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Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a leading indication for liver transplantation (LT), but also occurs after LT. The prevalence of de novo MASLD (dnMASLD) after LT, based on both surveillance (svLbx) and indication biopsies (indLbx), is unknown. Furthermore, the impact of the distinct cardiometabolic risk factors on histological disease activity has not been assessed. We aimed to evaluate the prevalence of dnMASLD and the association between the cardiometabolic risk factors and histological disease activity. Methods: We performed a retrospective single‐center study in a LT cohort with indLbx and svLbx. Patients with NAFLD before LT were excluded. Results: We analyzed 249 patients who underwent either svLbx or indLbx. Forty‐eight (19.2%) had either dnMASLD (n = 26/249, 10.4%) or metabolic dysfunction associated steatohepatitis (dnMASH) (n = 22/249, 8.8%). Although dnMASLD/dnMASH was more frequent in indLbx (35.1%, p < 0.01), still 16.5% of patients with svLbx had dnMASLD/dnMASH. While overweight (p < 0.01) and diabetes (p = 0.01) were more frequent in patients with dnMASH, only overweight was associated with histological disease activity in the multivariate analysis. No impact of dnMASLD on the overall survival was observed. Conclusion: While dnMASLD is more frequent in patients with indLBX, it also occurs in 16.5% of patients without signs of graft dysfunction. Overweight has the strongest impact on histological disease activity and should be monitored carefully after LT. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Non‐selective beta‐blockers (NSBB) are a well‐established treatment in patients with clinically significant portal hypertension. However, their potential role after insertion of a transjugular intrahepatic portosystemic shunt (TIPS) still needs to be determined. Of note, recent studies suggested that favourable anti‐inflammatory effects of NSBB might be independent from pressure reduction. This study aimed to evaluate whether NSBB‐treatment is associated with amelioration of systemic inflammation (SI), hepatic decompensation and survival after TIPS‐insertion. Methods: In a retrospective study comprising 305 consecutive patients, we investigated the impact of NSBB‐intake at TIPS‐placement on periinterventional cirrhosis‐associated complications and continued NSBB‐treatment after discharge on complications including hepatic decompensation and mortality during 1‐year follow‐up, employing multivariable competing‐risk‐analyses. In a prospective cohort including 45 patients, we performed a comprehensive analysis of SI analysing 48 soluble inflammatory markers (SIMs) at baseline plus 3 and 6 months after TIPS‐insertion. Results: Overall, 175 (57.4%) patients received NSBB‐therapy prior to TIPS‐insertion; upon discharge, this decreased to 131 (22.9%), with 36 (27.5%) discontinuing NSBB within 1‐year follow‐up. Neither NSBB‐therapy at TIPS‐insertion nor treatment‐continuation after discharge were associated with lower risks for hepatic decompensation, individual cirrhosis‐associated complications or mortality neither in the periinterventional period nor during follow‐up. Similarly, in the prospective cohort NSBB‐intake was not linked to lower levels or a more prominent change of WBC, CRP or any other SIM at any of the investigated time points. Conclusion: NSBB‐therapy at the time of TIPS‐insertion and its (dis‐)continuation afterwards seems to have no significant impact on SI, development of hepatic decompensation and survival. [ABSTRACT FROM AUTHOR]

Background and Aims: Chronic hepatitis delta represents a major global health burden. Clinical features of hepatitis D virus (HDV) infection vary largely between different regions worldwide. Treatment approaches are dependent on the approval status of distinct drugs and financial resources. Methods: The Hepatitis Delta International Network (HDIN) registry involves researchers from all continents (Wranke, Liver International 2018). We here report long‐term follow‐up data of 648 hepatitis D patients recruited by 14 centres in 11 countries. Liver‐related clinical endpoints were defined as hepatic decompensation (ascites, encephalopathy and variceal bleeding), liver transplantation, hepatocellular carcinoma or liver‐related death. Results: Patient data were available from all continents but Africa: 22% from Eastern Mediterranean, 32% from Eastern Europe and Central Asia, 13% from Central and Southern Europe, 14% from South Asia (mainly Pakistan) and 19% from South America (mainly Brazil). The mean follow‐up was 6.4 (.6–28) years. During follow‐up, 195 patients (32%) developed a liver‐related clinical event after 3.5 (±3.3) years. Liver cirrhosis at baseline and a detectable HDV RNA test during follow‐up were associated with a worse clinical outcome in multivariate regression analysis while patients receiving interferon alfa‐based therapies developed clinical endpoints less frequently. Patients from South Asia developed endpoints earlier and had the highest mortality. Conclusions: The HDIN registry confirms the severity of hepatitis D and provides further evidence for HDV viraemia as a main risk factor for disease progression. Hepatitis D seems to take a particularly severe course in patients born in Pakistan. There is an urgent need to extend access to antiviral therapies and to provide appropriate education about HDV infection. [ABSTRACT FROM AUTHOR]

There is an urgent need for new high‐quality markers for the early detection of hepatocellular carcinoma (HCC). Åström et al. suggested that S2‐bound α1‐acid glycoprotein (AGP) might be a promising marker. Consequently, we evaluated the predictive advantage of S2‐bound AGP in the early detection of HCC. In a retrospective case–control study of patients chronically infected with hepatitis C virus (HCV) and treated with direct‐acting antiviral agents (n = 93), we measured S2‐bound AGP using the HepaCheC® ELISA kit (Glycobond AB, Linköping, SE) at the start of treatment, end of treatment and follow‐up (maximum: 78 months). Patients were retrospectively propensity score matched (1:2). Thirty‐one patients chronically infected with HCV developed HCC after a sustained virological response, while 62 did not. In addition, samples of patients with chronic hepatitis B virus infection, metabolic dysfunction‐associated steatotic liver disease and HCC of different etiologies were analysed. S2‐bound AGP elevation in HCC patients was confirmed. However, we did not observe a predictive advantage of S2‐bound AGP for the early detection of HCC during treatment and follow‐up. Interestingly, S2‐bound AGP levels correlated with aspartate aminotransferase (ρ =.56, p = 9.5×10−15) and liver elastography (ρ =.67, p = 2.2×10−16). Of note, S2‐bound AGP decreased in patients chronically infected with HCV after treatment‐induced HCV clearance. Fucosylated S2‐bound AGP levels were elevated in patients with chronic HCV and HCC. The potential role of S2‐bound AGP as a novel tumour marker requires further investigation. [ABSTRACT FROM AUTHOR]

Background and Aims: Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of U.S. HDV prevalence. We aim to provide an updated assessment of HDV prevalence in the U.S. using a comprehensive literature review and meta-analysis approach. Methods: A comprehensive literature review of articles reporting HBsAg seropreva-lence and anti-HDV prevalence was conducted to calculate country-specific rates and pooled prevalence of CHB and HDV using meta-analyses. Country-specific CHB and HDV rate estimates were combined with number of foreign-born (FB) persons in the U.S. in 2022 from U.S. Census Bureau to estimate total numbers of FB with CHB and HDV, respectively. These estimates were further combined with updated estimates of U.S.-born persons with CHB and HDV to yield the total number of persons with CHB and HDV. Results: In 2022, we estimated 1.971 million (M) (95% CI 1.547-2.508) persons with CHB; 1.547 M (95% CI 1.264-1.831) were FB and 0.424 M (95% CI: 0.282-0.678) were U.S.-born. The weighted average HDV prevalence among FB persons in the U.S. was 4.20% (64938 [95% CI 33055-97392] persons), among whom 45% emigrated from Asia, 25% from Africa, and 14% from Europe. When combined with updated estimates of U.S.-born persons with HDV, we estimate 75005 (95% CI: 42187-108393) persons with HDV in the U.S. Conclusions: Including both FB and U.S.-born persons, we estimated that 1.971M and 75005 persons were living with CHB and HDV, respectively, in the U.S. in 2022. [ABSTRACT FROM AUTHOR]

