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Background: The hepatitis B core-related antigen (HBcrAg) correlates with HBV DNA in patients with chronic HBV infection without antiviral treatment. Its utility in monitoring patients during and after the cessation of nucleos(t)ide analog (NA) treatment is unknown., Methods: The levels of HBcrAg were longitudinally determined in two cohorts of chronic HBV-infected patients with (A) newly started NA treatment or (B) after NA cessation during a median follow up (FU) of 60 months or 48 weeks, respectively. The correlation of HBcrAg and HBV DNA and the predictive value for HBeAg seroconversion and HBsAg loss were evaluated., Results: Fifty-six patients with newly-started NA treatment and 22 patients with NA cessation were identified. HBcrAg and HBV DNA strongly correlated before NA treatment (r = 0.77, p < 0.0001) and at virological relapse (0.66, p = 0.0063). At the individual level, the discrepant kinetics of HBcrAg and HBV DNA became evident. During NA treatment, 33% (6/18) and 9% (5/56) of patients showed HBeAg seroconversion or HBsAg loss/HBsAg < 100 IU/mL, respectively. Low levels of HBcrAg were associated with these endpoints., Conclusion: HBcrAg levels before antiviral treatment help to identify patients with chances of HBsAg loss or HBeAg seroconversion. However, its utility in replacing quantitative HBV DNA to evaluate treatment efficacy or virological relapse off-treatment is limited.

The hepatitis B virus (HBV) continues to cause substantial health and economic burdens, and its target of elimination may not be reached in 2030 without further efforts in diagnostics, non-pharmaceutical prevention measures, vaccination, and treatment. Current therapeutic options in chronic HBV, based on interferons and/or nucleos(t)ide analogs, suppress the virus replication but do not eliminate the pathogen and suffer from several constraints. This paper reviews the progress on biotechnological approaches in functional and definitive HBV treatments, including gene-editing tools, i.e., zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9, as well as therapeutics based on RNA interference. The advantages and challenges of these approaches are also discussed. Although the safety and efficacy of gene-editing tools in HBV therapies are yet to be demonstrated, they show promise for the revitalization of a much-needed advance in the field and offer viral eradication. Particular hopes are related to CRISPR/Cas9; however, therapeutics employing this system are yet to enter the clinical testing phases. In contrast, a number of candidates based on RNA interference, intending to confer a functional cure, have already been introduced to human studies. However, larger and longer trials are required to assess their efficacy and safety. Considering that prevention is always superior to treatment, it is essential to pursue global efforts in HBV vaccination.

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.)

Chronic hepatitis B virus (HBV) infection may follow four different consecutive phases, which are defined by virology as well as biochemical markers and differ in terms of prognosis and need for antiviral treatment. Currently, host responses reflected by immune markers are not considered in this definition. We aimed to study soluble immune markers and their distribution in different phases of chronic HBV infection. In this cross-sectional retrospective study, we investigated a panel of 14 soluble immune markers (SIM) including CXCL10 in 333 patients with chronic HBV infection. In a small cohort of HBeAg positive patients we analyzed SIM before and after HBeAg seroconversion and compared seroconverters to patients with unknown outcome. Significant differences were documented in the levels of several SIM between the four phases of chronic HBV infection. The most pronounced difference among all investigated SIM was observed for CXCL10 concentrations with highest levels in patients with hepatitis. TGF-β and IL-17 revealed different levels between HBeAg negative patients. HBeAg positive patients with HBeAg seroconversion presented higher amounts of IL-12 before seroconversion compared to HBeAg positive patients with unknown follow up. SIM such as CXCL10 but also IL-12, TGF-β and IL-17 may be useful markers to further characterize the phase of chronic HBV infection.

Chronic hepatitis B has highly a dynamic course with significant fluctuations of HBV-DNA and ALT impeding assessment of disease activity. New biomarkers of inflammatory versus noninflammatory stages of HBV infection are urgently needed. Cytokeratin 18 epitope M30 (M30 CK-18) is a sensitive marker of cell death. We aimed to investigate an association between serum M30 CK-18 and histological activity and phase of HBV infection. 150 Caucasian patients with HBV-infection were included in the study. Serum M30 CK-18 levels reflected phase of disease, being significantly higher in both HBeAg(+) and HBeAg(-) hepatitis B in comparison to HBsAg(+) carrier groups. The highest serum M30 CK-18 levels were observed in subjects with the most advanced stages of HBV. Moreover, its serum concentrations correlated with both inflammatory activity and fibrosis advancement (ANOVA P < 0.001). Importantly, serum M30 CK-18 levels were able to discriminate patients with mild versus moderate-advanced fibrosis (AUC: 0.86) and mild versus active liver inflammation (AUC: 0.79). M30 CK-18 serum concentration has good sensitivity and specificity in discriminating mild versus moderate/severe fibrosis and inflammation even in patients with normal ALT activity. This study suggests M30 CK-18 as a potential noninvasive marker of disease activity and also a marker of phase of persistent HBV infection.

