The impact of hepatitis B surface antigen seroconversion on the durability of functional cure induced by pegylated interferon alpha treatment.

BACKGROUND: Hepatitis B surface antigen (HBsAg) loss is regarded as a pivotal criterion for assessing functional cure in patients diagnosed chronic hepatitis B (CHB). We conducted the research to investigate the real-world performance of HBsAg seroconversion in sustaining HBsAg loss. METHODS: This retrospective analysis confirmed 295 patients who attained HBsAg loss through combination therapy involving nucleos(t)ide analogues (NAs) and pegylated interferon alpha (peg-IFNα). Employing Kaplan-Meier estimates method to conduct survival analysis. The forest plot was used to visualize the results of multivariate Cox regression, and selected variables were included in the nomogram. RESULTS: HBsAg seroreversion was observed in 45 patients during follow-up periods, with a lower recurrence risk in patients with HBsAg seroconversion at the end of peg-IFNα therapy (EOT) (10.3% vs 37.3% at 96-week, P < 0.0001). Moreover, the sustainability of hepatitis B surface antibody (anti-HBs) in participants continuing therapy after HBsAg seroconversion was superior to those discontinued prematurely (72.5% vs 54.5% at 96 weeks, P = 0.012). Additionally, the former group was also relatively less likely to experience HBsAg reversion during long-term observation (8.4% vs 14.3% at 96 weeks, P = 0.280). Hepatitis B envelope antigen (HBeAg) status, anti-HBs status and consolidation treatment screened by multivariable analysis were utilized to construct a predictive model for HBsAg reversion. The concordance index(C-index = 0.77) and calibration plots indicated satisfactory discrimination and consistency of nomogram. CONCLUSIONS: HBsAg seroconversion was beneficial for sustaining functional cure in patients treated with peg-IFNα. Continuing consolidation therapy after HBsAg seroconversion also contributed to maintain HBsAg seroconversion and improve the durability of HBsAg loss. The nomogram illustrated its efficacy as a valuable instrument in showcasing survival probability of functional cure.

Differential T-cell profiles determined by Hepatitis B surface antigen decrease among people with Human Immunodeficiency Virus /Hepatitis B Virus coinfection on treatment.

BACKGROUND: Several studies have reported that combination antiretroviral therapy (cART) enhances the hepatitis B surface antigen (HBsAg) clearance rate in Human Immunodeficiency Virus-1/Hepatitis B Virus (HIV/HBV) coinfected patients, yet the associated immunological characteristics remain unclear. METHODS: Global and specific immune phenotypic profiles were examined in 48 patients with HIV/HBV coinfection before cART and at 1-year, and 3-year after cART using flow cytometry. In addition, 61 patients with HBV monoinfection were included for comparison. RESULTS: HBsAg response (sAg-R) was defined as > 0.5 log decrease within six months of cART initiation, and 16 patients achieved it. Patients with sAg-R (the sAg-R group) exhibited distinct immune phenotypes compared to those of HBsAg-retained patients (the sAg-NR group). Notably, patients with sAg-R had lower CD4+ T cell counts and a higher number of HBcAg-specific T cells. Further, the sAg-R group exhibited upregulation of HLA-DR, Ki67, and PD-1 in CD4+ T cells and heightened HLA-DR and T-bet in CD8+ T cells. However, the sAg-R group had fewer TEMRA cells but more TEM and Th17 cells than those in the sAg-NR group. Expression of various markers, including HLA-DR+CD4+, Ki67+CD4+, PD-1+CD4+, CD38+CD8+, HLA-DR+CD8+, TIM-3+CD8+, HBV-specific CD4+ T cell secreting IFN-γ and IL-2, and specific CD8+ T cell secreting IFN-γ and IL-2, correlated with HBsAg decrease. CONCLUSION: The decline in HBsAg levels during cART in HIV/HBV coinfection involves significant alterations in CD4+ and CD8+ T cells phenotypes, offering a novel perspective on a functional HBV cure.

Cigarette Smoking Is Associated With Lower Chance of Hepatitis B Surface Antigen Seroclearance and Altered Host Immunity.