Foreign‐born (FB) persons represent a large proportion of adults with chronic hepatitis B (CHB) in Canada due to higher prevalence rates in countries of birth for FB persons. Suboptimal awareness and low rates of hepatitis delta virus (HDV) testing contribute to underdiagnosis and gaps in accurate estimates of Canada HDV prevalence. We aim to provide an assessment of CHB and HDV prevalence in Canada using a comprehensive literature review and meta‐analysis. A comprehensive literature review of articles reporting HBsAg seroprevalence and anti‐HDV prevalence was conducted to calculate country‐specific rates and pooled prevalence of CHB and HDV using meta‐analyses. Country‐specific CHB and HDV rate estimates were combined with number of FB persons in Canada in 2021 from Statistics Canada to estimate total numbers of FB with CHB and HDV, respectively. These estimates were combined with estimates of Canada‐born persons with CHB and HDV to yield the total number of persons with CHB and HDV. In 2021, we estimated 0.550 million (M) (95% CI 0.488–0.615) persons with CHB; 0.344 M (95% CI 0.288–0.401) were FB and 0.206 M (95% CI: 0.200–0.214) were Canada‐born. The weighted average HDV prevalence among FB persons in Canada was 5.19% (17,848 [95% CI 9611–26,052] persons), among whom 50% emigrated from Asia and 31% from Africa. When combined with estimates of Canada‐born persons with HDV, we estimate 35,059 (95% CI: 18,744–52,083) persons with HDV in Canada. In conclusion, we estimate 0.550 M and 35,059 persons living with CHB and HDV, respectively, in Canada in 2021. [ABSTRACT FROM AUTHOR]

Summary: Background: Noninvasive tests (NITs) have been proposed as an alternative to liver biopsy for diagnosing liver cirrhosis. The evidence of NIT performance in patients with chronic hepatitis D (CHD) is limited. Aims: To evaluate the diagnostic performance of liver stiffness measurement (LSM) and other NITs in CHD patients. Methods: We evaluated the diagnostic performance of LSM by transient elastography for the detection of liver cirrhosis in a retrospective, multicentre cohort of 144 CHD patients with paired (±6 months) LSM and liver biopsies. Results: Cirrhosis was diagnosed histologically in 22 patients (15.3%). Mean LSM was significantly higher in patients with cirrhosis compared to those without fibrosis (23.4 vs 10.2 kPa, p < 0.0001) or with intermediate fibrosis (23.4 vs 13.5 kPa, p < 0.0001). In the detection of liver cirrhosis, LSM was superior to other NITs (AUROCs: 0.89 [LSM], 0.87 [D4FS], 0.74 [APRI], 0.73 [FIB‐4], and 0.69 [AAR]). The optimal cut‐off for identifying patients with liver cirrhosis was ≥15.2 kPa (Se 91%, Sp 84%, PPV 50%, NPV 98%). The ideal cut‐off for diagnosing non‐advanced liver fibrosis (Metavir ≤2) was <10.2 kPa (Se 55%, Sp 86%, PPV 90%, NPV 45%), correctly identifying 90% of patients. Data were validated in an independent cohort of 132 CHD patients. Conclusions: LSM is a useful tool for identifying patients at risk for liver cirrhosis and is superior to other NITs. The cut‐offs of <10.2 and < 15.2 kPa reliably diagnose non‐advanced liver fibrosis and exclude cirrhosis in the majority of patients. However, LSM cannot completely replace liver biopsy in CHD patients. [ABSTRACT FROM AUTHOR]

Background and Aims: Previous studies have shown suboptimal screening for hepatitis D virus (HDV) among patients with chronic hepatitis B (CHB). This study presents the cascade of care for HDV infection in a major secondary referral centre in Southern Stockholm, Sweden. Methods: HBsAg+ve patients attending Karolinska University Hospital (KUH) from 1992 to 2022 were identified. The prevalence of anti‐HDV and/or HDV RNA positivity, interferon (IFN) therapy and maintained virological responses (MVR) after HDV treatment were assessed. Also, time to anti‐HDV testing was analysed in relation to liver‐related outcomes with logistic regression. Results: Among 4095 HBsAg+ve persons, 3703 (90.4%) underwent an anti‐HDV screening; within a median of 1.8 months (range 0.0–57.1) after CHB diagnosis. This screening rate increased over time, to 97.9% in the last decade. Overall, 310 (8.4%) were anti‐HDV+ve, of which 202 (65.2%) were HDV RNA+ve. Eighty‐five (42%) received IFN, and 9 (10.6%) achieved MVR at the last follow‐up. The predictive factors for anti‐HDV screening were Asian origin, diagnosis after the year 2012, HIV co‐infection (negative factor) and HBV DNA level < 2000 IU/mL in univariable analysis, while HIV co‐infection was the only remaining factor in multivariable analysis. Delayed anti‐HDV test >5 years was independently associated with worsened liver‐related outcomes (adjusted odds ratio = 7.6, 95% CI 1.8–31.6). Conclusion: Higher frequency of HDV screening than previously published data could be seen among CHB patients at KUH in a low‐endemic setting. Receiving a delayed screening test seems to be associated with worse outcomes, stressing the need of a strategy for timely HDV diagnosis. [ABSTRACT FROM AUTHOR]

Background and Aims: The presence of significant liver fibrosis associated with non‐alcoholic steatohepatitis (NASH) is regarded as the major prognostic factor in non‐alcoholic fatty liver disease (NAFLD). Identification of patients at risk for NASH with significant fibrosis is therefore important. Although the established fibrosis score FIB‐4 is suitable to exclude advanced fibrosis, it does not allow the prediction of significant fibrosis in NAFLD patients. We therefore evaluated whether the hepatokine fibroblast growth factor 21 (FGF21), a regulator of glucose and lipid metabolism, might identify 'at‐risk NASH' in NAFLD. Methods: FGF21 levels were assessed by enzyme‐linked immunosorbent assay in sera from an exploration (n = 137) and a validation (n = 88) cohort of biopsy‐proven NAFLD patients with different disease activity and fibrosis stages. In addition, we evaluated whether the use of FGF21 could improve risk stratification in NAFLD patients with low (<1.3) or intermediate (1.3–2.67) FIB‐4. Results: FGF21 levels could significantly discriminate between NASH and non‐alcoholic fatty liver (NAFL) patients, even in the absence of diabetes. Moreover, patients with NASH and fibrosis ≥F2 showed significantly higher FGF21 levels compared to NAFLD patients without significant fibrosis. Significantly elevated FGF21 levels could even be detected in NAFLD patients with NASH and significant fibrosis despite low or intermediate FIB‐4. Conclusion: Serological FGF21 detection might allow the identification of NAFLD patients at risk and improves patient stratification in combination with FIB‐4. [ABSTRACT FROM AUTHOR]

Chronic hepatitis C virus (HCV) infections compromise natural killer (NK)‐cell immunity. Direct‐acting antivirals (DAA) effectively eliminate HCV, but the long‐term effects on NK cells in cured patients are debated. We conducted a proteomic study on CD56+ NK cells of chronic HCV‐infected patients before and 1 year after DAA therapy. Donor‐variation was observed in NK‐cell proteomes of HCV‐infected patients, with 46 dysregulated proteins restored after DAA therapy. However, 30% of the CD56+ NK‐cell proteome remained altered 1 year post‐therapy, indicating a phenotypic shift with low donor‐variation. NK cells from virus‐negative cured patients exhibited global regulation of RNA‐processing and pathways related to "stimuli response", "chemokine signaling", and "cytotoxicity regulation". Proteomics identified downregulation of vesicle transport components (CD107a, COPI/II complexes) and altered receptor expression profiles, indicating an inhibited NK‐cell phenotype. Yet, activated NK cells from HCV patients before and after therapy effectively upregulated IFN‐γ and recruited CD107a. Conversely, reduced surface expression levels of Tim‐3 and 2B4 were observed before and after therapy. In conclusion, this study reveals long‐term effects on the CD56+ NK‐cell compartment in convalescent HCV patients 1 year after therapy, with limited abundance of vesicle transport complexes and surface receptors, associated with a responsive NK‐cell phenotype. [ABSTRACT FROM AUTHOR]

