Predictors of functional cure of chronic hepatitis B virus infection - A long-term follow-up study.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Clinical performance of Circulating HBV RNA and iTACT-HBcrAg Assays in HBeAg-negative and HBsAg-cleared Chronic Hepatitis B Patients.

Hepatitis B virus (HBV) RNA and hepatitis B core-related antigen (HBcrAg) have been reported to reflect the transcriptional activity of covalently closed circular HBV DNA. We retrospectively investigated the proportions of quantifiable serum HBV RNA and immunoassay for total antigen including complex via pretreatment-hepatitis B core-related antigen (iTACT-HBcrAg) in chronic hepatitis B patients negative for hepatitis B e antigen (HBeAg) and/or with hepatitis B surface antigen (HBsAg) seroclearance. This study included 246 HBeAg-negative HBV-infected patients, who comprised 13 with liver cirrhosis (LC, the LC group), 118 chronic hepatitis (CH, the CH group), and 115 inactive carriers (IC, the IC group), and 44 patients with HBsAg seroclearance. iTACT-HBcrAg and HBV RNA levels were determined using stored serum samples. Higher proportions of the patients had quantifiable iTACT-HBcrAg than HBV RNA in all groups of HBeAg-negative patients (iTACT-HBcrAg: 84.6%, 90.7%, 35.7%, HBV RNA: 23.1%, 26.3%, 14.8%, for the LC, CH, IC groups). With HBsAg seroclearance (HBsAg <0.05 IU/mL), the proportions of quantifiable samples for HBV RNA were also lower than iTACT-HBcrAg (0% for HBV RNA). Thus, iTACT-HBcrAg was more often detectable than circulating HBV RNA in this study population. Further long-term prospective evaluation of iTACT-HBcrAg is desirable for its utilization in clinical practice.

A pilot integrated model nurse clinic increases the uptake of antiviral treatment for the prevention of mother-to-child transmission of HBV.

BACKGROUND AND AIMS: Mother-to-child-transmission (MTCT) of hepatitis B virus (HBV) may still occur despite birth-dose HBV vaccinations when pregnant women are positive for hepatitis B surface antigen (HBsAg) with high viral loads (HBV DNA ≥ 200 000 IU/mL). A pilot integrated model nurse clinic (IMNC) was started in 2020 to implement the pre-emptive antiviral therapy with tenofovir disoproxil fumarate (TDF). We aimed to evaluate the performance of IMNC on uptake of TDF. METHODS: This was a territory-wide retrospective cohort of all consecutive HBsAg-positive women of child-bearing age with pregnancy records in public hospitals 2019-2022. Demographic characteristics, liver biochemistries and virologic parameters, and TDF use were collected. Concurrently, data from a prospective audit in Union Hospital, the private hospital with the highest number of deliveries in Hong Kong, from June 2022 to May 2023 were compared. RESULTS: The prevalence rate of HBV DNA ≥ 200 000 IU/mL in pregnant women with available HBV DNA records was 29.2% (66/226) in 2019, 27.3% (99/363) in 2020, 15.9% (125/784) in 2021 and 17.2% (117/679) in 2022 (p < .001), out of 2052 pregnant women who had their HBV DNA checked within 1 year prior to delivery. An increasing uptake rate of TDF by highly viraemic pregnant women (i.e. ≥ 200 000 IU/mL) was noted after the commencement of IMNC in public hospitals, with 67% (45/67) in 2019, 83% (88/106) in 2020, 91% (117/128) in 2021 and 89% (149/167) in 2022. Moreover, all highly viraemic pregnant women from Union Hospital received TDF. Continuous use of TDF was associated with a reduced risk of postpartum biochemical flare. CONCLUSIONS: IMNC increases the uptake of antiviral treatment in pregnant women at risk of MTCT of HBV. IMNC contributes to hepatitis elimination through a structured care plan to prevent MTCT of HBV.

[HBeAg-positive patients hepatic tissue inflammatory activity and influencing factors during normal ALT and indeterminate phases].

