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Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was “very good” (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and “moderate” (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Introduction More than 70 million people are estimated to be infected with hepatitis C virus (HCV) globally. If left untreated, HCV infection can lead to complications such as extensive liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Evolution of treatments has resulted in highly effective and well-tolerated all-oral direct-acting antivirals. The pangenotypic regimen of glecaprevir/pibrentasvir is approved for treating HCV for patients without cirrhosis or with compensated cirrhosis (CC). Guidelines have evolved to simplify treatment to enable non-specialists to manage and treat HCV-infected patients. Simultaneously, such treatment algorithms provide guidance on the pretreatment identification of small subsets of patients who may require specialist treatment and long-term follow-up for advanced liver disease, including those at risk of developing HCC. This study describes the safety profile of glecaprevir/pibrentasvir in patients identified using previously described noninvasive laboratory measures who may be eligible for treatment by non-liver specialists. Methods This post hoc analysis of glecaprevir/pibrentasvir in patients, identified by noninvasive laboratory measures, intended to exclude patients with advanced liver disease and severe renal impairment, who can be managed within non-liver specialist settings. Patients were included from clinical trials and real-world studies of glecaprevir/pibrentasvir for HCV treatment. Baseline demographics, clinical characteristics, and safety assessments, including adverse events and laboratory abnormalities, were summarized. Results Data across these large-scale studies confirm that glecaprevir/pibrentasvir is well tolerated across different patient populations, with fewer than 0.1% of patients experiencing a serious adverse event related to treatment drugs, and few patients developing HCC during or after treatment. Conclusion The safety profile of glecaprevir/pibrentasvir enhances the confidence of non-liver specialists to treat the majority of HCV-infected patients, and provides an opportunity to expand the treater pool, potentially increasing diagnosis and treatment rates for HCV, contributing to elimination of HCV. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01753-3.

There are limited data examining the relationship between psychosocial factors and receipt of direct‐acting antiviral (DAA) treatment among patients with hepatitis C in large health care organizations in the United States. We therefore sought to determine whether such factors were associated with DAA initiation. We analyzed data from an extensive psychological, behavioral, and social survey (that incorporated several health‐related quality of life assessments) coupled with clinical data from electronic health records of patients with hepatitis C enrolled at four health care organizations during 2017‐2018. Of 2,681 patients invited, 1,051 (39.2%) responded to the survey; of 894 respondents eligible for analysis, 690 (77.2%) initiated DAAs. Mean follow‐up among respondents was 9.2 years. Compared with DAA recipients, nonrecipients had significantly poorer standardized scores for depression, anxiety, and life‐related stressors as well as poorer scores related to physical and mental function. Lower odds of DAA initiation in multivariable analysis (adjusted by age, race, sex, study site, payment provider, cirrhosis status, comorbidity status, and duration of follow‐up) included Black race (adjusted odds ratio [aOR], 0.59 vs. White race), perceived difficulty getting medical care in the preceding year (aOR, 0.48 vs. no difficulty), recent injection drug use (aOR, 0.11 vs. none), alcohol use disorder (aOR, 0.58 vs. no alcohol use disorder), severe depression (aOR, 0.42 vs. no depression), recent homelessness (aOR, 0.36 vs. no homelessness), and recent incarceration (aOR, 0.34 vs. no incarceration). Conclusion: In addition to racial differences, compared with respondents who initiated DAAs, those who did not were more likely to have several psychological, behavioral, and social impairments. Psychosocial barriers to DAA initiation among patients in care should also be addressed to reduce hepatitis C‐related morbidity and mortality., Even among persons with access to care, receipt of direct‐acting antiviral treatment for hepatitis C is suboptimal. We therefore conducted a detailed psychological, behavioral, and social survey among hepatitis C patients in care to determine whether such factors were associated with DAA initiation. Compared with respondents who initiated DAAs, those who did not were more likely to have several psychological, behavioral, and social impairments, suggesting that such factors should be addressed to reduce hepatitis C‐related morbidity and mortality.

Author(s): Lu, Mei; Bowlus, Christopher L; Lindor, Keith; Rodriguez-Watson, Carla V; Romanelli, Robert J; Haller, Irina V; Anderson, Heather; VanWormer, Jeffrey J; Boscarino, Joseph A; Schmidt, Mark A; Daida, Yihe G; Sahota, Amandeep; Vincent, Jennifer; Li, Jia; Trudeau, Sheri; Rupp, Loralee B; Gordon, Stuart C; FOLD Investigators | Abstract: BackgroundBiopsy remains the gold standard for determining fibrosis stage in patients with primary biliary cholangitis (PBC), but it is unavailable for most patients. We used data from the 11 US health systems in the FibrOtic Liver Disease Consortium to explore a combination of biochemical markers and electronic health record (EHR)-based diagnosis/procedure codes (DPCs) to identify the presence of cirrhosis in PBC patients.MethodsHistological fibrosis staging data were obtained from liver biopsies. Variables considered for the model included demographics (age, gender, race, ethnicity), total bilirubin, alkaline phosphatase, albumin, aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis 4 (FIB4) index, AST to alanine aminotransferase (ALT) ratio, and g100 DPCs associated with cirrhosis/decompensated cirrhosis, categorized into ten clusters. Using least absolute shrinkage and selection operator regression (LASSO), we derived and validated cutoffs for identifying cirrhosis.ResultsAmong 4328 PBC patients, 1350 (32%) had biopsy data; 121 (9%) were staged F4 (cirrhosis). DPC clusters (including codes related to cirrhosis and hepatocellular carcinoma diagnoses/procedures), Hispanic ethnicity, ALP, AST/ALT ratio, and total bilirubin were retained in the final model (AUROC=0.86 and 0.83 on learning and testing data, respectively); this model with two cutoffs divided patients into three categories (no cirrhosis, indeterminate, and cirrhosis) with specificities of 81.8% (for no cirrhosis) and 80.3% (for cirrhosis). A model excluding DPCs retained ALP, AST/ALT ratio, total bilirubin, Hispanic ethnicity, and gender (AUROC=0.81 and 0.78 on learning and testing data, respectively).ConclusionAn algorithm using laboratory results and DPCs can categorize a majority of PBC patients as cirrhotic or noncirrhotic with high accuracy (with a small remaining group of patients' cirrhosis status indeterminate). In the absence of biopsy data, this EHR-based model can be used to identify cirrhosis in cohorts of PBC patients for research and/or clinical follow-up.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition characterized by a pathologic immune dysregulation resulting in extreme inflammation. Clinical manifestations are varied but can include severe multiorgan failure and death. HLH has been associated with malignancies, autoimmune diseases, and infections, such as histoplasmosis. Histoplasmosis commonly has subclinical manifestations but can also present in its disseminated form. We present the case of an immunocompromised patient with worsening liver function caused by hepatic histoplasmosis that later triggered HLH with severe multiorgan dysfunction.

Limited evidence exists on the clinical and economic burden of advanced fibrosis in patients with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) due to the invasiveness of liver biopsies for accurately staging liver disease. The fibrosis‐4 (FIB‐4) score allows for noninvasive assessment of liver fibrosis by using clinical and laboratory data alone. This study aimed to characterize the comorbidity burden, health care resource use (HCRU), and costs among patients with NAFLD/NASH with FIB‐4‐defined F3 (bridging fibrosis) and F4 (compensated cirrhosis) fibrosis. Using the Optum Research Database, a retrospective cohort study was conducted among 251,725 commercially insured adult patients with ≥1 NAFLD/NASH diagnosis from January 1, 2008, to August 31, 2016, and laboratory data required to calculate FIB‐4 scores. Five criteria using varying FIB‐4 score cutoffs were identified based on expert clinical opinion and published literature. Date of the first valid FIB‐4 score marked the index date. Mean annual HCRU and costs were calculated during the pre‐index and post‐index periods. The prevalence of FIB‐4‐based F3 and F4 fibrosis was 0.40%‐2.72% and 1.03%‐1.61%, respectively. Almost 50% of patients identified with FIB‐4‐based F3 or F4 had type 2 diabetes, cardiovascular disease, or renal impairment. Total all‐cause health care costs increased significantly from pre‐index to post‐index for patients with FIB‐4‐based F3 fibrosis across most criteria (17%‐29% increase) and patients with FIB‐4‐based F4 fibrosis across all criteria (47%‐48% increase). Inpatient costs were the primary drivers of this increment. Conclusion: Significant increases in HCRU and costs were observed following FIB‐4‐based identification of F3 and F4 fibrosis among U.S. adults with NAFLD/NASH. These data suggest the importance of early identification and management of NAFLD/NASH that may halt or reduce the risk of disease progression and limit the underlying burden., Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients with FIB‐4 identified advanced fibrosis had high rates of comorbidity, most notably type 2 diabetes, cardiovascular disease, and renal impairment. Healthcare costs significantly increased once the patient was identified as having FIB‐4‐based advanced fibrosis; the increase was led by inpatient costs. Some FIB‐4 identified advanced fibrosis patients progressed to more advanced stages of disease and were eventually diagnosed with compensated or decompensated cirrhosis, hepatocellular carcinoma, and liver failure.