Background and Aims: Hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) development and progression. The aim of this study was to mechanistically investigate the involvement of Hippo signalling in HBV surface antigen (HBsAg)‐dependent neoplastic transformation. Methods: Liver tissue and hepatocytes from HBsAg‐transgenic mice were examined for the Hippo cascade and proliferative events. Functional experiments in mouse hepatoma cells included knockdown, overexpression, luciferase reporter assays and chromatin immunoprecipitation. Results were validated in HBV‐related HCC biopsies. Results: Hepatic expression signatures in HBsAg‐transgenic mice correlated with YAP responses, cell cycle control, DNA damage and spindle events. Polyploidy and aneuploidy occurred in HBsAg‐transgenic hepatocytes. Suppression and inactivation of MST1/2 led to the loss of YAP phosphorylation and the induction of BMI1 expression in vivo and in vitro. Increased BMI1 directly mediated cell proliferation associated with decreased level of p16INK4a, p19ARF, p53 and Caspase 3 as well as increased Cyclin D1 and γ‐H2AX expression. Chromatin immunoprecipitation and the analysis of mutated binding sites in dual‐luciferase reporter assays confirmed that the YAP/TEAD4 transcription factor complex bound and activated the Bmi1 promoter. In chronic hepatitis B patients, paired liver biopsies of non‐tumour and tumour tissue indicated a correlation between YAP expression and the abundance of BMI1. In a proof‐of‐concept, treatment of HBsAg‐transgenic mice with YAP inhibitor verteporfin directly suppressed the BMI1‐related cell cycle. Conclusion: HBV‐associated proliferative HCC might be related to the HBsAg‐YAP‐BMI1 axis and offer a potential target for the development of new therapeutic approaches. [ABSTRACT FROM AUTHOR]

Treatment of hepatitis D virus (HDV) infection has been based on the administration of interferon‐alfa for more than three decades. First studies to treat HDV‐infected patients with type 1 interferons were already performed in the 1980s. Several smaller trials and case series were reported thereafter. During the mid 2000s the use of pegylated interferons for hepatitis D was established. Since then, additional trials were performed in different countries exploring strategies to personalize treatment including extended treatment durations. The overall findings were that about one‐quarter to one‐third of patients benefit from interferon treatment with persistent suppression of HDV replication. However, only few patients achieve also functional cure of hepatitis B with HBsAg loss. Importantly, several studies indicate that successful interferon treatment is associated with improved clinical long‐term outcomes. Still, only a proportion of patients with hepatitis D can be treated with interferons. Even though alternative treatments are currently developed, it is likely that pegylated interferon‐alfa will still have an important role in the management of hepatitis D – either alone or in combination. Therefore, better biomarkers are needed to select patients with a high likelihood to benefit from interferon‐based treatments. In this review we are discussing basic principles of mode of action of interferon alpha against HDV, summarize previous data on interferon treatment of hepatitis D and give an outlook on potential combinations with novel drugs currently in development. [ABSTRACT FROM AUTHOR]

Bulevirtide (BLV) is an entry inhibitor blocking entry of HBsAg into hepatocytes by interfering with the bile acid transporter Na+‐taurocholate co‐transporting polypeptide. We here investigated if bile acid levels before or during BLV treatment would correlate with HDV RNA declines. We studied 20 patients with compensated HDV infection receiving a daily dose of 2 mg bulevirtide subcutaneously qd for at least 24 weeks. ALT levels improved in all patients including 13/20 patients showing normal ALT values at treatment Week 24. An HDV RNA drop of at least 50% was evident in 20/20 patients at Week 24 including 10 patients showing a ≥ 2 log HDV RNA decline. Elevated bile acid levels were detected already before treatment in 10 patients and further increased during BLV administration with different kinetics. Baseline bile acids were associated with higher transient elastography values (p =.0029) and evidence of portal hypertension (p =.0004). Bile acid levels before treatment were associated with HDV RNA declines throughout therapy, but not at Week 24 (rho = −0.577; p =.0078; rho = −0.635, p =.0026; rho = −0.577, p =.0077; rho = −0.519, p =.0191; rho = −0.564, p =.0119 and rho = −0.393, p =.087 at treatment Weeks 2, 8, 12, 16, 20 and 24, respectively). However, bile acid increases during treatment were not associated with HDV RNA or ALT declines at any of the time points. BLV‐induced increases in bile salts do not correlate with HDV RNA declines suggesting that the inhibitory effects of BLV on NTCP differ between blocking bile acid transport and hindering HBsAg entry. If baseline bile salt levels could be useful to predict virological response remains to be confirmed. [ABSTRACT FROM AUTHOR]

The entry inhibitor bulevirtide (BLV) is a new treatment option for patients with chronic hepatitis D virus (HDV) infection and compensated liver disease. The aim of this study was to investigate the kinetic and predictive value of markers reflecting HBV cccDNA transcriptional activity and host immune response activity during BLV treatment in a real‐life cohort of HDV infected patients. Levels of HDV RNA, HBV RNA, hepatitis B core related antigen (HBcrAg) and hepatitis B core antibodies (anti‐HBc) were measured in 16 patients before (BL), after three (3M) and six (6M) months of treatment with BLV. All patients received nucleos(t)ide analogue treatment. HDV RNA declined in all patients during treatment. 38% (6/16) showed ≥ 2 log HDV RNA decline from BL to 6M and 11 patients (69%) normalized ALT levels. HBV RNA levels were low and only detectable in two to four patients. HBcrAg levels declined in 75% (12/16) of patients. Median HBcrAg levels declined significantly from BL to 6M (3.75 logU/ml (IQR 2.93‐4.78) vs. 3.4 logU/ml (IQR 2‐4.68), p=0.002). A similar trend was shown for anti‐HBc between BL and 6M. Levels of HBcrAg or anti‐HBc did not differ significantly between patients with or without ≥ 2 log HDV RNA decline from BL to 6M.After 6 months treatment with BLV, levels of HBcrAg showed a significant decline, while HBV RNA and anti‐HBc levels did not change. Reduction of HBV cccDNA transcriptional activity and immunological effects of antiviral treatment might explain these changes. [ABSTRACT FROM AUTHOR]

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes—from the municipality level to the EU level—were launched, resulting in an overall decrease in viremic HCV infections and liver‐related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID‐19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct‐acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost‐saving than treating and caring for patients with liver‐related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale‐up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call‐to‐Action' statement supported by all the major relevant European associations in the field. [ABSTRACT FROM AUTHOR]

Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow‐up strategies in PSC with the hypothesis that regular imaging improves survival. Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow‐up from 1 January 2000, until death or last clinical follow‐up alive. The primary endpoint was all‐cause mortality. Results: A broad variety of different follow‐up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow‐up, was 0.61 (0.47–0.80) for scheduled imaging with and without ERCP; 0.64 (0.48–0.86) for US/MRI and 0.53 (0.37–0.75) for follow‐up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high‐grade dysplasia as a time‐dependent covariate, HR 0.57 (0.44–0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow‐up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed. Conclusions: Follow‐up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures. [ABSTRACT FROM AUTHOR]

Summary: Background: Acute kidney injury (AKI) is a frequent complication in patients with decompensated cirrhosis. Studies reported conflicting results regarding the nephrotoxic potential of iodinated contrast medium (CM) for computer tomography (CT). Aim: To investigate the impact of diagnostic CM application on kidney function in patients with decompensated cirrhosis. Methods: First, we evaluated the impact of diagnostic CM‐CT on AKI incidence in a cross‐sectional approach. Second, we analysed 28‐day AKI incidence post‐CM‐CT in patients with impaired kidney function (i.e., creatinine >133 μmoL/L). Third, we excluded all patients with relevant interventions besides CM‐CT. All remaining patients were matched via propensity score matching (PPSM) and further analysed. Last, we validated the results in an independent dataset of prospectively collected registry data of 118 patients with decompensated cirrhosis. Here, plasma samples were analysed regarding neutrophil‐gelatinase‐associated‐lipocalin (NGAL). Results: Of the 611 included patients, 98 (16%) received CM‐CT. CM‐CT was not associated with AKI in the cross‐sectional approach (CM‐CT:8% vs. no CM‐CT:15%; p = 0.08). Furthermore, CM‐CT was not associated with higher 28‐day AKI incidence among patients with impaired kidney function (HR:0.79; 95% CI 0.45–1.38; p = 0.40). The PPSM cohort revealed no association between CM‐CT and AKI or severe AKI (HR:1.28, p = 0.45 and HR:1.62; p = 0.43). Moreover, CM‐CT did not result in worsening of kidney function after CM application. In the validation cohort, CM‐CT was also not linked to AKI (p = 0.85) and NGAL levels were not increased in those with CM‐CT (CM‐CT:309 ng/ml vs. No CM‐CT:266 ng/ml, p = 0.35). Conclusion: Decompensated cirrhosis per se should not preclude diagnostic CM‐CT. [ABSTRACT FROM AUTHOR]