Cigarette smoking is associated with worse clinical outcomes in patients with chronic hepatitis B (CHB) infection, but the effects on hepatitis B surface antigen (HBsAg) seroclearance are unclear. This study aimed to investigate the effect of active smoking on HBsAg seroclearance (SC) and its impact on peripheral blood lymphocytes in patients with CHB infection. Longitudinal follow-up data was retrieved in 7833 antiviral-treated CHB subjects identified from a centralised electronic patient record database (Part 1). Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) from 27 CHB-infected patients (6 active smokers; 13 with SC) was performed by flow cytometry to assess programmed death-1 (PD-1) expression and proportion of regulatory T cells (CD4+CD25+CD127lo). Effector function of HBV-specific T cells was examined by comparing granzyme B (GZMB) and transforming growth factor beta (TGFß) production in undepleted PBMCs and Treg-depleted PBMCs after 7 days in vitro stimulation with HBV envelope protein overlapping peptides (Part 2). Over a median follow-up of 5 years, smoking was associated with lower probability of SC (aHR 0.70, 95% CI 0.57-0.87). PD-1 expression was increased in CD4+T cells, CD8+T cells and CD20+B cells among smokers compared to non-smokers and positively correlated with pack years (all p < 0.05). Treg depletion led to partial functional recovery of HBV-specific T cells, with significantly bigger magnitude in smokers (p = 0.0451, mean difference = 4.68%) than non-smokers (p = 0.012, mean difference = 4.2%). Cigarette smoking is associated with lower chance of HBsAg seroclearance, higher PD-1 expression on lymphocytes, and impairment of effector functions of HBV-specific T cells in CHB.

Concurrent HBsAg and anti-HBs induced by a preS deletion mutant in a chronic hepatitis B patient.

This study analyzed the origins of concurrent hepatitis B surface antigen (HBsAg) and HBsAg antibodies (anti-HBs) in a patient with chronic hepatitis B virus (HBV) infection. The levels of serological markers of HBV infection were determined by enzyme-linked immunosorbent assay (ELISA). The preS/S gene was analyzed by gene amplification and sequencing. The tests revealed that HBsAg and anti-HBs coexisted in this patient with mixed infections of the full-length preS/S virus strain and preS1 183 bp deletion mutant, and both the mutant and the anti-HBs were no longer present after one year, which means that the mutant strain was cleared by the detected antibodies. Thus, it is speculated that anti-HBs antibodies targeted specifically to the preS1 deletion mutant strain instead of the strain with the full-length large S protein were produced. This mechanism is quite different from other immunopathogenic mechanisms for concurrent HBsAg and anti-HBs.

Peripheral NK cell phenotypic alteration and dysfunctional state post hepatitis B subviral particles stimulation in CHB patients: evading immune surveillance.

Background: The relationship between chronic hepatitis B (CHB) infection and natural killer (NK) cell dysfunction is well-established, but the specific role of HBV viral antigens in driving NK cell impairment in patients with CHB remains unclear. This study investigates the modulatory effects of hepatitis B virus subviral particles (HBVsvp, a representative model for HBsAg) on the phenotypic regulation (activating and inhibitory receptors), cytokine production and cytotoxic potential of peripheral blood mononuclear cell-derived natural killer cells (PBMCs-derived NK cell), which contributes to NK cell dysfunction in CHB infection, potentially serving as an effective HBV immune evasion strategy by the virus. Methods: NK cells were isolated from peripheral blood of patients with CHB (n=5) and healthy individuals (n=5), stimulated with HBVsvp. Subsequent flow cytometric characterization involved assessing changes in activating (NKp46 and NKG2D) and inhibitory (CD94) receptors expression, quantifying TNF-α and IFN- γ cytokine secretion, and evaluating the cytotoxic response against HepG2.2.15 cells with subsequent HBVsvp quantification. Results: In CHB patients, in vitro exposure of PBMCs-derived NK cell with HBVsvp (represent HBsAg model) significantly reduced NK cell-activating receptors expression (P = 0.022), increased expression of CD94 + NK cells (p = 0.029), accompanied with a reduced TNF-α - IFN-γ cytokine levels, and impaired cytotoxic capacity (evidenced by increased cell proliferation and elevated HBVsvp levels in co-cultures with HepG2.2.15 cells in a time-dependent), relative to healthy donors. Conclusion: These findings suggest that HBVsvp may induce dysfunctional NK cell responses characterized by phenotypic imbalance with subsequent reduction in cytokine and cytotoxic levels, indicating HBVsvp immunosuppressive effect that compromises antiviral defense in CHB patients. These data enhance our understanding of NK cell interactions with HBsAg and highlight the potential for targeting CD94 inhibitory receptors to restore NK cell function as an immunotherapeutic approach. Further clinical research is needed to validate these observations and establish their utility as reliable biomarkers.

