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Background and Aims: HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes., Approach and Results: We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up., Conclusions: Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB., (© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Hepatitis B Virus (HBV) encoded miRNAs were previously described and suggested to play a role in HBV replication and pathogenesis. In this study we aim to identify novel HBV encoded miRNAs in plasma and liver tissue samples from chronic hepatitis B (CHB) patients and determine their role in CHB pathogenesis and HBV replication. RNA next generation sequencing was performed on plasma and liver tissue samples from ten CHB patients and uninfected controls. The interaction of the potential miRNA-like structures with the RNA-induced silencing complex (RISC) was determined using RNA immunoprecipitation. Expression levels of the HBV encoded miRNAs were measured in liver tissue samples derived from a conformation cohort. The effect of HBV encoded miRNAs overexpression on HBV replication, expression of predicted target genes, and induction of interferon stimulated genes in cell lines were assessed. Three potential miRNA-like structures transcribed by HBV were identified in liver tissue, of which one miRNA, HBV-miR-6, was recognized using RISC. HBV-miR-6 expression was demonstrated in liver tissue samples from 52 of the 87 CHB patients. HBV-miR-6 levels correlated with hepatic HBV-DNA and plasma HBsAg levels. Overexpression of HBV-miR-6 in vitro did not affect HBV replication, and predicted both target genes expression and interferon stimulated genes expression after stimulation. A potential novel HBV encoded miRNA was identified and validated in liver tissue from CHB patients. It is suggested that HBV-miR-6 may play a role in the process of viral excretion or particle formation in vivo.

Background: (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand., Methods: In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients., Results: Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10-6) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10-6) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele., Conclusions: Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies., Clinical Trials Registation: NCT01401400., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: We aimed to identify HBc amino acid differences between subgroups of chronic hepatitis B (CHB) patients., Methods: Deep sequencing of HBc was performed in samples of 89 CHB patients (42 HBeAg positive, 47 HBeAg negative). Amino acid types were compared using Sequence Harmony to identify subgroup specific sites between HBeAg-positive and -negative patients, and between patients with combined response and non-response to peginterferon/adefovir combination therapy., Results: We identified 54 positions in HBc where the frequency of appearing amino acids was significantly different between HBeAg-positive and -negative patients. In HBeAg negative patients, 22 positions in HBc were identified which differed between patients with treatment response and those with non-response. The fraction non-consensus sequence on selected positions was significantly higher in HBeAg-negative patients, and was negatively correlated with HBV DNA and HBsAg levels., Conclusions: Sequence Harmony identified a number of amino acid changes associated with HBeAg-status and response to peginterferon/adefovir combination therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Combining peginterferon-alfa-2a (pegIFN) with a nucleotide analogue can result in higher rates of HBsAg loss than either therapy given alone. Here, we investigated the durability of the response to combination therapy in chronic hepatitis B (CHB) patients after 5 years of follow-up. In the initial study, 92 CHB patients (44 HBeAg-positive, 48 HBeAg-negative) with HBV DNA >100 000 c/mL (~20 000 IU/mL) and active hepatitis were treated for 48 weeks with pegIFN 180 μg/week and 10 mg adefovir dipivoxil daily. For the long-term follow-up (LTFU) study, patients were followed up for 5 years after the end of treatment. At year 5, 70 (32 HBeAg-positive, 38 HBeAg-negative) patients remained in the study. At year 5, 19% (6/32) of HBeAg-positive patients and 16% (6/38) of HBeAg-negative patients lost HBsAg, and no HBsAg seroreversion was observed. The 5-year cumulative Kaplan-Meier estimate for HBsAg loss was 17.2% for HBeAg-positive patients and 19.3% for HBeAg-negative patients. Fourteen of sixteen patients who lost HBsAg at any time point during follow-up developed anti-HBs antibodies (>10 IU/L). At year 5, in total 63% (20/32) of HBeAg-positive and 71% (27/38) of HBeAg-negative patients were retreated with nucleos(t)ide analogues during follow-up. The cumulative Kaplan-Meier estimate for retreatment was 60% of patients at year 5. At year 5 of follow-up, 18% of CHB patients treated with pegIFN/nucleotide analogue combination therapy had durable HBsAg loss and 88% of these had developed anti-HBs antibodies., (© 2017 John Wiley & Sons Ltd.)

