also a need for clinical and financial accountability for CLD care. In this context, we describe the key elements required to shift the CLD care paradigm to a patient-centered and value-based system built upon the Porter model of value-based health care. The key elements include (1) organization into integrated practice units, (2) measuring and incorporating meaningful patient-reported outcomes, (3) enabling technology to allow innovation, (4) bundled care payments, (5) integrating palliative care within routine care, and (6) formalizing centers of excellence. These elements have been shown to improve outcomes, reduce costs, and improve overall patient experience for other chronic illnesses and should have similar benefits for CLD. Payers need to partner with providers and systems to build upon these elements and help align reimbursements with patients' values and outcomes. The national organizations such as the American Association for Study of Liver Diseases need to guide key stakeholders in standardizing these elements to optimize patient-centered care for CLD.

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.

Endoscopy Unit Level Interventions to Improve Adenoma Detection Rate: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Adenoma detection rate (ADR) is inversely correlated with the risk of interval colon cancer and is a key target for quality improvement in endoscopy units. We conducted a systematic review and meta-analysis to identify and evaluate the effectiveness of interventions that can be implemented at the endoscopy unit level to improve ADRs. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a systematic search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases between January 1990 and December 2022 to identify relevant studies. Both randomized controlled trials and observational studies were eligible. Data for the primary outcome of ADR were analyzed and reported on the log-odds scale with 95% CIs using a random-effects meta-analysis model using the empiric Bayes estimator. RESULTS: From 10,778 initial citations, 34 studies were included in the meta-analysis comprising 371,041 procedures and 1501 endoscopists. The provision of report cards (odds ratio [OR], 1.28; 95% CI, 1.13-1.45; P < .001) and the presence of an additional observer to identify polyps (OR, 1.25; 95% CI, 1.09-1.43; P = .002) were associated with significant increases in ADRs whereas multimodal interventions were borderline significant (OR, 1.18; 95% CI, 1.00-1.40; P = .05) and withdrawal time monitoring was not associated significantly with an increase in ADRs (OR, 1.35; 95% CI, 0.93-1.96; P = .11). CONCLUSIONS: The provision of report cards and the presence of an additional observer to identify polyps are associated with improved ADRs and should be considered for implementation in endoscopy facilities.

Liver transplantation with donation after medical assistance in dying: Case series and systematic review of the literature.

Medical assistance in dying (MAiD) has been a legally approved practice in Canada since 2016. Only recently have patients undergoing MAiD also been considered as donors for liver transplantation (LT). This study aimed to evaluate a case series of LT outcomes for recipients with MAiD donors and was paired with a systematic literature review of studies assessing the efficacy of MAiD-associated liver donation. A retrospective chart review of patients registered within the LT Registry at London Health Sciences Centre (LHSC) in London, Ontario, Canada, that had received MAiD donor LT was conducted to develop a case series. Descriptive statistics were produced based on available patient outcomes information. The systematic review included euthanasia due to MAiD being a term exclusive to Canada. Case series had a 100% 1-year graft survival rate, with 50% of patients experiencing early allograft dysfunction but having no significant clinical outcome. A single case of postoperative biliary complication was reported. Median warm ischemic time ranged from 7.8-13 minutes among case series and literature reviews. Utilization of donation after circulatory death allografts procured after MAiD appears to be promising. Mechanisms associated with potential impact in postoperative outcomes include relatively lower warm ischemic time relative to donation after circulatory death Maastricht III graft recipients.

Extra-hepatic morbidity and mortality in alcohol-related liver disease: Systematic review and meta-analysis.

BACKGROUND: Alcohol use increases the risk of many conditions in addition to liver disease; patients with alcohol-related liver disease (ALD) are therefore at risk from both extra-hepatic and hepatic disease. AIMS: This review synthesises information about non-liver-related mortality in persons with ALD. METHODS: A systematic literature review was performed to identify studies describing non-liver outcomes in ALD. Information about overall non-liver mortality was extracted from included studies and sub-categorised into major causes: cardiovascular disease (CVD), non-liver cancer and infection. Single-proportion meta-analysis was done to calculate incidence rates (events/1000 patient-years) and relative risks (RR) compared with control populations. RESULTS: Thirty-seven studies describing 50 302 individuals with 155 820 patient-years of follow-up were included. Diabetes, CVD and obesity were highly prevalent amongst included patients (5.4%, 10.4% and 20.8% respectively). Outcomes varied across the spectrum of ALD: in alcohol-related fatty liver the rate of non-liver mortality was 43.4/1000 patient-years, whereas in alcoholic hepatitis the rate of non-liver mortality was 22.5/1000 patient-years. The risk of all studied outcomes was higher in ALD compared with control populations: The RR of death from CVD was 2.4 (1.6-3.8), from non-hepatic cancer 2.2 (1.6-2.9) and from infection 8.2 (4.7-14.3). CONCLUSION: Persons with ALD are at high risk of death from non-liver causes such as cardiovascular disease and non-hepatic cancer.