Manganese inhibits HBV transcription and promotes HBsAg degradation at non-toxic levels.

Chronic hepatitis B virus (HBV) infection continues to pose a significant global health challenge. However, therapeutic measures for a cure are lacking in clinical practice. Manganese, an essential trace element, has garnered attention due to its potential to activate innate immune pathways and its significant role in antiviral and antitumor immunity. Yet, the specific impact of manganese on chronic hepatitis B has been largely unexplored. Our research reveals that manganese substantially inhibits HBV replication in hepatocellular carcinoma cells at non-toxic levels. This suppression occurs independently of well-known anti-HBV innate immune pathways, such as the cGAS-STING pathway. Mechanistically, manganese decreases HBV transcription by diminishing the levels of liver-specific transcription factors. Furthermore, it activates the mTOR pathway, enhancing HBsAg ubiquitination through the upregulation of the ubiquitin ligase ß-TrCP and increasing proteasome activity via the augmentation of its subunits, leading to a ubiquitin-dependent degradation of HBsAg. Significantly, our study also uncovers a notable clinical correlation between manganese levels and chronic hepatitis B infection. These findings position manganese as a critical element in diminishing HBV replication, offering a new direction in the management of chronic hepatitis B.

Evaluating the Status of Hepatitis B Vaccination in Healthcare Workers at a Central Laboratory in a Tertiary Care Hospital and Research Centre.

Introduction Hepatitis B virus is a significant occupational hazard for healthcare workers worldwide. Long-term protection against hepatitis B infection is conferred by the vaccine and the protective immune response is indicated by anti-hepatitis B surface antigen (HBsAg) titre. It is crucial to monitor anti-HBsAg titres as their levels decrease over time. The study aims to evaluate the status of hepatitis B vaccination among personnel working in the Central Laboratory of Shri B.M. Patil Medical College Hospital and Research Centre. The focus is on understanding the immunization practices and protection levels against HBV within this high-risk group. Materials and methods A cross-sectional analysis was conducted, including collecting demographic data, determining HBsAg status, evaluating anti-HBsAg titre value, and getting vaccination details of the laboratory personnel. The study participants included doctors, lab technicians, and attendants who were assessed for both vaccination coverage and immunity levels. After obtaining their written consent, 4 ml of blood was collected in sterile blood collection tubes. All the samples were tested for HBsAg. The negative samples were tested for anti-hepatitis B surface antigen antibody (HBsAg-Ab (IgG)) titre. The enzyme-linked immunosorbent assay (ELISA) method was used to evaluate the obtained samples for HBsAg and anti-HBsAg titre. Results A total of 99 healthcare workers were included in the study. Most of the laboratory healthcare workers were in the age range of 20-30 years. In 84.8% of the subjects, protective antibody levels (>10 IU/ml) were found. The highest protection was seen among doctors (94.5%), followed by lab technicians (82.9%) and attendants (66.6%). However, 15.2% exhibited inadequate immunity, predominantly among the attendants (33.3%). The highest vaccination coverage was among doctors (91.8%), followed by lab technicians (78.7%) and attendants (53.3%). Most doctors had completed the full vaccination schedule (70.2%) or received a booster dose (24.3%) compared to lab technicians (57.4%) and attendants (46.6%). Conclusion The study highlights effective preventive measures against HBV among laboratory healthcare workers, as indicated by the absence of active infections. But it also emphasizes the necessity of focused initiatives to raise vaccination rates, particularly among attendants, in order to guarantee complete protection against HBV for all levels of laboratory workers.

TCR-like bispecific antibodies toward eliminating infected hepatocytes in HBV mouse models.