Background and Aims: Low anti‐HBc serum levels at the time of therapy cessation were linked to a higher relapse risk in predominantly HBeAg‐positive cohorts. We investigated the association of anti‐HBc levels with relapse in HBeAg‐negative patients. Methods: Serum levels of anti‐HBc, HBsAg and HBcrAg were determined in 136 HBeAg‐negative patients, participating in a vaccination trial (ABX‐203, NCT02249988), before treatment cessation or vaccination. Importantly, vaccination showed no impact on relapse. The correlation between the biomarkers and their predictive value for relapse (HBV DNA >2000 IU/ml ± ALT >2xULN) was investigated. Results: After therapy cessation 50% (N = 68) of patients relapsed. Median anti‐HBc prior to treatment stop was significantly higher among relapsers compared to off‐treatment responders (520 IU/ml vs. 330 IU/mL, p =.0098). The optimal anti‐HBc cut‐off to predict relapse was 325 IU/ml according to the Youden‐Index. About 35% of patients with anti‐HBc level < 325 IU/ml versus 60% of those with values ≥325 IU/mL relapsed (p =.0103; sensitivity 50%, specificity 75%). Combining the optimal cut‐offs of HBsAg (>3008 IU/mL) or HBcrAg (≥1790 U/ml) with anti‐HBc increased the proportion of patients with relapse to 80% (p <.0001) and 74% (p =.0006), respectively. Conclusion: In contrast to predominantly HBeAg‐positive cohorts, in our cohort of HBeAg‐negative patients lower anti‐HBc levels are associated with a significantly lower relapse risk after nucleos(t)ide analogue cessation. The vast majority of included patients were either genotype B or C and the applicability to other genotypes has to be further evaluated. However, anti‐HBc level as an indicator of the host response might be prospectively further explored for prediction models. [ABSTRACT FROM AUTHOR]

Summary: Background: Onset of refractory ascites is the hallmark of end‐stage liver disease. If liver transplantation (LTx) is not available and contraindications for a transjugular portosystemic shunt (TIPS) are present, repeated paracentesis remains the standard of care (SOC). Home‐based, tunnelled peritoneal catheters (PeCa) have been suggested as an alternative treatment option. However, data on patients with cirrhosis are scarce. Aim: To evaluate the safety of PeCa in these patients compared to SOC. Methods: Overall, 223 patients with cirrhosis, a contraindication for TIPS and refractory ascites were included in this retrospective study. PeCa implant was performed in 152 patients, whereas 71 were treated with SOC. Analysed end points included device explant‐free survival, mortality, acute kidney injury (AKI) and hyponatraemia. In the second approach, propensity score matching (PPSM) was performed to adjust for confounding factors. Results: In patients with PeCa, median device explant‐free survival was 74 days and 52 explants were recorded within the first 90 days. Within 90 days, patients with PeCa had lower mortality than SOC (p = 0.11), and spontaneous bacterial peritonitis (SBP) incidence did not differ (p = 0.82). Regarding AKI and hyponatraemia, there was a trend towards a higher incidence in the PeCa group (p = 0.13 and p = 0.08), and the risk for rehospitalisation was higher in those with a PeCa (HR: 2.11, p = 0.04). After PPSM, mortality was lower in the PeCa group (HR:0.40; p = 0.03), whereas the incidence of SBP and hyponatraemia was comparable (p = 0.80 and p = 0.28) and AKI was more frequent in those with a PeCa (p = 0.08). Conclusion: The implant of PeCa allows home‐based therapy of patients with cirrhosis and refractory ascites and a contraindication for TIPS. However, the risk for complications has to be considered and prospective studies are needed. [ABSTRACT FROM AUTHOR]

Soluble inflammatory mediators (SIM) can be predictive of treatment outcome in antiviral treatment of chronic hepatitis C. Recently, it was shown that a subgroup of patients can be cured with four weeks of therapy. We here profiled patients for 70 SIM before and during treatment of hepatitis C with glecaprevir/pibrentasvir (GLE/PIB) +/− ribavirin. Proximity extension assay was performed in a total of 32 patients. Pre‐treatment SIM profiles did not distinguish patients achieving an SVR (n = 21) from patients experiencing antiviral relapse (n = 11). However, after 4 weeks of therapy, eight markers were identified that could distinguish patients with SVR from the relapsed group, namely MMP‐10, CCL20, CXCL11, FGF‐23, TNF, MCP‐2, IL‐18R1 and CXCL10. Thus, this study shows that a distinct on‐treatment immune profile is associated with cure of HCV infection after ultrashort treatment. [ABSTRACT FROM AUTHOR]

Background and Aims: Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. Methods: Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age‐adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N‐acetyl‐aspartate, choline, creatine, myo‐inositol and glutamine + glutamate in frontal‐ (fWM) and parietal white matter (pWM). One‐way analysis of variance and Kruskal‐Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. Results: HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N‐acetyl‐aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. Conclusion: The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC. [ABSTRACT FROM AUTHOR]

Unconventional T cells (UTCs) are a heterogeneous group of T cells that typically exhibit rapid responses toward specific antigens from pathogens. Chronic hepatitis C virus (HCV) infection causes dysfunction of several subsets of UTCs. This altered phenotype and function of UTCs can persist over time even after direct‐acting antiviral (DAA)‐mediated clearance of chronic HCV. However, it is less clear if and how UTCs respond in acute, symptomatic HCV infection, a rare clinical condition, and if rapid DAA treatment of such patients reverses the caused perturbations within UTCs. Here, we comprehensively analyzed the phenotype and reinvigoration capacity of three major UTC populations, mucosal‐associated invariant T (MAIT) cells, γδ T cells, and CD4 and CD8 double‐negative αβ T cells (DNT cells) before, during, and after DAA‐mediated clearance of acute symptomatic HCV infection. Furthermore, MAIT cell functionality was systematically studied. We observed a reduced frequency of MAIT cells. However, remaining cells presented with a near‐to‐normal phenotype in acute infection, which contrasted with a significant dysfunction upon stimulation that was not restored after viral clearance. Notably, DNT and γδ T cells displayed a strong activation ex‐vivo in acute HCV infection, which subsequently normalized during the treatment. In addition, DNT cell activation was specifically associated with liver inflammation and inflammatory cytokines. Altogether, these data provide evidence that UTCs respond in a cell type‐specific manner during symptomatic HCV infection. However, even if early treatment is initiated, long‐lasting imprints within UTCs remain over time. [ABSTRACT FROM AUTHOR]

LINKED CONTENT: This article is linked to Sandmann et al papers. To view these articles, visit https://doi.org/10.1111/apt.17878 and https://doi.org/10.1111/apt.17923 [ABSTRACT FROM AUTHOR]

Background and aims: Immunoglobulin G4‐associated cholangitis (IAC) is characterized by distinctly elevated immunoglobulin G4 in serum (sIgG4) and responds well to corticosteroid therapy. Primary Sclerosing Cholangitis (PSC) is a progressive liver disease without causal treatment options usually not responding to immunosuppression. Increased serum levels of sIgG4 in patients with PSC, that do not meet criteria of IAC, have been reported in 10%‐25%. Therefore, we aimed to characterize this subgroup of patients in a retrospective, multicenter study. Methods: sIgG4 values of 289 patients with PSC from three German university hospitals were analysed. Patients with elevated sIgG4 levels were identified and further characterized by clinical and biochemical parameters and by cholangiographic presentation. Clinical endpoints, death and liver transplantation were compared between groups. Parameters associated with outcome were identified with Cox regression analysis. Results: 14.5% of patients with PSC showed increased sIgG4 levels (PSC‐IgG4), presented with significantly higher (P <.02) albumin, aspartate‐aminotransferase, bilirubin and alkaline phosphatase and had a significant lower prevalence of a concomitant autoimmune hepatitis (P =.025). Cholangiogram obtained via ERC showed extrahepatic dominant strictures more often in the PSC‐IgG4 subgroup (P =.047). The disease severity models Amsterdam‐Oxford‐Score (P =.018) and Mayo‐Risk‐Score (P =.025) predicted lower survival rates for the PSC‐IgG4 subgroup. Transplant‐free survival after first diagnosis of PSC was shorter in patients with elevated sIgG4 (11.6 vs 15.1 years, P =.001). Conclusion: Patients with PSC and elevated sIgG4 should be considered as a distinct subgroup, characterized by different clinical and cholangiographical features and are associated with an inferior outcome. [ABSTRACT FROM AUTHOR]

