Hepatitis B E Antigen Research Articles

Development and validation of a multivariable nomogram predictive of hepatitis B e antigen seroconversion after pregnancy in hepatitis B virus-infected mothers

Background and aimsCurrent guidelines are controversial regarding the continuation of nucleos(t)ide analogues (NAs) therapy after delivery in Hepatitis B virus (HBV)-infected pregnant women. The postpartum period may be an opportune moment for achieving hepatitis B e antigen (HBeAg) seroconversion earlier with constant NAs therapy due to the restoration of immune function after delivery. We investigated prenatal and pregnant factors associated with HBeAg seroconversion after pregnancy and developed a nomogram to predict HBeAg seroconversion rates, aiding decision-making for optimal management in women.MethodsWe retrospectively included 489 HBeAg-positive mothers as the training cohort from January 2014 to December 2018 and prospectively enrolled 94 patients as the external validation cohort from January 2019 to December 2021 at the First Affiliated Hospital of Xi’an Jiaotong University. In the training cohort, independent predictors were identified using the least absolute shrinkage and selection operator (LASSO) regression algorithm. Subsequently, multivariate logistic regression was employed to establish the nomogram. Model performance was assessed using the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis (DCA). Both discrimination and calibration were evaluated through bootstrapping with 1,000 resamples. The external validation cohort was subsequently used to validate the nomogram.ResultsFactors such as pregnancy hepatitis flare (OR: 5.122, 95% CI: 2.725–9.928, p < 0.001), NAs therapy after delivery (OR: 15.051, 95% CI: 6.954–37.895, p: <0.001), hepatitis B surface antigen (HBsAg) (OR: 0.549, 95% CI: 0.366–0.812, p: 0.003) and HBV DNA level at delivery (OR: 0.785, 95% CI: 0.619–0.986, p: 0.041) were included in the final risk model. The AUC in the training set was 0.873 (95% CI: 0.839–0.904). The calibration curve of the nomogram closely resembled the ideal diagonal line. DCA showed a significantly better net benefit in the model. External validation also confirmed the reliability of the prediction nomogram. The AUC in the external validation set was 0.889 (95% CI: 0.801–0.953). The calibration curve for the external validation set was in close proximity to the ideal diagonal line. DCA also demonstrated a significant net benefit associated with the predictive model, consistent with the findings in the training set. Finally, the nomogram has been translated into an online risk calculator that is freely available to the public (https://wendyzhong.shinyapps.io/DynNomapp/).ConclusionWe developed a nomogram based on prenatal and pregnant factors to estimate HBeAg seroconversion after delivery in women. This tool provides clinicians with a precise and effective way to identify individuals likely to undergo HBeAg seroconversion postpartum, aiding in decision-making for optimal management.

A comparison of the therapeutic efficacy of Tenofovir Disoproxil Fumarate and Entecavir in patients with chronic Hepatitis-B

Objective: To compare the therapeutic efficacy of tenofovir disoproxil fumarate (TDF) and entecavir (ETV) in patients with chronic Hepatitis-B (CHB). Methods: This retrospective study included 110 patients with CHB who received treatment at The First People’s Hospital of Linping District, Hangzhou from January 2021 to January 2023. Clinical data of the patients were reviewed and the patients were classified according to the treatment received: TDF group (n=53, patients received TDF treatment) and ETV group (n=57, patients received ETV treatment). Hepatitis-B virus deoxyribonucleic acid (HBV DNA) levels, liver function indicators, hepatitis-B e antigen (HBeAg) seroconversion rate, alanine transaminase (ALT) normalization rate, HBV DNA negative conversion rate, overall efficacy, and incidence of adverse reactions were compared. Results: The total efficacy of the treatment in the TDF group was 94.33%, significantly higher than that in the ETV group (78.95%; P<0.05). After the treatment, the HBV DNA levels in both groups decreased compared to pretreatment levels, and were significantly lower in the TDF group compared to the ETV group (P<0.05). Both groups showed significant post-treatment improvement in liver function that was markedly better in the TDF group compared to the ETV group (P<0.05). The HBeAg seroconversion rate, ALT normalization rate, and HBV DNA conversion rate in the TDF group were significantly higher compared to the ETV group (P<0.05). There was no difference in the incidence of adverse reactions between the two groups. Conclusions: Compared with ETV, TDF has comparable adverse reaction profile but has more significant clinical effects in patients with CHB, improving HBeAg seroconversion rate, ALT normalization rate, and HBV DNA negative conversion rate. TDF is associated with lower HBV DNA levels after treatment and better improvements in liver function of patients. doi: https://doi.org/10.12669/pjms.40.10.10307 How to cite this: Wang H, Wu L. A comparison of the therapeutic efficacy of Tenofovir Disoproxil Fumarate and Entecavir in patients with chronic Hepatitis-B. Pak J Med Sci. 2024;40(10):2390-2394. doi: https://doi.org/10.12669/pjms.40.10.10307 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Determinants of HBeAg loss during follow-up of a multiethnic pediatric cohort.