Impact of Public Health Policies on Alcohol-Associated Liver Disease in Latin America: An Ecological Multinational Study.

BACKGROUND AND AIMS: Alcohol-associated liver disease (ALD) is the leading cause of liver-related mortality in Latin America, yet the impact of public health policies (PHP) on liver disease is unknown. We aimed to assess the association between alcohol PHP and deaths due to ALD in Latin American countries. APPROACH AND RESULTS: We performed an ecological multinational study including 20 countries in Latin America (628,466,088 inhabitants). We obtained country-level sociodemographic information from the World Bank Open Data source. Alcohol-related PHP data for countries were obtained from the World Health Organization Global Information System of Alcohol and Health. We constructed generalized linear models to assess the association between the number of PHP (in 2010) and health outcomes (in 2016). In Latin America, the prevalence of obesity was 27% and 26.1% among male and female populations, respectively. The estimated alcohol per capita consumption among the population at 15 years old or older was 6.8 L of pure alcohol (5.6 recorded and 1.2 unrecorded). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of male and 40.0% of female populations. A total of 19 (95%) countries have at least one alcohol-related PHP on alcohol. The most frequent PHP were limiting drinking age (95%), tax regulations (90%), drunk-driving policies and countermeasures (90%), and government monitoring systems and community support (90%). A higher number of PHP was associated with a lower ALD mortality (PR, 0.76; 95% CI, 0.61-0.93; P = 0.009), lower AUD prevalence (PR, 0.80; 95% CI, 0.65-0.99; P = 0.045), and lower alcohol-attributable road traffic deaths (PR, 0.81; 95% CI, 0.65-1.00; P = 0.051). CONCLUSIONS: Our study indicates that in Latin America, countries with higher number of PHP have lower mortality due to ALD, lower prevalence of AUD, and lower alcohol-attributable road traffic mortality.

Hepatitis C positive organ transplantation to negative recipients at a multiorgan Canadian transplant centre: ready for prime time.

BACKGROUND: Transplantation offers the best survival for patients with end stage organ disease. Transplant of hepatitis C virus (HCV) nucleic acid test (NAT) positive organs into negative recipients is a novel strategy that can expand the donor pool. We aim to evaluate our centre's experience. METHODS: We preformed a retrospective review of anti-HCV NAT positive and negative organs into negative recipients transplanted over 27 months. Primary outcome was the success rate of eradication of HCV post-transplant. Secondary outcomes were rate of transmission of HCV, treatment adverse events, and graft failure. RESULTS: 33 anti-HCV positive organs were transplanted into negative recipients. 22 (66.7%) were NAT positive. Median recipients age was 49 years (interquartile range [IQR] 44.5-62.0) with the majority being males (57.6%). NAT positive organ transplantations included 16 kidneys, 3 livers, 1 kidney-pancreas, 1 liver-kidney, and 1 heart. The most common HCV genotype was 1a (59.1%). The median time to initiating therapy was 41.5 days. SVR12 was 100% in patients who finished therapy. There were no adverse events with therapy and no graft failure. CONCLUSIONS: Anti-HCV NAT positive organ transplantation into negative recipients is safe with excellent eradication rates and no significant adverse events or graft failure. This would expand donor pool to close the gap between supply and demand.

Effectiveness and Renal Safety of Tenofovir Alafenamide Fumarate among Chronic Hepatitis B Patients: Real-World Study.

Tenofovir alafenamide fumarate (TAF) has high plasma stability resulting in fewer renal adverse events compared to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. We aimed to study the effectiveness and renal safety of TAF in a real-world setting, in patients with or without compromised kidney function. CHB patients (Nucleos(t)ide Analogue [NA]-naïve or experienced) who received TAF >1 year from 11 academic institutions as part of the Canadian Hepatitis B Network (CanHepB) were included. Kidney function was measured by estimated glomerular filtration rate (eGFR) as per Cockcroft-Gault. Patients were followed for up to 160 weeks. Of 176 patients receiving TAF, 143 switched from NA (88% TDF), and 33(19%) were NA naïve. Majority of NA-naïve patients (75%) achieved undetectable HBV DNA after one year of TAF treatment. Majority of patients with eGFR <60 mL/min who had renal deterioration during TDF (76%) reversed to eGFR increase after one year of TAF (p=0.009). Among patients with stage 2 chronic kidney disease (CKD) (eGFR 60-89), the estimated eGFR decline during TDF was halted after switching to TAF (p=0.09). NA-experienced patients with abnormal ALT before TAF showed a significant decline after switching to TAF: -0.005 [-0.006 - -0.004] log10 ULN U/L/month, p<0.001). In CHB patients, TAF was safe, well-tolerated and effective in this real-world cohort. Switching to TAF led to improved kidney function, particularly in those with stage 2 CKD, which suggests that the indication for TAF in the guidelines could be extended to patients with an eGFR higher than 60 mL/min.