Unlabelled: Lamivudine (LMV) is still the most commonly used nucleoside analogue in majority of the world. Its administration rapidly leads to resistance associated with mutations in HBV polymerase. THE AIM of the study was to assess the prevalence, nature and the time of LMV resistant variants appearence during a long term therapy., Patients and Methods: Study was carried out among 175 chronic hepatitis B patients treated with LMV. HBsAg, HBeAg as well as anti-HBe antibodies were detected by enzyme immunosorbent assay and HBV-DNA quantification was performed by RT-PCR. Mutations in HBV polymerase gen were detected by PCR using specific primers and direct sequencing. Liver biopsies were performed in 138 patients to evaluate grading and staging of chronic hepatitis by Scheuer's classification., Results: Mean pre-treatment viral load was comparable among HBeAg-positive and negative patients (4.24 x 10(8) vs. 1.26 x 10(8) IU/ml). Mutations in HBV polymerase gen were detected in 96 patients. After 5 years of LMV therapy the prevalence of mutations was 51.9% in HBeAg-positive and 56.1% in HBeAg-negative. The most common mutations were observed at position 180, followed by 204, 202, and 169 of HBV polymerase gen. After average treatment period of 25 months in HBeAg-positive and 35 months in HBeAg-negative additional mutation 204 was observed in 81% and 77% respectively., Conclusions: Large majority of patients develop point mutations at positions 180 and 204 of HBV polymerase gene after 2 years of treatment with LMV. These mutations limit the efficacy of LMV but also yield cross-resistance with entecavir.

In HBV/HIV-co-infected individuals, the course of hepatitis B is aggravated, leading to higher morbidity and mortality rates. Increasing evidence suggests an important role for hepatitis B surface antigen (HBsAg) quantification in monitoring treatment efficacy in HBV monoinfection. However, data concerning any HBsAg decline during treatment of HBV/HIV coinfection are limited. Fifty-one HBV/HIV-co-infected patients were retrospectively followed for a mean of 43 months (median 2 years, interquartile range 2 years). Baseline and on-treatment parameters were associated with longitudinal HBsAg levels. At baseline, serum HBsAg levels were comparable between patients on antiretroviral therapy (ART; n=43) and patients without (n=8). Longitudinally, HBsAg decreased in ART patients (-0.20±0.09 log(10) IU/mL/y), but slightly increased in subjects without therapy (0.22±0.26 log(10) IU/mL/y; p<0.001). In 58% of the ART subjects an HBsAg decline >10% was seen during the initial 24 mo. They showed higher baseline CD4 counts (401±42 versus 265±50 cells/μL, p=0.03), and had significantly higher CD4 counts at the last follow-up compared to patients without a decline (506±39 versus 310±51 cells/μL, p=0.01). A significant correlation was found between HBsAg decline from baseline to the last follow-up and the absolute increase of CD4 cells (r=0.44, p=0.003), as well the last CD4 count (r=0.41, p=0.006). This association was strongest in patients with complete suppression of HBV-DNA and HIV-RNA at the last follow-up visit. The highest HBsAg decline (-1.63±0.32 versus -0.43±0.24 log(10) IU/mL, p=0.001), and yearly HBsAg decline (-0.47±0.13 versus -0.19±0.12 log(10) IU/mL, p=0.03), were found in patients with CD4 increases >100 cells/μL at the last follow-up (n=21, 49%). Four cases of HBsAg loss were observed (8%). HBsAg declines steadily in >50% of HBV/HIV patients on ART. Long-term follow-up of HBV/HIV-co-infected patients is needed to identify distinct HBsAg patterns. Increasing CD4 counts indicating the restoration of immune competence in HBV/HIV-co-infected patients is associated with a stronger HBsAg decline.

Treatment of patients with neoplastic diseases of the lymphatic or lymphoreticular system and HBV infection can lead to reactivation of viral infection. Assessment of HBs antigen among this group is insufficient for the diagnosis of chronic HBV infection. Current research suggests the necessity of determining anti-HBc, antiHBs and HBV-DNA. Elimination of HBV as well as the influence of the virus on hepatocytes is associated with increased inflammatory and necrotic changes in the liver. Understandable, therefore, becomes a possibility of significant damage to hepatocytes caused by HBV during chemoimmunotherapy. Ofparticular importance in the reactivation of HBV are glicocorticosteroids acting as suppressants of the immune system and rituximab activating B cell apoptosis. Reactivation of HBV may occur in more than 60% of patients with positive HBs antigen and in approximately 50% of patients without HBsAg. Early therapy with nucleo(z)tide analogues significantly reduces the incidence ofHBV reactivation.