Hepatitis B e antigen (HBeAg) loss is a key event in the natural history of chronic hepatitis B virus infection. The rate and determinants of HBeAg loss depend upon cohort characteristics at baseline. Few studies have examined the age-dependent rate, and none have examined the effect of patient sex and ethnicity on the age-dependant rate. The study of age-dependent rates requires the identification and long-term follow-up of a pediatric cohort. We have studied the age-dependent rate of HBeAg loss, and the rate of HBeAg loss measured from baseline, in a multi-ethnic cohort of 454 pediatric patients. During observation, HBeAg loss was observed in 121/303 (39.9%) HBeAg-positive patients. The rate of HBeAg loss was greater in the second versus the first and third decades of life. The age-related rate of HBeAg loss was clearly affected by patient sex and ethnicity, with earlier loss observed for males and for White versus both South Asian and Chinese ethnicities. When measured from baseline, Chinese patients had a slower rate of HBeAg loss in comparison with White patients. In multivariate analysis of HBeAg loss during prolonged follow-up, male sex, older age, and White ethnicity were associated with HBeAg loss, but antiviral treatment was not.

Machine learning models to further identify advantaged populations that can achieve functional cure of chronic hepatitis B virus infection after receiving Peg-IFN alpha treatment

ObjectiveFunctional cure is currently the highest goal of hepatitis B virus(HBV) treatment.Pegylated interferon(Peg-IFN) alpha is an important drug for this purpose,but even in the hepatitis B e antigen(HBeAg)-negative population,there is still a portion of the population respond poorly to it.Therefore,it is important to explore the influencing factors affecting the response rate of Peg-IFN alpha and establish a prediction model to further identify advantaged populations. MethodsWe retrospectively analyzed 382 patients.297 patients were in the training set and 85 patients from another hospital were in the test set.The intersect features were extracted from all variables using the recursive feature elimination(RFE) algorithm, Boruta algorithm, and least absolute shrinkage and selection operator(LASSO) regression algorithm in the training dataset.Then,we employed six machine learning(ML) algorithms-Logistic Regression(LR),Random Forest(RF),Support Vector Machines(SVM),K Nearest Neighbors(KNN),Light Gradient Boosting Machine(LightGBM) and Extreme Gradient Boosting(XGBoost)-to develop the model.Internal 10-fold cross-validation helped determine the best-performing model,which was then tested externally.Model performance was assessed using metrics such as area under the curve(AUC) and other metrics.SHapley Additive exPlanations(SHAP) plots were used to interpret variable significance. Results138/382(36.13 %) patients achieved functional cure.HBsAg at baseline,HBsAg decline at week12,non-alcoholic fatty liver disease(NAFLD) and age were identified as significant variables.RF performed the best,with AUC value of 0.988,and maintained good performance in test set.The SHapley Additive exPlanations(SHAP) plot highlighted HBsAg at baseline and HBsAg decline at week 12 are the top two predictors.The web-calculator was designed to predict functional cure more conveniently(https://www.xsmartanalysis.com/model/list/predict/model/html?mid = 17054&symbol = 317ad245Hx628ko3uW51). ConclusionWe developed a prediction model,which can be used to not only accurately identifies advantageous populations with Peg-IFN alpha,but also determines whether to continue subsequent Peg-IFN alpha.

Up-regulation of MDSCs accumulation and Th2 biased response to co-stimulation of CsESP from Clonorchis sinensis and HBeAg in vitro

Co-infection with Clonorchis sinensis (C. sinensis) and Hepatitis B virus (HBV) are commonly observed in endemic areas of Clonorchiasis. Chronic infection of C. sinensis or HBV is more likely to happen. However, the immune mechanisms related to the pathogenesis of co-infection remain unknown. In the present study, Myeloid-derived suppressor cells (MDSCs) accumulation, bone marrow derived dendritic cells (BMDCs) reaction and the consequent effectors on Th1/Th2 polarization to co-incubation of excretory-secretory products from C. sinensis (CsESP) and Hepatitis B e antigen (HBeAg) in vitro were investigated for further understanding the immune response during co-infection. The results indicated that compared with CsESP or HBeAg alone, co-stimulation dominantly promoted MDSCs accumulation. Co-stimulation significantly downregulated the expression of CD80 and CD86, and reduced IL-12p70 release while augmented IL-10 levels of BMDCs. Higher transcription levels of mannose receptor (MR) while lower mRNA level of toll like receptor 4 (TLR-4) were detected among membrane receptors of BMDCs with co-treatment. In addition, after CD4 naïve T cells were stimulated by LPS-treated BMDCs with CsESP and HBeAg, the proportion of CD4+IL-4+ T cells and IL-4 increased, while CD4+INF-γ+ T cells percentage and INF-γ down-regulated. In conclusion, CsESP and HBeAg co-incubation more distinctly suppressed maturation of BMDCs resulting in increase of IL-10 and decrease of IL-12 highly possible by up-regulation of MR and down-regulation of TLR-4 of BMDCs, and successively induce Th2 immune skewing. These findings laid the cornerstone to further clarify immune responses during the co-infection contributing to the better precise treatment and progression assessment of co-infection patients.

