Pegylated Interferon Treatment for the Effective Clearance of Hepatitis B Surface Antigen in Inactive HBsAg Carriers: A Meta-Analysis

BackgroundExpanding antiviral therapy to benefit more populations and optimizing treatment to improve prognoses are two main objectives in current guidelines on antiviral therapy. However, the guidelines do not recommend antiviral therapy for inactive hepatitis B surface antigen (HBsAg) carriers (IHCs). Recent studies have shown that antiviral therapy is effective with good treatment outcomes in IHC populations. We conducted a systematic review and meta-analysis of HBsAg clearance and conversion in IHCs.MethodsWe searched PubMed, Embase, Medline, and Web of Science to retrieve articles on HBsAg clearance in IHCs published between January 2000 and August 2021. Data were collected and analysed using the random-effects model for meta-analysis.ResultsA total of 1029 IHCs from 11 studies were included in this analysis. The overall HBsAg clearance rate was 47% (95% confidence interval (CI): 31% - 64%), with a conversion rate of 26% (95% CI: 15% - 38%) after 48 weeks of Pegylated interferon (Peg-IFN) treatment. In the control group (including nucleos(t)ide analogue (NA) treatment or no treatment), the overall HBsAg clearance rate was only 1.54% (95% CI: 0.56% - 3.00%), which was markedly lower than that in the Peg-IFN group. Further analysis showed that a low baseline HBsAg level and long treatment duration contributed to a higher HBsAg clearance rate.ConclusionThis study showed that treatment of IHCs can be considered to achieve a clinical cure for chronic hepatitis B virus (HBV) infection. After Peg-IFN treatment, the HBsAg clearance rate was 47%, and the conversion rate was 26%, which are markedly higher than those reported by previous studies on Peg-IFN treatment in patients with chronic hepatitis B (CHB). A low baseline HBsAg level and long treatment duration were associated with HBsAg clearance in IHCs. Therefore, antiviral therapy is applicable for IHCs, a population who may be clinically cured.Systematic Review Registrationhttp://www.crd.york.ac.uk/PROSPERO, CRD): CRD42021259889.

Virological breakthrough after immune checkpoint inhibitor and nucleos(t)ide analog treatment in patients with hepatitis B surface antigen positive hepatocellular carcinoma: a real-world study

BackgroundImmune checkpoint inhibitors (ICIs) have been shown to be a promising and effective treatment for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, there is a lack of evidence-based data demonstrating the impact of ICIs on HBV DNA level in HBV-HCC patients undergoing nucleos(t)ide analog (NA) therapy and of HBV DNA variation on patient survival. In this study, we aimed to investigate this issue in the real world.MethodsIn this single-center retrospective study, we reviewed 182 baseline hepatitis B surface antigen (HBsAg)-positive HBV-HCC patients who were treated with ICIs and pre-emptive NAs. The demographic characteristics, tumor status, treatments, HBV DNA, HBsAg, liver function, antitumor response, and patient survival were investigated. The primary endpoints were the virological breakthrough (VB) rate, HBV reactivation (HBVr) rate, and long-term HBV DNA control; the secondary endpoints were the overall survival (OS) and progression-free survival (PFS).Results(1) VB and HBVr occurred in 18.1% (33/182) and 4.4% (8/182) of patients with a median occurrence time of 3.9 months (range, 0.7–16.0) and 8.0 months (range, 3.0–16.0), respectively. The HBV DNA negative rates were 26.1% and 0 at 24 and 48 weeks in the VB group and 12.5% and 0 in the HBVr group, respectively. A baseline HBsAg level ≥200 IU/mL was the only risk factor for VB (OR 9.9, 95% CI 2.2 to 45.2, p=0.003); (2) patients with VB had much shorter median OS and median PFS than those without (12.3 months vs 18.1 months, p=0.035; 4.5 months vs 7.5 months, p=0.011).ConclusionsThere was a high risk of VB and a moderate risk of HBVr in HBsAg-positive HBV-HCC patients (with poor long-term HBV DNA control) undergoing ICI and pre-emptive NA therapies. The only risk factor for VB was the pretreatment HBsAg level. Further, VB might be considered as a clinical biomarker predicting inferior OS and PFS in the patients.