Objective: To analyze the hepatic tissue inflammatory activity and influencing factors in HBeAg-positive patients during normal alanine aminotransferase (ALT) and indeterminate phases so as to provide a basis for evaluating the disease condition. Methods: Patients with HBeAg-positive with normal ALT and HBV DNA levels below 2 × 10(7) IU/ml from January 2017 to December 2021 were selected as the study subjects. A histopathologic liver test was performed on these patients. Age, gender, time of HBV infection, liver function, HBsAg level, HBV DNA load, genotype, portal vein inner diameter, splenic vein inner diameter, splenic thickness, and others of the patients were collected. Significant influencing factors of inflammation were analyzed in patients using logistic regression analysis, and its effectiveness was evaluated using receiver operating characteristic (ROC) curves. Results: Of the 178 cases, there were 0 cases of inflammation in G0, 52 cases in G1, 101 cases in G2, 24 cases in G3, and one case in G4. 126 cases (70.8%) had inflammatory activity ≥ G2. Infection time (Z=-7.138, P<0.001), γ-glutamyltransferase (t =-2.940, P=0.004), aspartate aminotransferase (t =-2.749, P=0.007), ALT (t =-2.153, P=0.033), HBV DNA level (t =-4.771, P=0.010) and portal vein inner diameter (t =-4.771, P<0.001) between the ≥G2 group and < G2 group were statistically significantly different. A logistic regression analysis showed that significant inflammation in liver tissue was independently correlated with infection time [odds ratio (OR)=1.437, 95% confidence interval (CI): 1.267-1.630; P<0.001)] and portal vein inner diameter (OR=2.738, 95% CI: 1.641, 4.570; P<0.001). The area under the curve (AUROC), specificity, and sensitivity for infection time and portal vein inner diameter were 0.84, 0.71, 0.87, 0.72, 0.40, and 0.95, respectively. Conclusion: A considerable proportion of HBeAg-positive patients have inflammation grade ≥G2 during normal ALT and indeterminate phases, pointing to the need for antiviral therapy. Additionally, inflammatory activity has a close association with the time of infection and portal vein inner diameter.

Kinetics changes in total cholesterol predict HBeAg seroconversion in chronic hepatitis B patients treated with pegylated interferon-alfa.

There is no satisfactory standard for predicting HBeAg seroconversion during Pegylated interferon alpha (PegIFNα) treatment. Studies have shown that IFNα therapy in chronic hepatitis C patients could alter serum lipid profiles. However, there have been no studies on lipid changes that predict the outcome of PegIFNα monotherapy in treated-naive chronic hepatitis B (CHB) patients. This retrospective study included 130 treated-naive HBeAg-positive CHB patients receiving PegIFNα monotherapy. The relationship between serum lipid changes and HBeAg seroconversion was analysed. The TC-ALT-HBsAg-HBeAg-Genotype-Age (CASEGA) model was established to predict HBeAg seroconversion after PegIFN-α monotherapy. Among 130 patients, 33 achieved HBeAg seroconversion (SR) and 97 did not achieve HBeAg seroconversion (NR). The decrease in serum total cholesterol (TC) in the NR group was significantly higher than in the SR group at Week 24 (-9.59% vs. -0.31%, p < 0.001). Multivariate logistic regression analysis showed that the change in TC at Week 24 (odds ratio = 1.065, p = 0.009) was an independent predictor of HBeAg seroconversion. The area under the receiver operating characteristic curve for the CASEGA model was 0.883. The model score at the maximum Youden index was 90, and the specificity, sensitivity, positive predictive value and negative predictive value were 0.727, 0.794, 0.546 and 0.895, respectively. The HBeAg seroconversion rate at Week 72 in patients with scores >90 was significantly higher than that in patients with scores <90 (54.55% vs. 10.47%, p < 0.001). This study indicated that the change in the TC level at 24 weeks in CHB patients treated with PegIFNα was associated with HBeAg seroconversion. The CASEGA prediction model based on the TC change rate of 24 weeks has good predictive efficiency for HBeAg seroconversion.

Baseline and on-treatment HBcrAg levels as predictors of HBeAg seroconversion in chronic hepatitis B patients treated with antivirals.

HBeAg seroconversion is an important treatment endpoint. We aimed to identify predictors of seroconversion using serum HBsAg and hepatitis B core-related antigen (HBcrAg) in HBeAg-positive patients treated with nucleos(t)ide analogs (NAs). Data and samples from 70 HBeAg-positive patients treated with entecavir or tenofovir between January 2007 and December 2017 were retrospectively analysed. The mean follow-up period was 11 years. The predictive power for HBeAg seroconversion of HBcrAg levels at baseline and 2 years after antiviral therapy was determined using receiver operating curve analysis. Twenty-one patients (30%) achieved HBeAg seroconversion at a mean of 28 (range, 12-84) months after antiviral treatment. The median baseline HBcrAg and HBsAg levels were 6.9(5.7-7.0) vs. 5.8(5.5-6.5) log10 U/mL (p = .006), 4.9(4.5-5.1) vs. 4.5(4.1-5.0) log10 IU/mL (p = .044) in the no seroconversion group and seroconversion group, respectively. In the multivariate analysis, the serum HBcrAg levels at baseline and 2 years after antiviral therapy were predictive factors for HBeAg seroconversion ([HR]; 0.326; [CI], 0.111-0.958; p = .042 and HR, 0.4555; CI, 0.211-0.984; p = .045). HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy had sensitivities of 53.1% and 69.8%, specificities of 95.2% and 70.6%, positive predictive values of 82.6% and 50.0%, and negative predictive values of 82.6% and 84.5%, respectively, with AUROCs of 0.712 (95%CI, 0.596-0.830) and 0.745 (95%CI, 0.599-0.891) for predicting HBeAg seroconversion. In chronic hepatitis B patients treated with NAs, HBcrAg levels≤6.5log10 U/mL at baseline and ≤5.3log10 U/mL at 2 years after antiviral therapy were useful predictive factors of HBeAg seroconversion.