Results of mother-to-child transmission in hepatitis B-positive mothers who underwent amniocentesis

PurposeThis study aims to analyze whether undergoing amniocentesis during pregnancy in women diagnosed with hepatitis B virus (HBV) infection leads to HBV transmission to newborns.MethodsRetrospective data collection was conducted from June 2019 to November 2022 on expectant mothers positive for hepatitis B surface antigen (HBsAg) who underwent amniocentesis at The Third Affiliated Hospital of Sun Yat-sen University, along with data on their newborns. The study summarized the HBV infection status of newborns born to mothers with different expressions of hepatitis B e antigen (HBeAg), antiviral treatment versus no treatment, and different HBV DNA viral loads before delivery.ResultsIn this study, 346 expectant mothers tested positive for HBsAg, along with 351 newborns (including 5 sets of twins, with 8 infants (2.28%) testing HBsAg-positive at birth. All newborns received dual immunotherapy and were followed up. At 7–12 months, retesting for HBsAg positivity and HBV DNA positivity among infants revealed that out of the infants born with HBsAg positivity, 7 cases had seroconverted to negative, while the remaining infant, who was positive for both HBsAg and HBeAg at birth, tested positive for both HBsAg and HBV DNA at 7–12 months. Thus, one case of vertical transmission of hepatitis B from mother to child occurred in this study. The proportion of infants born with HBsAg + among newborns born to HBeAg-positive mothers (4 cases, 6.06%) was significantly higher than that among newborns born to HBeAg-negative mothers (4 cases, 1.41%) (P < 0.05). The proportion of infants born with HBsAg + showed no significant difference between newborns born to mothers receiving antiviral therapy (2 cases, 2.90%) and those born to mothers not receiving antiviral therapy (6 cases, 2.13%) (P > 0.05). Among expectant mothers with viral load ≥ 6 log 10 IU/mL before delivery, 3 newborns (30.00%) were manifesting HBsAg positivity at birth, significantly higher than the group with viral load < 6 log 10 IU/mL before delivery (5 cases, 1.47%) (P < 0.05).ConclusionAmong HBsAg-positive expectant mothers, only a small number of infants are infected with the hepatitis B virus at birth, the proportion of which is relatively low. Infants born to mothers who are HBeAg-positive or have a viral load ≥ 6 log10 IU/mL have a higher risk of being born positive.

Correlates of Hepatitis B infection in pregnant women attending antenatal clinics in Wa Municipality, Ghana.

Despite the availability of an effective vaccine against viral hepatitis B infection, it remains prevalent, highly transmissible especially through mother-to-child, life-threatening, and a major public health challenge. A positive Hepatitis B e-Antigen (HBeAg) mother has a 90% risk of transmitting the virus to the unborn child in the perinatal period. This study sought to determine the prevalence and risk of Hepatitis B infection among pregnant women in the Wa Municipality of Ghana. A cross-sectional study employing systematic random sampling was conducted among 183 consented pregnant women who went for antenatal care in nine health facilities in the Wa Municipality. A structured validated questionnaire was used to collect information about socio-demographic and obstetric characteristics, awareness of Hepatitis B Virus (HBV) transmission and its prevention. Blood samples (3.0 mls) were collected from each participant to test for HBV serum markers using a Wondfo One Step HBV rapid immunochromatographic assay (Catalog number W003) for the Hepatitis B surface antigen (HBsAg). We conducted descriptive statistics including the prevalence and used multivariable logistic regression to determine the risk of Hepatitis B among study participants. Data was analysed using Stata/SE 15. About 20.2% of the 183 pregnant women screened tested positive for HBsAg. Generally, compared with younger pregnant women, older (> = 25) pregnant women were >9 times less likely to test positive for both chronic Hepatitis B core antibody (HBcAb) and (HBeAg) Hepatitis B infections. However, pregnant women in polygamous relationship were more likely to test positive for both (HBcAb) and (HBsAg and HBeAg) Hepatitis B infections compared with those in monogamous relationship. In a multivariable analysis, pregnant women in a polygamous relationships were about 5 times more likely to test positive for HBsAg (AOR = 4.61, 95% CI: 2.06-9.89) and HBcAb (AOR = 4.89, 95% CI:1.52-6.81) and HBeAg (AOR = 4.62, 95% CI:1.21-6.39) compared with those in a monogamous relationship. This study highlights a high HBsAg prevalence among pregnant women with those in polygamous relationship and younger age more likely to test positive. Facility and community-based health services should emphasize the need for regular screening, education, and vaccination of pregnant women, especially those at high risk, to prevent mother-to-child transmission of viral hepatitis B.