The number of patients diagnosed with hepatitis C virus (HCV) is markedly higher than the number initiating treatment indicating gaps in the care cascade, likely centred around reaching at‐risk populations. Understanding changing characteristics of patients with HCV allows for targeted programs that increase linkage to care. We investigated changes in demographic and clinical characteristics of patients registered in the German Hepatitis C‐Registry (DHC‐R) from 1 January 2014 to 31 December 2019. The DHC‐R is an ongoing, noninterventional, multicentre, prospective, observational cohort registry including 327 German centres. Patient characteristics were analysed over time in 7 phases for all patients completing a screening visit. Overall, 14,357 patients were enrolled. The percentage of treatment‐naïve/non‐cirrhotic patients increased from 34.4% in phase 1 (1 January–31 December 2014) to 68.2% in phase 7 (1 August–31 December 2019). The proportion of migrants, alcohol users, people who inject drugs, and those receiving opiate substitution therapy increased in later registry phases. Most patients (60.1%) were receiving comedication at baseline. The most prescribed comedications were drugs used to treat opioid dependence which increased from 9.2% in phase 1 to 24.0% in phase 7. The patients' mean age decreased from 52.3 years in phase 1 to 48.7 years in phase 7. From 2014 to 2019, the proportion of at‐risk patients enrolling in the registry increased. To eliminate viral hepatitis as a major public health threat, a continued commitment to engaging underserved populations into the HCV care cascade is needed. [ABSTRACT FROM AUTHOR]

Background & Aims: During chronic hepatitis B virus (HBV) infection, suppressed functionality of natural killer (NK) cells might contribute to HBV persistence but the underlying mechanisms remain elusive. A peculiar feature of HBV is the secretion of large amount of hepatitis B surface antigen (HBsAg). However, the effect of HBsAg quantities on NK cells is unclear. The aim was to determine the effects of HBsAg quantities on NK cell functionality in patients with chronic hepatitis B (CHB). Methods: Eighty CHB patients were included and categorized into four groups based on their HBsAg levels. As a control, 30 healthy donors were enrolled. NK cell frequency, phenotype and function were assessed using flow cytometry and correlated with HBsAg levels and liver enzymes. Results: Compared to the healthy controls, a reshaping of NK cell pool towards more CD56bright NK cells was observed during CHB infection. Importantly, NK cells in patients with low HBsAg levels (<100 IU/mL) displayed an activated phenotype with increased expression of activation makers CD38, granzyme B and proliferation marker Ki‐67 while presenting with defective functional responses (MIP‐1β, CD107a) at the same time. Furthermore, NK cell activation was negatively correlated with patient HBsAg levels while NK function correlated with patient age. Conclusions: The differential regulation of NK cell phenotype and function suggests that activation of NK cells in patients with low serum HBsAg levels may contribute to HBV clearance. [ABSTRACT FROM AUTHOR]

Improvement of health‐related quality of life (HRQoL) is frequently reported as a benefit when treating hepatitis C virus infection (HCV) with direct acting antivirals (DAA). As most of the available data were obtained from clinical trials, limited generalizability to the real‐world population might exist. This study aimed to investigate the impact of DAA therapy on changes in HRQoL in a real‐world setting. HRQoL of 1180 participants of the German Hepatitis C‐Registry was assessed by Short‐Form 36 (SF‐36) questionnaires. Scores at post‐treatment weeks 12–24 (FU12/24) were compared to baseline (BL). Changes of ≥2.5 in mental and physical component summary scores (MCS and PCS) were defined as a minimal clinical important difference (MCID). Potential predictors of HRQoL changes were analysed. Overall, a statistically significant increase in HRQoL after DAA therapy was observed, that was robust among various subgroups. However, roughly half of all patients failed to achieve a clinically important improvement in MCS and PCS. Low MCS (p <.001, OR = 0.925) and PCS (p <.001, OR = 0.899) BL levels were identified as predictors for achieving a clinically important improvement. In contrast, presence of fatigue (p =.023, OR = 1.518), increased GPT levels (p =.005, OR = 0.626) and RBV containing therapy regimens (p =.001, OR = 1.692) were associated with a clinically important decline in HRQoL after DAA therapy. In conclusion, DAA treatment is associated with an overall increase of HRQoL in HCV‐infected patients. Nevertheless, roughly half of the patients fail to achieve a clinically important improvement. Especially patients with a low HRQoL seem to benefit most from the modern therapeutic options. [ABSTRACT FROM AUTHOR]

Background: RNA detection in plasma/stool is the gold‐standard for diagnosis of hepatitis E virus (HEV) infection. The impact of viral extraction methods on HEV RNA detection is poorly investigated. Methods: We determined the limit of detection of the RealStar HEV RT‐PCR V2.0 Kit (altona Diagnostics, RS) utilizing 3 RNA extraction methods (COBAS® AmpliPrep Total Nucleic Acid Isolation Kit, TNAi Roche; MagNA Pure 96 DNA, Viral NA SV Kit, MgP; QIAamp Viral RNA mini Kit Qiagen; VRK) in plasma and stool. The most sensitive method was evaluated in a total of 307 longitudinal samples of patients with HEV infection (acute = 18/chronic = 36) and compared to results with the former diagnostic standard of our centre (TNAi/FastTrack Diagnostic; FTD). Results: The plasma‐LOD was 49, 94 and 329 IU/mL for extraction with MgP, VRK and TNAi respectively. In stool, the LOD was 21 IU/mL, 528 IU/mL and indefinable for extraction with TNAi, VRK and MgP respectively. Utilizing longitudinal patient plasma samples, MgP/RS revealed 56 HEV RNA‐positive samples in 158 negative samples as determined by TNAi/FTD. In stool, from 37 HEV negative samples (TNAi/FTD), 15 were positive with TNAi/RS. At end of treatment, 8 out of 27 chronically infected patients were RNA positive with MgP/RS, while classified negative with TNAi/FTD. A relapse occurred in 3 of these patients. Conclusion: Different methods for RNA extraction and quantification have a significant, compartment‐specific impact on the sensitivity of HEV detection. Knowledge about the favourable combinations of extraction and quantification has important implications for diagnosis and patients receiving antiviral therapy. [ABSTRACT FROM AUTHOR]

The hepatitis E virus (HEV) is one of the main causes of acute hepatitis and the de facto global burden is underestimated. HEV‐related clinical complications are often undetected and are not considered in the differential diagnosis. Convincing findings from studies suggest that HEV is clinically relevant not only in developing countries but also in industrialized countries. Eight HEV genotypes (HEV‐1 to HEV‐8) with different human and animal hosts and other HEV‐related viruses are in circulation. Transmission routes vary by genotype and location, with large waterborne outbreaks in developing countries and zoonotic food‐borne infections in developed countries. An acute infection can be aggravated in pregnant women, organ transplant recipients, patients with pre‐existing liver disease and immunosuppressed patients. HEV during pregnancy affects the fetus and newborn with an increased risk of vertical transmission, preterm and stillbirth, neonatal jaundice and miscarriage. Hepatitis E is associated with extrahepatic manifestations that include neurological disorders such as neuralgic amyotrophy, Guillain‐Barré syndrome and encephalitis, renal injury and haematological disorders. The risk of transfusion‐transmitted HEV is increasingly recognized in Western countries where the risk may be because of a zoonosis. RNA testing of blood components is essential to determine the risk of transfusion‐transmitted HEV. There are currently no approved drugs or vaccines for HEV infections. This review focuses on updating the latest developments in zoonoses, screening and diagnostics, drugs in use and under development, and vaccines. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) affects over 70 million people globally, with an estimated 399 000 HCV‐related deaths in 2016. The World Health Organization (WHO) has set a goal to eliminate HCV by 2030. Despite the availability of direct‐acting antivirals—highly effective and well‐tolerated therapies for HCV—many patients infected with HCV in Germany have not initiated treatment, including a majority of those who are aware of their positive diagnosis. Barriers to screening, diagnosis, and treatment are major factors taking many countries off track for HCV elimination by 2030. Identifying country‐specific barriers and challenges, particularly in at‐risk populations such as people who inject drugs or men who have sex with men, has the potential to create tailored programs and strategies to increase access to screening or treatment and engage at‐risk populations. This review aims to report the current steps toward HCV elimination in Germany, the country‐specific barriers and challenges that will potentially prevent reaching the 2030 HCV elimination goal and describe good practice examples to overcome these barriers. [ABSTRACT FROM AUTHOR]