The relationship of maternal hepatitis B e antigen and response to vaccination of infants born to women with chronic infection.

BACKGROUND: The relationship of maternal HBeAg and infants' response to hepatitis B vaccine remains controversial. This study aims to observe the dynamic changes in infant birth HBV markers and study the time-varying effects of maternal HBeAg on vaccination response of infants born to women with chronic HBV infection. METHODS: 3163 infants born to HBsAg positive mothers including 1737 with maternal HBeAg positive in group A and 1426 negative in group B were enrolled eventually. Demographic information and laboratory tests were collected at birth, 7-12th and 24th month. The dynamic changes of infant HBV markers and HBsAb titers at different time points were compared between the two groups. RESULTS: The infant HBV markers at birth displayed different modes. During the follow-up, we observed a significant downward trend in the positive rates of HBsAg, HBeAg, HBeAb and HBcAb. The HBsAg of two groups switched to negative at 7-12 months and HBeAg in Group A became negative at 24 months. The HBsAb titers of the infants in the two groups were 576.91(192.8-1000.0) vs 719.67(208.1-1000.0) at 7-12 months (Z = -3.049, P = 0.002) and 783.5(227.8-1000.0) vs 891.4(234.0-1000.0) at 24 months (Z = -0.853, P = 0.394). High HBV DNA viral load (OR 1.260, 95% CI 1.139-1.395, P < 0.001) and maternal HBeAg level (OR 1.003, 95% CI 1.002-1.003, P < 0.001) were associated with the higher HBeAg positive rate of infants. CONCLUSIONS: Maternal HBeAg did affect the infants' immune response to vaccination and reduce the anti-response at 7-12th month temporarily, but these influences were negligible by 24th months after birth, which proved that the maternal HBeAg would not induce immune tolerance of infants from a long-term perspective.

[Different treatment strategies in patients with HBeAg-positive and negative chronic hepatitis B].

Patients with HBeAg-positive and negative chronic hepatitis B (CHB) have different immunological states and disease progression. Hence, the previously recommended antiviral therapy strategies for the two are different. In recent years, the antiviral indications have gradually eased, and the treatment goal has began to pursue clinical cure, as experts and scholars have gradually attached importance to the potential risk of disease progression in hepatitis B patients. Antiviral treatment strategies are gradually becoming uniform for patients with HBeAg-positive and negative. However, among them, HBeAg-negative patients can be combined with HBsAg quantification and other indicators to further screen the clinically cured dominant population in order to formulate the next treatment strategy.

[Association between HBV viral load and severity of liver inflammation in patients with chronic hepatitis B virus infection].