Background: Hepatitis B surface antigen (HBsAg) clearance during chronic hepatitis B (CHB) infection is associated with improved long-term clinical outcome, so is considered an important therapeutic goal in CHB. Studies have shown that serum HBsAg quantification during, and at end of, treatment may predict long-term HBsAg loss., Objectives: Performance comparison of the qualitative Elecsys HBsAg II assay using a quantitative research protocol and an established quantitative HBsAg assay., Study Design: A dilution algorithm was developed for the Elecsys HBsAg II assay to allow quantification of HBsAg levels; this was used to measure HBsAg levels in a range of samples including sera from patients infected with different HBV genotypes, HBV mutants, and longitudinal samples from patients undergoing antiviral treatment. Results were compared with those from the quantitative Architect HBsAg assay., Results: There was significant overall correlation between Elecsys and Architect assays (correlation coefficient [r]=0.97; p<0.001). HBsAg levels measured with both assays correlated well in all phases of infection (r=0.80-0.96), across all genotypes tested (HBV genotype A, r=0.89; HBV genotype D, r=0.97), and in samples with lamivudine-resistant mutations (r=0.94). Bland-Altman analysis showed only minor discordance between assays in different phases of chronic HBV-infection (3.8-5.1%). This strong correlation was also present for sera with lower HBsAg concentrations. On-treatment HBsAg levels were similar when measured with either assay., Conclusions: Using a simple dilution algorithm, the quantitative Elecsys HBsAg II assay reliably determined serum HBsAg levels in a wide range of samples, and showed very high correlation with the Architect HBsAg assay., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background: Hepatitis B surface antigen (HBsAg) loss is the ultimate goal of antiviral therapy and its prediction may be important for treatment individualization. Quantitative HBsAg (qHBsAg) has been shown to predict response to interferon-α, but few studies have analysed qHBsAg during treatment with nucleoside/nucleotide analogues (NAs). Serum interferon-inducible protein-10 (IP-10) has been associated with treatment response in hepatitis C, but data in chronic hepatitis B are lacking. Here, we aimed to investigate potential factors predictive for HBsAg loss., Methods: HBsAg was quantified at multiple time points in 126 patients with chronic HBV infection; 95 received NA treatment for 6-107 months. At an early time point (first 6 months of therapy) and late time point after virological response (VR; HBV DNA<100 IU/ml), we distinguished three patterns of HBsAg decrease: strong decrease (>0.5 log(10)), moderate decrease (10% to 0.5 log(10)) and no decrease (<10%). In addition to conventional biochemical and virological parameters, we analysed serum IP-10 levels in 55 patients., Results: Early and late HBsAg kinetics did not correlate. Overall, 42% of patients with a strong HBsAg decrease 2 years after VR cleared HBsAg. Importantly, no patient without a late HBsAg decrease >0.5 log(10) cleared HBsAg. By contrast, early HBsAg decrease after 6 months of NA therapy was not associated with HBsAg loss. Baseline serum IP-10 levels were associated with late but not early HBsAg kinetics and were highest in patients with HBsAg loss., Conclusions: Monitoring qHBsAg after successful HBV DNA suppression might be useful to identify patients who clear HBsAg, implicating finite NA treatment. The role of IP-10 as predictive marker for HBsAg loss should be further evaluated., (© 2011 International Medical Press)

Approximately 350-420 million people worldwide are chronically infected with hepatitis B virus (HBV). Chronic hepatitis B can result in liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Reactivation of hepatitis B is possible in patients with inactive or resolved hepatitis B often leading to liver failure. Those sequelae may be prevented by effective antiviral therapy. Interferon alfa, pegylated interferon alfa and five direct antiviral nucleoside and nucleotide analogues are approved for the treatment of chronic hepatitis B. Still, whom to treat, which therapy regimen to use, and when to begin treatment remain the challenges in the management HBV-infected patients. This review focuses on the current treatment concepts for chronic hepatitis B.