Liver transplantation in adult polycystic liver disease: the Ontario experience.

BACKGROUND: Liver transplantation (LT) remains the curative treatment for symptomatic Polycystic Liver Disease (PCLD) patients and is associated with excellent survival rates. The aim of the study is to review the Ontario experience in LT for PCLD. METHODS: A retrospective study was performed from pre-existing LT databases from the LT Units at Toronto General Hospital and London Health Sciences Center, which are the two LT programs in Ontario, Canada. This database contains demographic, clinical parameters and follow-up of all patients transplanted for PCLD. Data was extracted for patients who underwent LT between January 2000-April 2017 and included follow up until December 31st, 2018. RESULTS: A total of 3560 patients underwent LT, of whom 51 (1.4%) had PCLD and met inclusion criteria. 43 (84%) of these patients were female. The median physiologic Model for End Stage Liver Disease (MELD-Na) score at time of referral was 13 (IQR = 7-22), however all patients required MELD-Na exception points to receive LT. The median age of transplant was 62 years (IQR = 59-64) for male vs. 52 (IQR = 45-56) for female patients. 33 (65%) of our cohort had PCLD while 9 (17.5%) had ADPKD and 9 (17.5%) had both diseases. 39 (76%) had LT due to symptoms of mass effect, while 8 (16%) had portal hypertensive complications. After a median follow-up of 6.3 (IQR = 2.9-12.5) years, the probability of survival was 96% (95% CI: 90%, 100%). Log-rank test, comparing survival analysis between males and females did not show a statistically significant difference (p = 0.26). CONCLUSION: Most patients underwent LT for PCLD due to symptoms of mass effect with women being more likely than men to undergo LT. LT for PCLD had excellent long-term survival.

Lower household income is associated with an increased risk of hospital readmission in patients with decompensated cirrhosis.

BACKGROUND AND AIM: The impact of household income, a surrogate of socioeconomic status, on hospital readmission rates for patients with decompensated cirrhosis has not been well characterized. METHODS: The Nationwide Readmission Database from 2012 to 2014 was used to study the association of lower median household income on 30-, 90-, and 180-day hospital readmission rates for patients with decompensated cirrhosis. RESULTS: From the 42 679 001 hospital admissions contained in the sample, there were 82 598 patients with decompensated cirrhosis who survived a hospital admission in the first 6 months of the year. During a uniform 6-month follow-up period, 25 914 (31.4%), 39 928 (48.3%), and 47 496 (57.5%) patients were readmitted at 30, 90, and 180 days, respectively. After controlling for demographic and clinical confounders, patients residing in the three lowest income quartiles were significantly more likely to be readmitted at 30 days than those in the fourth quartile (first quartile, odds ratio [OR] 1.32 [95% confidence interval, CI, 1.17-1.47, P < 0.01]; second quartile, OR 1.25 [95% CI 1.13-1.38, P < 0.01]; and third quartile, OR 1.08 [95% CI 0.97-1.20, P = 0.07]). The association between lower socioeconomic status and the higher risk of readmissions persisted at 90 days (first quartile, OR 1.21 [95% CI 1.14-1.30, P < 0.01]) and 180 days (first quartile, OR 1.32 [95% CI 1.20-1.44, P < 0.01]). CONCLUSION: Patients with decompensated cirrhosis residing in the lowest income quartile had a 32% higher odds of hospital readmissions at 30, 90, and 180 days compared with those in the highest income quartile.

Liver Transplant Tourism.

Liver transplant tourism is travel for transplantation involving organ trafficking and/or transplant commercialism. Various medical, financial, and organizational factors play a role in transplant care including waiting lists, Model for End-Stage Liver Disease scores, and financial aid. We outline the international experiences with transplant tourism (TT) and its effect on their medical communities and patients. For clinicians providing care to patients involved in TT, we also discuss pretransplant counseling and posttransplant care.

Lower 90-day Hospital Readmission Rates for Esophageal Variceal Bleeding After TIPS: A Nationwide Linked Analysis.