Objective: To explore the relationship and dynamic changes between virological markers and hepatic pathological damage due to host anti-hepatitis B virus (HBV) immunity in the natural course of disease in chronic HBV infected patients. Methods: Two hundred and thirty-eight adult chronic HBV-infected patients who underwent liver biopsy from January 2016 to June 2022 in Taizhou Hospital, Zhejiang Province, were retrospectively selected. General clinical data such as age, gender, platelets, ALT, AST, albumin, HBV DNA, qHBsAg, HBeAg, and liver pathology diagnostic indexes such as the grade of liver necroinflammation and liver fibrotic stages of the patients were collected. The patients were grouped according to HBeAg status, and subgrouped according to different grades of liver necroinflammation and different HBV DNA loads. Statistical analyses were performed to compare the differences in HBV virologic marker levels between the groups, and the correlation between them and the indicators of hepatic inflammatory injury, such as ALT,AST, and the grade of liver necroinflammation in the patients. Results: The levels of HBV virological markers in HBeAg-positive patients with moderate or higher liver necroinflammatory grade (G≥2) were significantly lower than those with mild (no) liver necroinflammatory grade (G < 2) (P < 0.01); whereas the opposite trend was observed in HBeAg-negative patients, with the levels of HBV DNA, and qHBsAg in the G≥2 subgroup being significantly higher than those in the G < 2 subgroup (P < 0.01). Correspondingly, HBV DNA level and qHBsAg showed weak to moderately strong negative correlation with liver necroinflammatory grade and AST which was an indicator of hepatic inflammatory injury in HBeAg-positive patients (P < 0.05); whereas in HBeAg-negative patients, they showed weak to moderately strong positive correlation with hepatic inflammatory activity and ALT, AST (P < 0.001), in which qHBsAg showed only a weak positive correlation with patients' liver necroinflammatory grade (P = 0.003). Further subgroup analyses of HBeAg-positive patients according to whether the HBV DNA level was > 2×10(6) IU/ml showed weak to moderate negative correlations between HBV virological markers and liver necroinflammatory grade as well as ALT and AST in the subgroup of patients with HBV DNA > 2×10(6) IU/ml (P < 0.05); however, the negative correlation disappeared in patients who were still HBeAg positive and had HBV DNA ≤ 2×10(6) IU/ml. Moreover, HBV DNA and ALT, HBeAg and AST showed moderate positive correlation (P < 0.05). Conclusion: We speculate that the activation of host anti-HBV immunity can efficiently inhibit HBV replication by targeting the infected hepatocytes, but only in the early phase of disease progression in HBeAg positive patients with HBV DNA high (> 2×10(6) IU/ml).

Clearance of Hepatitis B e Antigen in Untreated Chronic Hepatitis B Virus Infection: A Systematic Review and Meta-analysis.

BACKGROUND: In people with hepatitis B virus (HBV) infection, persistence of hepatitis B e antigen (HBeAg) is associated with clinical progression and need for treatment. HBeAg loss represents partial immune control and is a critical event in the natural history of chronic HBV. METHODS: We conducted a systematic review and meta-analysis of cohort studies that report HBeAg loss among people with untreated chronic HBV. We evaluated HBeAg loss using a random-effects model and conducted subanalysis on region. RESULTS: We screened 10 560 publications, performed 196 full-text analyses, and included 26 studies for meta-analysis. The pooled rate of HBeAg loss was 6.46/100 person-years (PYs) (95% confidence interval, 5.17-8.08). Meta-regression showed that older age of participants and studies in Europe were associated with higher rate of HBeAg loss. Rates per 100 PYs were 7.43 (95% confidence interval, 6.30-8.75; 1 study) in Africa, 3.24 (2.61--4.02; 1 study) in the Eastern Mediterranean, 13.67 (11.21-16.66; 4 studies) in Europe, 7.34 (4.61--11.70; 5 studies) in North America, and 5.53 (4.05--7.55; 15 studies) in the Western Pacific. CONCLUSIONS: Spontaneous HBeAg loss occurs at a rate of 6.46/100 PYs. Variations by region and age group may reflect epidemiological, immunological, or HBV genotype-related differences.

Combining the HBcrAg decline and HBV mutations predicts spontaneous HBeAg seroconversion in chronic hepatitis B patients during the immune clearance phase.

To assess predictive ability of hepatitis B virus (HBV) markers and genome mutations for spontaneous hepatitis B e antigen (HBeAg) seroconversion. A total of 113 chronic hepatitis B (CHB) patients were followed up for 76 weeks without antiviral treatment. Baseline basal core promoter (BCP) and precore mutations were detected and serum hepatitis B surface antigen (HBsAg), HBeAg, hepatitis B core-related antigen (HBcrAg), and HBV DNA levels were serially quantified. Eighteen patients experienced spontaneous HBeAg seroconversion (Group A), and the remaining 95 patients did not experience spontaneous HBeAg seroconversion (Group B). At Week 28, HBsAg (p = 0.03) and HBcrAg (p = 0.01) levels were significantly different between Groups A and B. Reduced HBsAg (p = 0.02) and HBcrAg (p < 0.01) levels from baseline to Week 28 were significantly different between two groups. Multivariate logistic regression showed that lower HBcrAg (odds ratio [OR] = 1.02, p = 0.03) levels at Week 28, and HBcrAg levels with sharp decrease at Week 28 (OR = 0.19, p = 0.02) were related with spontaneous HBeAg seroconversion. The areas under the receiver operating characteristic curve (AUROC) showed that reduction in HBcrAg levels from baseline to Week 28 (0.93, p = 0.001, 95% CI: 0.74-1.08) have excellent prediction value. The mutation frequencies of A1574T (51.11% vs. 18.18%, p = 0.001), G1862A (30.00% vs. 13.03%, p = 0.001), G1896A (27.22% vs. 5.45%, p = 0.001), and C1913G (32.78% vs. 12.73%, p = 0.001) in Group A were significantly higher than Group B. Baseline A1574T, G1862A, G1896A, and C1913G mutations and HBcrAg levels with a sharp decrease at Week 28 were associated with spontaneous HBeAg seroconversion.