Chronic viral hepatitis B still remains serious diagnostic and therapeutic problem, that is mostly related to insufficient efficacy of available treatment options. This is the main reason of search for new recommendations and algorithms for optimizing procedures of patients selection and treatment. In this article we summarize informations collected from published recommendations of hepatologic scientific societies (EASL, AASLD, APASL) and independent groups of hepatologists, as well as therapeutic programs of Polish National Health Fund (NFZ). Principal criteria for patients selection include sera HBV-DNA concentration and alanine aminotransferase activity, but in some cases additional evaluation of histologic activity in liver biopsy can be necessary. Currently available medication used for HBV infection treatment are: adefovir, entecavir, lamivudine and pegylated interferon alfa 2a. The last two are most frequently prescribed in Poland, whereas use of adefovir and entecavir is limited due to lack of appropriate therapeutic programs covered by NFZ.

Aim: To analyze the effectiveness and safety of lamivudine treatment in patients with chronic HBV infection undergoing hemodialysis or after kidney transplantation, and to study the frequency of tyrosine-methionine-aspartate-aspartate (YMDD) mutation occurrence after lamivudine treatment., Methods: We analyzed 91 patients with chronic hepatitis B, among whom, 16 patients underwent hemodialysis, 7 patients had kidney transplantation and 68 patients had normal function of kidney. The hemodialysis patients were treated by lamivudine 300 mg/wk. Patients after kidney transplantation and patients with normal function of kidney were treated with lamivudine 100 mg/d. Therapy lasted for 12 mo. HBV-DNA, HBsAg, HBeAg and anti-HBe, and anti-HCV antibodies were assessed in sera of patients. The analysis was performed before and 6 mo after the end of lamivudine treatment. Before, during and after the lamivudine therapy, the number of erythrocytes, leukocytes, platelets and hemoglobin concentration, ALT and AST activity, as well as bilirubin, urea and creatinine concentrations were analyzed in sera from patients., Results: After the 12-mo lamivudine treatment, elimination of HBV-DNA was observed in 56% patients undergoing hemodialysis and in 53% patients with normal kidney function. Only 1 from 7 (14%) kidney-transplanted patients eliminated HBV-DNA. Furthermore, HBeAg elimination was observed in 36% hemodialysis patients, in 51% patients with normal function of kidneys and in 43% kidney-transplanted patients. Among the patients undergoing dialysis, no YMDD mutation was found after 12 mo of therapy, while it was detected in 9 patients (13%) with normal function of kidney and in 2 kidney-transplanted patients (29%, P<0.006). We did not observe significant side effects of lamivudine treatment in studied patients., Conclusion: Effectiveness of lamivudine therapy in dialysis patients is comparable with that in patients with normal function of kidney. Lamivudine treatment is well tolerated and safe in patients with renal insufficiency undergoing hemodialysis and kidney-transplantation. However, in the latter group, high incidence of YMDD mutation after lamivudine treatment was observed.

Aim: Transforming growth factor (TGF)- beta1, metalloproteinase (MMP)-1 and its tissue inhibitor (TIMP)-1 are considered predictive biomarkers of chronic hepatitis activity and fibrosis. The aim of this study was to evaluate the effect of lamivudine treatment on the plasma levels of these peptides in patients with chronic hepatitis B., Methods: TGF-beta1, MMP-1 and TIMP-1 plasma concentrations were measured with an enzyme immunoassay in 40 patients treated with lamivudine for 48 wk. Elimination of HBV-DNA and HBV antigens was evaluated 24 wk after treatment completion., Results: Baseline TGF-beta1 (29.6+/-2.2 ng/mL) and TIMP-1 (1 578+/-93 ng/mL) significantly exceeded normal values (18.3+/-1.6 ng/mL and 1 102+/-67 ng/mL respectively). Lamivudine treatment resulted in a significant decrease of TGF-beta1 and TIMP-1 during treatment with an increase after 24 wk of treatment. Pretreatment MMP-1 levels (6.7+/-0.7 ng/mL) were significantly lower than normal values (11.9+/-0.9 ng/mL) and increased during treatment and follow-up. A significant correlation was noted between TGF-beta1 or TIMP-1 and aminotransferases as well as fibrosis scored in liver biopsy specimens. There were no statistically significant differences of TGF-beta1, TIMP-1 and MMP-1 between four groups at baseline, 24 and 48 wk of treatment. TGF-beta1 and TIMP-1 levels increased significantly in non-responders and normalized in responders at wk 72. MMP-1 also normalized in responders and decreased to values significantly lower than normal in non-responders., Conclusion: These findings support the role of TGF-beta1, TIMP-1 and MMP-1 in the pathogenesis of chronic hepatitis B. Because of their association with hepatic injury and antiviral treatment efficacy, determination of these peptides may be useful in disease management.