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Background and Aims: The incidence of biliary tract cancers (BTC) appears to be increasing worldwide. We analyzed the characteristics of BTC‐related hospitalizations under medical services across 28 hospitals in Ontario, Canada. Methods: This study uses data collected by GEMINI, a hospital research data network. BTC‐related hospitalizations from 2015 to 2021 under the Department of Medicine or intensive care unit were captured using the International Classification of Diseases, 10th revision, codes for intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma, and gallbladder cancers. Results: A total of 4596 BTC‐related hospitalizations (2720 iCCA, 1269 extrahepatic cholangiocarcinoma, 607 gallbladder cancers) were analyzed. The number of unique patients with BTC‐related hospitalizations increased over time. For iCCA‐related hospitalizations, the total number of hospitalizations increased (from 385 in 2016 to 420 in 2021, p =.005), the hospital length of stay decreased over the study period (mean 10 days [SD, 12] in 2016 to 9 days [SD, 8] in 2021, p =.04), and the number of in‐hospital deaths was stable (from 68 [18%] in 2016 to 55 [13%] in 2021, p =.62). Other outcomes such as 30‐day readmissions, medical imaging tests, intensive care unit–specific hospitalizations, and length of stay were stable over time for all cohorts. The cost of hospitalization for the BTC cohort increased from median $8203 CAD (interquartile range, 5063–15,543) in 2017 to $8507 CAD (interquartile range, 5345–14,755) in 2021. Conclusions: This real‐world data analysis showed a rising number of patients with BTC‐related hospitalizations and rising number of iCCA‐related hospitalizations across 28 hospitals in Ontario between 2015 and 2021. Based on the GEMINI research network database, we analyzed 4596 hospitalizations for biliary tract cancer in Ontario, Canada. Categorizing patients into intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancers, we comprehensively examined trends in hospitalizations, resource utilization (including cost analysis), and clinical outcomes, providing a detailed portrayal of real‐world data for these biliary tract cancers in Ontario, Canada. [ABSTRACT FROM AUTHOR]

We studied whether 48 weeks of PEG‐IFN alfa‐2a add‐on increases HBsAg‐decline and clearance in HBeAg‐negative patients on long‐term nucleo(s)tide analogue (NA) therapy. In this investigator‐initiated, randomized, controlled trial conducted in Europe and Canada, HBeAg‐negative patients treated with NA > 12 months, with HBVDNA < 200 IU/mL, were enrolled. Patients were randomized 2:1 to 48 weeks of PEG‐IFN alfa‐2a add‐on (180 μg per week) or continued NA‐monotherapy with subsequent follow‐up to Week 72. Endpoints were HBsAg decline (≥1 log10 IU/mL) and HBsAg clearance at Week 48. Of the 86 patients in the modified‐intention‐to‐treat analysis, 58 patients received PEG‐IFN add‐on, and 28 continued NA monotherapy. At Week 48, 16(28%) patients achieved HBsAg decline ≥1 log10 in the add‐on arm versus none on NA‐monotherapy (p <.001), and HBsAg clearance was observed in 6 (10%) PEG‐IFN add‐on patients versus 0% NA‐monotherapy (p =.01). HBVRNA was only detected in 2% after PEG‐IFN treatment versus 19% in NA‐monotherapy (p =.002) at Week 48. PEG‐IFN add‐on therapy was well tolerated in majority of patients. Low baseline HBsAg levels (<10 IU/mL) identified patients most likely to achieve HBsAg loss with PEG‐IFN add‐on, whereas an HBsAg level > 200 IU/mL at on‐treatment Week 12 was highly predictive of non‐response (NPV = 100%). Addition of PEG‐IFN to long‐term NA enhanced HBsAg decline and increased the chance of HBsAg clearance in HBeAg‐negative patients on long‐term NA. On‐treatment HBsAg levels >200 IU/mL identify patients unlikely to benefit from PEG‐IFN add‐on and could be used as a potential stopping‐rule for PEG‐IFN therapy. Our findings support further exploration of immune modulation add‐on to antiviral therapy, preferably using response‐guided strategies, to increase functional cure rates in patients with CHB. [ABSTRACT FROM AUTHOR]

Objectives: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival. Design: Retrospective cohort study. Setting: Multicentre study in large referral centres. Population: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020. Methods: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung‐to‐head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV). Main Outcome Measure: Survival to discharge. Results: We included 53 infants born at 30+4 (interquartile range 29+1–31+2) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left‐sided CDH and 33% (2/6) in right‐sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left‐sided CDH and 25% (2/8) in right‐sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07–1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88–1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13). Conclusions: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival. [ABSTRACT FROM AUTHOR]

Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment‐induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct‐acting antivirals (DAA) prevents establishment of, or reverses, T‐cell exhaustion, leading to a virus‐specific T‐cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV‐specific T‐cell responses before and after DAA or interferon‐based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme‐linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance (n = 17), acute interferon (n = 14), acute DAA (n = 13) and chronic DAA (n = 11). After controlling for sex, the magnitude of post‐treatment HCV‐specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV‐specific responses post‐treatment. However, individuals with spontaneous clearance had broader HCV‐specific responses. [ABSTRACT FROM AUTHOR]

When patients with chronic hepatitis B (CHB) stop nucleos(t)ide analogue (NA) therapy before achieving HBsAg loss, flares often ensue which are challenging to predict early. We determined the incidence, severity, outcome and predictors of flares after NA withdrawal. Forty-five patients enrolled in an RCT were included; 107 patients from an external, prospective cohort were used for validation. Retreatment criteria were pre-defined. Pre- and post-treatment predictors of alanine aminotransferase (ALT) flare (>5× ULN) were evaluated by Cox proportional-hazards regression. Seventy-two weeks after NA withdrawal, 23/45 (51%) patients had developed >5× ULN and 14 (31%) >20× ULN. Median time to develop ALT >5× ULN was 12 weeks after NA withdrawal. Independent predictors of ALT >5× ULN were male sex (HR [95% CI] 3.2 [1.2–8.9]; p = 0.03) and serum HBV DNA (1.2 [1.0–1.8]; p = 0.03) at Week 6 off-therapy. Specifically, week 6 HBV DNA >10,000 IU/ml predicted ALT >5× ULN (3.4 [1.4–8.4]; p = 0.01), which was externally validated. In conclusion, this study on post-treatment flares revealed a high cumulative incidence in CHB. Week 6 HBV DNA >10,000 IU/ml independently predicted flares. The proposed threshold enables prediction of imminent flares in patients who may benefit from closer monitoring and earlier retreatment. [ABSTRACT FROM AUTHOR]

As pegylated interferon alpha (PEG‐IFN‐α) is increasingly used in combination regimens of novel drugs, we aimed to characterize ALT flares and their relationship with serum HBsAg and HBV RNA kinetics in a large combined cohort of chronic hepatitis B (CHB) patients on PEG‐IFN‐α‐based therapy. In this post hoc analysis of four international randomized trials, 269/130/124/128 patients on PEG‐IFN‐α monotherapy, PEG‐IFN‐α plus nucleos(t)ide analogue (NA) de novo combination, PEG‐IFN‐α add‐on to NA or NA monotherapy were included, respectively. A flare was defined as an episode of ALT ≥5 × ULN. The association between flares and HBsAg and HBV RNA changes were examined. On‐treatment flares occurred in 83/651 (13%) patients (median timing/magnitude: week 8 [IQR 4–12], 7.6 × ULN [IQR 6.2–10.5]). Flare patients were more often Caucasians with genotype A/D and had higher baseline ALT, HBV DNA, HBV RNA and HBsAg levels than the no‐flare group. More flares were observed on PEG‐IFN‐α monotherapy (18%) and PEG‐IFN+NA de novo combination (24%) vs. PEG‐IFN‐α add‐on (2%) or NA monotherapy (1%) (p <.001). On‐treatment flares were significantly and independently associated with HBsAg and HBV RNA decline ≥1 log10 at the final visit declines started shortly before the flare, progressing towards 24 weeks thereafter. On‐treatment flares were seen in 16/22 (73%) patients who achieved HBsAg loss. In conclusion, ALT flares during PEG‐IFN‐α treatment are associated with subsequent HBsAg and HBV RNA decline and predict subsequent HBsAg loss. Flares rarely occurred during PEG‐IFN‐α add‐on therapy and associated with low HBsAg loss rates. Combination regimens targeting the window of heightened response could be promising. [ABSTRACT FROM AUTHOR]