Background and Aim: Precore (PC) and basal core promoter (BCP) mutations are associated with responses to interferon-based treatment in HBeAg-positive chronic hepatitis B (CHB) patients. Here, we identify viral minority variants in these regions and assess association with response to peginterferon-alfa (Peg-IFN) and adefovir combination therapy., Patients and Methods: Ultra-deep pyrosequencing analysis of the BCP and PC region was performed for 89 CHB patients (42 HBeAg-positive; 47 HBeAg-negative), at baseline and during treatment. Specifically, associations of individual positions with the HBeAg-negative phenotype were studied, as well as the association of the most prevalent mutations with combined response in HBeAg-positive and -negative patients at week 72 (HBeAg negativity, HBV-DNA <2000 IU/mL and ALT normalization at 24 weeks of treatment-free follow-up)., Results: The mutations most strongly correlated with the HBeAg-negative phenotype were at positions 1762/1764 and 1896/1899 in the BCP and PC region, respectively. No major changes in nucleotide composition of these positions were observed during treatment. In HBeAg-negative patients, a combined presence of 1764A and 1896A was correlated with lower ALT levels (p = 0.004), whereas the presence of 1899A was correlated with higher age (p = 0.030), lower HBV-DNA level (p = 0.036), and previous IFN therapy (p = 0.032). The presence of 1764A/1896A or the absence of 1899A at baseline, was associated with lower response rates, after adjustment for HBV genotype (p = 0.031 and p = 0.017) and HBsAg level (p = 0.035 and p = 0.022)., Conclusion: We identified novel correlations between common BCP and PC variants with response to Peg-IFN and adefovir in HBeAg-negative patients. Ultimately, this may guide the selection of those patients most likely to benefit from Peg-IFN-based treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Antiviral treatment is currently not recommended for patients with chronic hepatitis B with a low viral load. However, they might benefit from acquiring a functional cure (hepatitis B surface antigen [HBsAg] loss with or without formation of antibodies against hepatitis B surface antigen [anti-HBs]). We assessed HBsAg loss during peg-interferon-alfa-2a (peg-IFN) and nucleotide analogue combination therapy in patients with chronic hepatitis B with a low viral load., Methods: In this randomised controlled, open-label trial, patients were enrolled from the Academic Medical Center (AMC), Amsterdam, Netherlands. Eligible patients were HBsAg positive and hepatitis B e antigen (HBeAg) negative for more than 6 months, could be treatment naive or treatment experienced, and had alanine aminotransferase (ALT) concentrations less than 5 × upper limit of normal (ULN). Participants were randomly assigned (1:1:1) by a computerised randomisation programme (ALEA Randomisation Service) to receive peg-IFN 180 μg/week plus adefovir 10 mg/day, peg-IFN 180 μg/week plus tenofovir disoproxil fumarate 245 mg/day, or no treatment for 48 weeks. The primary endpoint was the proportion of patients with serum HBsAg loss among those who received at least one dose of study drug or had at least one study visit (modified intention-to-treat population [mITT]). All patients have finished the initial study of 72 weeks and will be observed for up to 5 years of follow-up. This study is registered with ClinicalTrials.gov, number NCT00973219., Findings: Between Aug 4, 2009, and Oct 17, 2013, 167 patients were screened for enrolment, of whom 151 were randomly assigned (52 to peg-IFN plus adefovir, 51 to peg-IFN plus tenofovir, and 48 to no treatment). 