The relationship between hepatitis B virus serum DNA, RNA and quantitative hepatitis B surface antigen, and the predictive value for mother-to-child transmission: an observational cohort study.

OBJECTIVE: To explore the relationships between hepatitis B virus (HBV) DNA, HBV RNA and hepatitis B surface antigen (HBsAg) and to evaluate their predictive value for mother-to-child transmission of HBV. DESIGN: An observational cohort study. SETTING: First Hospital of Jilin University. POPULATION: HBsAg-positive and hepatitis B e antigen (HBeAg) -positive pregnant women were recruited. METHODS: Blood samples were collected from mothers before delivery, and HBV infection of infants was evaluated at 7 months of age. RESULTS: Overall, 268 mothers and 271 infants were enrolled. HBV DNA and HBsAg levels were correlated (rs = 0.699; P < 0.001), and HBV DNA (rs = 0.500; P < 0.001) and HBsAg (rs = 0.372; P < 0.001) were both correlated with HBV RNA. The areas under the curve for HBV DNA, HBsAg and HBV RNA for prediction of infection were 0.69 (95% CI 0.57-0.82), 0.63 (95% CI 0.51-0.76) and 0.65 (95% CI 0.52-0.78), respectively. Higher HBV DNA (odds ratio [OR] 4.77, 95% CI 1.44-15.86), higher HBsAg (OR 4.13, 95% CI 1.12-15.25) and higher HBV RNA (OR 3.19, 95% CI 1.09-9.32) were risk factors for HBV infection. Analysis of the HBV DNA-RNA-HBsAg Score revealed that it was an independent predictive factor for mother-to-child transmission (the OR of Score 3 was 8.81, 95% CI 2.79-27.82). CONCLUSION: HBV DNA, HBV RNA and HBsAg were correlated in HBeAg-positive pregnant women. HBsAg could be considered as a substitute marker of HBV DNA for HBeAg-positive pregnant women in low-income regions. We should pay special attention to pregnant women with high levels of all three markers. TWEETABLE ABSTRACT: HBsAg could be considered as a substitute marker of HBV DNA for HBeAg-positive pregnant women in low-income regions. Special attention should be given to pregnant women with high levels of all three markers (HBV DNA, HBV RNA and HBsAg).

Tenofovir disoproxil fumarate for multiple nucleos(t)ide analogues treatment failure hepatitis B: Is monotherapy enough?

BACKGROUND AND AIM: Tenofovir disoproxil fumarate (TDF) is a first-line treatment for chronic hepatitis B virus (HBV) infection for its high potency and a low rate of drug resistance. This study investigated the efficacy and safety of TDF in Chinese patients with chronic hepatitis B (CHB) infection after treatment failure with multiple nucleos(t)ide analogues (NAs). METHODS: Patients included were aged 18-65 years, with treatment failure with multiple NAs (serum HBV DNA > 200 IU/mL after more than two different NA treatments). The primary endpoint was proportion of patients with serum HBV DNA < 20 IU/mL at Week 144 of TDF monotherapy. Secondary endpoints and safety were also assessed. RESULTS: Overall, 213 patients were enrolled. At Week 144, mean HBV DNA decreased significantly from baseline (4.4 vs 1.4 log10 IU/mL), with 77.0% patients (95% confidence interval: 71.1, 82.9) achieving serum HBV DNA < 20 IU/mL. Three (1.4%) patients experienced virological breakthrough during TDF monotherapy, without hepatitis flare. At Week 144, 15.3% and 4.7% patients (hepatitis B e antigen [HBeAg]-positive at baseline) experienced HBeAg loss and HBeAg seroconversion, respectively; 68.3% patients achieved normalized alanine aminotransferase levels. Overall, 58.7% patients experienced more than one adverse event (AE). Most common AEs were upper respiratory tract infection and blood creatine phosphokinase increase; 8.5% patients experienced study drug-related AEs; 9.4% patients experienced serious AEs (none were TDF-related). Among renal safety parameters, overall trend of mean serum phosphorous level remained stable, while mean estimated glomerular filtration rate increased slightly. CONCLUSIONS: Tenofovir disoproxil fumarate monotherapy is efficacious in CHB patients with multiple NAs treatment failure with no new safety findings.

Anti-HBc IgG Levels: A Predictor of HBsAg Seroclearance in Chronic Hepatitis B Patients with Nucleos(t)ide Analogue-Induced HBeAg Seroclearance.