The cure of chronic hepatitis C infection has a major impact on the morbidity and mortality of infected patients. It is now clear that sustained virologic response improves overall survival and significantly reduces the risk of liver failure, fibrosis progression, need of liver transplantation, and incidence of hepatocellular carcinoma. Moreover, hepatitis C eradication improves a broad range of extrahepatic manifestations, such as dermatologic, neoplastic, cardiovascular, and endocrine, and improves quality of life.

Background Changing US demographics and evolving chronic hepatitis B (CHB) treatments may affect longitudinal trends in CHB-related complications. We studied trends in the prevalence of cirrhosis (past or present) and incidence of all-cause mortality, stratified by patient age, sex, race, and antiviral treatment status, in a sample from US health care systems. Methods Joinpoint and Poisson regression (univariate and multivariable) were used to estimate the annual percent change in each outcome from 2006 to 2016. Results Among 5528 CHB patients, cirrhosis prevalence (including decompensated cirrhosis) rose from 6.7% in 2006 to 13.7% in 2016; overall mortality was unchanged. Overall rates of cirrhosis and mortality were higher among treated patients, but adjusted annual percent changes (aAPC) were significantly lower among treated than untreated patients (cirrhosis: aAPC +2.4% vs. +6.2%, mortality: aAPC -3.9% vs. +4.0%). Likewise, among treated patients, the aAPC for mortality declined -3.9% per year whereas among untreated patients, mortality increased +4.0% per year. Conclusions From 2006 to 2016, the prevalence of cirrhosis among CHB patients doubled. Notably, all-cause mortality increased among untreated patients but decreased among treated patients. These results suggest that antiviral treatment attenuates the progression of cirrhosis and the risk of death among patients with CHB.

OBJECTIVES As the prevalence of nonalcoholic steatohepatitis (NASH) in the elderly population increases, healthcare resource utilization (HCRU) and costs are also predicted to rise substantially. METHODS This retrospective, observational cohort study used the Medicare 20% sample data set to evaluate the impact of NASH severity on HCRU and costs over 8 years (2007-2015). The sample included 255,681 patients with nonalcoholic fatty liver disease (NAFLD)/NASH: 185,407 (72.5%) with NAFLD/NASH and no further progression to advanced liver disease, 3,454 (1.3%) with compensated cirrhosis (CC), 65,926 (25.8%) with decompensated cirrhosis (DCC), 473 (0.2%) with liver transplant (LT), and 421 (0.2%) with hepatocellular carcinoma (HCC). RESULTS Rates of comorbid diabetes, hypertension, hyperlipidemia, and cardiovascular disease were significantly higher in patients with CC or more severe liver disease compared with NAFLD/NASH and no progression. The annual mean number of all-cause healthcare visits increased from 32.1 for NAFLD/NASH with no progression to 37.3 for CC, 59.8 for DCC, 74.1 for LT, and 59.3 for HCC (P < 0.05). Total annual costs for inpatient, outpatient, physician, and pharmacy services rose from $19,908 in NAFLD/NASH with no progression to $129,276 for LT (P < 0.05). Generalized linear model adjusted for patient characteristics and comorbidities revealed that costs were 1.19, 3.15, 5.02, and 3.33 times significantly higher in patients diagnosed with CC, DCC, LT, or HCC, respectively, compared with NAFLD/NASH and no progression. DISCUSSION These results confirm the substantial impact of NASH, particularly more severe disease, on HCRU and costs and identify patients who may benefit from interventions to prevent progression and subsequently reduce HCRU and costs.

The role of ribavirin (RBV) in the era of direct-acting antivirals (DAA) is not clear, and DAA studies have been largely genotype- and regimen-specific. Using data from the Chronic Hepatitis Cohort Study, we evaluated the role of RBV and increased DAA treatment duration among patients with chronic hepatitis C (HCV) in routine clinical care. We performed multivariable analysis of data from 4133 patients receiving any of the following: sofosbuvir (SOF); daclatasvir + SOF; grazoprevir + elbasvir; paritaprevir/ritonavir + ombitasvir; simeprevir + SOF; and SOF + ledipasvir; SOF + velpatasvir ± voxilaprevir; and glecaprevir + pibrentasvir—all with/ without RBV. Inverse probability treatment weighting was used to adjust for treatment selection bias. Sustained virological response (SVR) was defined by undetectable HCV RNA 12 weeks after end of therapy. The overall SVR rate was 95%. Mean treatment duration was 12 ± 4.5 weeks. The final model included treatment duration and diabetes, as well as the interaction of RBV with previous treatment status (treatment naïve, interferon treatment failure [TF] or previous DAA TF), cirrhosis status, and HCV genotype (GT). Each one-month increment of treatment duration increased odds of SVR by 99% (aOR = 1.99). Diabetes, previous DAA TF, and decompensated cirrhosis significantly reduced odds of SVR. RBV significantly increased the likelihood of SVR among patients with decompensated cirrhosis (aOR = 5.05), previous DAA treatment failure (aOR = 5.43), and GT3 (aOR = 13.28). Among RBV-free regimens, patients with GT3 were less likely to achieve SVR than those with GT1 or 2 (aOR 0.07). Diabetes, decompensated cirrhosis, and prior DAA TF independently reduced the likelihood of SVR. Longer treatment duration increased likelihood of SVR. Conclusion: RBV increased likelihood of SVR among patients with GT3, previous DAA TF, or decompensated cirrhosis.

Given the goal of hepatitis C virus elimination by 2030, World Health Organization guidelines recommend treatment of chronic hepatitis C (CHC) with pan-genotypic direct-acting antivirals, such as sofosbuvir/velpatasvir (SOF/VEL), SOF/VEL/voxilaprevir (VOX) or glecaprevir/pibrentasvir (GLE/PIB). The study evaluated the cost-effectiveness of pan-genotypic regimens in initial (SOF/VEL or GLE/PIB) and re-treatment (SOF/VEL/VOX or GLE/PIB+SOF+ribavirin (RBV)) of CHC.A Markov state-transition model projected lifetime CHC health and economic outcomes from the US payer perspective. Model inputs were sourced from clinical trials or published literature and validated by hepatologists. Model outcomes included numbers of advanced liver disease events, life-years and quality-adjusted life-years (QALYs) gained, and total lifetime costs. One-way sensitivity analyses were performed on model results.SOF/VEL followed by SOF/VEL/VOX resulted in comparable cure rates to the GLE/PIB treatment pathway (99.94% vs. 99.93%, respectively). SOF-based regimens provided similar QALYs at a lower lifetime cost versus a GLE/PIB treatment pathway ($30,749 vs. $36,255), resulting in cost savings of $5,506 per patient. Results were robust in sensitivity analyses.SOF/VEL followed by SOF/VEL/VOX leads to comparable cure rates in the overall CHC population relative to the GLE/PIB treatment pathway. Based on wholesale acquisition prices, the SOF/VEL treatment pathway led to lower lifetime costs.