Background: Cytomegalovirus (CMV) infection is one of the most common infectious complications after solid organ transplant; it is associated with morbidity and mortality and with many direct and indirect effects. However, monitoring and therapeutic procedures are very heterogeneous across treatment centers. Additionally, factors that place patients at risk of CMV infection are poorly defined. Methods: Clinical and demographic data from 833 LT recipients and their donors were retrospectively analyzed. Univariate and multivariate analysis were applied. CMV infection was detected by quantitative nucleic acid testing with a lower limit of detection of 40 IU/mL. Results: In total, 192 of 833 patients (23%) experienced at least one episode of CMV infection after LT; CMV infection occurred to a large extent during the first year after transplant (70%). Multivariate analysis demonstrated that CMV donor‐recipient risk constellation (OR 2.05, 95% CI) and primary sclerosing cholangitis (PSC) before LT (OR 3.76, 95% CI) are independent risk factors for CMV infection after LT. Conclusion: Patients with high‐risk serostatus, PSC, or both should be monitored more thoroughly and should receive prolonged prophylaxis against CMV infection. [ABSTRACT FROM AUTHOR]

Background: Tenofovir disoproxil fumarate (TDF) is frequently used for treatment of and prophylaxis against reactivation of hepatitis B virus (HBV) after liver transplant (LT). Because TDF can lead to renal impairment and a decrease in bone mineral density (BMD), the prodrug tenofovir alafenamide (TAF) may be considered a viable alternative with fewer adverse effects. Only limited information is available about the use of TAF for LT recipients. We report a European single‐center experience with TAF as treatment for LT patients. Methods: This retrospective analysis involved 29 LT recipients receiving standard immunosuppressants (mainly calcineurin inhibitors). Demographic and clinical data were documented at baseline upon switch to TAF and at various time points thereafter. Results: None of the patients experienced HBV reactivation after the switch to TAF. Liver and renal function remained stable. Drug levels of immunosuppressive agents did not change significantly after the switch. After 1 year, 22 patients were still taking TAF; two patients had been lost to follow‐up; one patient had died; and four patients had discontinued therapy because of TAF‐related adverse effects. No serious adverse effects were reported. Conclusions: Tenofovir alafenamide exhibits high antiviral efficacy and a good safety profile for LT recipients. Still, the safety and tolerability of TAF for organ transplant patients should be evaluated in larger cohorts. [ABSTRACT FROM AUTHOR]

Glecaprevir/pibrentasvir is a pangenotypic direct‐acting antiviral regimen approved for treating chronic hepatitis C virus. Real‐world use of protease‐inhibitor–containing regimens requires further evaluation in patients with cirrhosis. We evaluated the real‐world safety and effectiveness of glecaprevir/pibrentasvir in patients with cirrhosis from the German Hepatitis C‐Registry who initiated treatment between 2 August 2017 and 30 June 2019. Overall, 131 patients received 12‐week (on‐label) treatment and 51 received 8‐week (off‐label) treatment. No patient discontinued treatment due to adverse events. Four patients had serious adverse events; none were considered related to glecaprevir/pibrentasvir. Two patients had total bilirubin > 5 × upper limit of normal (ULN) during treatment. Three patients had alanine aminotransferase and three patients had aspartate aminotransferase > 3 × ULN. Rates of sustained virologic response were 100% (86/86) for 86 patients with available data. Glecaprevir/pibrentasvir treatment was well‐tolerated and highly effective in patients with chronic hepatitis C and cirrhosis in real‐world practice. [ABSTRACT FROM AUTHOR]

HBV‐DNA levels are low or even undetectable in the majority HDV‐infected patients. The impact of PEG‐IFNα on HBV‐DNA kinetics in HDV‐infected patients has not been studied in detail. We analysed data of a prospective treatment trial where 120 HDV‐RNA–positive patients were randomized to receive PEG‐IFNα‐2a plus tenofovir‐disoproxil‐fumarate (PEG‐IFNα/TDF, n = 59) or placebo (PEG‐IFNα/PBO; n = 61) for 96 weeks. At week 96, HBV‐DNA was still quantifiable in 71% of PEG‐IFNα/PBO‐treated patients but also in 76% of PEG‐IFNα/TDF‐treated patients, despite low HBV‐DNA baseline values. Surprisingly, a transient HBV‐DNA increase between weeks 12 and 36 was observed in 12 in PEG‐IFNα/TDF‐treated and 12 PEG‐IFNα/PBO‐treated patients. This increase was positively associated with HBsAg loss [(P = 0.049, odds ratio (OR) 5.1] and HDV‐RNA suppression (P = 0.007, OR 4.1) at week 96. Biochemical markers of cell death (M30 and ALT) were higher during the HBV‐DNA peak but no distinct systemic immune pattern could be observed by screening 91 soluble inflammatory markers. In conclusion, an early increase in HBV‐DNA during PEG‐IFNα‐2a therapy occurred in more than 20% of patients, even in TDF‐treated patients. This transient HBV‐DNA rise may indicate PEG‐IFNα–induced cell death and lead to long‐term HDV‐RNA suppression and HBsAg loss. [ABSTRACT FROM AUTHOR]

The role of low levels of HDV‐RNA during and after interferon therapy of hepatitis D is unknown. We re‐analysed HDV RNA in 372 samples collected in the HIDIT‐2 trial (Wedemeyer et al, Lancet Infectious Diseases 2019) with the Robogene assay (RA; Jena Analytics). Data were compared with the previously reported in‐house assay (IA). We detected HDV‐RNA in one‐third of samples previously classified as undetectable using the highly sensitive RA. Low HDV viraemia detectable at week 48 or week 96 was associated with a high risk for post‐treatment relapse, defined as HDV RNA positivity in both assays at week 120. HDV RNA relapses occurred in 10/15 (67%) patients with detectable low HDV RNA at week 48 and in 10/13 (77%) patients with low viraemia samples at week 96. In contrast, the post‐treatment relapse rate was lower in patients with undetectable HDV RNA in both assays during treatment. [ABSTRACT FROM AUTHOR]

The hepatitis E virus (HEV) is one of the most common causes of hepatitis worldwide. HEV is also widespread in many developed countries, where the number of infections is steadily increasing. In those countries, the virus is transmitted mainly through consumption of undercooked or raw food or through contact with animals. Especially, pigs serve as a main reservoir of HEV. Here, we investigated the prevalence of HEV RNA in pork livers and pork meat products to assess the actual risk of HEV infection through food consumption in Germany. A total of 131 pork products were collected from grocery stores and butcher shops between October 2019 and February 2020 and screened for HEV RNA using nested PCR and subsequent sequencing. Overall, 10% of the samples were positive for HEV, including pork livers (5%), spreadable liver sausages (13%) and liver pâté samples (15%). Sequence analyses indicated that the large majority of HEV strains belonged to subtype HEV‐3c, representing the most frequent subtype in Germany. One sample belonged to subtype HEV‐3f. Further sequence analysis revealed large sequence variation between the samples; however, most of the mutations identified were synonymous. Although infectivity of the virus was not tested, the results suggest a considerable risk of HEV infection through food consumption. Therefore, preventive measures should be taken according to a One Health approach. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG‐interferon alpha‐2a (PEG‐IFNα‐2a) is the only effective treatment but its long‐term clinical impact is unclear. The aim of this study was to investigate the long‐term outcome after 48 weeks of pegylated interferon alpha‐2a therapy. We performed a retrospective follow‐up study of the Hep‐Net‐International‐Delta‐Hepatitis‐Intervention‐Study 1 (HIDIT‐I trial). Patients had received 48 weeks of treatment with either PEG‐IFNα‐2a plus adefovir dipivoxil (ADV) (Group I), PEG‐IFNα‐2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver‐related complications were defined as liver‐related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child‐Pugh scores B or C or an increase in Model for End‐stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG‐IFNα‐2a. Follow‐up data (at least 1 visit beyond post‐treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow‐up was 8.9 (1.6 ‐ 13.4) years. 19 patients were retreated with IFN‐based therapy: 42% (n = 8) in PEG‐IFNα‐2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long‐term follow‐up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event‐free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long‐term follow‐up of a large randomized clinical trial suggests that off‐treatment HDV RNA response to PEG‐IFNα‐2a treatment leads to improved clinical long‐term outcome. [ABSTRACT FROM AUTHOR]