Earlier identification of potentially efficacious treatments in early development trials requires on‐treatment response markers. We hypothesized that mean week 12 or 24 HBsAg decline could be a useful marker for subsequent off‐treatment sustained HBsAg clearance at the treatment arm level in HBV trials. We used individual patient data from the studies HBV 9901 (peginterferon [PEG‐IFN] versus PEG‐IFN+lamivudine for HBeAg‐positive CHB), PARC (PEG‐IFN±ribavirin for HBeAg‐negative CHB) and published data from 0149 (PEG‐IFN±tenofovir for HBeAg‐positive and HBeAg‐negative CHB) and LIRA‐B (PEG‐IFN for HBeAg‐positive CHB) to define the relationship between mean week HBsAg decline and HBsAg loss at 6 months post‐treatment. A within‐study comparison of HBsAg decline at weeks 12 and 24 between patients with or without HBsAg clearance was used to make projections beyond the observed HBsAg data. Across trials, a more pronounced mean HBsAg decline at week 24 was associated with higher rates of subsequent HBsAg loss. Mean HBsAg decline data at week 24 for patients with or without HBsAg clearance from HBV 9901 (4.3 vs 0.5), PARC (4.8 vs 0.3) and 0149 (PEG‐IFN+TDF arm; 4.6 vs 0.6) were used to extrapolate this relationship beyond observed rates of HBsAg. An additional mean 1 log10 decline at week 24 versus a comparator arm is expected to translate into a 20%–30% increase in subsequent HBsAg loss during off‐treatment follow‐up. Observations were similar for week 12 data, but the relationship was less strong. Mean week 24 HBsAg decline predicts subsequent HBsAg loss and could be a valuable and useful early endpoint in HBV‐treatment trials. [ABSTRACT FROM AUTHOR]

Summary: Background: Liver disease is an increasing burden on population health globally. Aims: To characterise burden of liver disease among general internal medicine inpatients at seven Toronto‐area hospitals and compare it to other common medical conditions. Methods: Data from April 2010 to October 2017 were obtained from hospitals participating in the GEMINI collaborative. Using these cohort data from hospital information systems linked to administrative data, we defined liver disease admissions using most responsible discharge diagnoses categorised according to international classification of diseases, 10th Revision—enhanced Canadian version (ICD‐10‐CA). We identified admissions for heart failure, chronic obstructive pulmonary disease (COPD) and pneumonia as comparators. We calculated standardised mortality ratios (SMRs) as the ratio of observed to expected deaths. Results: Among 239 018 discharges, liver disease accounted for 1.7% of most responsible discharge diagnoses. Liver disease was associated with marked premature mortality, with SMR of 8.84 (95% CI 8.06‐9.67) compared to 1.06 (95% CI 0.99‐1.12) for heart failure, 1.05 (95% CI 0.96‐1.15) for COPD and 1.28 (95% CI 1.20‐1.37) for pneumonia. The majority of deaths were among patients younger than 65 years (57.7%) compared to 3.3% in heart failure, 5.6% in COPD and 10.7% in pneumonia. Liver disease patients presented with worse Laboratory‐Based Acute Physiology Scores, were more frequently admitted to the intensive care unit (14.4%), incurred higher average total costs (median $6723 CAD), had higher in‐hospital mortality (11.4%), and were more likely to be a readmission from 30 days prior (19.8%). Non‐alcoholic fatty liver disease admissions increased from 120 in 2011‐2012 to 215 in 2016‐2017 (P < 0.01). Conclusion: In Canada's largest urban centre, liver disease admissions resulted in premature morbidity and mortality with higher resource use compared to common cardio‐respiratory conditions. Re‐evaluation of approaches to caring for inpatients with liver disease is timely and justified. [ABSTRACT FROM AUTHOR]

Summary: Background: Nucleos(t)ide analogue (NA) discontinuation may be attempted in carefully selected patients with chronic hepatitis B (CHB) infection. Aim: To investigate whether a novel serum marker of quantitative hepatitis B virus (HBV) RNA levels could predict biochemical relapse after NA discontinuation. Methods: We prospepctively followed non‐cirrhotic Asian patients with CHB who stopped NA according to pre‐specified stopping criteria. The primary endpoint was biochemical relapse (HBV DNA >2000 IU/mL and alanine transaminase >2x upper limit of normal), which were also the re‐treatment criteria. Results: Biochemical relapse occurred in 50 patients (48.3% at year 6). Multivariable analysis showed that higher HBV RNA levels (HR 1.34; P < 0.001) at the time of NA discontinuation were associated with increased biochemical relapse risk. The area under the curve of HBV RNA at the time of NA discontinuation for the incidence of biochemical relapse was 0.760 at 6 years. Six years after treatment discontinuation, all patients with HBV RNA levels ≥20 000 copies/mL at the end of treatment developed a biochemical relapse compared with 23.8% of patients with HBV RNA levels<1000 copies/mL (P < 0.001). More patients with HBV RNA levels <1000 copies/mL at end of treatment achieved loss of hepatitis B surface antigen than patients with higher levels (30.9% vs 1.6%; P = 0.027). Conclusions: The HBV RNA level at end of treatment predicted biochemical relapse after treatment discontinuation and may be used to guide decisions on treatment discontinuation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Aims: A variety of auto‐antibody assays are available as part of the clinical care of patients with liver disease. We sought to better understand the clinical utility of immune serological testing in patients with primary biliary cholangitis (PBC). Methods: We retrospectively analysed data from 2846 patients investigated for liver disease at a UK liver centre between 2001 and 2017. A total of 499 patients with PBC were identified. Immune serology results were examined for their diagnostic utility and prognostic significance to predict transplant‐free survival. Results: Antimitochondrial antibodies (AMAs) were specific (94.5%) and sensitive (85.6%) for PBC; antinuclear antibodies (ANAs) against glycoprotein 210 (gp210) and sp100 were specific (>98%) but not sensitive (<25%). The disease‐specific ANAs were detectable in 29.6% of AMA‐negative patients. Anti‐gp210 auto‐antibodies were significantly associated with elevated serum aminotransferase activity, bilirubin and liver stiffness at presentation (P <.010). Anti‐gp210 auto‐antibodies predicted non‐response to ursodeoxycholic acid (UDCA) by GLOBE criteria (39.3% vs 16.7%, P =.005). Moreover, anti‐gp210 was independently associated with death or liver transplantation (HR 3.22, 95% CI 1.49‐6.96; P =.003), after accounting for other significant baseline determinants of outcome. Serologic finding of anti‐gp210 antibodies conferred an independent risk of death or transplantation (HR 4.13, 95% CI 1.85‐9.22; P =.001) after accounting for treatment response. Conclusion: In our single‐centre cohort of patients with PBC, the presence of anti‐gp210 was associated with an adverse presenting phenotype, predicted treatment non‐response and independently predicted reduced transplant‐free survival. [ABSTRACT FROM AUTHOR]