46 participants in the peg-IFN plus adefovir group, 45 in the peg-IFN plus tenofovir group, and 43 in the no treatment group began treatment or observation and were included in the mITT population. At week 72, two (4%) patients in the peg-IFN plus adefovir group and two (4%) patients in the peg-IFN plus tenofovir group had achieved HBsAg loss, compared with none of the patients in the no treatment group (p=0·377). The most frequent adverse events (>30%) were fatigue, headache, fever, and myalgia, which were attributed to peg-IFN dosing. Two (4%) serious adverse events were reported in the peg-IFN plus adefovir group (admission to hospital for alcohol-related pancreatitis [week 6; n=1] and pregnancy, which was electively aborted [week 9; n=1]), three (7%) in the peg-IFN plus tenofovir group (admission to hospital after a suicide attempt during a severe depression [week 23; n=1], admission to hospital for abdominal pain [week 2; n=1], and an elective laminectomy [week 40; n=1]), and three (7%) in the no treatment group (admission to hospital for septic arthritis [week 72; n=1], endocarditis [week 5; n=1], and hyperthyroidism [week 20; n=1])., Interpretation: In patients with chronic hepatitis B with a low viral load, combination treatment (peg-IFN plus adefovir and peg-IFN plus tenofovir) did not result in significant HBsAg loss compared with no treatment, which does not support the use of combination treatment in this population of patients., Funding: Roche, Fonds NutsOhra., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Hepatitis B virus (HBV) modulates microRNA (miRNA) expression to support viral replication. The aim of this study was to identify miRNAs associated with hepatitis B e antigen (HBeAg) status and response to antiviral therapy in patients with chronic hepatitis B (CHB) , and to assess if these miRNAs are actively secreted by hepatoma cells., Methods: Plasma miRNA levels were measured by reverse-transcription quantitative polymerase chain reaction in healthy controls (n = 10) and pretreatment samples of an identification cohort (n = 24) and a confirmation cohort (n = 64) of CHB patients treated with peginterferon/nucleotide analogue combination therapy. Levels of HBV-associated miRNAs were measured in cells, extracellular vesicles, and hepatitis B surface antigen (HBsAg) particles of hepatoma cell lines., Results: HBeAg-positive patients had higher plasma levels of miR-122-5p, miR-125b-5p, miR-192-5p, miR-193b-3p, and miR-194-5p compared to HBeAg-negative patients, and levels of these miRNAs were associated with HBV DNA and HBsAg levels. Pretreatment plasma levels of miR-301a-3p and miR-145-5p were higher in responders (combined response or HBsAg loss) compared to nonresponders. miR-192-5p, miR-193b-3p, and miR-194-5p were present in extracellular vesicles and HBsAg particles derived from hepatoma cells., Conclusions: We identified miRNAs that are associated with HBeAg status, levels of HBV DNA and HBsAg, and treatment response in CHB patients. We demonstrated that several of these miRNAs are present in extracellular vesicles and HBsAg particles secreted by hepatoma cells., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Current treatment for chronic hepatitis B infection (CHB) consists of interferon-based therapy. However, for unknown reasons, a large proportion of patients with CHB do not respond to this treatment. Hence, there is a pressing need to establish response markers to select patients who will benefit from therapy and to spare potential nonresponders from unnecessary side effects of antiviral therapy. Here, we assessed whether HLA-C and KIR genotypes were associated with treatment outcome for CHB. Twelve SNPs in or near the HLA-C gene were genotyped in 86 CHB patients (41 HBeAg positive; 45 HBeAg negative) treated with peginterferon alfa-2a + adefovir. Genotyping of killer immunoglobin-like receptors (KIRs) was performed by SSP-PCR. One SNP in HLA-C (rs2308557) was significantly associated with combined response in HBeAg-positive CHB patients (P = 0.003). This SNP is linked to the HLA-C group C1 or C2 classification, which controls KIR binding. The combination of KIR2DL1 with its ligand HLA-C2 was observed significantly more often in HBeAg-positive patients with a combined response (13/14) than in nonresponders (11/27, P = 0.001). Patients with the KIR2DL1/C2 genotype had significantly higher baseline ALT levels (136 vs 50 U/L, P = 0.002) than patients without this combination. Furthermore, KIR2DL1-C2 predicted response independent of HBV genotype and ALT at baseline. HLA-C and KIR genotype is strongly associated with response in HBeAg-positive CHB patients treated with interferon-based therapy. In combination with other known response markers, HLA-C/KIR genotype could enable the selection of patients more likely to respond to interferon-based therapy., (© 2016 John Wiley & Sons Ltd.)