BACKGROUND: Six-monthly hepatocellular carcinoma (HCC) screening in cirrhotic patients has been recommended since 2011. HCC prognosis is associated with diagnosis at an early stage. We examined the prevalence and correlates of 6-monthly HCC surveillance in a cohort of HCV-infected cirrhotic patients. METHODS: Data were obtained from the medical records of patients receiving care from four hospitals between January 2011 and December 2016. Frequencies and logistic regression were conducted. RESULTS: Of 2,933 HCV-infected cirrhotic patients, most were ≥ 60 years old (68.5%), male (62.2%), White (65.8%), and had compensated cirrhosis (74.2%). The median follow-up period was 3.5 years. Among these patients, 10.9% were consistently screened 6 monthly and 21.4% were never screened. Patients with a longer history of cirrhosis (AOR = 0.86, 95% CI = 0.80–0.93) were less likely to be screened 6 monthly while decompensated cirrhotic patients (AOR = 1.39, 95% CI = 1.06–1.81) and cirrhotic patients between 18 and 44 years (AOR = 2.01, 95% CI = 1.07–3.74) were more likely to be screened 6 monthly compared to compensated cirrhotic patients and patients 60 years and older respectively. There were no significant differences by race, gender, or insurance type. CONCLUSION: The prevalence of consistent HCC surveillance remains low despite formalized recommendations. One in five patients was never surveilled. Patients with a longer history of cirrhosis were less likely to be surveilled consistently despite their greater HCC risk. Improving providers’ knowledge about current HCC surveillance guidelines, educating patients about the benefits of consistent HCC surveillance, and systemic interventions like clinical reminders and standing HCC surveillance protocols can improve guideline-concordant surveillance in clinical practice.

Chronic hepatitis B (CHB) comorbidity data are limited. Using insurance claims databases, our aims were to determine the prevalence and incidence of nonliver comorbidities in CHB patients over time and the predictors of select comorbidities in CHB patients. Patients were adults with continuous coverage (commercial/Medicare or Medicaid) 6 months prior to and after the first CHB diagnosis and matched non‐CHB patients. Deyo‐Charlson Comorbidity Index (DCCI) and comorbidities were analyzed (cardiovascular disease [CVD], carcinoma, diabetes mellitus [DM], obesity, hypertension [HTN], hyperlipidemia, alcohol use, renal impairment, chronic kidney disease [CKD], and osteoporosis/fracture [OF]). The study population included 44,026 CHB cases and 121,568 matched controls. CHB patient mean age increased from 48.1 ± 11.9 years in 2006 to 51.8 ± 12.4 years in 2015 for commercial/Medicare and from 44.1 ± 11.1 years to 50.2 ± 10.2 years for Medicaid (P < 0.001 for both). The Medicaid CHB cohort was the sickest (DCCI, 2.6, P < 0.001). The commercial/Medicare 2006 CKD prevalence rate was 36.1/1,000 in CHB patients and 10.2/1,000 in controls, increasing to 97.6 and 38.8 in 2015, respectively. The 2006 CKD incidence (per 1,000 person‐years) was 10.3 and 4.8 and 15.2 and 11.3 by 2015, respectively (P < 0.05 for all). The strongest predictors for CKD were DM (hazard ratio [HR], 2.48), HTN (HR, 3.29), and CVD (HR, 2.61) (all P < 0.0001). Similar prevalence and incidence changes were observed for OF. The strongest predictors for OF were female gender (HR, 2.22), alcohol use (HR, 2.02), and viral coinfection (HR, 1.37) (all P < 0.0001). Conclusion: Insured CHB patients were older, had more comorbidities, and experienced higher incidence and prevalence of CKD and OF than controls.

[Background & Aims] Globally, nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. We assessed the clinical presentation and patient-reported outcomes (PROs) among NAFLD patients from different countries., [Methods] Clinical, laboratory, and PRO data (Chronic Liver Disease Questionnaire–nonalcoholic steatohepatitis [NASH], Functional Assessment of Chronic Illness Therapy–Fatigue, and the Work Productivity and Activity Index) were collected from NAFLD patients seen in real-world practices and enrolled in the Global NAFLD/NASH Registry encompassing 18 countries in 6 global burden of disease super-regions., [Results] Across the global burden of disease super-regions, NAFLD patients (n = 5691) were oldest in Latin America and Eastern Europe and youngest in South Asia. Most men were enrolled at the Southeast and South Asia sites. Latin America and South Asia had the highest employment rates (>60%). Rates of cirrhosis varied (12%–21%), and were highest in North Africa/Middle East and Eastern Europe. Rates of metabolic syndrome components varied: 20% to 25% in South Asia and 60% to 80% in Eastern Europe. Chronic Liver Disease Questionnaire–NASH and Functional Assessment of Chronic Illness Therapy–Fatigue PRO scores were lower in NAFLD patients than general population norms (all P < .001). Across the super-regions, the lowest PRO scores were seen in Eastern Europe and North Africa/Middle East. In multivariate analysis adjusted for enrollment region, independent predictors of lower PRO scores included younger age, women, and nonhepatic comorbidities including fatigue (P < .01). Patients whose fatigue scores improved over time experienced a substantial PRO improvement. Nearly 8% of Global NAFLD/NASH Registry patients had a lean body mass index, with fewer metabolic syndrome components, fewer comorbidities, less cirrhosis, and significantly better PRO scores (P < .01)., [Conclusions] NAFLD patients seen in real-world practices in different countries experience a high comorbidity burden and impaired quality of life. Future research using global data will enable more precise management and treatment strategies for these patients.

Background and aims There is an unmet need for alternative treatments for patients with primary biliary cholangitis (PBC) who do not respond to treatment with ursodeoxycholic acid (UDCA). A proof-of-concept study of baricitinib, an orally administered Janus kinase 1 and 2 inhibitor, was initiated to evaluate its use in PBC patients. Approach and results Patients with PBC showing inadequate response or intolerance to UDCA were eligible. This was a randomized, double-blinded placebo-controlled trial. Enrollees were assigned 1:1 to baricitinib (2 mg/day) or placebo. Endpoints included change in alkaline phosphatase (ALP), itch Numeric Rating Score (NRS), and fatigue NRS at 12 weeks post-baseline; exploratory markers included high sensitivity C-reactive protein (hs-CRP) and Enhanced Liver Fibrosis (ELF) score. Due to low enrollment, the study was terminated early. Two patients were enrolled and completed the trial; 1 was randomized to receive baricitinib and 1 to placebo. Over the treatment period, the baricitinib-treated patient demonstrated a 30% decrease in ALP and a 7-point improvement in the itch NRS, but a 2-point increase in the Fatigue NRS. Markers of inflammation and liver fibrosis (hs-CRP and ELF score) also improved over the study period. In contrast, the placebo-treated patient showed no improvement in primary or secondary endpoints. A single non-serious treatment-emergent adverse event of moderate sinusitis was reported by the baricitinib-treated patient at day 47. Conclusions In a 12-week trial, a patient with PBC showing inadequate response to treatment with UDCA demonstrated a dramatic response to treatment with baricitinib., Highlights • Baricitinib is an orally administered Janus kinase 1 and 2 inhibitor FDA-approved for rheumatoid arthritis. • A primary biliary cholangitis patient with inadequate response to UDCA demonstrated a dramatic response to treatment with baricitinib. • Response included rapid reduction in alkaline phosphatase and in self-reported measures of pruritus and depression during the 12-week trial.

Background TAF demonstrated noninferior efficacy to TDF with a superior bone and renal safety profile, in viremic chronic HBV (CHB) patients through week 96, and in virally suppressed patients switched from TDF to TAF at 48 weeks. The duration of prior TDF therapy may influence the degree and rate of recovery of bone and renal function following switch to TAF. Here, we evaluate the impact of prior TDF treatment duration on the safety profile of TAF in virally suppressed patients. Methods In a double-blind, randomized, multicenter, active-controlled, Phase 3 study, 488 CHB patients who were virologically suppressed on TDF for 1 year, and on TDF monotherapy for 6 months were randomized 1:1 to switch to TAF or continue TDF for 48 weeks. In patients originally randomized to receive TAF, renal, bone, and lipid parameters were categorically evaluated by the duration of prior TDF treatment: Results Of the 243 patients switched to TAF from TDF, 105 (43%) and 138 (57%) had received TDF for 50 years, 74% male, 80% Asian, median eGFRCG91 mL/min, 4% and 12% had osteoporosis at hip and spine, respectively. Similar changes in renal, bone, and lipid parameters following 48 weeks of TAF treatment were observed by TDF treatment duration. A comparable increase in median eGFRCG, decreases in tubular biomarkers (beta-2 microglobulin/creatinine ratio, retinol binding protein/creatinine ratio), increases in mean percent change in hip and spine BMD, and decreases in bone turnover markers (C-type collagen sequence, procollagen type 1 N-terminal propeptide) were observed among patients previously treated with Conclusions In virally suppressed patients on TDF a median of 4 years who switched to TAF treatment, improvements in bone and renal parameters and changes in fasting lipids were not impacted by prior duration of TDF use.

