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Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS)., Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time., Results: On the 1 st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged <45 years, females aged 45-64 years (adjusted incidence rate ratio 4.21, 95% CI 3.76-4.71, p <0.001) and males ≥65 years (adjusted incidence rate ratio 14.41, 95% CI 9.62-21.60, p <0.001) were at the highest risk of being diagnosed with PBC. The male-to-female ratio of patients newly diagnosed with PBC during the study period was 1:14 in those <45 years, 1:10 in patients aged 45-64 years, and 1:4 in those ≥65 years. Point prevalence increased from 11.9 in 2008 to 21.5 per 100,000 persons in 2018. Average annual percent change in this time period was 5.94% (95% CI 5.77-6.15, p <0.05), and was the highest among the population aged ≥65 years (5.69%, 95% CI 5.32-6.36, p <0.001)., Conclusions: In this nationwide cohort study, we observed an increase in both the incidence and prevalence of PBC in the Netherlands over the past decade, with marked age and sex differences., Impact and Implications: This nationwide Dutch primary biliary cholangitis (PBC) Cohort Study, including all hospitals in the Netherlands, showed that the incidence and prevalence of PBC have increased over the last decade. The age-dependent PBC incidence rate differed for males (highest risk ≥65 years) and females (highest risk between 45 and 65 years), which may be related to a difference in the timing of exposure to environmental triggers of PBC. The largest increase in PBC prevalence over time was observed in the population aged ≥65 years, which may have implications for the use of second-line therapies. These results therefore indicate that further studies are needed to elaborate on the advantages and disadvantages of add-on therapies in the elderly population., (© 2024 The Authors.)

Background: Azathioprine (AZA) and mercaptopurine (MP) are the cornerstone of steroid-sparing strategies in autoimmune hepatitis (AIH). Up to 20% of patients do not tolerate or respond to these regimens., Aim: To evaluate retrospectively the tolerability and efficacy of tioguanine (thioguanine) (TG) therapy in selected patients with AIH and AIH variant syndromes., Methods: Records of 52 patients who received TG therapy were retrieved from nine hospitals in the Netherlands. Indications for TG treatment were intolerable side effects on AZA or MP (n = 38), insufficient response (n = 11) or first-line treatment (n = 3). Treatment efficacy was defined as normalisation of serum aminotransferases and serum immunoglobulin G., Results: No serious adverse events occurred in patients treated with TG during a median follow-up of 18 months (range 1-194). Treatment was well tolerated in 41 patients (79%), whereas four had tolerable (8%) and seven (13%) intolerable side effects. Thirty-eight patients were treated with TG after intolerable side effects on AZA or MP; 29 patients continued TG therapy of whom 24 (83%) achieved complete biochemical remission, four (14%) had incomplete and one (3%) had no response; nine discontinued treatment. Seven of 11 patients with insufficient response to AZA or MP were responsive to TG, three with complete and four with incomplete biochemical remission; four discontinued due to intolerance (n = 2) and non-response (n = 2). TG was effective in all AIH patients as first-line maintenance treatment., Conclusion: In our retrospective review of TG therapy in selected patients with AIH or AIH variants who previously failed on AZA or MP, TG appeared tolerable with biochemical efficacy., (© 2018 The Authors. Alimentary Pharmacology & Therapeutics Published by John Wiley & Sons Ltd.)

Background & Aims: In low-endemic countries it is debated whether first-generation migrants should be screened for chronic hepatitis B infection. We describe the clinical impact of five large-scale Dutch screening projects for hepatitis B in first-generation Chinese migrants., Methods: Between 2009 and 2013 five independent outreach screening projects for hepatitis B targeting first-generation Chinese migrants were conducted in five main Dutch regions. To explore the relevance of our screening we defined clinical impact as the presence of an indication for: (i) antiviral therapy, (ii) strict follow-up because of high hepatitis B DNA levels and/or (iii) surveillance for hepatocellular carcinoma., Results: In total, 4423 persons participated in the projects of whom 6.0% (n = 264) were HBsAg positive. One hundred and twenty-nine newly diagnosed HBsAg-positive patients were analysed in specialist care. Among these patients prevalence of cirrhosis was 6.9% and antiviral therapy for hepatitis B was started in 32 patients (25%). In patients without a treatment indication, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma was considered indicated in 64 patients (50%)., Conclusions: In our screening project in first-generation Chinese migrants, antiviral treatment, strict follow-up because of high hepatitis B DNA levels and/or surveillance for hepatocellular carcinoma were considered indicated in three of four analysed HBsAg-positive patients. These data show that detection of hepatitis B in Chinese migrants can have considerable impact on patient care., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Goals and Background: Spontaneous rupture is a rare complication of hepatocellular carcinoma (HCC). Treatment options consist of transcatheter arterial embolization (TAE), hepatic resection, and conservative therapy. The best approach is under debate., Study: This study presents a review of clinical data of patients with a ruptured HCC admitted to a European tertiary care center., Results: Eleven patients were included; six (55%) had underlying cirrhosis. The majority of patients (73%) had no previous history of HCC. Spontaneous HCC rupture was diagnosed using abdominal computed tomography with or without a diagnostic paracentesis. Computed tomography showed one or two tumors in eight (73%) patients; the other patients had multiple tumors or diffuse infiltrative HCC. Seven (64%) patients were initially treated by TAE and one (9%) patient underwent hepatic resection. The remaining three (27%) patients, all of whom had liver cirrhosis, received conservative therapy. Two patients initially treated by TAE underwent a delayed resection and ultimately received systemic therapy. Overall, at the end of the follow-up period, three patients were still alive at 84, 991, and 1026 days after the initial presentation. Eight (73%) patients had died after a median of 88 days (range 7-417). One year after presentation, none of the conservatively treated patients was alive compared with three out of seven (43%) patients treated with TAE with or without delayed resection., Conclusion: Patients with a spontaneously ruptured HCC have a poor prognosis. In selected patients, however, prolonged survival is possible using TAE as initial therapy with or without a delayed resection and systemic therapy.