BACKGROUND/AIMS: We investigated the efficiency of the indirect ratio of anti-HBc IgG at predicting HBsAg seroclearance in patients with nucleos(t)ide analogue (NA)-induced HBeAg seroclearance. METHODS: We performed a retrospective study that included 366 chronic hepatitis B patients (March 2007 to December 2016) at a single tertiary hospital. These patients were HBsAg seropositive, and experienced NA-induced HBeAg seroclearance. The indirect ratio of light absorbance of anti-HBc IgG levels were measured with chemiluminescent microparticle immunoassay using the Architect Anti-HBc assay (Abbott Laboratories, IL, USA) as a qualitative method prior to antiviral therapy. We calculated the cumulative incidences of HBsAg seroclearance based on the anti-HBc IgG levels. RESULTS: After a 10-year follow-up, 48 patients experienced HBsAg seroclearance (13.1%). Thirty-three of 179 patients who had an indirect ratio of light absorbance of anti-HBc IgG < 11 RLU (relative light unit) showed HBsAg seroclearance (18.4%); 15 of 187 patients who had an indirect ratio of light absorbance of anti-HBc IgG ≥ 11 RLU showed HBsAg seroclerance (8.0%) (p = 0.003). In multivariate analysis, age, and ALT at the time of HBeAg seroclearance were predictors of HBsAg seroclearance. Especially, the relative risk of HBsAg seroclearance in patients with baseline anti-HBc IgG levels < 11 RLU was 2.213 (95% CI, 1.220-4.014), compared to that in patients with higher levels of anti-HBc IgG at baseline (p = 0.009). CONCLUSION: Using an indirect method for anti-HBc IgG levels, baseline anti-HBc IgG levels (< 11RLU), age (≥ 50 years), and ALT (≥ 40 IU/L) might be associated with HBsAg seroclearance in patients with NA-induced HBeAg seroclearance.

[Natural history and disease progression of chronic hepatitis B virus infection].

OBJECTIVE: To better understand and revise the natural history and disease progression of chronic hepatitis B virus (HBV) infection through analysis of a single-center large-scale cohort of indivi-duals with chronic HBV infection. METHODS: Patients with chronic HBV infection who had undergone liver biopsy in the Fifth Medical Center of Chinese People's Liberation Army (PLA) General Hospital from January 2014 to October 2020 were retrospectively recruited. Based on patient's hepatitis B e antigen (HBeAg) states and pathologic diagnosis, they were categorized into four disease progression statuses (or phases according to the old-terminology in the updated guidelines of chronic hepatitis B (CHB), such as European Association for the Study of the Liver (EASL) 2017, Clinical Practice Guidelines on the Management of Hepatitis B Virus Infection: HBeAg-positive chronic HBV infection (immune tolerance), HBeAg-positive CHB (immune active HBeAg positive), HBeAg-negative chronic HBV infection (inactive carrier), and HBeAg-negative CHB (immune reactive HBeAg negative). Then the demographic, laboratory tests and liver histological results of the patients in different disease progression stages were compared. Age differences between the two groups were evaluated using Mann-Whitney U test. RESULTS: A total of 760 eligible patients with a median age of 29 (interquartile range: 16-39) years were enrolled. Among them, 197 were underage individuals (age < 18 years) and 563 were adults; and 456 were males and 304 females. According to the pathological diagnosis, the patients were classified, and in each of the above four natural disease phases there were 173, 329, 95, and 163 individuals, respectively. Further comparison of the ages of the patients of the four disease progression statuses revealed that patients of HBeAg-negative CHB had a median age at 37 years, which was reasonably higher than those with HBeAg-positive CHB in immune active phase (37 vs. 24 years, P < 0.001), but was relatively younger than those with HBeAg-negative chronic HBV infection (37 vs. 39 years, P= 0.240). CONCLUSION: According to this study, it could be speculated that HBeAg-negative CHB patients probably not all reactivate from individuals of HBeAg-negative chronic HBV infection. Instead, certain HBeAg-negative CHB patients may also come from HBeAg-positive CHB patients who have undergone HBeAg clearance or seroconversion and still remain in the immune active state.

Osteopetrosis-Associated Transmembrane Protein 1 Recruits RNA Exosome To Restrict Hepatitis B Virus Replication.