Background TDF and ETV are first-line treatments for CHB virus infection. A recent analysis of nationwide insurance data from Korea suggested that the risk of HCC may vary by type of CHB treatment; however, this finding was based on a limited follow-up period following TDF approval in Korea in 2012 and has not been replicated in large datasets outside of Asia. The objective of this analysis was to explore the long-term risk of HCC with TDF vs. ETV in treatment naive (TN) CHB patients in a US administrative claims dataset. Methods Among 158,272 patients with evidence of CHB and administrative medical claims between January 2006 and September 2018, we identified TN patients exposed to TDF (N=6,145) or ETV (N=4,046) with at least 1 year of continuous enrollment prior to cohort entry. Exclusion criteria included coinfection with HCV, HDV, or HIV; prior exposure to peginterferon or nucleos(t)ide analogues; HCC or liver transplant prior or up to 6 months after initiating treatment. Absolute rates and corresponding 95% CIs were determined for each treatment group, Cox proportional hazards methods were used to estimate the risk of incident HCC associated with TDF vs ETV. To account for the effects of potential differences in demographics and baseline health status, we incorporated multivariable adjustment and weighting based on treatment propensity scores. Results Median follow-up duration was comparable in TDF- vs ETV-treated patients among TDF-treated CHB patients, the absolute rate of HCC was approximately half that of patients treated with ETV (0.32 per 100 PY (CI: 0.23 – 0.43) vs 0.61 per 100 PY (CI: 0.45 – 0.80)). After adjustment for age group, sex, baseline health conditions and propensity score weighting, TDF remained associated with a significantly decreased risk of HCC compared to treatment with ETV (HR: 0.56, CI: 0.37 – 0.86). Conclusions In this analysis of commercially insured, TN CHB patients in the US, the absolute rate of HCC was lower in those treated with TDF than with ETV. After adjustment, treatment with TDF remained associated with a significantly decreased long term risk of HCC, consistent with recent findings from Asia.

Using electronic health records, we found that hepatitis C virus (HCV) reporting on death certificates of 2901 HCV-infected decedents from 4 US healthcare organizations during 2011–2017 was documented in only 50% of decedents with hepatocellular carcinoma and less than half with decompensated cirrhosis. National figures likely underestimate the US HCV mortality burden.

Introduction Despite recognized differences in the rates of cardiovascular and renal disease between men and women in the general population, studies of the downstream effects of antiviral treatment for hepatitis C (HCV) have not investigated differences in outcomes based on sex. We analyzed sex differences in risk of acute coronary syndrome (ACS), end-stage renal disease (ESRD), and ischemic stroke by treatment and response in a large US-based multisite cohort of HCV patients. Methods Observation started at the HCV diagnosis date (untreated) or last antiviral treatment start (treated). Treatment selection bias was addressed using an inverse probability-weighting approach. We estimated the effect of treatment on the cumulative incidence of outcomes using the Fine-Gray method (subdistribution hazard ratios [sHR] and 95% confidence intervals [95% CI]). Death was a competing risk. Results Roughly 40% of 15,295 HCV patients were women. After controlling for other risk factors, sustained virological response (SVR) (interferon-based [IFN] or direct-acting antiviral [DAA]) significantly reduced risk of all outcomes, particularly among female patients. Female patients who achieved SVR after IFN-based treatment had significantly lower risk of ACS compared with male patients with SVR from either treatment type (sHR 0.45 [95% CI 0.35-0.59] vs 0.81 [95% CI 0.69-0.96, for DAA SVR] and sHR 0.72 [95% 0.62, 0.85, for IFN SVR]). Successful treatment seemed to be most protective against ESRD; female patients who achieved SVR were at 66%-68% lower risk than untreated patients (sHR 0.32 [95% CI 0.17-0.60 for DAA SVR] and 0.34 [95% CI 0.20-0.58 for IFN SVR]), whereas men were at 38%-42% lower risk (sHR 0.62 [95% CI 0.46-0.85 for DAA SVR] and 0.58 [95% CI 0.43-0.76 for IFN SVR]). IFN treatment failure significantly increased risk of all outcomes by 50%-100% among female patients. Compared with no treatment, female patients who experienced IFN treatment failure were at 63% increased risk of ACS (sHR 1.63 [95% CI 1.35-1.96]), almost twice the risk of ESRD (sHR 1.95 [95% CI 1.43-2.66]) and 51% increased risk of stroke (sHR 1.49 [95%CI 1.11-2.00]). Discussion SVR reduced the risk of extrahepatic complications, particularly in females. The significantly increased risk associated with IFN TF in women-a subset who represented roughly 10% of that group-underscores the importance of prioritizing these patients for DAA treatment irrespective of the fibrosis stage.

Summary Exposure to hepatitis viruses is a recognized occupational risk for health care personnel (HCP). This report establishes new CDC guidance that includes recommendations for a testing algorithm and clinical management for HCP with potential occupational exposure to hepatitis C virus (HCV). Baseline testing of the source patient and HCP should be performed as soon as possible (preferably within 48 hours) after the exposure. A source patient refers to any person receiving health care services whose blood or other potentially infectious material is the source of the HCP’s exposure. Two options are recommended for testing the source patient. The first option is to test the source patient with a nucleic acid test (NAT) for HCV RNA. This option is preferred, particularly if the source patient is known or suspected to have recent behaviors that increase risk for HCV acquisition (e.g., injection drug use within the previous 4 months) or if risk cannot be reliably assessed. The second option is to test the source patient for antibodies to hepatitis C virus (anti-HCV), then if positive, test for HCV RNA. For HCP, baseline testing for anti-HCV with reflex to a NAT for HCV RNA if positive should be conducted as soon as possible (preferably within 48 hours) after the exposure and may be simultaneous with source-patient testing. If follow-up testing is recommended based on the source patient’s status (e.g., HCV RNA positive or anti-HCV positive with unavailable HCV RNA or if the HCV infection status is unknown), HCP should be tested with a NAT for HCV RNA at 3–6 weeks postexposure. If HCV RNA is negative at 3–6 weeks postexposure, a final test for anti-HCV at 4–6 months postexposure is recommended. A source patient or HCP found to be positive for HCV RNA should be referred to care. Postexposure prophylaxis of hepatitis C is not recommended for HCP who have occupational exposure to blood and other body fluids. This guidance was developed based on expert opinion (CDC. Updated U.S. Public Health Service guidelines for the management of occupational exposures to HBV, HCV, and HIV and recommendations for postexposure prophylaxis. MMWR Recommend Rep 2001;50[No. RR-11]; Supplementary Figure, https://stacks.cdc.gov/view/cdc/90288) and reflects updated guidance from professional organizations that recommend treatment for acute HCV infection. Health care providers can use this guidance to update their procedures for postexposure testing and clinical management of HCP potentially exposed to hepatitis C virus.