Background & Aims: Chronic hepatitis B virus (HBV) infection is characterized by functional impairment of HBV-specific T cells. Understanding the mechanisms behind T cell dysfunction and restoration is important for the development of optimal treatment strategies., Methods: In this study we have first analysed the phenotype and function of HBV-specific T cells in patients with low viral load (HBV DNA <20,000IU/ml) and spontaneous control over the virus. Subsequently, we assessed HBV-specific T cells in patients with high viral load (HBV DNA >17,182IU/ml) treated with peginterferon/adefovir combination therapy who had various treatment outcomes., Results: HBV-specific T cells could be detected directly ex vivo in 7/22 patients with low viral load. These showed an early differentiated memory phenotype with reduced ability to produce IL-2 and cytotoxic molecules such as granzyme B and perforin, but with strong proliferative potential. In a cohort of 28 chronic hepatitis B patients with high viral load treated with peginterferon and adefovir, HBV-specific T cells could not be detected directly ex vivo. However, HBV-specific T cells could be selectively expanded in vitro in patients with therapy-induced HBsAg clearance (HBsAg loss n=7), but not in patients without HBsAg clearance (n=21). Further analysis of HBV-specific T cell function with peptide pools showed broad and efficient antiviral responses after therapy., Conclusions: Our results show that peginterferon based combination therapy can induce HBV-specific T cell restoration. These findings may help to develop novel therapeutic strategies to reconstitute antiviral functions and enhance viral clearance., (Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Treatment of patients with chronic hepatitis B (CHB) with nucleos(t)ide analogues (NAs) suppresses hepatitis B virus (HBV) DNA production but does not affect the synthesis of the RNA pregenome or HBV messenger RNA. Whether HBV RNA-containing particles continue to be secreted into the bloodstream remains controversial., Methods: We developed a sensitive polymerase chain reaction (PCR) assay to quantify the HBV RNA load in a supernatant of NA-treated HepG2-2.2.15 cells and in plasma specimens from 20 patients with CHB who were receiving NA therapy and 86 patients treated with pegylated interferon alfa (Peg-IFN) and adefovir., Results: Treatment of HepG2-2.2.15 cells with NAs for 9 days reduced HBV DNA levels (by 1.98 log10 copies/mL), whereas HBV RNA levels increased (by 0.47 log10 copies/mL; P < .05). During long-term NA treatment of patients with CHB, HBV RNA levels remained higher than HBV DNA levels. Peg-IFN-based treatment induced a stronger decrease in the HBV RNA load than NA monotherapy, and this decline was more pronounced in responders than in nonresponders. In HBV e antigen-negative patients, a lower baseline plasma HBV RNA level was independently associated with response to Peg-IFN and adefovir (odds ratio, 0.44; P = .019). Immunoprecipitation with HBV core antigen-specific antibodies after removal of the HBV surface antigen envelope demonstrated the association of plasma HBV RNA with virions., Conclusions: HBV RNA is present in virions in plasma specimens from patients with CHB. HBV RNA levels vary significantly from those of established viral markers during antiviral treatment, which highlights its potential as an independent marker in the evaluation of patients with CHB., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: The role of natural killer (NK) cells in the process of hepatitis B virus (HBV) surface antigen (HBsAg) clearance and whether their phenotype is related to treatment outcome in patients with chronic hepatitis B are currently unknown., Methods: Patients with chronic hepatitis B (HBV DNA load, >17 000 IU/mL) were treated with pegylated interferon alfa-2a and adefovir for 48 weeks. NK cell phenotype and function were analyzed in 7 responders (defined as individuals with HBsAg clearance by week 72; 3 HBV e antigen [HBeAg]-positive and 4 HBeAg-negative), 7 matched nonresponders, and 7 healthy controls. Subsequently, 34 baseline samples from HBeAg-positive patients with chronic hepatitis B were analyzed., Results: During treatment, the percentage and absolute number of CD56(bright) NK cells increased significantly, whereas the percentage and absolute number of CD56(dim) NK cells decreased. At baseline, responders had a significantly lower expression of chemokine receptor CX3CR1 on CD56(bright) NK cells and inhibitory receptor NKG2A on CD56(dim) NK cells, compared with nonresponders. In addition, responders had higher CD56(bright) TRAIL expression and interferon γ production at end of treatment. These baseline differences were not found in HBeAg-positive patients who had HBeAg seroconversion without HBsAg clearance., Conclusions: Combination therapy significantly influences NK cell phenotype and function. Differences between patients with chronic hepatitis B with HBsAg clearance and nonresponders suggest that NK cells play a role in the clearance of HBsAg during interferon-based combination therapy., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background & Aims: Differences in intrahepatic gene expression patterns may be associated with therapy response in