Summary: Background: Serum hepatitis B virus (HBV) RNA may reflect intrahepatic HBV replication. Novel anti‐viral drugs have shown potent HBV RNA decline without concomitant hepatitis B surface antigen (HBsAg) decrease. How this relates to off‐treatment response is yet unclear. Aim: To study the degree of on‐treatment viral antigen decline among patients with pronounced HBV RNA decrease in relation to off‐treatment sustained response and HBsAg loss. Methods: HBV RNA, HBsAg and hepatitis B core‐related antigen (HBcrAg) were quantified in patients with chronic hepatitis B who participated in two randomised controlled trials of peginterferon‐based therapy. Sustained response (HBV DNA <2000 IU/mL) and/or HBsAg loss were assessed in patients with and without on‐treatment HBV RNA response (either >2 log HBV RNA decline or >1 log decline resulting in an undetectable value at on‐treatment week 24), stratified by concomitant HBsAg decline (<0.5/0.5‐1/>1 log). Results: We enrolled 279 patients; 176 were hepatitis B e antigen (HBeAg)‐positive, and 103 were HBeAg‐negative. Sustained response was achieved in 20.4% of patients. At on‐treatment week 24, HBV RNA response was associated with higher sustained response rates (27.4% vs 13.0% in non‐responders, P = 0.004). However, among patients with an HBV RNA response (n = 135), 56.4% did not experience >0.5 log HBsAg decline. Among HBV RNA responders, sustained response was achieved in 47.6% of those with >1 log HBsAg decline (n = 20/42), vs 16.0% with <0.5 log decline (n = 12/75, P = 0.001). Similar results were obtained with HBcrAg and when response was defined as HBsAg loss. Conclusions: In this cohort, many patients with HBV RNA response during peginterferon‐based treatment did not experience HBsAg and/or HBcrAg decline. The absence of concomitant decline in these viral antigens was associated with low rates of treatment response and HBsAg loss. Future trials should therefore consider kinetics of combined biomarkers to assess anti‐viral efficacy. Trial registration, ClinicalTrials.gov: NCT00114361, NCT00146705. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate (TDF) effectively suppresses viral replication in chronic hepatitis B (CHB), but occasionally leads to renal impairment. We evaluated the prevalence of viral and biochemical breakthrough and renal function kinetics in renally impaired patients with CHB on reduced and on full‐dose TDF. This clinic‐based longitudinal cohort study included patients receiving full and reduced dose TDF (due to eGFR [Cockcroft‐Gault] <60 mL/min/1.73 m2). Viral and biochemical breakthroughs were assessed 1 month after starting full and reduced TDF dose until the end‐of‐follow‐up. Breakthroughs were studied in full and reduced dose TDF, and renal function (MDRD) longitudinally before and after dose reduction within patients starting on full‐dose TDF. Of 750 patients on TDF, 78 (10%) had reduced dose and 672 (90%) full dose. At the time of dose reduction, 36 (46%) patients had chronic kidney disease stage G3B. A viral breakthrough occurred in one cirrhotic dialysis‐dependent patient (dosed 300 mg weekly) which resolved without signs of decompensation, and in one patient on full dose which resolved spontaneously. One biochemical breakthrough occurred during dose reduction and resolved naturally without viral breakthrough. The MDRD improved within the first year of dose reduction (+3.0 [2.5] mL/min per year; P <.005) and remained stable thereafter. Fifty‐three (79%) patients reached an MDRD >50 mL/min during dose reduction. Low dose TDF maintains renal function and viral suppression in most renally impaired patients with CHB, even in those with advanced liver disease. This useful, yet simple strategy could be particularly viable in resource‐constrained settings. [ABSTRACT FROM AUTHOR]

Summary: Background: Guidelines recommend liver biopsy to rule out significant inflammatory activity in chronic hepatitis B (CHB) patients with elevated hepatitis B virus (HBV) DNA but without other indications for treatment. Aim: To study rates and determinants of clinically significant liver inflammation. Methods: We selected patients with HBV DNA > 2000 IU/mL from the SONIC‐B database. The presence of significant inflammation (METAVIR ≥ A2 or HAI ≥ 9) was assessed by liver biopsy and correlated with alanine aminotransferase (ALT) levels (according to AASLD upper limits of normal [ULN]) and stratified by the presence of significant liver fibrosis (Ishak ≥ 3 or METAVIR ≥ F2). Results: The cohort included 2991 patients; 1672 were HBeAg‐positive. ALT was < ULN in 270 (9%), 1‐2 times ULN in 852 (29%) and > 2 times ULN in 1869 (63%). Significant fibrosis was found in 1419 (47%) and significant inflammatory activity in 630 (21%). Significant inflammatory activity was found in 34% of patients with liver fibrosis, compared to 9.5% of those without (P < 0.001). Among patients without fibrosis, significant inflammatory activity was detected in 3.6% of those with normal ALT, 5.0% of those with ALT 1‐2 times ULN and in 13% of those with ALT > 2 times ULN (P < 0.001). ALT < 2 times ULN had a negative predictive value of 95% for ruling out significant inflammatory activity among patients without liver fibrosis. Conclusions: Among patients without significant fibrosis, an ALT level < 2 times ULN is associated with < 5% probability of significant inflammatory activity. If fibrosis can be ruled out using non‐invasive methods, liver biopsy solely to assess inflammatory activity should be discouraged. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) RNA in serum is a novel biomarker that reflects cccDNA activity. We investigated whether HBV RNA can predict serological response to peginterferon (PEG‐IFN) treatment. Serum HBV RNA levels were retrospectively measured at weeks 0, 12, 24 and 52 of therapy and after treatment discontinuation (week 78) in 266 HBeAg‐positive chronic HBV patients who had participated in a global randomized controlled trial (HBV99‐01 study). Patients received 52 weeks PEG‐IFN monotherapy (n = 136) or PEG‐IFN and lamivudine (n = 130). The primary end point was HBeAg loss 24 weeks after PEG‐IFN discontinuation. At baseline, the mean serum level of HBV RNA was 6.8 (SD 1.2) log c/mL. HBV RNA levels declined to 4.7 (1.7) log c/mL after one year of PEG‐IFN therapy alone and to 3.3 (1.2)log c/mL after combination therapy. From week 12 onward, HBV RNA level was significantly lower in patients who achieved HBeAg loss at the end of follow‐up as compared to those who did not, regardless of treatment allocation (week 12:4.4 vs 5.1 log c/mL, P =.01; week 24:3.7 vs 4.9 log c/mL, P <.001). The performance of a multivariable model based on HBV RNA level was comparable at week 12 (AUC 0.68) and 24 (AUC 0.72) of therapy. HBV RNA level above 5.5 log c/mL at week 12 showed negative predictive values of 93/67/90/64% for HBV genotypes A/B/C/D for the prediction of HBeAg loss. In conclusion, HBV RNA in serum declines profoundly during PEG‐IFN treatment. Early on‐treatment HBV RNA level may be used to predict nonresponse. [ABSTRACT FROM AUTHOR]

Background & Aims: Primary sclerosing cholangitis (PSC) is associated with an increased risk of gallbladder cancer (GBC). Gallbladder polyps potentially harbour malignancy and thus international guidelines recommend prophylactic cholecystectomy for gallbladder polyps of any size in patients with PSC. To best inform patient care we sought to quantify the malignant risk of gallbladder polyps in patients with PSC. Methods: A retrospective cohort study of patients followed in secondary and tertiary care settings in two large PSC clinics in North America was performed. Results: In total, 453 patients were included with a median (IQR) follow‐up time of 7.7 (4.1‐12) years. A gallbladder polyp was radiographically detected in 16% (n = 71) with median size (range) of 4 (2‐18) mm. In this group, post‐cholecystectomy histology (n = 17) reported benign or no polyp in 77% (n = 13), dysplasia in 5.9% (n = 1) and malignancy in 18% (n = 3). The GBC rate was 8.8 (95% CI 1.8‐25.7) per 1000 person‐years in patients with a radiographically detected gallbladder polyp. GBC was associated with polyps >10 mm, interval growth or mass‐like lesions on pre‐operative imaging. In patients who did not have cholecystectomy (n = 50), the polyp was only transiently seen in 80% (n = 40), remained stable or decreased in size in 10% (n = 5) and increased in size in 6% (n = 3). The majority of gallbladder polyps did not show significant growth over time (0.041 mm/year [95% CI −0.017 to 0.249]). Conclusions: Most gallbladder polyps in patients with PSC are benign. Short‐term surveillance imaging may be considered prior to recommending immediate cholecystectomy in patients with PSC without high‐risk imaging features. [ABSTRACT FROM AUTHOR]