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Normal ranges of serum alanine aminotransferase (ALT) may vary by race. However, results from research studies are contradictory, and many of these studies have included only small numbers of African Americans. We investigated ALT values in patients without evidence of liver disease to determine whether normal ranges differ across race groups. We also evaluated whether a race- and sex-dependent upper limit of normal (ULN) would improve the ability of ALT to predict liver disease compared to the sex-dependent ULN currently in use. We identified ICD9 codes for liver conditions and diabetes in medical records from a sample of 6719 patients. Analysis of variance (ANOVA) was used to assess differences in ALT log-transformed distributions by race. Logistic regression was used to evaluate whether the addition of race to the current sex-dependent ULN improves the ability of ALT to predict liver disease (assessed by area under the receiver operating characteristic curve (AUROC)). Among 1200 patients with BMI 18.5

Supplemental Digital Content is available in the text., Goals: This study evaluates the real-world comorbidity burden, health care resource utilization (HRU), and costs among nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) patients with advanced liver diseases [compensated cirrhosis (CC), decompensated cirrhosis (DCC), liver transplantation (LT), hepatocellular carcinoma (HCC)]. Background: NAFLD/NASH is a leading cause of liver diseases. Materials and Methods: Adult NAFLD/NASH patients were identified retrospectively from MarketScan Commercial claims (2006-2016). Following initial NAFLD/NASH diagnosis, advanced liver diseases were identified using the first diagnosis as their index date. Mean annual all-cause HRU and costs (2016 USD) were reported. Adjusted costs were estimated through generalized linear models. Cumulative costs were illustrated for patient subsets with variable follow-up for each stage. Results: Within the database, 485,774 NAFLD/NASH patients met eligibility criteria. Of these, 93.4% (453,564) were NAFLD/NASH patients without advanced liver diseases, 1.6% (7665) with CC, 3.3% (15,833) with DCC, 0.1% (696) with LT, and 0.1% (428) with HCC. Comorbidity burden was high and increased as patients progressed through liver disease severity stages. Compared with NAFLD/NASH without advanced liver diseases (adjusted costs: $23,860), the annual cost of CC, DCC, LT, and HCC were 1.22, 5.64, 8.27, and 4.09 times higher [adjusted costs: $29,078, $134,448, $197,392, and $97,563 (P

Goals To determine the proportion and characteristics of adults with hepatitis C at health care organizations in 4 US states who initiated direct-acting antivirals (DAAs). Background There are almost no data to assess the penetrance of treatment of the hepatitis C population in general US health care settings. Study We conducted a prospective observational study using electronic clinical, pharmacy, and mortality data to determine the fraction of patients who initiated DAAs between January 2014 and December 2017, by start date and regimen. We used stepwise multivariate logistic regression analysis to identify sociodemographic and clinical characteristics associated with receipt of DAAs. Results Of 8823 patients, 2887 (32.7%) received DAAs. Quarterly (Q) uptake ranged from 1.1% in Q3 2014 to a high of 5.6% in Q2 2015. Characteristics associated with receipt of DAAs included age 51 to 70 years, higher income, pre-2014 treatment failure, and higher noninvasive fibrosis score (FIB4); however, over one half of patients with FIB4 scores >3.25, consistent with severe liver disease, were not treated. A lower likelihood of initiation was associated with Medicaid coverage. Of 5936 patients who did not initiate treatment, 911 (15.3%) had died and 2774 (46.7%) had not had a clinical encounter in ≥12 months by the end of the study. Fewer than 1% of DAA prescriptions originated from nonspecialty providers. Conclusions During 4 calendar years of follow-up, one third of patients initiated DAAs. Large fractions of untreated patients had advanced liver disease, died, or were lost to follow-up. Even among patients in integrated health care systems, receipt of DAAs was limited.

Despite widespread use of lactulose and rifaximin for the treatment of hepatic encephalopathy, this complication of advanced liver disease remains a major burden on the health care system in the United States and continues to predispose to high morbidity and mortality. Several agents have surfaced over recent years with promise to treat hepatic encephalopathy and mitigate the cognitive impairment associated with this disease process. The purpose of this article is to highlight the leading emerging therapies in hepatic encephalopathy as well as their therapeutic targets.

BACKGROUND According to death certificates, approximately 1800 persons die from hepatitis B annually in the United States; however, this figure may underestimate true mortality from chronic hepatitis B (CHB). METHODS We analyzed data from CHB patients seen in the Chronic Hepatitis Cohort Study (CHeCS) between 1 January 2006 and 31 December 2013. We compared overall and cause-specific death rates and mean ages at death between CHeCS CHB decedents and U.S. decedents from the Multiple Cause of Death (MCOD) file. RESULTS Of 4389 CHB patients followed for a mean of 5.38 years, 492 (11%) CHB patients died after a mean follow-up of 3.00 years. Compared to survivors, decedents were older, more likely to be White (40.6%), African-American (27.1%), or male (74.2%); and more likely to have had cirrhosis (59.8%), diabetes (27.2%), alcohol abuse (17.7%), hepatocellular carcinoma (17.5%), or a liver transplant (5.7%); whereas survivors were more likely to be Asian (48.8%; all P < .001). CHB patients died at an average age of 59.8 years-14 years younger than the general U.S. population-and at higher rates for all causes (relative risk [RR] = 1.85, 95% confidence interval [CI], 1.851-1.857) and liver-related causes (RR = 15.91, 95% CI, 15.81-16.01). Only 19% of CHB decedents and 40% of those dying of liver disease had hepatitis B reported on their death certificates. CONCLUSIONS Compared to the general population, CHB patients die at younger ages and higher rates from all causes and liver-related causes. Death certificates underrepresent the true mortality from CHB.

Chronic Hepatitis Cohort Study (CHeCS) publications using data from "real-world" patients with hepatitis C virus (HCV) have described demographic disparities in access to care; rates of advanced liver disease, morbidity, and mortality (2.5%-3.5% per year during 2006-10, although only 19% of all CHeCS decedents, and just 30% of those with deaths attributed to liver disease, had HCV listed on death certificate); substantial comorbidities, such as diabetes, advanced liver fibrosis (29% prevalence), renal disease, and depression, and partial reversal of all these with successful antiviral therapy; patient risk behaviors; and use of noninvasive markers to assess liver disease.

Surveillance of chronic hepatitis C virus (HCV) cases faces limitations that result in delays and underreporting. With increasing use of electronic health records (EHRs), the authors evaluated the predictive value of using International Classification of Diseases, Ninth Revision (ICD-9) codes to identify chronic HCV cases from EHR data. Longitudinal EHR data from 4 health care systems during 2006–2012 were evaluated. Using chart abstraction and review to confirm chronic HCV cases (“gold standard” definition), the authors calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 2 case definitions: (1) ≥2 ICD-9 codes separated by ≥6 months and (2) ≥1 positive HCV RNA (ribonucleic acid) test. Among 2,718,995 patients, 20,779 (0.8%) with ICD-9 codes indicating a likely diagnosis of chronic HCV infection were identified; 13,595 (65.4%) of these were randomly selected for review. Case definition 1 (≥2 ICD-9 codes separated by ≥6 months) had 70.3% ...

Methods: MAGELLAN-1 Part 2 was a randomized, open-label, phase 3 study to evaluate the efficacy and safety of ribavirin (RBV)-free glecaprevir and pibrentasvir (G/P; 300 mg/120 mg) in patients with chronic HCV and prior virologic failure on at least one NS3/4A protease and/or NS5A inhibitor-containing therapy. Patients with compensated liver disease, with or without cirrhosis, and HCV genotype (GT) 1, 4, 5, or 6 were randomized 1:1 to receive 12 or 16 weeks of G/P. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12). Results: Among 91 patients treated, 87 had GT1 and four had GT4 infection. SVR12 was achieved by 89% (39/44) and 91% (43/47) of patients who received 12 and 16 weeks of G/P, respectively. Virologic relapse occurred in 9% (4/44) of patients treated with 12 weeks of G/P; there were no relapses with 16 weeks of treatment. Prior treatment history with one class of inhibitor (protease or NS5A) had no impact on SVR12, while prior treatment with both classes of inhibitors was associated with lower SVR12 rate. The most common adverse event was headache (≥10% of patients) and there were no serious adverse events (AEs) assessed as related to study drugs or AEs leading to discontinuation. Conclusions: Sixteen weeks of G/P treatment achieved a high SVR12 rate in patients with HCV GT1 infection and prior failure to regimens containing either NS5A inhibitors or NS3 protease inhibitors. Background: Patients with hepatitis C virus (HCV) who have virologic failure after treatment containing an NS5A inhibitor have limited retreatment options. This article is protected by copyright. All rights reserved.