peginterferon-treated chronic hepatitis B (CHB) patients., Methods: We employed gene expression profiling in baseline liver biopsies of 40 CHB patients (19 HBeAg-positive; 21 HBeAg-negative) treated with peginterferon and adefovir for 48 weeks, and compared expression patterns of combined responders (HBeAg loss, HBV-DNA <2000 IU/ml, alanine aminotransferase normalization after 1 year of treatment-free follow-up) with non-responders. Genes identified by transcriptome analysis in 15 biopsies were confirmed in 25 additional biopsies by RT-qPCR., Results: Transcriptome analysis demonstrated significant differences in expression of 41 genes between responders and non-responders. In responders, pathway analysis showed specific upregulation of genes related to the immune response, including chemotaxis and antigen processing and presentation. Genes upregulated in responders exhibited strongest similarity with a set of genes induced in livers of chimpanzees with acute Hepatitis B infection. Differential expression was confirmed for eight selected genes. A 2-gene subset (HLA-DPB1, SERPIN-E1) was found to predict response most accurately. Incorporation of these genes in a multivariable model with HBeAg status, HBV genotype and baseline HBsAg level correctly classified 90% of all patients, in which HLA-DPB1 and SERPIN-E1 were independent predictors of response., Conclusion: We identified an intrahepatic transcriptional signature associated with enhanced immune activation which predicts therapy response. These novel associations could lead to better understanding of responsiveness to peginterferon in CHB patients, and may assist in selecting possible responders to interferon-based treatment., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background & Aims: Achievement of HBsAg loss remains the hallmark of chronic hepatitis B treatment. In order to identify host factors contributing to treatment-induced HBsAg loss, we performed a genome-wide screen of single nucleotide polymorphisms (SNPs) and studied its immunological consequence., Methods: Chronic hepatitis B patients (40 HBeAg-positive and 44 HBeAg-negative) treated with peginterferon alfa-2a and adefovir were genotyped for 999,091 SNPs, which were associated with HBsAg loss at week 96 (n = 9). Plasma carnitine levels were measured by tandem-mass spectrometry, and the effect of carnitine on the proliferative capacity of hepatitis B virus (HBV)-specific and non-specific CD8 T cells was studied in vitro., Results: One polymorphism, rs12356193 located in the SLC16A9 gene, was genome-wide significantly associated with HBsAg loss at week 96 (p = 1.84 × 10(-8)). The previously reported association of rs12356193 with lower carnitine levels was confirmed in our cohort, and baseline carnitine levels were lower in patients with HBsAg loss compared to patients with HBsAg persistence (p = 0.02). Furthermore, we demonstrated that carnitine suppressed HBV-specific CD8 T cell proliferation., Conclusions: In chronic hepatitis B patients treated with peginterferon and adefovir, we identified strong associations of SLC16A9 gene variation and carnitine levels with HBsAg loss. Our results further suggest that a lower baseline plasma carnitine level increases the proliferative capacity of CD8 T cells, making patients more susceptible to the immunological effect of this treatment. These novel findings may provide new insight into factors involved in treatment-induced HBsAg loss, and play a role in the prediction of treatment outcome., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To compare the diagnostic accuracy of TE and MRE and establish cutoff levels and diagnostic strategies for both techniques, enabling selection of patients for liver biopsy., Methods: One hundred three patients with chronic hepatitis B or C and liver biopsy were prospectively included. Areas under curves (AUROC) were compared for TE and MRE for METAVIR fibrosis grade ≥ F2 and ≥F3. We defined cutoff values for selection of patients with F0-F1 (sensitivity >95%) and for significant fibrosis F2-F4 (specificity >95%)., Results: Following exclusions, 85 patients were analysed (65 CHB, 19 CHC, 1 co-infected). Fibrosis stages were F0 (n = 3), F1 (n = 53), F2 (n = 15), F3 (n = 8) and F4 (n = 6). TE and MRE accuracy were comparable [AUROCTE ≥ F2: 0.914 (95% CI: 0.857-0.972) vs. AUROCMRE ≥ F2: 0.909 (0.840-0.977), P = 0.89; AUROCTE ≥ F3: 0.895 (0.816-0.974) vs. AUROCMRE ≥ F3: 0.928 (0.874-0.982), P = 0.42]. Cutoff values of <5.2 and ≥8.9 kPa (TE) and <1.66 and ≥2.18 kPa (MRE) diagnosed 64% and 66% of patients correctly as F0-F1 or F2-F4. A conditional strategy in inconclusive test results increased diagnostic yield to 80%., Conclusion: TE and MRE have comparable accuracy for detecting significant fibrosis, which was reliably detected or excluded in two-thirds of patients. A conditional strategy further increased diagnostic yield to 80%., Key Points: • Both ultrasound-based transient elastography and magnetic resonance elastography can assess hepatic fibrosis. • Both have comparable accuracy for detecting liver fibrosis in viral hepatitis. • The individual techniques reliably detect or exclude significant liver fibrosis in 66 %. • A conditional strategy for inconclusive findings increases the number of correct diagnoses.