Background and Aim: A recently carried out randomized controlled trial showed the benefit of a novel 20‐G fine‐needle biopsy (FNB) over a 25‐G fine‐needle aspiration (FNA) needle. The current study evaluated the reproducibility of these findings among expert academic and non‐academic pathologists. Methods: This study was a side‐study of the ASPRO (ASpiration versus PROcore) study. Five centers retrieved 74 (59%) consecutive FNB and 51 (41%) FNA samples from the ASPRO study according to randomization; 64 (51%) pancreatic and 61 (49%) lymph node specimens. Samples were re‐reviewed by five expert academic and five non‐academic pathologists and rated in terms of sample quality and diagnosis. Ratings were compared between needles, expert academic and non‐academic pathologists, target lesions, and cytology versus histological specimens. Results: Besides a higher diagnostic accuracy, FNB also provided for a better agreement on diagnosing malignancy (ĸ = 0.59 vs ĸ = 0.76, P < 0.001) and classification according to Bethesda (ĸ = 0.45 vs ĸ = 0.61, P < 0.001). This equally applied for expert academic and non‐academic pathologists and for pancreatic and lymph node specimens. Sample quality was also rated higher for FNB, but agreement ranged from poor (ĸ = 0.04) to fair (ĸ = 0.55). Histology provided better agreement than cytology, but only when a core specimen was obtained with FNB (P = 0.004 vs P = 0.432). Conclusion: This study shows that the 20‐G FNB outperforms the 25‐G FNA needle in terms of diagnostic agreement, independent of the background and experience of the pathologist. This endorses use of the 20‐G FNB needle in both expert and lower volume EUS centers. [ABSTRACT FROM AUTHOR]

Serum Hepatitis B core‐related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG‐IFN) therapy for HBeAg‐negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg‐negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG‐IFN alfa‐2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was −3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (−2.4 vs −1.0 log U/mL, P = 0.001), but no cut‐off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg −2.5 log U/mL; HBV DNA: −4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI‐95% [0.0.629‐0.855], P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI‐95% [0.629‐0.855] P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI‐95% [0.641‐0.867], P < 0.001). In conclusion, in Caucasian patients with HBeAg‐negative CHB, decline of HBcrAg during PEG‐IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG‐IFN treatment. [ABSTRACT FROM AUTHOR]

Background & Aims: The use of complementary and alternative medicine (CAM) in patients with chronic hepatitis B (CHB) can interact with antiviral treatment or influence health‐seeking behaviour. We aimed to study the use of individual CAM modalities in CHB and explore determinants of use, particularly migration‐related, socio‐economic and clinical factors. Methods: A total of 436 CHB outpatients who attended the Toronto Centre for Liver Disease in 2015‐2016 were included in this cross‐sectional study. Using the comprehensive I‐CAM questionnaire and health records, data were collected on socio‐demographic and clinical variables and on usage of 16 CAM modalities in the last year. Results: Sixty percent of patients were male, 74% were Asian and 46% were using antiviral treatment. Three‐hundred and nine (71%) patients used CAM. Vitamin/mineral preparations (45% of patients) were most commonly used. Overall CAM use and the specific use of potentially injurious CAM, such as green tea extract (9.2%) and St. John's wort (0.2%), were not associated with liver disease severity. Female sex, family history of CHB, lower serum HBV DNA, and higher socio‐economic status were independently associated with bio‐holistic CAM use, the clinically most‐relevant CAM group (P < 0.05); ethnicity, antiviral therapy use and liver disease severity were not. Conclusions: CAM use among CHB patients was extensive, especially use of vitamin and mineral preparations, but without direct influence on liver disease severity. Bio‐holistic CAM use appeared to be associated with socio‐economic status rather than with ethnicity or liver disease severity. Despite the rare use of hepatotoxins, physicians should actively inquire about it. [ABSTRACT FROM AUTHOR]

Summary: Background: Various treatment combinations of peginterferon (PEG‐IFN) and nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the optimal regimen remains unclear. Aims: To study whether PEG‐IFN add‐on increases response compared to entecavir (ETV) monotherapy, and whether the duration of ETV pretreatment influences response. Methods: Response was evaluated in HBeAg positive patients previously treated in two randomized controlled trials. Patients received ETV pretreatment for at least 24 weeks and were then allocated to 24‐48 weeks of ETV+PEG‐IFN add‐on, or continued ETV monotherapy. Response was defined as HBeAg loss combined with HBV DNA <200 IU/mL 48 weeks after discontinuing PEG‐IFN. Results: Of 234 patients, 118 were assigned PEG‐IFN add‐on and 116 continued ETV monotherapy. Response was observed in 38/118 (33%) patients treated with add‐on therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest response to add‐on therapy compared to monotherapy was observed in PEG‐IFN naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below 50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cut‐off levels, response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both P < 0.005), but not with response (P = 0.82). Conclusions: PEG‐IFN add‐on to ETV therapy was associated with higher response compared to ETV monotherapy in patients with HBeAg positive CHB. Response doubled in PEG‐IFN naive patients with HBsAg below 4000 IU/mL and HBV DNA below 50 IU/mL, and therefore identifies them as the best candidates for PEG‐IFN add‐on (Identifiers: NCT00877760, NCT01532843). [ABSTRACT FROM AUTHOR]

Summary: Background: The importance of primary biliary cholangitis as an indication for liver transplantation has probably been influenced by the introduction of therapies, and changes in selection criteria and disease epidemiology. Aims: To assess the time trends in liver transplantation for primary biliary cholangitis and to evaluate the characteristics of the patient population during the past three decades. Methods: Patients undergoing liver transplantation from 1986 to 2015 in centres reporting to the European Liver Transplantation Registry were included. We excluded combined organ transplantations and patients <18 years. Trends were assessed using linear regression models. Results: We included 112 874 patients, of whom 6029 (5.3%) had primary biliary cholangitis. After an initial increase in the first decade, the annual number of liver transplantation for primary biliary cholangitis remained stable at around 200. The proportion of liver transplantations for primary biliary cholangitis decreased from 20% in 1986 to 4% in 2015 (P < 0.001). Primary biliary cholangitis was the only indication showing a consistent proportional decrease throughout all decades. From the first to the third decade, the age at liver transplantation increased from 54 (IQR 47‐59) to 56 years (IQR 48‐62) and the proportion of males increased from 11% to 15% (both P < 0.001). Conclusions: We have found a proportional decrease in primary biliary cholangitis as indication for liver transplantation. However, despite treatment with ursodeoxycholic acid and improved disease awareness, the absolute annual number of liver transplantations has stabilised. [ABSTRACT FROM AUTHOR]