CXCR7 genetic variant predicts treatment response of pegylated-interferon α in HBeAg-positive chronic hepatitis B patients

ObjectivesCXC chemokine receptor 7 (CXCR7) plays pivotal roles in different virus infections. However, no research focused on the role of CXCR7 in hepatitis B virus (HBV)-infected patients. The primary aim of this study is to elucidate the role of CXCR7 in predicting the treatment response of chronic hepatitis B (CHB) patients undergoing pegylated interferon-alpha (PegIFNα) therapy. MethodsTwo cohorts with a total of 945 Chinese CHB patients (Cohort 1, n = 238; Cohort 2, n = 707) were enrolled in this retrospective study, all the patients were positive for hepatitis B e antigen (HBeAg) and received PegIFNα treatment for 48 weeks and followed-up for 24 weeks post-treatment. Nineteen tag single-nucleotide polymorphisms (SNPs) were selected within and surrounding the CXCR7 gene region. The associations of CXCR7 SNPs and polygenic score (PGS) with PegIFNα treatment response were investigated in the two cohorts. ResultsAmong the 19 candidate SNPs of CXCR7, rs2952665 (A > G) was significantly associated with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <3.3log10IU/mL, P = 0.002) and hepatitis B surface antigen (HBsAg) decline (P = 0.015) in the two cohorts at week 72. Furthermore, a PGS comprising CXCR7_rs2952665 and five additional SNPs, which were previously recognized as biomarkers of PegIFNα treatment response, demonstrated a robust correlation with both CR (P = 1.38 × 10−12) and HBsAg decline (P = 0.003) in all the patients. ConclusionThis research illustrated that CXCR7_rs2952665 is a promising predictor of the PegIFNα therapy efficiency in Chinese HBeAg-positive CHB patients. A PGS consisting of CXCR7_rs2952665 and five previously reported SNPs predicts treatment response to PegIFNα better.

Investigation of Mother-to-Child Transmission of Hepatitis B in Yinchuan, China: Cross-Sectional Survey Study.

Hepatitis B poses a significant global public health challenge, with mother-to-child transmission (MTCT) being the primary method of hepatitis B virus (HBV) transmission. The prevalence of HBV infection in China is the highest in Asia, and it carries the greatest burden globally. This study aims to critically evaluate the existing local strategies for preventing MTCT and the proposed potential enhancements by analyzing the prevalence of hepatitis B among pregnant women and their neonates in Yinchuan. From January 2017 to December 2021, 37,557 prenatal screening records were collected. Among them, 947 pregnant women who tested positive for hepatitis B surface antigen (HBsAg) near delivery and their 960 neonates were included in an HBV-exposed group, while 29 pregnant women who tested negative and their 30 neonates were included in an HBV-nonexposed group. HBV markers in maternal peripheral blood and neonatal cord blood were analyzed using the least absolute shrinkage and selection operator (LASSO) regression, logistic regression, chi-square test, t-test, and U-test. Additionally, to further evaluate the diagnostic value of HBsAg positivity in cord blood, we conducted an additional follow-up study on 103 infants who tested positive for HBsAg in their cord blood. The prevalence of HBV among pregnant women was 2.5% (947/37,557), with a declining trend every year (χ²4=19.7; P=.001). From 2018 to 2020, only 33.0% (35/106) of eligible pregnant women received antiviral medication treatment. Using LASSO regression to screen risk factors correlated with HBsAg positivity in cord blood (when log [λ] reached a minimum value of -5.02), 5 variables with nonzero coefficients were selected, including maternal hepatitis B e-antigen (HBeAg) status, maternal hepatitis B core antibody (HBcAb) status, maternal HBV DNA load, delivery method, and neonatal birth weight. Through univariate and multivariate logistic regression, delivery by cesarean section (adjusted odds ratio [aOR] 0.52, 95% CI 0.31-0.87), maternal HBeAg positivity (aOR 2.05, 95% CI 1.27-3.33), low maternal viral load (aOR 2.69, 95% CI 1.33-5.46), and high maternal viral load (aOR 2.69, 95% CI 1.32-5.51) were found to be strongly associated with cord blood HBsAg positivity. In the additional follow-up study, 61 infants successfully completed the follow-up, and only 2 were found to be infected with HBV. The mothers of both these infants had detectable HBV DNA levels and should have received standard antiviral therapy. The results of the hepatitis B surface antibody (HBsAb) positivity rate and titer test indicated a gradual decline in the immunity of vaccinated infants as the interval after vaccination increased. The clinical relevance of HBV marker detection in cord blood is restricted within the current prevention measures for MTCT. There is an emphasis on the significance of public education regarding hepatitis B and the reinforcement of postnatal follow-up for the prevention of MTCT.

Positivity of high-sensitivity HBsAg test, not previous HBV infection, indicates poor prognosis in patients with non-HBV-related HCC.