Objective: Peginterferon (PEG-IFN) is considered as a first-line treatment option for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients., Methods: All patients enrolled in the PARC study who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN α-2a (180 μg weekly) ± ribavirin (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after the initial follow-up period of 24 weeks (mean duration 2.1 ± 0.2 years). Retreated patients were considered nonresponders., Results: Of 117 patients who completed the treatment phase, 79 (68%) were included in this LTFU study. Among 19 patients with a combined response at 24 weeks after treatment [initial responders; hepatitis B virus DNA<10 000 copies/ml (<1714 IU/ml) and normal alanine aminotransferase], 12 (63%) sustained this response through LTFU. Three additional patients showed such a response at LTFU, resulting in a total of 15 (19%) combined responders at LTFU. A marked decrease in the serum hepatitis B surface antigen (HBsAg) levels was observed in initial responders, resulting in HBsAg clearance in 26% of the patients (6% of all LTFU participants)., Conclusion: About one-third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks after treatment subsequently had a relapse during 2 years of follow-up. Despite the limited overall efficacy of PEG-IFN, patients responding to PEG-IFN treatment showed a marked decrease in serum HBsAg, resulting in a high rate of HBsAg clearance, which indicates the need for predictors of response to PEG-IFN in HBeAg-negative disease.

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., (Copyright © 2011 Wiley-Liss, Inc.)

Unlabelled: Peginterferon alfa-2a results in a sustained response (SR) in a minority of patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). This study investigated the role of early on-treatment serum hepatitis B surface antigen (HBsAg) levels in the prediction of SR in HBeAg-negative patients receiving peginterferon alfa-2a. HBsAg (Architect from Abbott) was quantified at the baseline and during treatment (weeks 4, 8, 12, 24, 36, and 48) and follow-up (weeks 60 and 72) in the sera from 107 patients who participated in an international multicenter trial (peginterferon alfa-2a, n = 53, versus peginterferon alfa-2a and ribavirin, n = 54). Overall, 24 patients (22%) achieved SR [serum hepatitis B virus (HBV) DNA level < 10,000 copies/mL and normal alanine aminotransferase levels at week 72]. Baseline characteristics were comparable between sustained responders and nonresponders. From week 8 onward, serum HBsAg levels markedly decreased in sustained responders, whereas only a modest decline was observed in nonresponders. However, HBsAg declines alone were of limited value in the prediction of SR [area under the receiver operating characteristic curve (AUC) at weeks 4, 8, and 12 = 0.59, 0.56, and 0.69, respectively]. Combining the declines in HBsAg and HBV DNA allowed the best prediction of SR (AUC at week 12 = 0.74). None of the 20 patients (20% of the study population) in whom a decrease in serum HBsAg levels was absent and whose HBV DNA levels declined less than 2 log copies/mL exhibited an SR (negative predictive value = 100%)., Conclusion: At week 12 of peginterferon alfa-2a treatment for HBeAg-negative CHB, a solid stopping rule was established with a combination of declines in serum HBV DNA and HBsAg levels from the baseline. Quantitative serum HBsAg in combination with HBV DNA enables on-treatment adjustments of peginterferon therapy for HBeAg-negative CHB.