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

Purpose: Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are liver tumors that require different management. We assessed the potential of point shear wave elastography (pSWE) to differentiate FNH from HCA and the interobserver and intraobserver reliability of pSWE in the examination of these lesions and of native liver tissue (NLT).Methods: The study included 88 patients (65 FNH, 23 HCA). pSWE was performed by two experienced liver sonographers (observers 1 [O1] and 2 [O2]) and acquired within the lesion of interest and NLT. Group differences, optimal cutoff for characterization and interobserver reliability was assessed with Mann-Whitney-U, area under the ROC curce (AUROC) and intraclass correlation coefficient (ICC). Intraobserver reliability in NLT was assessed in 20 healthy subjects using ICC.Results: Median stiffness was significantly higher in FNH than in HCA (7.01 kPa vs 4.98 kPa for O1 (P = 0.017) and 7.68 kPa vs 6.00 kPa for O2 (P = 0.031)). A cutoff point for differentiation between the two entities could not be determined with an AUROC of 0.67 (O1) and 0.69 (O2). Interobserver reliability was good for lesion- stiffness (ICC = 0.86) and poor for NLT stiffness (ICC = 0.09). In healthy subjects, intraobserver reliability for NLT-stiffness was poor for O1 (ICC = 0.23) and moderate for O2 (ICC = 0.62).Conclusion: This study shows that pSWE cannot reliably differentiate FNH from HCA. Interobserver and intraobserver reliability for pSWE in NLT were insufficient. Interpretation of results gained with this method should be done with great caution. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms of immune resistance in pancreatic and ampullary cancers is crucial for the development of suitable biomarkers and effective immunotherapeutics. Our aim was to examine the expression of the immune inhibiting molecules PD-L1, Galectin-9, HVEM, IDO and HLA-G, as well as CD8+ and FoxP3+ tumor infiltrating lymphocytes (TIL), in pancreatic and ampullary cancers, and to relate their individual, as well as their combined expression, to cancer survival. Tumor tissue from 224 patients with resected pancreatic ( n = 148) and ampullary ( n = 76) cancer was used to construct tissue-microarrays. Expression of immune inhibitory molecules and TIL was examined by immunohistochemistry. We show that immune inhibitory molecules are prevalently expressed. Moreover, high tumor expression of PD-L1 ( p = 0.002), Gal-9 ( p = 0.003), HVEM ( p = 0.001), IDO ( p = 0.049), HLA-G ( p = 0.004) and high CD8/FoxP3 TIL ratio ( p = 0.006) were associated with improved cancer-specific survival. All immune biomarkers, with the exception of IDO, were individually predictive of cancer-specific survival when adjusted for clinicopathologic characteristics. For every additional immune biomarker present survival was almost two-fold prolonged (HR 0.57 95%CI 0.47-0.69, p < 0.0001). When patients with pancreatic and ampullary cancer were analyzed separately the results were similar. We conclude that pancreas and ampullary cancers are rich in expression of immune-inhibitory molecules. These molecules can be targets for future immunotherapeutics, as well as form powerful immunological biomarkers. We propose that such immune biomarker panels be included in future prospective immunotherapy trials. [ABSTRACT FROM AUTHOR]

Background and Aims Very potent direct acting antivirals for the treatment of chronic hepatitis C virus infection were recently introduced into daily clinical practice. Currently, treatment uptake is hampered by their high costs, eliciting prioritization of treatment. We aimed to evaluate the direct medical costs during interferon (IFN)-based antiviral treatment and the costs per sustained virological response (SVR) among patients with advanced hepatic fibrosis. Methods This retrospective cohort study included all consecutive patients with chronic hepatitis C virus infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) treated with IFN-based regimens in five hepatology units of tertiary care centers in Europe and Canada. Direct medical costs, expressed in 2013 Euros, during therapy were assessed. The components of care were quantified by three distinct categories: treatment, safety/ monitoring, and complications. Cost per SVR was calculated by dividing the mean cost by the SVR rate. Results In total, 672 interferon-based treatments administered to 455 patients were included. Total medical costs per patient were averaged to €14 559 (95% confidence interval [CI], €13 323-€15 836). The mean cost per SVR was €38 514 (95% CI, €35 244-€41 892). The costs per SVR were €26 105 (95% CI, €23 068-€29 296) for patients with a normal platelet count and €50 907 (95% CI, €44 151-€59 612) for patients with thrombocytopenia, with the costs per SVR of €74 961 (95% CI, €55 463-€103 541) among those patients with a platelet count below 100 * 109/L. Conclusions Because of the lower SVR rates, the cost per SVR of IFN-based treatment increased when patients with more advanced liver disease were treated. Additional costs of IFN-free therapy could be limited among these patients. [ABSTRACT FROM AUTHOR]

Background and Aim The incidence and consequences of flares during first-line nucleos(t)ide analogue therapy are largely unknown. We aimed to investigate the incidence and outcome of alanine aminotransferase (ALT) flares during long-term entecavir (ETV) in chronic hepatitis B (CHB). Methods CHB patients treated with ETV monotherapy from 11 European centers were studied. Flare was defined as > 3× increase in ALT compared with baseline or lowest on-treatment level and an absolute ALT > 3× ULN. Flares were designated as host-induced (preceded by hepatitis B virus (HBV)-DNA decline), virus-induced (HBV-DNA increase), or indeterminate (stable HBV-DNA). Results Seven hundred and twenty-nine patients were treated with ETV for median of 3.5 years. Thirty patients developed a flare with cumulative incidence of 6.3% at year 5. Baseline hepatitis B e antigen (HBeAg)-positivity (HR 2.84; P = 0.005) and high HBV-DNA (Hazard ratio (HR) 1.30; P = 0.003) predicted flares. There were 12 (40%) host-induced, 7 (23%) virus-induced, and 11 (37%) indeterminate flares. Host-induced flares occurred earlier than virus-induced (median: 15 vs 83 weeks; P = 0.027) or indeterminate flares (15 vs 109 weeks; P = 0.011). Host-induced flares were associated with biochemical remission, and HBeAg ( n = 3) and hepatitis B surface antigen ( n = 2) seroconversions were exclusively observed among patients with these flares. Virus-induced flares were associated with ETV resistance ( n = 2) and non-compliance ( n = 1). Conclusion The incidence of ALT flares during ETV was low in this real-life cohort. ETV can be safely continued in patients with host-induced flares. Treatment adherence and drug resistance must be assessed in patients with virus-induced flares. [ABSTRACT FROM AUTHOR]

Background and Aims: Patients with chronic hepatitis C virus (HCV) infection may develop cirrhosis with portal hypertension, reflected by decreased platelet count and splenomegaly. This retrospective cohort study aimed to assess changes in platelet counts after antiviral therapy among chronic HCV-infected patients with advanced fibrosis. Methods: Platelet counts and spleen sizes were recorded in an international cohort of patients with Ishak 4-6 fibrosis who started antiviral therapy between 1990 and 2003. Last measured platelet counts and spleen sizes were compared with their pre-treatment values (within 6 months prior to the start of therapy). All registered platelet count measurements from 24-week following cessation of antiviral therapy were included in repeated measurement analyses. Results: This study included 464 patients; 353 (76%) had cirrhosis and 187 (40%) attained sustained virological response (SVR). Among patients with SVR, median platelet count, increased by 35 × 109/L (IQR 7-62, P < 0.001). In comparison, patients without SVR showed a median decline of 17 × 109/L (IQR −5-47, P < 0.001). In a subgroup of 209 patients, median decrease in spleen size was 1.0 cm (IQR 0.3-2.0) for patients with SVR, while median spleen size increased with 0.6 cm (IQR −0.1-2.0, P < 0.001) among those without SVR. The changes in spleen size and platelet count were significantly correlated ( R = −0.41, P < 0.001). Conclusions: Among chronic HCV-infected patients with advanced hepatic fibrosis, the platelet counts improved following SVR and the change in platelets correlated with the change in spleen size following antiviral therapy. These results suggest that HCV eradication leads to reduced portal pressure. [ABSTRACT FROM AUTHOR]

Background & Aim Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic hepatitis C virus ( HCV) infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. Methods This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis ( Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500-749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively. Results This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (odds ratio [ OR] 2.85, 95% confidence interval [ CI] 1.38-5.90, P = 0.005) and severe neutropenia at the previous visit ( OR 5.42, 95% CI 1.34-22.0, P = 0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with pegylated interferon, severe neutropenia was not significantly associated ( OR 1.63, 95% CI 0.19-14.2, P = 0.660). Conclusions In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict. [ABSTRACT FROM AUTHOR]