The prognostic impact of previous-HBV-infection (pHBV) in non-HBV-related hepatocellular carcinoma (non-HBV-related-HCC) and the prevalence, characteristics and significance of recently developed high-sensitivity HBs antigen positivity (hHBsAg+) in these patients remain unclear. We aimed to close these gaps. We retrospectively screened patients with newly diagnosed non-HBV-related-HCC (standard HBsAg-test negative) at Hokkaido University. Patients with complete clinical information and preserved serum for hHBsAg+ were included. We evaluated the prevalence, characteristics and prognostic impact of pHBV and hHBsAg+ in non-HBV-related-HCC. A total of 401 non-HBV-related-HCC patients were included (288 with pHBV/113 without pHBV). In non-HBV-related-HCC, pHBV did not affect overall survival (OS). Among non-HBV-related-HCC patients with pHBV, 11.8% (34/288) were hHBsAg+ and had more advanced stages of HCC, higher AFP levels, higher vascular invasion rates, and significantly shorter OS than others (OS: 19.3 vs. 61.4 months, p = 0.012). Comparison of OS among non-HBV-related-HCC patients without pHBV (group 1), those with pHBV and without hHBsAg+ (group 2), and those with pHBV and hHBsAg+ (group 3) revealed significantly shorter OS in group 3 (19.3, 56.6 and 66.4 months in groups 1, 2 and 3, respectively; p = 0.036). Multivariate Cox regression indicated that compared with group 1, only group 3 was significantly and independently associated with shorter OS (HR: 2.044, p = 0.011). Subgroup analysis revealed that this association was particularly evident in non-HBV-related-HCC patients with non-B-non-C aetiology and advanced HCC. In non-HBV-related-HCC patients, hHBsAg+, not pHBV, is significantly and independently associated with poor prognosis.

The salivary microbiome and oral health status in HBeAg-negative chronic hepatitis B

Background/purposeDysbiosis of oral microbiota has been reported in late stage of chronic hepatitis B (CHB) infection with cirrhosis. CHB is characterized by the constant virus-induced liver injury which may lead to liver cirrhosis and hepatocellular carcinoma (HCC). However, some patients show normal liver function without antiviral treatment, associating with favourable prognosis. The oral microbiota composition and oral health status in these patients is unidentified. Materials and methodsThe study focuses on the composition of oral microbiota and oral health status in individuals with CHB and HBV vaccinees as controls. The CHB patients were hepatitis B 'e' antigen (HBeAg)-negative, with or without elevated liver enzyme increase at time of sampling, The 16S rRNA high-throughput sequencing and bioinformatic analysis were applied to investigate oral bacterial diversity, and oral examination including decay-missing-filled teeth (DMFT) index, probing depth (PD) and mucosal status was performed, along with oral health questionnaire, to assess the oral health status in CHB patients and healthy controls. ResultsOur results indicate that their oral microbiome compositions are not significantly different though some have increased ALT/AST liver enzyme levels at the time of sampling, compared to the healthy control participants who are vaccinated e.g. protected from this viral disease. CHB patients here bore a good oral health status and life-style habits as comparing to healthy controls. ConclusionThese findings suggest that a health-associated salivary microflora is present in CHB without severe liver injury. Continued regular dental health and lifestyle support in liver disease patients is therefore justified.

Age of hepatitis B e antigen loss in Aboriginal, Torres Strait Islander and non-Indigenous residents of tropical Australia; implications for clinical care.

This study determined the hepatitis B e antigen (HBeAg) status of people living with chronic hepatitis B (CHB) in Far North Queensland (FNQ), Australia and their age of HBeAg loss. It was hoped that this would provide data to explain the stark difference in the incidence of hepatocellular carcinoma (HCC) between Aboriginal and Torres Strait Islander individuals living with CHB in FNQ, a finding that has been hypothesised to relate to differences in hepatitis B virus genotype. We identified every FNQ resident with CHB, determined their country of birth, their HBeAg status, the age they lost HBeAg and whether they identified as an Aboriginal, a Torres Strait Islander or a non-Indigenous individual. We then ascertained whether these demographic and virological variables were correlated. Of 1,474 individuals living with CHB in FNQ, 278 (19%) were Aboriginal, 507 (34%) were Torres Strait Islanders and 689 (47%) were non-Indigenous. Aboriginal individuals were less likely to be HBeAg positive (26/278, 9%) than Torres Strait Islander (91/507, 18%) and non-Indigenous (126/689, 18%) individuals, p < 0.0001. Aboriginal individuals lost HBeAg at an earlier age (median (interquartile range): 30 (23-39) years) than Torres Strait Islander (38 (29-49) years) and non-Indigenous (36 (29-47) years) individuals, p < 0.0001. Aboriginal individuals with CHB in FNQ are more likely to be HBeAg negative than Torres Strait Islander and non-Indigenous individuals and lose HBeAg at a younger age. This provides a biological basis for local clinicians' observation that Aboriginal individuals with CHB in FNQ are at a lower risk of HCC and data to support the principle of genotype-based care in the region.