Summary Background Many patients with primary biliary cholangitis have an inadequate response to first-line therapy with ursodeoxycholic acid. Seladelpar is a potent, selective agonist for the peroxisome proliferator-activated receptor-delta (PPAR-δ), which is implicated in bile acid homoeostasis. This first-in-class study evaluated the anti-cholestatic effects and safety of seladelpar in patients with an inadequate response to ursodeoxycholic acid. Methods The study was a 12-week, double-blind, placebo-controlled, phase 2 trial of patients with alkaline phosphatase of at least 1·67 times the upper limit of normal (ULN) despite treatment with ursodeoxycholic acid. Patients, recruited at 29 sites in North America and Europe, were randomly assigned to placebo, seladelpar 50 mg/day, or seladelpar 200 mg/day while ursodeoxycholic acid was continued. Randomisation was done centrally (1:1:1) by a computerised system using an interactive voice–web response system with a block size of three. Randomisation was stratified by region (North America and Europe). The primary outcome was the percentage change from baseline in alkaline phosphatase over 12 weeks, analysed in the modified intention-to-treat (ITT) population (any randomised patient who received at least one dose of medication and had at least one post-baseline alkaline phosphatase evaluation). This study is registered with ClinicalTrials.gov (NCT02609048) and the EU Clinical Trials Registry (EudraCT2015-002698-39). Findings Between Nov 4, 2015, and May 26, 2016, 70 patients were screened at 29 sites in North America and Europe. During recruitment, three patients treated with seladelpar developed fully reversible, asymptomatic grade 3 alanine aminotransferase increases (one on 50 mg, two on 200 mg), ranging from just over five to 20 times the ULN; as a result, the study was terminated after 41 patients were randomly assigned. The modified ITT population consisted of 12 patients in the placebo group, 13 in the seladelpar 50 mg group, and 10 in the seladelpar 200 mg group. Mean changes from baseline in alkaline phosphatase were −2% (SD 16) in the placebo group, −53% (14) in the seladelpar 50 mg group, and −63% (8) in the seladelpar 200 mg group. Changes in both seladelpar groups versus placebo were significant (p vs placebo), with no significant difference between the two seladelpar groups (p=0·1729). All five patients who received seladelpar for 12 weeks had normal alkaline phosphatase values at the end of treatment, based on a central laboratory ULN for alkaline phosphatase of 116 U/L. The most frequently reported adverse events were pruritus (16%; one patient on placebo, four on seladelpar 50 mg, and one on seladelpar 200 mg), nausea (13%; one patient on placebo, three on seladelpar 50 mg, and one on seladelpar 200 mg), diarrhoea (10%; two patients on placebo, one on seladelpar 50 mg, and one on seladelpar 200 mg), dyspepsia (8%; two patients on seladelpar 50 mg and one on seladelpar 200 mg), muscle spasms (8%; three patients on seladelpar 200 mg), myalgia (8%; one patient on placebo and two on seladelpar 200 mg), and dizziness (8%; one patient on placebo and two on seladelpar 50 mg). Interpretation Seladelpar normalised alkaline phosphatase levels in patients who completed 12 weeks of treatment. However, treatment was associated with grade 3 increases in aminotransferases and the study was stopped early. The effects of seladelpar should be explored at lower doses. Funding CymaBay Therapeutics.

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.

Mei Lu,1 Wadih Chacra,2 David Rabin,3 Loralee B Rupp,4 Sheri Trudeau,1 Jia Li,1 Stuart C Gordon5 On behalf of the Chronic Hepatitis Cohort Study (CHeCS) Investigators 1Department of Public Health Sciences, Henry Ford Health System, Detroit, MI, USA; 2Division of Gastroenterology and Hepatology, University of Illinois College of Medicine, Chicago, IL, USA; 3Atlanta Gastroenterology Associates, Atlanta, GA, USA; 4Center for Health Policy& Health Services Research, Henry Ford Health System, Detroit MI, USA; 5Division of Gastroenterology and Hepatology, Henry Ford Health System, Detroit, MI, USA Abstract: Viral hepatitis-induced cirrhosis can progress to decompensated cirrhosis. Clinical decompensation represents a milestone event for the patient with cirrhosis, yet there remains uncertainty regarding precisely how to define this important phenomenon. With the development of broader treatment options for cirrhotic hepatitis patients, efficient identification of liver status before evolving to decompensated cirrhosis could be life-saving, but research on the topic has been limited by inconsistencies across studies, populations, and case-confirmation methods. We sought to determine whether diagnosis/procedure codes drawn from electronic health records (EHRs) could be used to identify patients with decompensated cirrhosis. In our first step, chart review was used to determine liver status (compensated cirrhosis, decompensated cirrhosis, noncirrhotic) in patients from the Chronic Hepatitis Cohort Study. Next, a hybrid approach between Least Absolute Shrinkage and Selection Operator regression and Classification Regression Trees models was used to optimize EHR-based identification of decompensated cirrhosis, based on 41 diagnosis and procedure codes. These models were validated using tenfold cross-validation; method accuracy was evaluated by positive predictive values (PPVs) and area under receiver operating characteristic (AUROC) curves. Among 296 patients (23 with hepatitis B, 268 with hepatitis C, and 5 co-infected) with a 2:1 ratio of biopsy-confirmed cirrhosis to noncirrhosis, chart review identified 127 cases of decompensated cirrhosis (Kappa=0.88). The algorithm of five liver-related conditions—liver transplant, hepatocellular carcinoma, esophageal varices complications/procedures, ascites, and ­cirrhosis—yielded a PPV of 85% and an AUROC of 92%. A hierarchical subset of three conditions (hepatocellular carcinoma, ascites, and esophageal varices) demonstrated a PPV of 81% and an AUROC of 86%. Given the excellent predictive ability of our model, this EHR-based automated algorithm may be used to successfully identify patients with decompensated cirrhosis. This algorithm may contribute to timely identificationand treatment of viral hepatitis patients who have progressed to decompensated cirrhosis. Keywords: chronic viral hepatitis, hepatitis B, HBV, hepatitis C, HCV, classification and regression tree modeling, CART modeling

Although direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA‐containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open‐label study (MAGELLAN‐1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1–infected patients with prior virologic failure to HCV DAA‐containing therapy. A total of 50 patients without cirrhosis were randomized to three arms: 200 mg GLE + 80 mg PIB (arm A), 300 mg GLE + 120 mg PIB with 800 mg once‐daily RBV (arm B), or 300 mg GLE + 120 mg PIB without RBV (arm C). By intent‐to‐treat analysis, sustained virologic response at posttreatment week 12 was achieved in 100% (6/6, 95% confidence interval 61‐100), 95% (21/22, 95% confidence interval 78‐99), and 86% (19/22, 95% confidence interval 67‐95) of patients in arms A, B, and C, respectively. Virologic failure occurred in no patients in arm A and in 1 patient each in arms B and C (two patients were lost to follow‐up in arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin were observed. Conclusion: The combination of GLE and PIB was highly efficacious and well tolerated in patients with HCV genotype 1 infection and prior failure of DAA‐containing therapy; RBV coadministration did not improve efficacy. (Hepatology 2017;66:389–397).

Background We used data from the Fibrotic Liver Disease Consortium to evaluate the impact of ursodeoxycholic acid (UDCA) treatment across race/ethnicity, gender, and clinical status among patients with primary biliary cholangitis. Methods Data were collected from "index date" (baseline) through December 31, 2016. Inverse Probability of Treatment Weighting was used to adjust for UDCA treatment selection bias. Cox regression, focusing on UDCA-by-risk factor interactions, was used to assess the association between treatment and mortality and liver transplant/death. Results Among 4,238 patients with primary biliary cholangitis (13% men; 8% African American, 7% Asian American/American Indian/Pacific Island [ASINPI]; 21% Hispanic), 78% had ever received UDCA. The final multivariable model for mortality retained age, household income, comorbidity score, total bilirubin, albumin, alkaline phosphatase, and interactions of UDCA with race, gender, and aspartate aminotransferase/alanine aminotransferase ≥1.1. Among untreated patients, African Americans and ASINPIs had higher mortality than whites (adjusted hazard ratio [aHR] = 1.34, 95% confidence interval [CI] 1.08-1.67 and aHR = 1.40, 95% CI 1.11-1.76, respectively). Among treated patients, this relationship was reversed (aHR = 0.67, 95% CI 0.51-0.86 and aHR = 0.88, 95% CI 0.67-1.16). Patterns were similar for liver transplant/death. UDCA reduced the risk of liver transplant/death in all patient groups and mortality across all groups except white women with aspartate aminotransferase/alanine aminotransferase ≥1.1. As compared to patients with low-normal bilirubin at baseline (≤0.4 mg/dL), those with high-normal (1.0 > 0.7) and mid-normal bilirubin (0.7 > 0.4) had significantly higher liver transplant/death and all-cause mortality. Discussion African American and ASINPI patients who did not receive UDCA had significantly higher mortality than white patients. Among African Americans, treatment was associated with significantly lower mortality. Regardless of UDCA treatment, higher baseline bilirubin, even within the normal range, was associated with increased mortality and liver transplant/death compared with low-normal levels.