Objectives: Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B patients are at high risk of treatment relapse after any antiviral therapy. Combining peginterferon alpha-2a with ribavirin might improve sustained response rates., Methods: Overall, 138 HBeAg-negative chronic hepatitis B patients were randomized to receive monotherapy (peginterferon alpha-2a 180 microg weekly plus placebo) or combination therapy (peginterferon alpha-2a weekly plus ribavirin 1,000 or 1,200 mg daily, depending on body weight) for 48 weeks. Post-treatment follow-up lasted 24 weeks. Analyses were based on the modified intention-to-treat population after exclusion of five patients., Results: At the end of follow-up, 14 (20%) of 69 patients assigned to monotherapy and 10 (16%) of 64 assigned to combination therapy had a combined response (hepatitis B virus (HBV) DNA <10,000 copies/ml (<1,714 IU/ml) and a normal alanine aminotransferase level, P=0.49). At the end of treatment, more patients had a combined response (25 (36%) vs. 26 (41%) in the monotherapy and combination therapy group, respectively, P=0.60), but subsequently relapsed during follow-up. Serum HBV DNA and hepatitis B surface antigen (HBsAg) levels decreased during treatment (mean change at week 48 compared with baseline -3.9 vs. -2.6 log copies/ml, P<0.001 and -0.56 vs. -0.34 log IU/ml, P=0.23, respectively). HBV DNA levels relapsed after treatment discontinuation; HBsAg remained at end-of-treatment levels. In general, combination therapy was well tolerated, although it was associated with a higher risk of anemia and neutropenia., Conclusions: Treatment with peginterferon alpha-2a resulted in a limited sustained response rate in HBeAg-negative chronic hepatitis B patients. Addition of ribavirin did not improve response to therapy.

A 62-year-old Turkish woman presented at the emergency department with severe chest pain caused by a large, submucosal oesophageal haematoma.

Background: The glycosphingolipid alpha-galactosylceramide (alpha-GalCer) is known to stimulate invariant natural killer T-cells (iNKTs) and is able to induce powerful antiviral immune responses. The present dose-escalating randomized placebo-controlled Phase I/II trial aimed to investigate antiviral activity and safety of alpha-GalCer as a novel class of treatment for chronic hepatitis B patients., Methods: Patients were randomly assigned to 0.1 microg/kg (n=8), 1 microg/kg (n=6) or 10 microg/kg (n=6) alpha-GalCer or placebo (n=7) treatment., Results: Almost all alpha-GalCer-treated patients showed a rapid and strong decrease in natural killer T-cell (NKT) numbers. Patients with high baseline NKT numbers showed immune activation, including natural killer cell activation, increased serum tumour necrosis factor-alpha and interleukin-6 levels, and development of fever. Three patients demonstrated a transient decrease in hepatitis B virus (HBV) DNA. Only one alpha-GalCer-treated patient had a sustained decrease in HBV DNA at the end of follow-up. Four patients discontinued therapy because of fever shortly after drug administration. No significant side effects were observed., Conclusions: alpha-GalCer (0.1-10 microg/kg) used as monotherapy for chronic hepatitis B infection resulted in a strong decrease of NKTs, but did not clearly affect HBV DNA and alanine aminotransferase levels. alpha-GalCer was poorly tolerated and is unlikely to be suitable as an alternative monotherapy to the current treatment regimen.

Background: Alanine aminotransferase (ALT) is one of the main indicators for inflammatory activity in chronic hepatitis B. During interferon-based therapy, approximately 25%-40% of patients exhibit an ALT flare., Objectives and Study Design: To analyze the relation between ALT and HBV-DNA during pegylated interferon alpha-2b (PEG-IFN) treatment and compare different patterns of on-treatment viral load decline with the occurrence of ALT flares., Results: Of the 123 patients included in this study 31 (25%) exhibited an ALT flare during treatment or follow-up. Six out of 8 (75%) host-induced flares, i.e. ALT flares which were followed by a HBV-DNA decrease associated with a favorable treatment outcome, occurred in patients with a delayed HBV-DNA decline pattern (delayed vs. non-delayed decline, p=.022); 5 of these 8 patients exhibited HBeAg loss and 4 even HBsAg loss at the end of follow-up. The prediction of ALT normalization was possible using on-treatment viral load. Based on the difference from baseline, the evolution of viral load and ALT level were strongly interrelated during treatment and follow-up. With a joint model we estimated a correlation coefficient of 0.38 (p<0.001) during the first 4 weeks of the treatment and of 0.72 (p<0.0001) thereafter., Conclusion: There was a strong relation between ALT and viral load in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN alpha-2b, especially after 4 weeks of treatment. Patients with a delayed decline in viral load often exhibited a host-induced flare associated with a favorable outcome.