Therapeutics for eradicating hepatitis B virus (HBV) infection are still limited and current nucleos(t)ide analogs (NAs) and interferon are effective in controlling viral replication and improving liver health, but they cannot completely eradicate the hepatitis B virus and only a very small number of patients are cured of it. The TCR-like antibodies recognizing viral peptides presented on human leukocyte antigens (HLA) provide possible tools for targeting and eliminating HBV-infected hepatocytes. Here, we generated three TCR-like antibodies targeting three different HLA-A2.1-presented peptides derived from HBV core and surface proteins. Bispecific antibodies (BsAbs) were developed by fuzing variable fragments of these TCR-like mAbs with an anti-CD3ϵ antibody. Our data demonstrate that the BsAbs could act as T cell engagers, effectively redirecting and activating T cells to target HBV-infected hepatocytes in vitro and in vivo. In HBV-persistent mice expressing human HLA-A2.1, two infusions of BsAbs induced marked and sustained suppression in serum HBsAg levels and also reduced the numbers of HBV-positive hepatocytes. These findings highlighted the therapeutic potential of TCR-like BsAbs as a new strategy to cure hepatitis B.

Microbial infection among SARS-COV-2-infected patients in a COVID-19-dedicated tertiary care hospital of Bangladesh: a cross-sectional study.

Objectives. This study aimed to determine patterns of respiratory, blood-borne and uropathogenic microbial pathogens among SARS-CoV-2-infected patients in a COVID-19-(coronavirus disease 2019) dedicated tertiary care hospital in Dhaka, Bangladesh. Design.This was a cross-sectional study. Setting. In a COVID-19-dedicated tertiary care hospital in Dhaka, Bangladesh, conducted from March to June 2021. Participants. Hospitalized individuals with COVID-19 infection regardless of age or sex. Primary and secondary outcome measures. The percentage of co-infected COVID-19 patients and the characterization of the micro-organisms responsible for co-infection served as the primary outcome measures. Finding any associations between co-infection and age, co-infection and sex and co-infection and comorbidity was the secondary outcome variable. Interventions. Not applicable. Results.Out of 79 patients, 61 % were male, and the mean age was 49.53 years. Co-infection was seen in 7.7 % of patients, out of which 5.1 % of isolates were from urine samples, followed by 2.6 % from blood. Bacteria isolated from urine were Enterococcus (2.6 %), coagulase-negative Staphylococcus (CONS) (1.3 %) and Enterobacter spp. (1.3 %). Pseudomonas spp. was the only organism isolated from blood sample. Mixed growth was found in nasopharyngeal and throat swabs, with the predominant species being Staphylococcus aureus and Streptococcus spp. At the time of data collection, 55.7 % of patients had been given antimicrobials, and 30.4 % of patients had been given a single antimicrobial. HBsAg was positive in 1.3 % of patients and none were anti-hepatitis C or dengue NS1Ag positive. Conclusion. Microbial infection has been seen to be associated with SARS-CoV-2 infections and is of great value in prescribing antimicrobials and reducing fatal outcomes of hospitalized patients.

Infectivity of Hepatitis B Virus Surface Antigen-Positive Plasma With Undetectable HBV-DNA: Can HBsAg Screening Be Discontinued in Egyptian Blood Donors?

Hepatitis B Virus (HBV) infectivity data were reviewed and the 50% infectious dose (ID50) was reassessed in different HBsAg-positive infection stages enabling modelling of transfusion-transmitted (TT)-HBV infection risk if HBsAg donor screening was replaced by individual donation nucleic acid amplification technology (ID-NAT). Quantitative HBsAg and HBV-DNA assays were performed against international standards to compare the ratio between potential infectious HBV virions and subviral HBsAg particles in Egyptian HBsAg-positive blood donors as well as in Japanese chimpanzee samples of known infectivity. HBV-DNA load below the quantification limit of detection was estimated against a reference standard by replicate NAT testing (n = 25). Infectivity of chimpanzee samples collected during ramp-up and declining viremic phase were tested in a human liver chimeric mice (HLCM) model and compared with published infectivity data from different HBsAg-positive infection stages. Lowest estimates of ID50 in HBsAg-positive plasma were 3-6 HBV virions in chimpanzee studies. Infectivity decreased approximately 10-100-fold in the declining viremic phase using HLCM. In acute phase samples, HBV to HBsAg particle ratios varied between 1:102-104 but in HBsAg-positive blood donors this particle ratio reached 1:106-1012 when viral load was below 100 HBV-DNA copies/mL. Modelled TT-HBV risk of an HBsAg-positive/ID-NAT nonreactive blood transfusion was estimated at 5.5%-27% for components containing 20-200 mL of plasma when assuming an ID50 of 316 (point estimate between 100 and 1000) virions. It cannot be ensured that discontinuation of HBsAg donor screening and reliance on ID-NAT alone is safe.