MicroRNA levels in patients with chronic hepatitis B virus and HIV coinfection in a high-prevalence setting; KwaZulu-Natal, South Africa

BackgroundHepatitis B virus (HBV) and human immunodeficiency virus (HIV) co-infection are significant public health issues, despite the availability of an effective HBV vaccine for nearly three decades and the great progress that has been made in preventing and treating HIV. HBV and HIV both modulate micro-ribonucleic acids (microRNA) expression to support viral replication. The aim of this study was to describe the pattern of microRNA expression in patients coinfected with chronic HBV and HIV with varying disease severity, as indicated by Hepatitis B e antigen (HBeAg) status, HBV viral load, alanine transaminase (ALT) levels, and HIV viral load.MethodsPlasma microRNAs, specific to HBV, were measured by quantitative real-time polymerase chain reaction (qRT-PCR) in HBV and HIV-negative healthy controls (n = 23) and patients coinfected with chronic HBV-HIV (n = 50). MicroRNA expression levels were compared between patients with high vs low HBV viral load, HBeAg positive vs HBeAg negative, high vs low ALT levels, and high vs low HIV viral load. Additionally, HBV viral load, ALT levels, and HIV viral load were correlated with microRNA expression levels.ResultsSignificantly higher expression levels of selected microRNAs were observed in chronic HBV-HIV coinfected patients compared to healthy controls. Significantly higher expression levels of hsa-miR-122-5p, hsa-miR-192-5p, and hsa-miR-193b-3p were observed in patients with high HBV viral load compared with low HBV viral load patients, and the levels of these microRNAs were correlated with HBV viral load levels. Significantly higher levels of hsa-miR-15b-5p and hsa-miR-181b-5p were observed in HBeAg-negative patients.ConclusionThis study demonstrates the potential use of hsa-miR-15b-5p, hsa-miR-122-5p, hsa-miR-181b-5p, hsa-miR-192-5p and hsa-miR-193b-3p as additional diagnostic biomarkers in chronic HBV disease progression.

Predictors of Functional Cure of Chronic Hepatitis B Virus Infection: A Long-Term Follow-Up Study

Functional cure is an essential endpoint in the management of patients with chronic hepatitis B virus (HBV) infection. We evaluated the cumulative probability and predictors of functional cure in patients with chronic HBV infection after hepatitis B e antigen (HBeAg)-seroconversion. We retrospectively analyzed 413 (249 males and 164 females) initially HBeAg-positive chronic HBV-infected patients, who were followed up for a mean of 26.36 ± 0.53 years. All underwent HBeAg-seroconversion during follow-up. A functional cure was defined as durable HBsAg and HBV DNA loss without antiviral treatment for more than 24 weeks. After 10,888 person-years of follow-up, the cumulative probability of functional cure was 14.53% (n = 60). There were 24 (40%) subjects with functional cure after antiviral therapy. The annual functional cure rate was 0.55% per perperson-year, and increased to 0.96% per person-year after HBeAg-seroconversion. In subjects with functional cure, the HBsAg and HBV DNA titers after HBeAg-seroconversion were positively correlated with the time to functional cure (P < .001 and < .001, respectively). Multivariate Cox proportional hazard analysis of the cohort revealed that HBeAg-seroconversion at < 18 years of age, high genetic barrier nucleos(t)ide analogue(s) therapy before HBeAg-seroconversion, and a serum HBsAg titer < 1,000 IU/mL at 18 months after HBeAg-seroconversion were significant predictors of functional cure (P < .001, .001, and .001, respectively). In a cohort of chronic HBV-infected patients with long-term follow-up, HBeAg-seroconversion in childhood, high genetic barrier nucleos(t)ide analogue(s) therapy, and low HBsAg titers after HBeAg-seroconversion were significant predictors of functional cure.

Baseline Viral Load and On-treatment Hepatocellular Carcinoma Risk in Chronic Hepatitis B: A Multinational Cohort Study

Hepatocellular carcinoma (HCC) risk persists in chronic hepatitis B (CHB) patients despite antiviral therapy. The relationship between pre-treatment baseline hepatitis B virus (HBV) viral load and HCC risk during antiviral treatment remains uncertain. This multinational cohort study aimed to investigate the association between baseline HBV viral load and on-treatment HCC risk in 20,826 noncirrhotic, hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with baseline HBV DNA levels ≥2,000 IU/mL (3.30 log10 IU/mL) who initiated entecavir or tenofovir treatment. The primary outcome was on-treatment HCC incidence, stratified by baseline HBV viral load as a categorical variable. In total, 663 patients developed HCC over a median follow-up of 4.1 years, with an incidence rate of 0.81 per 100 person-years (95% confidence interval [CI], 0.75-0.87). Baseline HBV viral load was significantly associated with HCC risk in a non-linear parabolic pattern, independent of other factors. Patients with baseline viral load between 6.00 and 7.00 log10 IU/mL had the highest on-treatment HCC risk (adjusted hazard ratio, 4.28; 95% CI, 2.15-8.52; P < .0001) compared to those with baseline viral load ≥8.00 log10 IU/mL, who exhibited the lowest HCC risk. Baseline viral load showed a significant, non-linear, parabolic association with HCC risk during antiviral treatment in noncirrhotic CHB patients. Early initiation of antiviral treatment based on HBV viral load may help prevent irreversible HCC risk accumulation in CHB patients.