Hepatitis B virus (HBV) chronically infects approximately 350 million people worldwide, and 600,000 deaths are caused by HBV-related hepatic failure, liver cirrhosis, and hepatocellular carcinoma annually. It is important to reveal the mechanism underlying the regulation of HBV replication. This study demonstrated that osteopetrosis-associated transmembrane protein 1 (Ostm1) plays an inhibitory role in HBV replication. Ostm1 represses the levels of HBeAg and HBsAg proteins, HBV 3.5-kb and 2.4/2.1-kb RNAs, and core-associated DNA in HepG2, Huh7, and NTCP-HepG2 cells. Notably, Ostm1 has no direct effect on the activity of HBV promoters or the transcription of HBV RNAs; instead, Ostm1 binds to HBV RNA to facilitate RNA decay. Detailed studies further demonstrated that Ostm1 binds to and recruits the RNA exosome complex to promote the degradation of HBV RNAs, and knockdown of the RNA exosome component exonuclease 3 (Exosc3) leads to the elimination of Ostm1-mediated repression of HBV replication. Mutant analyses revealed that the N-terminal domain, the transmembrane domain, and the C-terminal domain are responsible for the repression of HBV replication, and the C-terminal domain is required for interaction with the RNA exosome complex. Moreover, Ostm1 production is not regulated by interferon-α (IFN-α) or IFN-γ, and the expression of IFN signaling components is not affected by Ostm1, suggesting that Ostm1 anti-HBV activity is independent of the IFN signaling pathway. In conclusion, this study revealed a distinct mechanism underlying the repression of HBV replication, in which Ostm1 binds to HBV RNA and recruits RNA exosomes to degrade viral RNA, thereby restricting HBV replication.IMPORTANCE Hepatitis B virus (HBV) is a human pathogen infecting the liver to cause a variety of diseases ranging from acute hepatitis to advanced liver diseases, fulminate hepatitis, liver cirrhosis, and hepatocellular carcinoma, thereby causing a major health problem worldwide. In this study, we demonstrated that Ostm1 plays an inhibitory role in HBV protein production, RNA expression, and DNA replication. However, Ostm1 has no effect on the activities of the four HBV promoters; instead, it binds to HBV RNA and recruits RNA exosomes to promote HBV RNA degradation. We further demonstrated that the anti-HBV activity of Ostm1 is independent of the interferon signaling pathway. In conclusion, this study reveals a distinct mechanism underlying the repression of HBV replication and suggests that Ostm1 is a potential therapeutic agent for HBV infection.

[The relationship between serum HBV pgRNA and antigen status in patients with chronic hepatitis B after long-term nucleotide analogues treatment].

Objective: To study the relationship between serum HBV pgRNA and antigen status in patients with chronic hepatitis B treated with long-term nucleotide analogues, and to elucidate the reason and possible mechanism of high relapse rate in antiviral therapy of nucleotide analogues in chronic hepatitis B. Methods: 94 patients with chronic hepatitis B who had been treated with long-term antiviral therapy with nucleotide analogues (more than 2 years) were divided into 5 groups according to their HBeAg and HBsAg levels: e antigen positive group(group1), e antigen negative and HBsAg > 1 500 IU/L group(group2), e antigen negative and 100 IU/L< HBsAg < 1 500 IU/L group(group3), e antigen negative and HBsAg < 100 IU/L group(group4), e antigen negative and HBsAg negative group(group5). The level and detection rate of HBVpgRNA in different antigen states groups were analyzed and compared. In addition, in order to exclude the influence of other factors on the results of this study. The study was divided into groups according to age, gender and treatment time. Results: The detection rate of HBVpgRNA was 95.0% in patients with e antigen positive, while 43.2% in patients with e antigen seroconversion, which was significantly lower than that in patients with e antigen positive (P < 0.05). The detection rate of serum HBVpgRNA was 95.0% in e antigen positive group, 75.0% in group 2, 65.0% in e antigen negative with group 3, 15.0% in group 4 and 0% in group 5. Among them, group 1, group 2 and group 3 was significantly higher than that in group 4 and group 5. There was significant difference between the two groups (P < 0.05). However, there was no difference in the positive rate of serum HBV pgRNA among group 1, group 2 and group 3 (P > 0.05). Similarly, there was no difference in the positive rate of serum HBV pgRNA between group 4 and group 5 (P > 0.05). Moreover, the detection rate of serum HBV pgRNA was not correlated with age, gender and treatment time of nucleotide analogues (P > 0.05). Conclusion: There is a significant correlation between the serological antigen status and the presence of HBV pgRNA in chronic hepatitis B after long-term treatment of nucleotide analogues. The persistence of HBV pgRNA is closely related to the low seroconversion rate of e antigen and the high level of HBsAg. HBV pgRNA can be used as one of the biomarkers to judge the transcription activity and replication status of HBV cccDNA in liver.

[The Clinical Significance and Mechanism of the Effect for Hepatitis B Virus Protein on Host Immune].