Sociodemographic and clinical features related to hepatitis B virus infection among rejected blood donors in Luanda, Angola.

Background: Hepatitis B virus (HBV) remains a public health concern. Blood donors screened for HBV surface antigen (HBsAg) along with aspartate transaminase (AST)/alanine aminotransferase (ALT) could play a key in providing safe blood products. We investigated the features related to HBV infection among rejected blood donors in Luanda, Angola. Methods: This was a cross-sectional study conducted with 164 rejected donors. Donors were screened for HBsAg from March to May 2022. Overall, 63.4% tested positive for HBV. Results: The mean age of the HBV-positive (29.2 ± 8.02) was lower than the HBV-negative (33.9 ± 10.0) (p < 0.001). Donors between 20 and 40 years (odds ratio [OR]: 2.34, p = 0.045), females (OR: 1.40, p = 0.516), residents in urbanized areas (OR: 1.23, p = 0.530), low educational (OR: 1.54, p = 0.458), unemployed (OR: 1.65, p = 0.271), and unmarried (OR:1.41, p = 0.616) might be likely to contract HBV. AST/ALT ratio was higher in HBV-infected (2.07 ± 1.42) than in HBV-uninfected (1.90 ± 1.14). About 20% of HBV-positive were classified as having acute liver disease, while 80% with chronic liver disease, based on AST/ALT ratio. Age ranged from 20 to 40 years (OR: 1.97, p = 0.305), females (OR: 1.61, p = 0.557), donors from non-urbanized (OR: 1.69, p = 0.557), a low educational (OR: 1.64, p = 0.571), and unemployed donors (OR: 1.81, p = 0.289) were likely to develop chronic liver disease. Conclusions: Our findings indicated the failure of viral hepatitis control measures. Authorities should consider including HBV nucleic acid testing to ensure early identification of HBV in Angola.

Successful hepatitis B and C screening in the health check-up in the German primary care setting.

Background & Aims: A goal of the World Health Organization's global hepatitis strategy is the elimination of chronic hepatitis C virus (HCV) infection by 2030. As part of its strategy, the Federal Joint Committee (Germany) decided to include hepatitis B and C screening in a preventive medical examination, which is performed at the primary care level in Germany. We investigated the results 1 year after implementation of screening between October 2021 and September 2022. Methods: HBsAg/HBV DNA and anti-HCV/HCV RNA screenings were identified by billing categories in 286,192 individuals of 11 ambulatory healthcare centers. Results: Compared to 30,106 HBsAg and 31,266 anti-HCV laboratory requisitions in the year 2018, the number of tests increased to 286,192 during the screening period. Compared to routine care, additional anti-HCV positive tests age dependently increased the tally by 98% (177 plus 170 positive cases in males) and 123% (96 plus 118 positive cases in females) in those aged 35-44 years up to 518% (17 plus 88 positive cases in males) and 514% (29 plus 149 positive cases in females) in those aged 75-84 years. Similar results were observed for HBsAg. Prevalences of HBsAg, anti-HCV and HCV RNA were 0.54%, 0.79% and 0.13%, respectively. Conclusions: A structured hepatitis screening program at the primary care level has been successfully established and leads to age- and-sex-dependent large additional effects compared to routine care. Impact and implications: Strategies to eliminate chronic hepatitis B and C virus infection are country specific and vary between clinical scenarios. Our analysis proves the efficacy of a screening program by primary care physicians compared to routine care in a low-prevalence country. This program should be accompanied by additional efforts in risk populations like people who inject drugs who are under-represented in the current screening approach.

The association between serum vitamin A concentrations and virus hepatitis among U.S. adults from the NHANES database: a cross-sectional study.