Background & Aims We aimed to assess the association between the patatin-like phospholipase domain-containing-3 ( PNPLA3) I148M polymorphism, liver histology and long-term outcome in chronic hepatitis B ( CHB) patients. Methods We enrolled 531 consecutive treatment naïve CHB patients diagnosed from 1985 to 2012 with an available liver biopsy for reassessment, and sample for genetic testing. Data on all-cause mortality and hepatocellular carcinoma ( HCC) at long-term follow-up were obtained from national database registries. Results The prevalence of steatohepatitis increased with PNPLA3 CC (14%), CG (20%) and GG (43%) ( P < 0.001). The association was altered by both gender ( P = 0.010) and overweight ( P = 0.015): the effect of PNPLA3 on steatohepatitis was most pronounced among non-overweight females (adjusted OR 13.4, 95% CI: 3.7-51.6, P < 0.001), and non-overweight males (adjusted OR 2.4, 95% CI: 1.4-4.3, P = 0.002). Furthermore, PNPLA3 GG genotype was associated with iron depositions ( OR 2.8, 95% CI: 1.2-6.4, P = 0.014) and lobular inflammation ( OR 2.2, 95% CI: 1.1-4.5, P = 0.032), but not with advanced fibrosis ( OR 1.1, 95% CI: 0.7-1.8, P = 0.566). The median follow-up was 10.1 years (interquartile range 5.6 - 15.8), during which 13 patients developed HCC and 28 died. Steatohepatitis was associated with all-cause mortality [Hazard ratio ( HR) 3.1, 95% CI: 1.3-7.3, P = 0.006] and HCC ( HR 2.8, 95% CI: 0.9-9.2, P = 0.078), but no significant association was observed for PNPLA3. Conclusions In this cohort of biopsied CHB patients, PNPLA3 was independently associated with steatosis, steatohepatitis, lobular inflammation and iron depositions, but not with advanced fibrosis, HCC development or all-cause mortality. The effect of PNPLA3 on steatohepatitis was particularly pronounced among female patients without severe overweight. [ABSTRACT FROM AUTHOR]

Background & Aims Little is known about the association of serum liver enzymes with long-term outcome in the elderly. We sought to clarify the association of serum gamma-glutamyltransferase ( GGT), alkaline phosphatase ( ALP), alanine aminotransferase ( ALT) and aspartate aminotransferase ( AST) with all-cause and cause-specific mortality in an elderly population. Methods This study was embedded in the Rotterdam Study, a large population-based cohort of persons aged 55 years or older. Cox-regression analyses were performed to examine the association of baseline serum GGT, ALP, and aminotransferase levels with mortality, adjusted for age, sex, education, smoking status, alcohol intake, hypertension, diabetes mellitus, body mass index and total cholesterol levels. Liver enzyme levels were categorized according to sample percentiles; levels <25th percentile were taken as a reference. Results During a follow-up of up to 19.5 years, 2997 of 5186(57.8%) participants died: 672 participants died of causes related to cardiovascular diseases ( CVD) and 703 participants died of cancer. All serum liver enzymes were associated with all-cause mortality (all P < 0.001). Moreover, GGT was associated with increased CVD mortality ( P < 0.001), and ALP and AST with increased cancer-related mortality ( P = 0.03 and P = 0.005 respectively). Participants with GGT and ALP in the top 5% had the highest risk for all-cause mortality ( HR1.55; 95% CI 1.30-1.85 and HR1.49; 95% CI 1.25-1.78 respectively). AST and ALT <25th percentile were also associated with a higher risk of all-cause mortality. Conclusions All serum liver enzymes were positively associated with long-term mortality in this elderly population. Why participants with low ALT and AST levels have higher risk of mortality remains to be elucidated. [ABSTRACT FROM AUTHOR]

Aims In the western world, idiopathic non-cirrhotic portal hypertension ( INCPH) is a rare disease. This study aimed to investigate the histopathological features in western INCPH patients and to assess pathological differences between liver specimens of INCPH with and without HIV. Methods and results Biopsies of 70 INCPH patients (of which 15 were HIV-infected) were compared to 23 patients with non-cirrhotic portal vein thrombosis ( PVT), which served as a control group for non-cirrhotic portal hypertension. Phlebosclerosis, nodular regeneration ( NR), sinusoidal dilatation, paraportal shunting vessels, perisinusoidal fibrosis and portal tract remnants were the most prevalent morphological features of INCPH. There were significant ( P < 0.01) morphological differences between INCPH and PVT liver specimens with regard to portal tract remnants (46% versus 0%), phlebosclerosis (95% versus 65%), portal vein dilatation (34% versus 78%) and NR (56% versus 22%). The degree of NR correlated with the severity of phlebosclerosis ( P < 0.01). NR was seen more frequently in the HIV- INCPH group, compared to the non- HIV-infected patients ( P < 0.001). Conclusion Portal tract remnants, phlebosclerosis and nodular regeneration are typical features of INCPH. Sinusoidal dilatation, paraportal shunting vessels and increased portal and parenchymal vessels might represent pressure-related morphological signs of portal hypertension. Finally, more nodular regeneration was observed in HIV-associated INCPH. [ABSTRACT FROM AUTHOR]

Purpose: To explore the potential use of magnetic resonance imaging (MRI) in predicting the outcome for patients with hepatocellular carcinoma (HCC), imaging characteristics were correlated with pathological findings and clinical outcome. Materials and Methods: With permission from the Ethical Board, clinical data and tissues of resected HCC patients were collected, including the preoperative MRI. The role of MRI characteristics on recurrence and survival were evaluated with univariate and multivariate analyses. Results: Between January 2000 and December 2008, 87 patients with 104 HCCs were operated on. Microvascular invasion was present in 55 lesions (53%). HCC was characterized as well differentiated in 15 lesions (14%), as moderate in 50 lesions (48%), and as poorly differentiated in 34 lesions (33%). Due to preoperative treatment in five lesions (5%) no vital tumor was left. In 85 lesions (88%) washout of contrast was noted. Of the 87 patients, 28 (32%) with 37 lesions developed HCC recurrence; these patients had microvascular invasion significantly more often and a moderate or poorly differentiated tumor ( P < 0.001 and P = 0.025, respectively). MRI more often showed washout when HCC was moderately or poorly differentiated ( P < 0.001) or microvascular invasion was present ( P = 0.032). Conclusion: Differentiation grade and microvascular invasion are significantly associated with the presence of washout demonstrated on dynamic contrast-enhanced MRI. J. Magn. Reson. Imaging 2012;36:641-647. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Fibrosis determines prognosis and management in patients with chronic hepatitis B and C ( CHB and CHC). Transient elastography ( TE) is a promising non-invasive method to assess fibrosis. We prospectively studied the performance of TE compared to histology and also whether there are differences between CHB and CHC. Only large biopsies (≥25 mm) were used. Methods We included 241 patients with CHB ( n = 125) and CHC ( n = 116), of whom we acquired 257 liver biopsies, all preceded by elastography. We correlated liver stiffness with fibrosis stage according to the METAVIR system, inflammation (Histology Activity Index), steatosis and iron. The impact of gender, age, body mass index, alcohol, alanine aminotransferase levels, platelet count, viral load and genotype on liver stiffness was evaluated. Results The AUROC's for F ≥ 2 were 0.85 for CHB and 0.76 for CHC. AUROC's for F ≥ 3 were 0.91 for CHB and 0.87 for CHC and 0.90 and 0.91 for F4 for CHB and CHC respectively. For F ≥ 2 the cut-off value was 6.0 kPa for CHB and 5.0 kPa for CHC. The cut-off values for ≥F3 were 9.0 and 8.0 kPa for CHB and CHC, respectively, and 13.0 kPa for F4 in both CHB and CHC patients. Besides inflammation, all other remaining factors do not influence liver stiffness. Conclusion For the diagnosis of fibrosis stages F ≤ 2 TE is suboptimal, and inflammation may induce higher values. For stages F ≥ 3 TE performance is good and equal in both CHB and CHC patients. [ABSTRACT FROM AUTHOR]