PURPOSE: Little is known about health-related quality of life (HRQoL) in patients with chronic hepatitis B virus (CHB) infection in the United States. Our goal is to understand factors associated with HRQoL in this population. METHODS: We conducted a survey to assess HRQoL and behavioral risks among patients with CHB infection from four large U.S. health care systems. Primary outcomes were generated from the SF-8 scale to assess HRQoL, as measured by the mental component scores (MCS) and physical component scores (PCS). The survey also measured socio-demographic information, hepatitis-related behavioral risk factors, treatment exposure/history, stress, and social support. We supplemented survey data with electronic health records data on patient income, insurance, disease severity, and comorbidities. Multivariate analysis was used to estimate and compare adjusted least square means of MCS and PCS, and examine which risk factors were associated with lower MCS and PCS. RESULTS: Nine hundred sixty-nine patients (44.6%) responded to the survey. Current life stressors and unemployment were associated with both lower MCS and PCS results in multivariate analyses. Lower MCS was also associated with White race and low social support, while lower PCS was also associated with Medicaid insurance. CONCLUSIONS: Stressful life events and unemployment were related to mental and physical health status of CHB patients. Those who have social support have better mental health; White and Medicaid patients are more likely to have poorer mental and physical health, respectively. Management of CHB patients should include stress management, social support, and financial or employment assistance.

Background Direct-acting anti-virals (DAA) are highly effective for hepatitis C virus (HCV) treatment, but perceived risks of medication non-adherence may restrict access to care. Digital medicine programme (DMP) has improved adherence and outcomes for some conditions. Aims To conduct a prospective, single-arm, open-label study across the United States to assess the impact of DMP on adherence and efficacy in adults with chronic HCV infection at high risk for non-adherence. Methods Eligible participants were placed on the DMP to evaluate real-time adherence; primary outcome was sustained virological response (SVR) at ≥10 weeks post-treatment. Results Between August 2017 and April 2019, 288 participants (Medicaid, 64.9%; psychiatric disorders, 61.1%; homeless, 9.4%) received DAAs for 8-12 weeks (sofosbuvir/velpatasvir or ledipasvir, 45%; glecaprevir/pibrentasvir, 55%). SVR was achieved in 99.1% of 218 participants who had HCV RNA assessed at ≥10 weeks post-treatment; of the 70 participants who did not have SVR assessed, 17 had SVR4 with HCV RNA assessed at a median (IQR; interquartile range) 5.6 weeks (4.1, 7.9) post-treatment; one completed treatment but did not have HCV RNA assessed, and 52 discontinued treatment early without assessment. Overall, the primary analysed participants (n = 218) actively used the DMP for median (range) 92.9% (12.5%, 100%) of their prescribed treatment time, and overall pill-taking adherence was 95.0% (57.1%, 100%). Participants reported the programme was useful and easy to use through satisfaction surveys. Conclusions HCV treatment with DMP was accepted by patients and clinicians and may support HCV treatment outcomes among patients at high risk for treatment non-adherence (Clinical trials.gov NCT03164902).

BACKGROUND Risk factors and timing associated with disease progression and mortality in nonalcoholic fatty liver disease (NAFLD) are poorly understood. AIMS To evaluate the impact of disease severity, demographics and comorbidities on risk of mortality and time to progression in a large, real-world cohort of diagnosed NAFLD patients. METHODS Claims data from a 20% Medicare representative sample between 2007 and 2015 were analysed retrospectively. Adults were categorised into disease severity groups: NAFLD/nonalcoholic steatohepatitis (NASH) alone, compensated cirrhosis, decompensated cirrhosis, liver transplant or hepatocellular carcinoma. Cumulative incidence of mortality and disease progression were calculated for each group and multivariate analyses performed adjusting for demographics, comorbidities and disease severity. RESULTS A total of 10 826 456, patients were assessed and the prevalence of NAFLD was 5.7% (N = 621 253). Among patients with NAFLD, 71.1% had NAFLD/NASH alone and 28.9% had NAFLD cirrhosis. Overall, 85.5% of patients had hypertension, 84.1% dyslipidemia, 68.7% had cardiovascular disease and 55.5% diabetes. The cumulative risk of progression of NAFLD to cirrhosis, and compensated cirrhosis to decompensated cirrhosis was 39% and 45%, respectively, over 8 years of follow-up. The independent predictors of progression included cardiovascular disease, renal impairment, dyslipidemia and diabetes. The cumulative risk of mortality for NAFLD, NAFLD cirrhosis, decompensated cirrhosis and hepatocellular carcinoma was 12.6%, 31.1%, 51.4% and 76.2%, respectively. CONCLUSIONS The present report (a) demonstrates that NAFLD is grossly underdiagnosed in real-world clinical settings and (b) provides new evidence on the progression rates of NAFLD and risk factors of mortality across the spectrum of severity of NAFLD and cirrhosis.

Summary Background There is a medical need for highly effective, safe, and well tolerated treatments for patients infected with hepatitis C virus (HCV) with severe renal impairment. We investigated the safety and efficacy of sofosbuvir with ribavirin or ledipasvir combined with sofosbuvir in a prospective study of patients with genotype 1 or 3 HCV infection and stage 4–5 chronic kidney disease (creatinine clearance by Cockcroft-Gault ≤30 mL/min) who were not on dialysis. Methods This phase 2b, open-label, non-randomised, multicentre study in the USA and New Zealand investigated three sequentially enrolled cohorts of patients. Patients were recruited from ten hospitals and clinical research centres and were included if they had genotype 1 or 3 HCV infection, a creatinine clearance less than or equal to 30 mL/min, and were not on dialysis. In cohorts 1 and 2, patients received sofosbuvir (200 mg in cohort 1 and 400 mg in cohort 2) plus ribavirin 200 mg once per day for 24 weeks. In cohort 3, 18 patients received ledipasvir combined with sofosbuvir (90 mg ledipasvir and 400 mg sofosbuvir) once per day for 12 weeks. The primary efficacy endpoint was the proportion of patients achieving sustained virological response 12 weeks after the end of treatment (SVR12). Safety and pharmacokinetic data were also collected. The trial is registered with ClinicalTrials.gov , number NCT01958281 , and is completed. Findings This study was done between Oct 7, 2013, and Oct 29, 2017. In the sofosbuvir plus ribavirin cohorts, 32 patients were screened, of whom 20 were enrolled and assessed for efficacy and safety (ten patients in each cohort). In the ledipasvir plus sofosbuvir cohort, 33 patients were screened, of whom 18 were enrolled and assessed for treatment efficacy and safety. Four (40%, 95% CI 12–74) of ten patients in cohort 1 and six (60%, 26–88) of ten patients in cohort 2 achieved SVR12. All 18 (100%, 82–100) patients in cohort 3 achieved SVR12. Adverse events were mostly mild or moderate in severity. The most commonly reported adverse events overall were headache (eight [21%] of 38 patients), anaemia (seven [18%] of 38 patients), and fatigue (six [16%] of 38 patients). Eight patients had serious adverse events, none of which were treatment related. There were no treatment-related cardiac events or clinically significant changes in echocardiographic parameters or creatinine clearance by Cockcroft-Gault. Interpretation In this phase 2b study, ledipasvir combined with sofosbuvir for 12 weeks was safe and effective in patients with genotype 1 HCV infection and stage 4–5 chronic kidney disease who were not on dialysis. Funding Gilead Sciences.