Objective: According to the present study, the relationship between vitamin A (VA) levels and hepatitis virus carriage has been unclear and controversial. This study aimed to determine the potential relationship between serum VA levels and viral hepatitis and to provide ideas for future clinical treatments. Methods: A cross-sectional study was performed using the 2005-2006 and 2017-2018 National Health and Nutrition Examination Survey (NHANES) datasets. Multiple linear regression and logistic regression were adopted to analyze the association between serological hepatitis B surface antigen (HBsAg) or hepatitis C RNA (HCV-RNA) positivity and VA levels. There were 5,351 HBsAg-related responders and 242 HCV-RNA-related responders, including 52 HBsAg (+) and 104 HCV-RNA (+) responders. Results: Compared with HBsAg (-) and HCV-RNA (-) respondents, HBsAg (+) and HCV-RNA (+) respondents tended to have lower serum VA levels, respectively [1.63 (1.33 ~ 2.01) vs. 1.92 (1.57 ~ 2.34), P < 0.001; 1.54 (1.25 ~ 1.83) vs. 1.78 (1.46 ~ 2.26), P < 0.001]. A greater percentage of responders in the subclinical VA deficiency (SVAD) group were HBsAg (+) and HCV-RNA (+) than were those in the normal VA (VAN) group [2.4% (9/374) vs. 0.9% (43/4977), p = 0.003; 61.5% (16/26) vs. 40.7% (88/215), p = 0.043]. According to the results of the multiple regression analyses of the different models, the serum VA concentration was negatively correlated with HBsAg (+) and HCV-RNA (+) status (ß = -0.14, 95% CI = -0.30 to -0.01, p = 0.066; ß = -0.29, 95% CI = -0.50 ~ -0.09, p = 0.005, respectively). Compared to those with SVAD, patients with VAN were less likely to be serologically HBsAg (+) or HCV-RNA (+) (OR = 0.53, 95% CI = 0.25 ~ 1.10, p = 0.089; OR = 0.39, 95% CI = 0.18 ~ 0.84, p = 0.016, respectively). Conclusion: Our study provides evidence that patients who are HBsAg (+) or HCV-RNA (+) have a high incidence of SVAD. Moreover, HBsAg and HCV-RNA positivity are negatively correlated with VA levels, and patients with SVAD are more likely to carry HBsAg (+) or HCV-RNA (+). These findings suggest that the relationship between hepatitis viruses and vitamin A needs to be validated by more basic studies and clinical large-sample randomized controlled trials to provide ideas for new therapeutic targets.

Impact of preS1 Evaluation in the Management of Chronic Hepatitis B Virus Infection.

Background and Objectives: The measurement of hepatitis B surface antigen (HBsAg) is essential for managing chronic hepatitis B virus infection (CHB). HBsAg consists of three different surface envelope proteins: large, middle, and small HB surface proteins. However, in clinical practice, it is not common to evaluate each of these HB surface proteins separately. Materials and Methods: In this study, we investigated preS1 expression using seven monoclonal antibodies (mAbs) in 68 CHB patients, as well as examining their antigenicity. Results: Although the seven mAbs had been derived from genotype (Gt) C, they could recognize preS1 with Gts A to D. The epitopes were concentrated within the aa33-47 region of preS1, and their antigenicity was significantly reduced by an aa45F substitution. We found that preS1 expression remained consistent regardless of HBsAg levels and different Gts in CHB patients, in contrast to what was observed in SHBs. Conclusions: These results suggest that the antigenic epitope is preserved among different Gts and that the expression pattern of preS1 is altered during CHB, highlighting its vital role in the HBV infection cycle. Our present results suggest preS1 is a promising therapeutic target in CHB.

Diagnostic Utility of Pre-Genomic Hepatitis B RNA in the Evaluation of HBV/HIV Coinfection.

Background: Newer biomarkers of Hepatitis B virus (HBV) infection and treatment response have not been well-characterized in individuals with HBV/HIV coinfection. Methods: Pre-genomic RNA (pgRNA) and quantitative HBsAg (qHBsAg) were used to evaluate the associations with baseline characteristics. Participants included two separate groups - 236 with HBV/HIV coinfection enrolled in a cross-sectional cohort in Ghana and 47 from an HBV nucleoside/nucleotide treatment trial comparing tenofovir to adefovir in the United States. Results: In both cohorts, HBe antigenemia was highly associated with pgRNA and HBV DNA levels. In the treatment cohort, pre-treatment pgRNA serum concentration was 7.0 log10 U/mL, and mean qHBsAg was 201,297 IU/mL. The observed treatment-associated decrease in pgRNA was consistent with a biphasic decline curve that reached second-phase kinetics following treatment week 12. Changes from baseline were significantly correlated with changes in serum ALT (r = - 0.518; P = 0.023) but not with changes in HBV DNA (r = 0.132, P = NS). qHBsAg also correlated with ALT change (r = - 0.488, P = 0.034). Conclusion: pgRNA and qHBsAg represent newer biomarkers of HBV replication that may help monitor response and treatment outcomes. HBV pgRNA is highly associated with both HBeAg and ALT and may predict both active replication from the closed circular DNA (cccDNA) template as well as hepatic injury.