Differences of Efficacy Between Tenofovir Alafenamide Fumarate and Tenofovir Disoproxil Fumarate in Pregnant Women with Different Hepatitis B Virus DNA Loads

Abstract Tenofovir alafenamide fumarate (TAF) has been endorsed by guidelines for blockade of mother-to-child transmission of hepatitis B virus (HBV), given that its efficacy and safety are comparable to tenofovir disoproxil fumarate (TDF). However, there is a lack of comparative studies regarding the treatment efficacy in patients with diverse viral loads. This study retrospectively analyzed 96 hepatitis B e antigen (HBeAg)-positive pregnant women with HBV DNA levels ≥2 × 105 IU/mL. Based on viral loads (HBV DNA levels), participants in the TAF and TDF groups were stratified into three subgroups, namely the High-G (titer ≥8 log10 IU/mL), Middle-G (7 log10 IU/mL ≤ titer &lt;8 log10 IU/mL) and Low-G (titer &lt;7 log10 IU/mL) subgroups. The primary endpoint was effectiveness of TAF and TDF in patients with varying viral loads, while secondary endpoints were hepatitis B surface antigen (HBsAg) positivity in infants at 7 -12 months and the safety profile for mothers and children. Compared to baseline levels, median HBV DNA levels in mothers were decreased by 4.51 and 4.09 log10 IU/mL in the TAF and TDF groups (P = 0.04) pre-delivery, respectively. In the High-G subgroup, the titers were significantly lower in the TAF group (P = 0.045), a higher proportion of patients experienced a virus decline of ≥4 log10 IU/mLin the TAF group compared with the TDF group, with rates of 78.26% versus 58% (P = 0.034), respectively. Moreover, the median serum phosphate levels significantly decreased from baseline to pre-delivery in the TDF group (P = 0.04). Finally, infants in both cohorts tested negative for HBsAg at 7-12 months after delivery. Overall, our findings indicated that TAF can be considered the preferred option for treatment of HBeAg-positive pregnant women with HBV DNA levels ≥8 log10 IU/mL.

Impaired HBsAg release and antiproliferative/antioxidant cell regulation by HBeAg-negative patient isolates reflects an evolutionary process.

The hepatitis B e antigen (HBeAg)-negative infection Phase 3 is characterized by no or minimal signs of hepatic inflammation and the absence of hepatic fibrosis. However, underlying molecular mechanisms leading to this benign phenotype are poorly understood. Genotype A, B and D HBeAg-negative patient isolates with precore mutation G1896A from Phase 3 were analysed in comparison with respective HBeAg-positive rescue mutant and HBeAg-positive wild-type reference genomes regarding differences in viral replication, morphogenesis, infectivity and impact on NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE)-dependent gene expression and cellular kinome. In comparison with reference genomes, the patient isolates are characterized by a lower intra- and extracellular hepatitis B surface antigen (HBsAg)-amount, and HBsAg-retention in the endoplasmic reticulum. Rescue of HBeAg expression increased HBsAg-amount but not its release. Expression of the isolated genomes is associated with a higher Nrf2/ARE-dependent gene expression as compared to reference genomes independent of HBeAg expression. Kinome analyses revealed a decreased activity of receptors involved in regulation of proliferative pathways for all patient isolates compared to the reference genomes. No specific conserved mutations could be found between all genomes from Phase 3. HBeAg-negative genomes from Phase 3 exhibit distinct molecular characteristics leading to lower HBsAg synthesis and release, enhanced oxidative stress protection and decreased activity of key kinases, triggering an antiproliferative stage, which might contribute to the lower probability of hepatocellular carcinoma. The observed differences cannot be associated with loss of HBeAg or specific mutations common to all analysed isolates, indicating the phenotype of Phase 3 derived genomes to be the result of a multifactorial process likely reflecting a conserved natural selection process.

Differential HBV replicative markers and covalently closed circular DNA transcription in immune-active chronic hepatitis B with and without HBeAg.