Data on the prevalence of resistance‐associated substitutions (RASs) and their implications for treatment with direct‐acting antivirals (DAAs) are sparse in European patients with HCV genotype 4. This study investigated RASs before and after DAA failure in different genotype 4 subtypes and evaluated retreatment efficacies. Samples of 195 genotype 4‐infected patients were collected in the European Resistance Database and investigated for NS3, NS5A and NS5B RASs. Retreatment efficacies in DAA failure patients were analysed retrospectively. After NS5A inhibitor (NS5Ai) failure, subtype 4r was frequent (30%) compared to DAA‐naïve patients (5%) and the number of NS5A RASs was significantly higher in subtype 4r compared to 4a or 4d (median three RASs vs no or one RAS, respectively, P <.0001). RASsL28V, L30R and M31L pre‐existed in subtype 4r and were maintained after NS5Ai failure. Typical subtype 4r RASs were located in subdomain 1a of NS5A, close to membrane interaction and protein‐protein interaction sites that are responsible for multimerization and hence viral replication. Retreatment of 37 DAA failure patients was highly effective with 100% SVR in prior SOF/RBV, PI/SOF and PI/NS5Ai failures. Secondary virologic failures were rare (n = 2; subtype 4d and 4r) and only observed in prior NS5Ai/SOF failures (SVR 90%). In conclusion, subtype 4r harboured considerably more RASs compared to other subtypes. A resistance‐tailored retreatment using first‐ and second‐generation DAAs was highly effective with SVR rates ≥90% across all subtypes and first‐line treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Guidelines regarding treatment for autoimmune hepatitis (AIH) favour two strategies for azathioprine (AZA) introduction: concurrent with steroids at induction or delayed by 2‐4 weeks. The safety and efficacy of both strategies have been unexplored. Methods: We established a cohort of 900 AIH patients from 12 centres in 7 European countries. There were 631 patients who used AZA as part of the therapeutic regimen. We distinguished two groups: patients with early AZA (<2 weeks) or delayed AZA initiation (≥2 weeks). Primary outcome was discontinuation of AZA in the first year of treatment. Cox regression and propensity score matching was performed to determine difference in outcomes between groups. Results: Patients with early AZA initiation had significantly lower transaminases and bilirubin at baseline. Discontinuation rates of AZA did not differ between early and delayed starters (16.6% vs 14.2%), which did not reach statistical significance (hazard ratio 0.97, 95% confidence interval 0.61‐1.55, P =.90). Stratification according to baseline disease activity or propensity score matching did not alter the results. Main reason for AZA discontinuation was intolerance to treatment (14.0% vs 13.2%, P =.78) with nausea and vomiting as main side effects. AIH remission rates were comparable among groups. Conclusion: The discontinuation rate of AZA in AIH treatment is ~15% in the first year of treatment. Early or delayed AZA initiation does not differ in remission and discontinuation rates in AIH induction therapy. Our data suggest that either strategy may be used as part of AIH treatment. [ABSTRACT FROM AUTHOR]

Background and aims: Achieving sustained virological response (SVR; cure) in hepatitis C patients using a simple regimen is key to making elimination by 2030 possible. In the largest real‐world analysis to date, the effectiveness of pangenotypic, panfibrotic, single‐tablet, sofosbuvir/velpatasvir (SOF/VEL) once‐daily for 12 weeks was assessed in 12 clinical real‐world cohorts from various geographical areas, settings and treatment practices. Factors affecting risk of not achieving SVR were assessed. Methods: Adults treated with SOF/VEL 400/100 mg, without ribavirin, were included. All HCV patients reaching Week 12 or 24 post‐treatment were assessed for SVR12/24. Factors associated with not achieving SVR12/24 for virological reasons were evaluated using logistic regression analysis. Results: Overall, 5552 patients were included: 13.3% treatment‐experienced; 20.7% compensated cirrhotic; 30.2% genotype 1; 29.5% genotype 2; 32.9% genotype 3; 4.7% genotype 4; 3.7% HIV coinfection; 13.4% current/former intravenous drug use. Of the 5196 patients evaluated for effectiveness, 98.9% achieved SVR12/24. High SVR12/24 rates occurred in all genotypes including genotype 3 (98.3%; 1649/1677) and in those with compensated cirrhosis (97.9; 1055/1078). Only 55 patients did not achieve SVR12/24 due to a virological reason; the only factor statistically significantly associated with an increased risk of not achieving SVR12/24 was compensated cirrhosis (P =.002). Overall, 6% (332/5552) of patients did not achieve SVR12/24 for non‐virological reasons (67% lost to follow‐up; 26.5% early treatment discontinuation). Conclusions: In this large cohort, representative of clinical practice, a simple 12‐week regimen of SOF/VEL without ribavirin resulted in high SVR12/24 rates in diverse patient populations, even among those with compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Background and aims: Autophagy is a critical process in cell survival and the maintenance of homeostasis. However, the implementation of therapeutic approaches based on autophagy mechanisms after liver damage is still challenging. Methods: We used a hepatospecific Atg7‐deficient murine model to address this question. Results: We showed that the proliferation and regeneration capacity of Atg7‐deficient hepatocytes was impaired. On the one hand, Atg7‐deficient hepatocytes showed steady‐state hyperproliferation. On the other hand, external triggers such as partial hepatectomy (PHx) or cell transplantation did not induce hepatocellular proliferation or liver repopulation. After PHx, hepatocyte proliferation was strongly decreased, accompanied by high mortality. This increase in mortality could be overcome by pharmacological mTOR inhibition. In accordance with hepatocyte hypoproliferation after damage, Atg7‐deficient hepatocytes failed to repopulate the liver in a hepatic injury model. Atg7‐deficient mice showed hepatic hypertrophy, transient cellular hypertrophy, and high transaminase levels followed by strong perisinusoidal/pericellular fibrosis with age. Their elevated modified hepatic activity index (mHAI) was almost exclusively due to apoptosis without any inflammation. These parameters were associated with variations in the triglyceride content and compromised lipid droplet formation after PHx. Mechanistically, we also observed a modulation of HGF, PAK4, NOTCH3 and YES1, which are proteins involved in cell cycle regulation. Conclusion: We demonstrated the important role of autophagy in the regeneration capacity of hepatocytes. We showed the causative relationship between autophagy and triglycerides that is essential for promoting liver recovery. Finally, pharmacological mTOR inhibition overcame the impact of autophagy deficiency after liver damage and prevented mortality. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis B virus (HBV) contains three viral surface proteins, large, middle and small hepatitis B surface protein (LHBs, MHBs, SHBs). Proportions of LHBs and MHBs are lower in patients with inactive vs active chronic infection. Interferon alfa may convert hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B (CHB) to an inactive carrier state, but prediction of sustained response is unsatisfactory. The aim of this study was to test the hypothesis that quantification of MHBs and LHBs may allow for a better prognosis of therapeutic response than total hepatitis B surface antigen (HBsAg) concentration. Methods: Hepatitis B surface proteins were measured before and during peginterferon alfa‐2a therapy in serum from 127 Asian patients with HBeAg‐positive CHB. Sustained response was defined as HBeAg seroconversion 24 weeks post‐treatment. Results: Mean total HBs levels were significantly lower in responders vs nonresponders at all time points (P <.05) and decreased steadily during the initial 24 weeks treatment (by 1.16 vs 0.86 ng/mL in responders/nonresponders respectively) with unchanged relative proportions. Genotype B had a two‐fold higher proportion of LHBs than genotype C (13% vs 6%). HBV DNA, HBeAg, HBsAg and HBs protein levels predicted response equally well but not optimally (area under the receiver operating characteristic curve values >0.70). Conclusions: Hepatitis B surface protein levels differ by HBV genotype. However, quantification of HBs proteins has no advantage over the already established HBsAg assays to predict response to peginterferon alfa‐2a therapy in HBeAg‐positive patients. [ABSTRACT FROM AUTHOR]