The cytotoxic effect targeting hepatitis B virus (HBV) infected hepatocytes from virus-specific cytotoxic T cells and the neutralizing antibodies secreted by virus-specific B cells play an important role in the immune control and elimination of HBV. In patients with chronic hepatitis B, the liver immune microenvironment usually presents a suppression state, and virus-specific immune cells are mostly exhausted. Studies on the interaction between HBV and host immunity during infection, especially the influence of various viral proteins on immune cell function, will contribute to understanding the mechanism of the chronicity of HBV infection, disease progression, and optimization of immunotherapy against HBV. The review summarized the suppressive effects of HBV viral proteins on the host innate immunity and adaptive immune system, to help us understanding the mechanism(s) relevant to the observation that a CHB patient with HBeAg loss and lower HBsAg level is more likley achieving functionall cure. and expect to provide new sights for accelerate virus clearance and achieve functional cure of chronic hepatitis B, by removing the HBV viral proteins and consequently, liberting host immune from suppression state.

Predictive score for hepatocellular carcinoma after hepatitis B e antigen loss in patients treated with entecavir or tenofovir.

The risk of developing hepatocellular carcinoma (HCC) after hepatitis B e antigen seroclearance (ESC) remains unclear. We established and validated a new risk prediction model for HCC development after ESC in patients with chronic hepatitis B (CHB) receiving antiviral therapy (AVT). Between 2006 and 2016, 769 patients (training cohort) and 1,061 patients (validation cohort) with CHB who experienced ESC during AVT using entecavir (ETV) or tenofovir disoproxil fumarate (TDF) were recruited. In the multivariate analysis, male sex (hazard ratio [HR] = 2.092; 95% confidence interval [CI] = 1.152-3.800), cirrhosis (HR = 5.141; 95% CI = 2.367-11.167) and fibrosis-4 index (FIB-4) of >3.25 (HR = 2.070; 95% CI = 1.184-3.620) were the independent risk factors for HCC development (all P < .05). Accordingly, a novel HCC-ESCAVT model was developed (1x[sex: male = 1, female = 0] + 3x(cirrhosis = 1, noncirrhosis = 0) + 1x(FIB-4: >3.25 = 1, ≤3.25 = 0). The cumulative risk for HCC development was significantly different among the risk groups based on the HCC-ESCAVT category (0-1, 2-4 and 5 for the low-, intermediate- and high-risk groups, respectively) (overall P < .001, log-rank test). The area under the receiver operating characteristic curve (AUC) for predicting HCC development 3, 5 and 10 years after ESC was 0.791, 0.771 and 0.790, respectively (all P < .05). The predictive value of the HCC-ESCAVT model was similar in the validation cohort (AUC = 0.802, 0.774 and 0.776 at 3, 5 and 10 years, respectively; all P < .05). Hence, we have developed and validated a new HCC-ESCAVT model for HCC development, which includes male sex, cirrhosis and FIB-4 of >3.25 as constituent variables.

Clinical features of hepatitis B patients at immune-tolerance phase with basal core promoter and/or precore mutations.

Little data exist on basal core promoter/precore (BCP/PC) mutations in chronic hepatitis B (CHB) patients at the immune-tolerance (IT) phase. We studied consecutive treatment-naïve, CHBe-antigen (HBeAg)-positive patients who had undergone liver biopsy and genotyping. Those in the IT phase or immune-clearance (IC) phase were enrolled for comparison of the frequency of BCP/PC mutations and their clinical presentations. Subgroup analyses for the IT group were also performed between patients with and without mutations, and IC patients between fibrosis stages ≤2 vs fibrosis >2. Among 301 patients enrolled, 88/301 (29.24%) and 213/301 (70.76%) were at the IT and IC phase, respectively. The frequency of BCP/PC mutations in IT phase was significantly lower than those in IC phase (15.91% vs 64.79%, P < .001). The BCP mutation only was significantly more frequent than the PC mutation in both groups and also in all IC subgroups. IT patients with BCP/PC mutations had significantly higher quantitative anti-HBc levels compared with those of patients with wild-type virus (P < .05). They also had significantly lower mean levels of alanine transaminase, aspartate transaminase, total bilirubin and qAnti-HBc compared with those of IC patients (all P < .05). Additionally, they were significantly younger in mean age, had higher platelet count, higher levels of HBV DNA and surface antigen, as well as higher frequency of genotype B than those of IC patients with fibrosis >2 (all P < .05). BCP/PC mutations were found in IT patients with CHB. They had distinct clinical characteristics when compared with patients with wild-type or at IC phase. Further studies are needed to understand their natural history and treatment outcomes.