Exchanges in the 'a' determinant of the hepatitis B virus surface antigen revisited.

The hepatitis B virus surface antigen's (HBsAg) 'a' determinant comprises a sequence of amino acid residues located in the major hydrophilic region of the S protein, whose exchanges are closely associated with compromising the antigenicity and immunogenicity of that antigen. The HBsAg is generally present in the bloodstream of individuals with acute or chronic hepatitis B virus (HBV) infection. It is classically known as the HBV infection marker, and is therefore the first marker to be investigated in the laboratory in the clinical hypothesis of infection by this agent. One of the factors that compromises the HBsAg detection in the bloodstream by the assays adopted in serological screening in both clinical contexts is the loss of S protein antigenicity. This can occur due to mutations that emerge in the HBV genome regions that encode the S protein, especially for its immunodominant region - the 'a' determinant. These mutations can induce exchanges of amino acid residues in the S protein's primary structure, altering its tertiary structure and the antigenic conformation, which may not be recognized by anti-HBs antibodies, compromising the infection diagnosis. In addition, these exchanges can render ineffective the anti-HBs antibodies action acquired by vaccination, compromise the effectiveness of the chronically HBV infected patient's treatment, and also the HBsAg immunogenicity, by promoting its retention within the cell. In this review, the residues exchange that alter the S protein's structure is revisited, as well as the mechanisms that lead to the HBsAg antigenicity loss, and the clinical, laboratory and epidemiological consequences of this phenomenon.

Higher hepatitis B core-specific T cell response is associated with a lower risk of clinical relapse after discontinuation of oral antiviral treatment.

BACKGROUND: Hepatitis B virus (HBV)-specific T cell response is a major host immune response to control the virus. However, it is still unclear how it affects long-term outcomes of chronic hepatitis B patients, especially those who stop nucleos(t)ide analogue (NA) therapy. We aimed to explore whether the HBV-specific T cell response at the end of treatment (EOT) was associated with clinical outcomes. METHODS: In a prospective cohort study, 51 HBeAg-negative patients who discontinued NA therapy were enrolled. RESULTS: In a mean follow-up of 25.3 months, 25 patients developed clinical relapse. We found that a stronger hepatitis B core (HBc)-specific T cell response at EOT was associated with a lower risk of clinical relapse. Compared to the low-response group, the high-response group had a lower risk of clinical relapse with hazard ratio of 0.21 (95% CI: 0.05-0.88). The high HBc-specific T cell response was associated with reduced surge of HBV DNA and HBcrAg during the first year of follow-up. The T cell response at EOT was comparable between different NA treatments. Notably, the overall HBV-specific T cell response could be partially restored along with clinical relapse; however, such reinvigorated T cell response was not associated with HBsAg seroclearance. CONCLUSIONS: A higher HBc-specific T cell response at EOT was associated with lower risk of clinical relapse and reduced surge of HBV DNA and HBcrAg levels off NA therapy.

Interferon alpha induces a stronger antiviral effect than interferon lambda in HBV/HDV infected humanized mice.

Recent studies indicate that treatment of chronic hepatitis D virus (HDV) with either pegylated interferon (IFN)λ or pegylated IFNα monotherapy leads to a dramatic decline in HDV RNA. Herein, we investigated the innate antiviral efficacy of IFNλ and IFNα in humanized mice that lack an adaptive immune response. Humanized mice were either co-infected with hepatitis B virus (HBV) and HDV simultaneously, or HDV infection was performed subsequent to HBV infection (i.e., superinfected). After steady viral replication was achieved, mice received either IFNλ (n = 6) or IFNα (n = 7) for 12 (or 13) weeks. Pretreatment median levels of serum HBV DNA (8.8 [IQR:0.2] log IU/ml), HDV RNA (9.8 [0.5] log IU/ml), HBsAg (4.0 [0.4] log IU/ml) and human albumin, hAlb (6.9 [0.1] log ng/mL) were similar between mice treated with IFNα or IFNλ and between those coinfected versus superinfected. Compared to mice treated with IFNλ, mice treated with IFNα had a significantly greater decline in HBV, HDV, and HBsAg levels. In conclusion, IFNα induces stronger inhibition of HBV and HDV than IFNλ in humanized mice that lack an adaptive immune response. Further studies are needed to assess the respective role of the combined innate-and adaptive-immune systems in the treatment of HBV and HDV with IFNα and IFNλ.