The priming of T cells in the liver is widely accepted. Nonetheless, it is controversial whether immune activation in autoimmune hepatitis (AIH) occurs in the liver or in the spleen. To address this issue, we splenectomized mice and induced experimental murine AIH (emAIH) with an adenovirus (Ad)‐expressing formiminotransferase cyclodeaminase (FTCD). Post‐splenectomy, the experimental mice developed emAIH to a higher extent than the control mice. In addition, splenectomized mice harboured more intrahepatic B cells and a disproportionately small number of regulatory T cells (Tregs) within a reduced T cell population at the site of inflammation. These results imply that the spleen is not the site of AIH induction. In contrast, the spleen seems to have a protective function since the pathological score was more severe in splenectomized animals. These findings have important implications for the aetiology of AIH. [ABSTRACT FROM AUTHOR]

Background and Aims: Sporadic hepatitis E is an emerging indigenous disease in Europe induced by genotype 3 of the virus. While the disease takes an acute self‐limited course in immunocompetent individuals, under immunocompromised conditions chronic hepatitis E might develop. The histology of chronic hepatitis E has not been described in detail systematically. Methods: Liver biopsies from 19 immunosuppressed patients with chronic hepatitis E were collected: 17 were organ transplant recipients, one had a CD4‐deficiency and one had received steroid therapy because of ulcerative colitis. Biopsies were processed with standard stains. Evaluation of histologic activity and fibrosis was performed according to Ishak. Additionally, immunohistochemistry with antibodies directed against open reading frame 2 and 3 of the virus was performed and liver biopsies were tested for hepatitis E virus RNA. Results: Biochemical data showed an increase in alanine transaminase, aspartate transaminase, gamma‐glutamyl transferase and total bilirubin. Histopathology displayed typical features of chronic hepatitis with mild to moderate activity. The number of polymorphonuclear leucocytes was considerably increased and all patients had a florid cholangitis that presented as a destructive form in five of them. Hepatocytes and bile duct epithelia stained positive for hepatitis E virus by immunohistochemistry. Conclusions: Chronic hepatitis E in immunocompromised individuals runs a similar course as hepatitis B and C and shows similar histopathology. However, the presence of destructive cholangitis in some cases accompanied by an increased number of polymorphonuclear leucocytes is markedly different. Immunohistochemically the virus is present in bile duct epithelia, seemingly the cause for cholangitis. [ABSTRACT FROM AUTHOR]

Persistent infection with hepatitis C virus (HCV) is a known risk factor for the development of hepatocellular carcinoma (HCC). The lack of the tumor suppressor promyelocytic leukemia protein (PML) in combination with HCV fosters hepatocarcinogenesis via induction of HCC using diethylnitrosamine (DEN) in a rodent model. However, the spontaneous development of malignant lesions in PML‐deficient mice with an HCV‐transgene (HCVtg) has not been investigated thus far. We crossed PML‐deficient mice with HCV transgene expressing mice and observed the animals for a period of 12 months. Livers were examined macroscopically and histologically. Gene expression analysis was performed on these samples, and compared with expression of selected genes in human samples of patients undergoing liver transplantation for HCC. In vitro studies were performed in order to analyze the selected pathways. Genetic depletion of PML in combination with HCVtg coincided with an increased hepatocyte proliferation, resulting in development of HCCs in 40% of the PML‐deficient livers. No tumor development was observed in mice with either the PML‐knockout (PML−/−) or HCVtg alone. Gene expression profiling uncovered pathways involved in cell proliferation, such as NLRP12 and RASFF6. These findings were verified in samples from human livers of patients undergoing liver transplantation for HCC. Further in vitro studies confirmed that lack of PML, NLRP12, and RASFF6 leads to increased cell proliferation. The lack of PML in combination with HCV is associated with increased cell proliferation, fostering tumor development in the liver. Our data demonstrate that PML acts as an important tumor suppressor in HCV‐dependent liver pathology. [ABSTRACT FROM AUTHOR]

For decades, intranuclear inclusions in many normal and neoplastic cells have been considered to be mere invaginations of cytoplasm into the nucleus without any notable function or influence on disease. We investigated such inclusions in 75 specimens of hepatocellular carcinoma (HCC). In this context we demonstrate that these inclusions are true inclusions, completely closed and delimited by the nuclear membrane, containing degenerate cell organelles and lysosomal proteins. Moreover, their occurrence was positively associated with patient survival but not with tumour grade or stage. In a standardised area a mean of 124 inclusions per specimen was present in the tumorous liver tissue in contrast to 5 inclusions in the non‐tumorous adjacent section and 89% of all scrutinised HCC showed at least one membrane‐bound nuclear inclusion. Ultrastructural characterisation by transmission electron microscopy revealed degenerative materials such as residues of lysosomes, endoplasmic reticulum and Golgi apparatus within the inclusions. Due to the fact that the content of the inclusions appears to be more condensed than cytoplasm and contains fewer intact cell organelles, we assume that they are not mere invaginations of cytoplasm. Three dimensional (3D) reconstruction of isolated and immunofluorescence stained nuclei showed that the inclusions are completely located within the nucleus without any connection to the cytoplasm. The limiting membrane of the inclusions contained lamin B suggesting nuclear membrane origin. The content of the inclusions stained for the autophagy‐associated proteins p62, ubiquitin, LC3B, cathepsin B and cathepsin D. Triple immunofluorescence staining followed by 3D reconstruction revealed co‐localisation of p62, ubiquitin and LC3B in the same inclusion. Our observations uncover that these inclusions are real inclusions completely surrounded by the nucleus. We propose that the presence of autophagy‐associated proteins and proteases within the inclusions contribute to beneficial survival. [ABSTRACT FROM AUTHOR]

Summary: The natural course of acute Hepatitis C Virus (aHCV) infection is highly heterogeneous, and only few biomarkers have been identified to reliably predict the outcome of infection. We analysed a large panel of soluble inflammatory mediators, immune cell frequencies and phenotypes using peripheral blood samples from 26 patients with symptomatic aHCV infection from a controlled randomized clinical trial (ISRCTN88729946, www.isrctn.com). We found that patients with a spontaneous early HCV control demonstrated a distinct expression pattern of various soluble immune mediators including IFNα and IL‐16. Immune cell phenotype and frequency differed between patients who cleared the viral infection early (n=13) and those who remained HCV RNA positive after 12 weeks of observation (n=13) with a reduced ratio of CD4+ T cells to NK cells in the non–early clearer. Further, correlation analyses of 50 cytokines and chemokines revealed more positive correlations in between the distinct cytokines, especially for IFNα and IL‐16, and between the cytokines and HCV RNA levels in spontaneous early clearer patients. Beyond that, in vitro stimulation of CD4+ T cells with IL‐16 reduced the susceptibility of these cells to killing by IFNα‐activated NK cells. These data indicate that the immune cell composition and cytokine pattern varies considerably in patients with symptomatic aHCV infection. NK cell–mediated killing of CD4+ T cells might affect early control of HCV infection. [ABSTRACT FROM AUTHOR]

Summary: Chronic fatigue, mood alterations and cognitive impairment are frequent accessory symptoms of HCV infection. Fatigue and mood alterations have also been observed in autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC), but not in hepatitis B virus (HBV)‐infection, thus indicating an autoimmune response as possible cause of HCV infection‐associated encephalopathy. Data, however, are sparse. This study aimed to prove that HCV patients feature similar to those with autoimmune liver disease but contrary to HBV patients regarding neuropsychiatric symptoms. A total of 132 noncirrhotic patients (HCV: 46, HBV: 22, AIH: 27, PBC: 29, AIH/PBC: 8) completed questionnaires addressing the domains mentioned above. Eighty‐eight underwent a comprehensive neuropsychological assessment. Patient groups were compared among each other and to 33 healthy controls. Fatigue, anxiety and depression scores were significantly increased, and the SF‐36 mental score significantly decreased in all patient groups compared to controls. Fatigue was significantly more pronounced in HCV than in HBV patients. HCV patients scored significantly worse than HBV patients but not AIH and PBC patients in the SF‐36. HCV, AIH and PBC but not HBV patients did significantly worse than controls in word learning. Recognition of words was impaired in HCV, AIH and PBC patients and recognition of figures in HCV patients, exclusively (P ≤ 0.002). HCV patients did also worse than controls and HBV patients concerning alertness and working memory (P ≤ 0.001). The neuropsychiatric profiles of HCV patients are similar to those of AIH and PBC patients but differ from those of HBV patients, suggesting an autoimmune response as a possible cause for these differences. [ABSTRACT FROM AUTHOR]