During pregnancy several alterations in the immune status allow mothers to tolerate the genetically different foetal tissues. We investigated the evolution of liver disease during and after pregnancy in chronic hepatitis B patients. Between 1998 and 2006 there were 38 pregnancies in 31 chronic hepatitis B 's' antigen-positive women at our liver unit. Twenty-four subjects (63%) were hepatitis B 'e' antigen (HBeAg)-positive, 14 (37%) HBeAg-negative. In 13 pregnancies (34%), lamivudine therapy was started during the last trimester of pregnancy to lower hepatitis B virus (HBV) DNA levels to reduce the risk of vertical transmission. A significant increase in liver disease activity after pregnancy, defined as a three times increase in alanine aminotransferase (ALT) within 6 months after delivery, occurred in 17 of 38 patients (45%). In those treated with lamivudine during the last trimester of pregnancy, this occurred in even 8/13 patients (62%). Prediction during pregnancy of these exacerbations was not possible using HBV DNA, ALT level, HBeAg status or any other characteristic. The median maximal ALT of these exacerbations was 4.0 x ULN and none led to decompensated liver disease. In conclusion, a significant increase in liver inflammation occurs often after pregnancy. This may be due to a reactivation of the immune system after delivery. Based on our data we recommend monitoring closely and if necessary treating women with chronic HBV shortly after delivery.

Background: Strong suppression of viral replication and normalization of alanine aminotransferase is feasible with nucleos(t)ide analogues. It is estimated viral replication and liver inflammation can be controlled in 90% of patients with chronic hepatitis B with the current available treatments., Aim: To review the studies currently available on the management of chronic hepatitis B with nucleos(t)ide analogues., Results: Although very potent, nucleos(t)ide analogues are not effective in every patient. Some factors are known to influence treatment outcome, but many host and viral factors are still unknown. Stopping rules have to be defined to assess treatment efficacy in an early stage and change the regimen. Discontinuation of nucleos(t)ide analogues is often followed by reactivation of HBV. Data on the risk factors for relapse are necessary in order to decide if treatment can be safely discontinued. Another major drawback of nucleos(t)ide analogues is the emergence of resistance. The efficacy of compounds for the treatment of mutant virus and the impact of cross-resistance is largely unknown. The use of combination therapy to prevent resistance looks promising, but has to be proven., Conclusions: HBV has become a treatable disease, however much research is needed to optimize treatment for individual patients and treatment failures.

Background: Pegylated interferon alpha2b (PEG-IFN-alpha(2b) is effective for the treatment of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, although its mechanism of action remains unclear. HBeAg loss is achieved in 36% of patients after one year of PEG-IFN-alpha2b treatment and combination therapy with lamivudine is not superior to PEG-IFN-alpha2b monotherapy., Methods: Early pharmacokinetics and viral kinetics were analysed in patients treated for 52 weeks with PEG-IFN-alpha2b with or without lamivudine., Results: After 4 weeks of treatment, there was a median viral decline of 2.94 log10 copies/ml in those treated with PEG-IFN-alpha2b and lamivudine and only 0.45 log10 copies/ml in the PEG-IFN-alpha2b monotherapy group. Peak PEG-IFN-alpha2b levels were reached approximately one day after administration and subsequently declined exponentially, consistent with a viral load rebound near to baseline levels at the end of the dosing period in most patients receiving PEG-IFN-alpha2b monotherapy. Modelling of pharmacokinetics and viral kinetics data in this group revealed that viral load was minimal 3.6 days after PEG-IFN-alpha2b administration, the mean maximal and mean antiviral effectiveness was 70% and 48% with a mean infected cell loss rate of 0.07 per day, while no significant biphasic decline was observed., Conclusions: PEG-IFN-alpha2b induces a sustained response in a considerable number of patients despite limited direct antiviral activity during the first weeks of antiviral therapy.

In chronic hepatitis B, it is difficult to predict an early therapeutic response. We investigated the viral decline during therapy with pegylated interferon alpha-2b (PEG-IFN) with or without lamivudine in 266 HBeAg-positive chronic hepatitis B patients. In patients treated with PEG-IFN and lamivudine, a uniform biphasic viral decline pattern was found during therapy and there were no marked differences in viral load between those who lost HBeAg at the end of follow-up (response) or not. In contrast, those treated with PEG-IFN monotherapy exhibited different viral decline patterns. A delayed decline of at least two log from baseline HBV DNA after week 4 but before week 32 was associated with the highest response rate (63%). In comparison, response was 52% for patients with an early decline (week 0-4), 38% for a late decline (week 32-52), 27% for a posttreatment decline (week 52-78) and 11% for patients with no substantial decline. The HBsAg loss was 22% in the delayed decline pattern compared to 4% for those with early decline and none for other decline patterns. In conclusion, different patterns of decline in viral load during treatment with PEG-IFN monotherapy were associated with different rates of HBeAg and HBsAg loss at the end of follow-up. Since there was a considerable response, even in patients with a late or posttreatment decline pattern, prediction of response based on viral decline during the first months of therapy was difficult.