Background: We studied whether hepatitis B surface antigen (HBsAg)/anti-HBs immune complex levels in chronic hepatitis B (CHB) patients receiving antiviral therapy could be used as a response marker at baseline (BL) or early during treatment to predict treatment outcome., Methods: An experimental array-based assay (immunological multi-parameter chip technology [IMPACT]; Roche Diagnostics, Penzberg, Germany) served to determine HBsAg, anti-HBs and complex levels. We tested a panel of serum samples of 40 hepatitis B e antigen (HBeAg)-positive and 44 HBeAg-negative patients who received pegylated interferon and adefovir for 48 weeks., Results: HBsAg loss occurred in 4 of 40 HBeAg-positive and 4 of 44 HBeAg-negative patients. A total of 14 of 40 HBeAg-positive patients lost HBeAg and 12 of them formed anti-HBe. At BL, complexes were present in 83 (99%) patients, whereas free anti-HBs levels were detectable in 5 patients. Complex levels at BL and week 12 were higher in HBeAg-positive patients with HBeAg loss, compared to patients who retained HBeAg (P=0.002 and P=0.005, respectively). Receiver operating characteristic analysis for HBeAg loss in HBeAg-positive patients at BL and week 12 showed area-under-the-curve values of 0.79 (P=0.002) and 0.82 (P=0.003) for complex levels. We found no correlation in either HBeAg-positive or -negative patients between complex levels and HBsAg loss., Conclusions: We demonstrated for the first time that before and during treatment HBsAg/anti-HBs immune complex levels can predict HBeAg loss in HBeAg-positive CHB patients treated with pegylated interferon and adefovir. Complexes were present in almost all patients at BL and were higher in patients who lost HBeAg. In conclusion, determining HBsAg/anti-HBs immune complex levels before and early during treatment could aid in selecting CHB patients with an optimal chance to achieve HBeAg loss.

Background: In this study, we aimed to identify baseline predictors of response in chronic hepatitis B patients treated with a combination of pegylated interferon (PEG-IFN)-α2a and adefovir., Methods: We treated 92 chronic hepatitis B patients (44 hepatitis B e antigen [HBeAg]-positive and 48 HBeAg-negative) with HBV DNA > 100,000 copies/ml (> 17,182 IU/ml) with PEG-IFN and adefovir for 48 weeks and followed them up for 2 years. Baseline markers for HBeAg loss, combined response (HBeAg negativity, HBV DNA levels ≤ 2,000 IU/ml and alanine aminotransferase [ALT] normalization) and hepatitis B surface antigen (HBsAg) loss were evaluated., Results: Two years after the end of treatment, rates of HBeAg loss and HBsAg loss in HBeAg-positive patients were 18/44 (41%) and 5/44 (11%), respectively. In HBeAg-negative patients, rates of combined response and HBsAg loss were 12/48 (25%) and 8/48 (17%), respectively. HBeAg-negative patients with HBsAg loss had lower baseline HBsAg levels than those without HBsAg loss (mean HBsAg 2.35 versus 3.55 log10 IU/ml; P < 0.001). They also had lower HBV DNA levels and were more often (PEG-)IFN experienced. Baseline HBsAg was the only independent predictor of HBsAg loss (OR 0.02; P = 0.01)., Conclusions: With combination therapy of PEG-IFN and adefovir for 48 weeks, a high rate of HBsAg loss was observed in both HBeAg-positive (11%) and HBeAg-negative (17%) patients 2 years after treatment ended. In HBeAg-negative patients, a low baseline HBsAg level was a strong predictor for HBsAg loss.