A high functional cure rate was induced by pegylated interferon alpha-2b treatment in postpartum hepatitis B e antigen-negative women with chronic hepatitis B virus infection: an exploratory study.

Background and aims: Limited data have been reported on achieving functional cure using pegylated interferon (Peg-IFN) alpha-2b treatment for postpartum hepatitis B e antigen (HBeAg)-negative women with chronic hepatitis B virus (HBV) infection. This study was to assess the effectiveness and safety of Peg-IFN alpha-2b in HBV postpartum women without HBeAg and identify factors linked to the functional cure. Methods: A total of 150 HBeAg-negative postpartum women were retrospectively recruited.47 patients received Peg-IFN alpha-2b [Peg-IFN(+) group] and 103 patients did not [Peg-IFN(-) group]. Propensity score matching (PSM) was used to adjust the baseline imbalance between the two groups. The patients were followed for at least 48 weeks. The primary endpoints were hepatitis B surface antigen(HBsAg) loss and HBsAg seroconversion at 48 weeks. Logistic regression analysis was used to assess factors associated with HBsAg loss at 48 weeks. Results: At week 48,the HBsAg loss and seroconversion rate in Peg-IFN(+) group were 51.06%(24/47) and 40.43%(19/47), respectively. Even after PSM, Peg-IFN(+) group still showed higher HBsAg loss rate (50.00% vs 7.14%,p<0.001) and higher HBsAg seroconversion rate (38.10% vs 2.38%,p<0.001). Baseline HBsAg levels (Odds Ratio [OR]: 0.051, 95% Confidence Interval [CI]: 0.003-0.273, P=0.010), HBsAg at week 24 (OR:0.214, 95%CI:0.033-0.616, P=0.022), HBsAg decline at week 24 (OR:4.682, 95%CI: 1.624-30.198, P=0.022) and postpartum flare (OR:21.181, 95%CI:1.872-633.801, P=0.030) were significantly associated with HBsAg loss at week 48 after Peg-IFN alpha-2b therapy. Furthermore, the receiver operating characteristic curve (ROC) showed that the use of baseline HBsAg<182 IU/mL, HBsAg at week24 < 4 IU/mL and HBsAg decline at week24>12IU/mL were good predictors of HBsAg loss. No serious adverse events were reported. Conclusion: Peg-IFN alpha-2b treatment could achieve a high rate of HBsAg loss and seroconversion in HBeAg-negative postpartum women with reliable safety, particularly for patients experience postpartum flare and have low baseline HBsAg levels.

Discontinuation of Nucleos(t)ide Analogues in HBeAg Negative Chronic Hepatitis B Patients: Risks and Benefits.

Chronic hepatitis B (CHB) remains a major threat to global public health, affecting 296 million people worldwide. Although there is no curative treatment for CHB today, the virus can be effectively controlled with current antiviral treatment strategies. Since HBsAg loss can rarely (1%) be achieved with current nucleos(t)ide analogues (NA) options, lifelong treatment is usually required in HBeAg-negative patients. In recent years, guidelines have stated that long-term NA treatments can be discontinued for HBeAg-negative patients without achieving HBsAg loss. There is no general consensus on how discontinuation of NA can be included in the treatment approach. This review aimed to evaluate the current literature regarding the discontinuation of NA treatment in HBeAg-negative patients. Patients with HBeAg-negative CHB who have a higher chance of response after discontinuation of NA therapy can be defined as non-cirrhotic patients who have low HBsAg, HBcrAg, and HBV RNA levels at the discontinuation of treatment and accept close follow-up. The management of relapses that develop after NA discontinuation in patients is also unclear. The agent used in NA treatment itself may also affect the pattern of relapse development. Relapse after NA treatment occurs significantly slower and less frequently with entecavir compared to other regimens, including tenofovir dipivoxil. Prospective studies are needed in order to maintain the chance of HBsAg clearance in case of exacerbation and to treat acute exacerbations that can be fatal in a timely manner. Algorithms to be developed for use after discontinuation of NA treatment will help the clinician manage the patient safely.