Objective: NAFLD/NASH patients with AF (bridging fibrosis/F3 and compensated cirrhosis/F4) have an increased risk of liver disease progression leading to higher costs, which may be compounded by presence of DM. The study evaluated the impact of DM on HRU and associated healthcare costs among NAFLD/NASH-AF patients in the U.S. Methods: Adult NAFLD/NASH-AF patients with available lab results were identified from 2008-2016 Optum Research claims database, to calculate their Fibrosis-4 (FIB-4) score. Using the FIB-4 score, patients were categorized as F3 or F4 (first date of FIB-4 cut-off score marked the index date), and then stratified by DM (ICD codes). Mean annual HRU/costs were obtained via per patient per month values (2016 USD). Results: Among 91,122 NAFLD/NASH patients with FIB-4 scores, 2,482 (2.7%) had F3, among which 36% had DM, and 939 (1.0%) had F4, among which 35% had DM. The mean annual costs of F3 and F4 patients with DM were 12-53% higher than non-DM (Figure) before and after the development of AF. Conclusions: NAFLD/NASH-AF patients with DM had higher mean annual HRU-associated costs compared to those without DM - primarily driven by ambulatory and pharmacy costs. Management options are needed to improve clinical care and optimize healthcare costs among NAFLD/NASH-AF patients with DM. Disclosure S. Gordon: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. N. Kachru: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. A. Ozbay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Wong: Advisory Panel; Self; Gilead Sciences, Inc. Consultant; Self; Gilead Sciences, Inc. Research Support; Self; Gilead Sciences, Inc. Speaker's Bureau; Self; Gilead Sciences, Inc.

Objective: Comorbidities such as DM accelerate the progression of NAFLD/NASH to AdvLD [compensated cirrhosis (CC)/decompensated cirrhosis (DCC)/liver transplant (LT)/hepatocellular carcinoma (HCC)]. This study examined the impact of DM on healthcare costs among NAFLD/NASH patients with AdvLD in the U.S. Methods: Adult NAFLD/NASH patients identified from IBM Watson Health MarketScan claims database (2006-2016) were followed from initial NAFLD/NASH diagnosis to identify development of AdvLD (first diagnosis as index date), stratified by presence of DM (ICD codes/medications). Mean annual healthcare costs for each stage was obtained from per patient per month values (2016 USD). Results: Overall 468,017 NAFLD/NASH patients were identified with 24% having DM (mean age 51 years, 58% females, high comorbidity burden - 56% hypertension, 55% hyperlipidemia). Mean annual costs were higher (p Conclusions: Comorbid DM is associated with significantly higher (23-31%) healthcare costs in patients with NAFLD/NASH, CC, and DCC, which represents the majority clinical burden of NAFLD in the U.S. Novel treatment options are needed among NAFLD/NASH patients with DM to prevent progression and subsequent healthcare costs. Disclosure R. Wong: Advisory Panel; Self; Gilead Sciences, Inc. Consultant; Self; Gilead Sciences, Inc. Research Support; Self; Gilead Sciences, Inc. Speaker's Bureau; Self; Gilead Sciences, Inc. N. Kachru: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. D. Martinez: None. M. Moynihan: Employee; Self; IBM. A. Ozbay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. S. Gordon: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc.

Background Prior to the availability of Phase 1 drug interaction data, concomitant proton pump inhibitor (PPI) use was prohibited in clinical trials of sofosbuvir/velpatasvir (SOF/VEL). Later clinical studies allowed for the use of up to 20 mg omeprazole or equivalent dosing. This analysis evaluated the efficacy and safety of patients with and without compensated cirrhosis who received SOF/VEL for 12 weeks and reported concomitant use of a PPI. Methods This was a retrospective analysis from 12 Phase 2 and Phase 3 clinical studies in which patients of all genotypes with and without compensated cirrhosis received 12 weeks of SOF/VEL and reported concomitant use of a PPI. Efficacy was assessed by SVR12 and relapse rates and safety was assessed by treatment-emergent adverse events (AEs). Results 87 patients reported concomitant use of a PPI. The mean age (range) was 57 years (26–78), 79% were male and 75% white; 56% of patients were infected with genotype 3 and 29% with genotype 1; 37% of patients had compensated cirrhosis and 39% were treatment experienced. The most common PPI was omeprazole reported by 68% of patients. The SVR12 rate was 97% (84 of 87 patients). Of the 3 patients who did not achieve SVR12, 2 patients relapsed (relapse rate 2%) and one patient with a history of diabetes discontinued SOF/VEL after 7 days of dosing due to hyperglycemia. No other patient had an AE which led to discontinuation or interruption of SOF/VEL. 78% of patients had an AE, most of which were mild, and 11% had a serious AE. These efficacy and safety are comparable to patients enrolled in the same studies who received SOF/VEL for 12 weeks without concomitant use of a PPI (SVR12 rate 97% [2445 of 2517 patients]; relapse rate 2% [40 of 2488 patients]). Conclusions In Phase 2 and Phase 3 clinical studies, the single-tablet regimen of SOF/VEL for 12 weeks was effective and safe in patients with concomitant PPI use. These data support the use of SOF/VEL according to labeled recommendations with respect to co-administration of PPIs and other acid reducing agents.

Background: One of the common comorbidities in NAFLD/NASH patients is DM. This study evaluated HCU and costs in NAFLD/NASH patients with varying liver disease severity by DM status. Methods: This was a retrospective study from 2007-2015 of a 20% sample of U.S. Medicare beneficiaries and included NAFLD/NASH patients (ICD codes) with and without DM (ICD codes/medications). Mean annual healthcare costs were reported in 2015 USD and stratified by NAFLD/NASH only, compensated cirrhosis (CC), decompensated cirrhosis (DCC), liver transplant (LT), and hepatocellular carcinoma (HCC) and presence of DM. Results: This study identified 260,950 NAFLD/NASH patients, of which 144,862 (55.5%) also had comorbid DM. NAFLD/NASH CC patients with DM had high rates of additional metabolic comorbidities: 77.5% with cardiovascular disease and 87.5% with both hypertension and hyperlipidemia. Mean annual number of hospitalizations in NAFLD/NASH only with DM was 0.6, which significantly increased in CC (0.8) and DCC (2.2) DM patients. Mean annual healthcare costs were significantly higher in those with comorbid DM (except HCC) (Figure). Conclusions: Comorbid DM among NAFLD/NASH patients is associated with high metabolic comorbidity burden and significantly higher HCU and healthcare costs in U.S. Medicare patients. Disclosure S. Gordon: Consultant; Self; Gilead Sciences, Inc., Intercept Pharmaceuticals, Inc. J. Fraysse: Employee; Self; Gilead Sciences, Inc. S. Li: Consultant; Self; Gilead Sciences, Inc. A. Ozbay: Employee; Self; Gilead Sciences, Inc. Stock/Shareholder; Self; Gilead Sciences, Inc. R. Wong: Advisory Panel; Self; Gilead Sciences, Inc. Consultant; Self; Gilead Sciences, Inc. Research Support; Self; Gilead Sciences, Inc. Speaker's Bureau; Self; Gilead Sciences, Inc.

Background Trends in the epidemiology of chronic hepatitis B (CHB) among routine clinical care patients in the United States are not well documented. We used data from the Chronic Hepatitis Cohort Study to investigate changes in prevalence and newly recorded cases of CHB from 2006 to 2015. Methods Annual percentage changes (APCs) were estimated using join point Poisson regression. Analyses were adjusted by study site; when an interaction with the trend was observed, APCs were estimated by subgroups. Differences in rates based on race, age, and sex were calculated with rate ratios. Results We identified 5492 patients with CHB within select health systems with total populations that ranged from 1.9 to 2.4 million persons. From 2006 to 2014, the prevalence of diagnosed CHB increased from 181.3 to 253.0 per 100 000 persons in the health system population; from 2014 to 2015, it declined to 237.0 per 100 000 persons. APC was +3.7%/y through 131 December 2014 (P < .001) and −15.0%/y (P < .001) thereafter. The rate of newly reported cases of CHB did not change significantly across the study period (APC, −1.1%/y; P = .07). The rates of newly reported cases were 20.5 times higher among patients in the Asian American/American Indian/Pacific Islander (ASINPI) category, compared with white patients, and 2.8 times higher among African American patients. The ratio of male to female patients was roughly 3:2. Conclusions The prevalence of diagnosed CHB in this US patient population increased from 2006 to 2014, after which it decreased significantly. Rates declined most rapidly among patients ≤40 or 61–70 years old, as well as among ASINPI patients. The rate of newly reported cases remained steady over the study period., Prevalence of chronic hepatitis B increased from 2006 to 2014, then decreased significantly. Rates declined most rapidly among patients ≤40 or 61–70 years old, as well as among Asian American/ American Indian/ Pacific Islanders. Newly reported cases remained steady.