OBJECTIVE: Hospital readmission rates following a transjugular intrahepatic portosystemic shunt (TIPS) insertion after an episode of esophageal variceal bleeding (EVB) has not been well studied. We aimed to address this gap in knowledge on a population level. METHODS: The Nationwide Readmission Database (NRD) was used to study the readmission rates for patients with decompensated cirrhosis who had a TIPS insertion performed for EVB. The NRD is a national database that tracks patients longitudinally for hospital readmissions. A propensity score matching model was created to match patients who received TIPS with those who did not. RESULTS: A total of 42,679,001 hospital admissions from the 2012 to 2014 NRD sample were analyzed. There were 33,934 patients with EVB who met inclusion criteria for the study, of whom, 1527 (4.5%) received TIPS after EVB and were matched with 1527 patients with EVB who did not undergo TIPS. With a uniform follow-up of 3 months, patients with TIPS were less likely to be readmitted to hospital with a recurrent EVB [odds ratio (OR): 0.33, 95% confidence interval (CI): 0.24-0.47, P<0.01], although were more likely to be readmitted with hepatic encephalopathy (OR: 1.66; 95% CI: 1.31-2.11, P<0.01). At 3 months, there was no difference in all cause hospital readmission rate between the 2 groups (OR: 38.8%; 95% CI: 38.1-44.9 TIPS vs. OR: 41.5%; 95% CI: 34.1-43.3 non-TIPS: P=0.17). CONCLUSIONS: In this large nationally representative study, TIPS insertion after an episode of EVB was associated with a significantly lower risk of 3-month readmission for recurrent EVB compared with patients who did not receive TIPS. Although those receiving TIPS had a higher rate of hepatic encephalopathy the overall readmission remained unchanged.

Alcohol, tobacco and coffee consumption and liver disease severity among individuals with Chronic Hepatitis B infection in North America.

INTRODUCTION AND OBJECTIVES: The prevalence of alcohol, tobacco, and coffee use and association with liver health among North Americans with Chronic Hepatitis B (CHB) infection has not been well described. MATERIALS AND METHODS: The Hepatitis B Research Network includes an observational study of untreated CHB adults enrolled at 21 sites in the United States and Canada. Alcohol use was categorized as none, moderate, and at-risk based on the definition from the National Institute on Alcohol Abuse and Alcoholism; tobacco use as never, current and former; coffee use as none, 1-2 cups/day, and ≥3 cups/day. Linear regression and linear mixed models were used to associate lifestyle behaviors with ALT and FIB-4 values. RESULTS: 1330 participants met eligibility: 53% males, 71% Asian and the median age was 42 years (IQR: 34-52). Median ALT was 33U/L (IQR: 22-50), 37% had HBV DNA <103IU/mL, 71% were HBeAg negative, and 65% had a FIB-4 <1.45. At baseline, 8% of participants were at-risk alcohol drinkers, 11% were current smokers and 92% drank <3 cups of coffee/day. Current tobacco and 'at-risk' alcohol use, were significantly associated with elevated ALT levels in univariable analyses, however, these associations were not statistically significant when controlling for sociodemographic and HBV characteristics. CONCLUSIONS: In this large diverse cohort of untreated CHB participants, at-risk alcohol use, current tobacco use and limited coffee consumption did not have an association with high ALT and FIB-4 values. In contrast, significant associations were found between the frequency of these lifestyle behaviors and sociodemographic factors.

Genome-wide Association Study Identifies Genetic Variants Associated With Early and Sustained Response to (Pegylated) Interferon in Chronic Hepatitis B Patients: The GIANT-B Study.

BACKGROUND: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. METHODS: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. RESULTS: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. CONCLUSIONS: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. CLINICAL TRIALS REGISTATION: NCT01401400.

Development, Validation, and Comparative Assessment of an International Scoring System to Determine Risk of Upper Gastrointestinal Bleeding.