The aim of the present study was to compare the decline of HBV DNA during peginterferon (PEG-IFN) therapy with spontaneous HBV DNA decline in placebo-treated patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. A total of 136 patients who participated in a randomized trial were treated with PEG-IFN alfa-2b for 52 weeks. These patients were compared with 167 patients who received a placebo for 48 weeks using linear mixed regression analysis. Response was defined as loss of HBeAg at the end of treatment (EOT). Overall, decline of HBV DNA at the EOT was significantly greater in the PEG-IFN group than in the placebo group (mean decline 2.3 log vs. 1.0 log, P < 0.001) and varied according to HBV genotype. Viral suppression was greater in the PEG-IFN group from week 4 throughout the entire treatment period ( P < 0.001). The response rate was 32% for the PEG-IFN group and 11% for the placebo group ( P < 0.001). Among responders, HBV DNA decline was greater for patients treated with PEG-IFN than with a placebo: the mean difference in HBV DNA decline was 0.7 log ( P = 0.001) at 4 weeks and 2 log ( P < 0.001) at the EOT. ALT flares (>5 times the upper limit) were associated with a greater HBV DNA decline during PEG-IFN. In conclusion, PEG-IFN therapy resulted in a greater HBV DNA decline in positive HBeAg patients than a placebo. The decline of HBV DNA was greater in patients with HBeAg loss or who exhibited an ALT flare during PEG-IFN than in patients with spontaneous HBeAg loss or flares during placebo therapy. J. Med. Virol. 83:1917-1923, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

We have developed a method to longitudinally classify subjects into two or more prognostic groups using longitudinally observed values of markers related to the prognosis. We assume the availability of a training data set where the subjects' allocation into the prognostic group is known. The proposed method proceeds in two steps as described earlier in the literature. First, multivariate linear mixed models are fitted in each prognostic group from the training data set to model the dependence of markers on time and on possibly other covariates. Second, fitted mixed models are used to develop a discrimination rule for future subjects. Our method improves upon existing approaches by relaxing the normality assumption of random effects in the underlying mixed models. Namely, we assume a heteroscedastic multivariate normal mixture for random effects. Inference is performed in the Bayesian framework using the Markov chain Monte Carlo methodology. Software has been written for the proposed method and it is freely available. The methodology is applied to data from the Dutch Primary Biliary Cirrhosis Study. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Peginterferon (PEG-IFN) results in HBeAg loss combined with virologic response in only a minority of patients with HBeAg positive chronic hepatitis B. Baseline predictors of response to PEG-IFN include HBV-genotype, pre-treatment HBV DNA levels, and ALT. The aims of this study were to develop a model, which improves the baseline prediction of response to PEG-IFN for individual patients by including early HBV DNA measurements during treatment and to establish an early indication for cessation of treatment. One hundred thirty-six patients treated with PEG-IFN were included in the study. Response was defined as loss of HBeAg and HBV DNA <10,000 copies/ml at 26 weeks post-treatment. Logistic regression analysis techniques were used to develop a dynamic prediction model with HBV DNA during the first 32 weeks of therapy. An early clinically useful rule for dis(continuation) of treatment was identified with a grid of cut-off values of HBV DNA decline during treatment. Adding HBV DNA decline to baseline prediction increased c-statistics from 0.846 to 0.857, 0.855 to 0.866 at weeks 4, 12, and 24. A HBV DNA decline of at least 2 log10 within 24 weeks was strongly associated with response when added to the baseline prediction model: OR 5.7 (95% CI: 1.70-20.0; P = 0.004). A dynamic model including HBV DNA decline during treatment provides more accurate predictions of response to PEG-IFN. The model strongly supports individual decision making on treatment (dis)continuation in patients with HBeAg positive chronic hepatitis B. It is recommended that PEG-IFN treatment is stopped by 24 weeks if HBV DNA declined <2 log10. J. Med. Virol. 82: 1135-1142, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Background: The clinical outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt (TIPS) for patients with Budd–Chiari syndrome (BCS) is as yet largely unknown. Objectives: To compare patency rates of bare and polytetrafluoroethylene (PTFE)-covered stents, and to investigate clinical outcome using four prognostic indices [Child–Pugh score, Rotterdam BCS index, modified Clichy score and Model for End-Stage Liver Disease (MELD)]. Methods: Consecutive patients with BCS who had undergone TIPS between January 1994 and March 2006 were evaluated in a retrospective review in a single centre. Results: Twenty-three TIPS procedures were performed on 16 patients. The primary patency rate at 2 years was 12% using bare and 56% using covered stents ( P=0.09). We found marked clinical improvement at 3 months post-TIPS as determined by a drop in median Child–Pugh score (10–7, P=0.04), Rotterdam BCS index (1.90–0.83, P=0.02) and modified Clichy score (7.77–2.94, P=0.003), but not in MELD (18.91–17.42, P=0.9). Survival at 1 and 3 years post-TIPS was 80% (95% CI: 59–100%) and 72% (95% CI: 48–96%). Four patients (25%) died and one required liver transplantation. Conclusions: A transjugular intrahepatic portosystemic shunt using PTFE-covered stents shows better patency rates than bare stents in BCS. Moreover, TIPS leads to an improvement in important prognostic indicators for the survival of patients with BCS. [ABSTRACT FROM AUTHOR]

Background: High-dose peginterferon-α (PegIFN-α) induction and prolongation of therapy may be an option to improve sustained virological response (SVR) rates among hepatitis C virus (HCV) non-responders, although a higher and a longer dosing of PegIFN-α may intensify side effects. Methods: We randomized 53 patients, who previously failed with standard IFN-α±ribavirin, to a high-dose induction and an extended regimen with PegIFN-α-2b [3.0 μg/kg once weekly (q.w.) 12 weeks→2.0 μg/kg q.w. 12 weeks→1.5 μg/kg q.w. 48 weeks] or a standard regimen (1.5 μg/kg q.w. 48 weeks). All patients received daily weight-based ribavirin (800–1200 mg/day). The short-form 36 health survey was used to evaluate health-related quality of life (HRQL). Results: Intention-to-treat analysis showed no significant difference in SVR rate (44% vs. 37%, P=0.62) and relapse rate (9% vs. 31%, P=0.17) between experimental and standard treatment. Overall, 80% of the [positive predictive value (PPV)] patients with rapid virological response (RVR, HCV-RNA negativity at week 4) achieved SVR. No significant dose-related differences in HRQL were seen between both groups. At baseline, genotype 2 or 3 [odds ratio (OR): 7.4, 95% confidence interval (CI): 1.4–33.3, P=0.01] and γ-glutamyltransferase (GGT) levels <2 × ULN (upper limit of normal) (OR: 6.76, 95% CI: 1.5–31.3, P=0.009) were significantly associated with SVR. Multivariate logistic regression at week 4 showed that only baseline GGT <2 × ULN (OR: 7.3, 95% CI: 1.4–38.5, P=0.01) and RVR (OR: 15.6, 95% CI: 3.2–76.9, P<0.001) were independently predictive for SVR. Conclusion: Retreatment with PegIFN-α-2b and ribavirin for a minimum of 48 weeks should be considered in all patients unresponsive to previous IFN-based therapies. Baseline GGT values and RVR are highly predictive for retreatment outcome. [ABSTRACT FROM AUTHOR]

Tha-In T, Hesselink DA, Tilanus HW, Elshove L, Wilschut AL, Hansen BE, van Gelder T, Metselaar HJ. Clinical outcome after cyclosporine dose reduction based on C2 levels in long-term liver transplant patients. Clin Transplant 2005: 19: 537–542. © Blackwell Munksgaard, 2005 Recent studies suggest that cyclosporine dose adjustment based on C2 levels results in improvement of renal function. This study investigates the effect on renal function after dose reduction based on the C2 levels in long-term liver transplant patients. In 60 patients (>1 yr after transplantation), C2 levels were assessed (target 600 ng/mL ± 20%). Dose reduction was performed when C2 >720 ng/mL. Serum creatinine concentrations were measured and creatinine clearance was calculated. Twenty-three patients (38%) had C2 values >720 ng/mL. After dose reduction, mean cyclosporine dose decreased by 25% (p < 0.01). Mean C2 value decreased by 42% (p < 0.01). Serum creatinine concentrations remained stable. After dose reduction two patients experienced recurrence of PBC, in one patient AIH recurred and rejection was diagnosed in one patient. Cyclosporine C2 concentrations above 720 ng/mL are common in long-term liver transplant patients. Dose reduction of 25% did not improve kidney function and was accompanied by immune activation. [ABSTRACT FROM AUTHOR]