Molecular processes driving immune-active chronic hepatitis B (CHB) with and without hepatitis B e antigen (HBeAg) remain incompletely understood. This study aimed to investigate expression profiles of serum and intrahepatic HBV markers and replicative activity of HBV in CHB patients with or without HBeAg. This study recruited 111 untreated immune-active CHB (60 HBeAg-positive and 51 HBeAg-negative) patients and quantified intrahepatic covalently closed circular DNA (cccDNA), pre-genomic RNA (pgRNA), total HBV DNA (tDNA), and replicative intermediates as well as serum HBV markers (HBV DNA, hepatitis B surface antigen, hepatitis B core-related antigen). Correlations between HBV markers and clinico-virological factors influencing expression levels of HBV markers were analysed. Levels of all serum markers and intrahepatic cccDNA/tDNA as well as cccDNA transcriptional activity and virion productivity were significantly reduced in HBeAg-negative patients compared to those in HBeAg-positive patients. Additionally, correlations between intrahepatic cccDNA/pgRNA and serum markers were impaired in HBeAg-negative individuals. Aminotransferase levels were positively correlated with cccDNA transcriptional activity in HBeAg-positive patients, but not in HBeAg-negative patients. Notably, among HBeAg-positive patients, there was a progressive decline in pgRNA level, transcriptional activity, and serum HBV markers as liver fibrosis advanced, which was not observed in HBeAg-negative patients. HBeAg loss is correlated with diminished intrahepatic HBV reservoirs and cccDNA transcription, leading to decreased serum HBV marker levels. Circulating HBV markers are not reliable indicators of intrahepatic HBV replicative activity for HBeAg-negative patients. Our findings reveal distinct disease phenotypes between immune-active CHB with and without HBeAg, highlighting the need to establish optimal surrogate biomarkers that can accurately mirror intrahepatic viral activity to aid in decision-making for antiviral therapy for immune-active CHB.

Insights into the Natural and Treatment Courses of Hepatitis B in Children: A Retrospective Study.

Chronic Hepatitis B virus (HBV) infection in children remains a significant public health challenge. The natural history and treatment outcomes of HBV can vary widely, influencing management strategies. This retrospective study was conducted in Northeast Romania and involved a cohort of 148 pediatric patients diagnosed with chronic viral Hepatitis B. Of these, 59 children underwent antiviral treatment while 89 were not treated. One of the main objectives was the rate of HBeAg (Hepatitis B-e antigen) seroconversion, a marker of disease progression and response to therapy. Among the treated group, 26 children (44%) achieved HBeAg seroconversion following therapy. In contrast, 44 of the untreated children (49%) experienced spontaneous HBeAg seroconversion, indicating a substantial rate of natural resolution within this population subset. The findings highlight a significant proportion of spontaneous seroconversion in untreated pediatric patients, suggesting a potential re-evaluation of treatment criteria and timing for children with chronic HBV infection. The comparable rates of seroconversion between treated and untreated cohorts underscore the need for individualized treatment approaches based on a combination of virological, biochemical, and clinical parameters. Further studies are required to refine management strategies to optimize long-term outcomes in pediatric HBV infections.

Clinical Efficacy and Safety of Long-Term Treatment of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate for Chronic Hepatitis B in Vietnam.

Hepatitis B virus (HBV) infection is a contagious condition posing a major public health risk in various nations, including Vietnam. In 2019, the Ministry of Health introduced tenofovir alafenamide (TAF) to treat patients with chronic HBV infection and reduce the long-term toxicity of tenofovir disoproxil fumarate (TDF). This study aimed to assess the effectiveness and safety of these 2 medications in individuals with hepatitis B e antigen (HBeAg)-positive chronic HBV. This retrospective cohort study included data collected from the medical records of patients with chronic HBV who visited the Liver Clinic at University Medical Center Ho Chi Minh City between 2018 and 2020. After 2 years of treatment, the proportion of HBeAg loss in the TAF group was twice that of the TDF group (22.4% vs 11.2%), indicating a statistically significant difference in the probability of HBeAg loss (adjusted hazard ratio = 2.22; 95% confidence interval [CI] 1.43-3.42; P < 0.01). In addition, there was a statistically significant difference in the rate and ability of antiviral response between patients treated with TAF and TDF (65% vs 54.5%, respectively; adjusted hazard ratio = 1.34; 95% CI 1.08-1.69; P < 0.01). A total of 93.9% of patients achieved the goal of restoring alanine aminotransferase to normal, a higher percentage compared with the 81.2% in the TDF group, and the likelihood of achieving normal alanine aminotransferase levels with TAF was greater compared with those on TDF (adjusted hazard ratio = 1.67; 95% CI 1.38-2.01; P < 0.01). Moreover, there was a statistically significant difference in the variation in renal function between the TAF and TDF groups. Serum creatinine levels in the TAF group increased less than those in the TDF group by 0.03 mg/dL every 6 months (95% CI -0.04 to -0.01, P < 0.01), and the estimated glomerular filtration rate in the TAF group was higher than that in the TDF group every 6 months by 2.78 mL/min/1.73 m 2 (95% CI 0.98-4.57, P < 0.01). However, there was no statistically significant difference in the likelihood of HBeAg seroconversion between patients with chronic hepatitis B treated with TAF or TDF (adjusted hazard ratio = 1.79; 95% CI 0.91-3.53; P = 0.09), nor in the risk of adverse events between the 2 groups (adjusted odds ratio = 1.34; 95% CI 0.88-2.05; P = 0.17). In addition, although the HBsAg concentration in the TAF group was lower than in the TDF group by an average of 0.05 log 10 IU/mL every 6 months (95% CI -0.15 to 0.05), this difference also did not reach statistical significance ( P = 0.35). TAF has been demonstrated to achieve some therapeutic efficacy goals and reduce nephrotoxicity better than TDF. However, no differences were found in seroconversion or adverse events between the patient groups.