BACKGROUND & AIMS: The Glasgow-Blatchford score (GBS) and pre-endoscopy Rockall score (pRS) are used in determining prognoses of patients with acute upper gastrointestinal bleeding, but neither predicts outcomes of patients with a high level of accuracy. A scoring system is needed to identify patients at risk of adverse outcomes and patients at low risk of harm. METHODS: We pooled data from 5 data sets in Canada, the United Kingdom, and Australia on 12,711 patients with acute upper gastrointestinal bleeding. The GBS and pRS were calculated for each patient. We performed multivariable logistic regression modeling of data from 10,639 cases to develop the new scoring system Canada - United Kingdom - Adelaide (CANUKA). We performed area under the receiver operating characteristic analyses to test the ability of CANUKA to identify patients who died or had rebleeding within 30 days, surgical or radiologic intervention to control bleeding, need for therapeutic endoscopy, and transfusion-a poor outcome was defined as 1 or more of these outcomes. Patients at low risk of a poor outcome (safe for management as an outpatient) were identified based on lack of transfusion, rebleeding, therapeutic endoscopy, interventional radiology or surgery, or death. We validated in 2072 patients from a separate cohort compiled from 2 datasets. RESULTS: In the development data set there was no difference between GBS and pRS in identifying patients who died without 30 days of bleeding (area under the receiver operating characteristic curve [AUROC], 0.67; 95% CI, 0.62-0.72 for GBS; AUROC, 0.70; 95% CI, 0.66-0.74 for pRS; P = .21). The GBS was superior to the pRS in identifying patients with rebleeding, hemostatic interventions, and transfusions. In the validation data set, CANUKA had higher accuracy than the GBS in identifying patients who died within 30 days of bleeding (AUROC, 0.77 vs 0.74; P = .047), but there was no significant difference in the accuracy of these scoring systems in identifying patients who required hemostatic intervention. The GBS more accurately identified patients who required therapeutic endoscopy (AUROC, 0.78; 95% CI, 0.76-0.81 for GBS; AUROC, 0.77; 95% CI, 0.74-0.79 for CANUKA; P = .47). For patients classified as low-risk patients by CANUKA (score ≤1), 96.3% were safely discharged, whereas 16 patients with a GBS ≤1 had an adverse outcome (a 95.3% probability of safe discharge). CONCLUSIONS: In an international validation analysis of the GBS and pRS for patients with acute upper gastrointestinal bleeding, we found the GBS to more accurately identify those who later required hemostatic interventions and transfusions; the scoring systems identified 30-day mortality or rebleeding with equal levels of accuracy. We developed a scoring system (CANUKA) that had similar performance to the GBS in predicting patient outcomes and it more accurately identifies patients at low risk for adverse outcomes.

Association Between Severe Serum Alanine Aminotransferase Flares and Hepatitis B e Antigen Seroconversion and HBV DNA Decrease in Untreated Patients With Chronic HBV Infection.

BACKGROUND & AIMS: The incidence and outcomes of alanine aminotransferase (ALT) flares during the natural history of chronic HBV infection has not been determined in a large, racially heterogeneous group of patients in North America. METHODS: We collected data from the Hepatitis B Research Network-an observational cohort study of untreated adults with chronic HBV infection enrolled at 21 sites in the United States and Canada. Clinical and laboratory data were collected from 1587 participants (49.9% male, 73.7% Asian, 35.2% genotype B infection, mean age of 42.6 years) at enrollment, at weeks 12 and 24, and every 24 weeks thereafter for a planned 5 years of follow up (from January 2011 through May 2016). Participants were excluded if they had a history of hepatic decompensation, hepatocellular carcinoma, solid organ or bone marrow transplantation, chronic immune suppression, or antiviral therapy within 6 months before enrollment. Levels of ALT were measured in serum samples and flares were defined as at least 10 times the upper limit of normal (300 U/L in males and 200 U/L in females). RESULTS: ALT flares occurred in 102 participants (6%), with 31 flares (30%) occurring at baseline. The 4-year cumulative incidence of ALT flares was 5.7%. The median peak level of ALT was 450 U/L (25th-75th percentile, 330 U/L to 747 U/L) with a maximum of 2578 U/L. In multivariable analysis, factors associated with the occurrence of an ALT flares were: male sex (odds ratio [OR], 3.02; P=.0007), higher baseline HBV DNA values (OR per log10, 1.41; P<.0001), at risk alcohol use (OR, 2.27 vs none or moderate; P=.02), and higher FIB-4 values (OR, 1.85 per log2; P<.0001). Older age was associated with lower odds of an ALT flare (OR, 0.63 per 10 years; P=.004). Rate of decrease in level of HBV DNA by 1 log10 or more (59 vs 23 per 100 person-years for HB e antigen (HBeAg)-positive vs HBeAg-negative patients; P=.003) and HBeAg loss (47 vs 15 per 100 person-years; P=.002) were higher in patients with an ALT flare than in patients without, but the rate of HBsAg loss was similar (4 vs 2 per 100 person-years; P=.26). No hepatic decompensation, liver transplants, or deaths were observed in participants with ALT flares. CONCLUSION: In a large racially heterogeneous cohort of adults with chronic HBV infection, the cumulative incidence of severe ALT flares was low and associated with greater decreases in HBV DNA and loss of HBeAg, but not with loss of HBsAg.