Linked Content This article is linked to Harms et al and Gerussi et al papers. To view these articles, visit https://doi.org/10.1111/apt.15060 and https://doi.org/10.1111/apt.15095. [ABSTRACT FROM AUTHOR]

Rationale and aim: Recently, we described a first-order decay model for the description of a decrease in viral load during treatment with lamivudine for a chronic hepatitis B virus infection (HBV). However, more frequent sampling of viral load during the first month of treatment shows a bi-phasic viral decline. We therefore compared several mathematical models which are currently in use to describe the dynamics of various viruses and treatments. Methods: HBV DNA positive chronic hepatitis B patients were treated with lamivudine 150–600 mg daily for four weeks. During the first two days, blood samples were drawn every 6 h, then daily during the first week and weekly during the following three weeks. HBV DNA was measured with the Digene Hybrid Capture II HBV DNA test and the sensitive Roche PCR assay, both calibrated on the Eurohep standard. Results: Our HBV DNA data are most accurately described if we use the bi-phasic model previously described by Neumann et al. while introducing all consecutive data of all patients simultaneously (mixed effects model). This results in an effectiveness of blocking of viral replication of 93%, a half-life of free virus of 17 h and a half-life of infected hepatocytes of 7 day in patients treated with 150 mg of lamivudine. Conclusion: HBV dynamics during treatment with lamivudine can be explained by blocking of virion production with or without blocking of de novo infection. The bi-phasic model as described by Neumann et al. in combination with frequent blood sampling provides the most accurate fit and can be used to compare new nucleoside analogue profiles to lamivudine therapy. [ABSTRACT FROM AUTHOR]

Objectives: To describe the outcomes of preterm born infants with congenital diaphragmatic hernia (CDH; ≤32.0 weeks of gestation) and the associations between prenatal imaging markers and survival., Design: Retrospective cohort study., Setting: Multicentre study in large referral centres., Population: Infants with an isolated unilateral CDH, live born at 32.0 weeks or less of gestation, between January 2009 and January 2020., Methods: Neonatal outcomes were evaluated for infants that were expectantly managed during pregnancy and infants that underwent fetoscopic endoluminal tracheal occlusion (FETO) therapy, separately. We evaluated the association between prenatal imaging markers and survival to discharge. Prenatal imaging markers included observed to expected lung-to-head ratio (o/e LHR), side of the defect, liver position, stomach position grade, and observed to expected total fetal lung volume (o/e TFLV)., Main Outcome Measure: Survival to discharge., Results: We included 53 infants born at 30 +4 (interquartile range 29 +1 -31 +2 ) weeks. Survival in fetuses expectantly managed during pregnancy was 48% (13/27) in left-sided CDH and 33% (2/6) in right-sided CDH. Survival in fetuses that underwent FETO therapy was 50% (6/12) in left-sided CDH and 25% (2/8) in right-sided CDH. The o/e LHR at baseline was positively associated with survival in cases expectantly managed during pregnancy (odds ratio [OR] 1.20, 95% CI 1.07-1.42, p < 0.01), but not in cases that received FETO therapy (OR 1.01, 95% CI 0.88-1.15, p = 0.87). Stomach position grade (p = 0.03) and o/e TFLV were associated with survival (p = 0.02); liver position was not (p = 0.13)., Conclusions: In infants with CDH born at or before 32 weeks of gestation, prenatal imaging markers of disease severity were associated with postnatal survival., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

Background and Aims: Patients with primary biliary cholangitis (PBC) and insufficient response to ursodeoxycholic acid (UDCA), currently assessed after 1 year, are candidates for second-line therapy. The aims of this study are to assess biochemical response pattern and determine the utility of alkaline phosphatase (ALP) at six months as a predictor of insufficient response., Methods: UDCA-treated patients in the GLOBAL PBC database with available liver biochemistries at one year were included. POISE criteria were used to assess response to treatment, defined as ALP <1.67 × upper limit of normal (ULN) and normal total bilirubin at one year. Various thresholds of ALP at six months were evaluated to predict insufficient response based on negative predictive value (NPV) and that with nearest to 90% NPV was selected., Results: For the study, 1362 patients were included, 1232 (90.5%) female, mean age of 54 years. The POISE criteria were met by 56.4% (n = 768) of patients at one year. The median ALP (IQR) of those who met POISE criteria compared to those who did not was 1.05 × ULN (0.82-1.33) vs. 2.37 × ULN (1.72-3.69) at six months (p < .001). Of 235 patients with serum ALP >1.9 × ULN at six months, 89% did not achieve POISE criteria (NPV) after one year of UDCA. Of those with insufficient response by POISE criteria at one year, 210 (67%) had an ALP >1.9 × ULN at six months and thus would have been identified early., Conclusions: We can identify patients for second-line therapy at six months using an ALP threshold of 1.9 × ULN, given that approximately 90% of these patients are non-responders according to POISE criteria., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: After 1 year of ursodeoxycholic acid (UDCA), patients with primary biliary cholangitis (PBC) may have a normal GLOBE score despite high alkaline phosphatase (ALP) levels., Aim: To assess the association between ALP and liver transplantation (LT)-free survival according to the GLOBE score METHODS: Among patients with a normal or elevated GLOBE score in the Global PBC cohort, the association between ALP after 1 year of UDCA and the risk of LT/death was assessed. The LT-free survival was compared with that of a matched general population., Results: After 1 year of UDCA, ALP was associated with the risk of LT/death (aHR 1.31, 95% CI 1.003-1.72, p = 0.048) among 2729 patients with a normal GLOBE score. The 10-year LT-free survival among these patients with an ALP >2.0 × ULN was 94.0% (95% CI 90.1-97.9) for those <50 years, and 82.6% (95% CI 76.5-88.7) for those ≥50 years, which was significantly lower (p = 0.040) and similar (p = 0.736) to that of the matched population, respectively. The 10-year LT-free survival in patients ≥50 years with normal GLOBE score and normal ALP (90.8%, 95% CI 87.7-93.9) was significantly higher (p = 0.022) than the matched population. Among 1045 patients with an elevated GLOBE score, ALP was associated with LT/death only in those <50 years (aHR 1.38, 95% CI 1.06-1.81, p = 0.016)., Conclusion: The LT-free survival of patients with PBC with a normal GLOBE score is optimal in case of normal ALP levels, also in relation to the general population. Despite their generally favourable prognosis, an elevated ALP level may still indicate a need for add-on therapy., (© 2022 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Machine learning (ML) provides new approaches for prognostication through the identification of novel subgroups of patients. We explored whether ML could support disease sub-phenotyping and risk stratification in primary biliary cholangitis (PBC)., Methods: ML was applied to an international dataset of PBC patients. The dataset was split into a derivation cohort (training set) and a validation cohort (validation set), and key clinical features were analysed. The outcome was a composite of liver-related death or liver transplantation. ML and standard survival analysis were performed., Results: The training set was composed of 11,819 subjects, while the validation set was composed of 1,069 subjects. ML identified four clusters of patients characterized by different phenotypes and long-term prognosis. Cluster 1 (n = 3566) included patients with excellent prognosis, whereas Cluster 2 (n = 3966) consisted of individuals at worse prognosis differing from Cluster 1 only for albumin levels around the limit of normal. Cluster 3 (n = 2379) included young patients with florid cholestasis and Cluster 4 (n = 1908) comprised advanced cases. Further sub-analyses on the dynamics of albumin within the normal range revealed that ursodeoxycholic acid-induced increase of albumin >1.2 x lower limit of normal (LLN) is associated with improved transplant-free survival., Conclusions: Unsupervised ML identified four novel groups of PBC patients with different phenotypes and prognosis and highlighted subtle variations of albumin within the normal range. Therapy-induced increase of albumin >1.2 x LLN should be considered a treatment goal., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)