Highly significant differences in HBsAg kinetics among patients with two types of hepatitis B flare, with and without retreatment

Background Off-therapy hepatitis flare may be detrimental or, conversely, facilitate hepatitis B surface antigen (HBsAg) decline. Retreatment decisions are crucial. Methods HBsAg was quantified before and during flares, at peak/retreatment start and at Months 6 and 12 in 336 entecavir/tenofovir-retreated and 105 non-retreated hepatitis B e antigen (HBeAg)-negative patients. Increasing HBsAg during ALT flare defined a ‘virus-dominating flare’ and decreasing HBsAg a ‘host-dominating flare’. Results Two hundred and eighty-eight retreated patients with a virus-dominating flare showed greater 1 year HBsAg decline (−1.0 versus −0.01 log10 IU/mL; P < 0.0001), more frequent rapid decline (69.8% versus 8.3%; P < 0001) and higher 3 year incidence of HBsAg < 100 IU/mL (32% versus 12%; P = 0.026) than 48 patients with a host-dominating flare, of whom 16 (33.3%) showed 3.8-fold (2 to 52-fold) HBsAg rebound on retreatment (versus 2/288; P < 0.0001). Compared with non-retreated controls, 1 year HBsAg decline was greater (−1.0 versus −0.47 log10 IU/mL; P < 0.0001) and faster (69.8% versus 42.5%; P < 0.0001) in patients with a virus-dominating flare, whereas 1 year HBsAg decline (−0.01 versus −0.16 log10 IU/mL) and 3 year HBsAg loss rate (0% versus 21%; P = 0.009) were lower in patients with a host-dominating flare. Conclusions Entecavir/tenofovir retreatment effectively decreases HBsAg level in patients with a virus-dominating flare but is ineffective/worse in patients with a host-dominating flare. These results support the use of combined HBsAg/ALT kinetics for the decision to retreat patients with a virus-dominating flare and withhold retreatment for patients with a host-dominating flare.

Tenofovir Disoproxil Fumarate Is Superior to Entecavir in Reducing Hepatitis B Surface Antigen for Chronic Hepatitis B in China: 2-Year Comprehensive Comparative Result of a Matched Comparative Study

Aim: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) are equally recommended as the first-line antiviral treatments for chronic hepatitis B (CHB) at present. We aimed to compare the long-term efficacy and safety between ETV and TDF therapy in CHB patients who had not received nucleoside analog treatment.Method: In this single-center retrospective study, 414 patients who received ETV (290 patients) or TDF (124 patients) therapy at our center from January 2017 to May 2019 were included. To reduce the imbalance of baseline variables, propensity score matching (PSM) was employed to yield 124 pairs of patients at a ratio of 1:1 based on the treatment regimen.Result: After PSM, the cumulative rate of patients who achieved complete virological response (CVR) was not different by drug therapy at each inspection time (1, 3, 6, 12, 18, and 24 months). Subgroup analysis on HBeAg status and level of HBV DNA demonstrated that evolution of proportion of achieving CVR was not significantly different between groups. Despite the insignificant incidence of HBsAg seroclearance in either group, patients in TDF group achieved higher on-treatment HBsAg decline at each inspection time (1, 3, 6, 9, 12, 18, and 24 months), 0.39, 0.51, 0.61, 0.64, 0.68, 0.76, and 0.91 log IU/mL, respectively; while the corresponding reduction were 0.27, 0.37, 0.40, 0.45, 0.48, 0.55, and 0.66 log IU/mL in ETV group (p < 0.05). In subgroup analysis, we found that the significant difference still existed in patients with high baseline HBsAg level (>3 log IU/mL). Additionally, the proportion of patients who achieved on-treatment HBsAg decline >1 log IU/mL in TDF and ETV group was 33.3 and 17.1% (p < 0.01) at the 12th month, 44.4 and 29.5% (p = 0.03) at the 24th month, respectively. Mean increase in serum creatinine from baseline was 0.10 and 0.08 mg/dL in TDF and ETV group (p = 0.11), with no patient experienced acute kidney injury.Conclusions: TDF has higher potency in reducing HBsAg than ETV in this study. Considering the effect still existed in patients with high HBsAg level (>3 log IU/mL), TDF might be a superior therapeutic regimen combining with its relatively safety.

A Simple-to-use Tool for Predicting Response to Peginterferon in HBV DNA Suppressed Chronic Hepatitis B Patients

Background: Rational administration of peginterferon can remarkably reduce serum HBsAg level and improve the rate of HBsAg loss. Considering the high cost and low tolerability of peginterferon, we aimed to develop a simple-to-use scoring system at early stage of treatment to predict low HBsAg level or HBsAg loss at the end of treatment in virological suppressed chronic hepatitis B (CHB) patients.Methods: Non-cirrhotic CHB patients with NA (nucleoside/nucleotide analogues)-induced virological suppression initiated peginterferon treatment by either add-on or switch-to strategy for 48 weeks were enrolled from January 2012 to June 2017 in two tertiary centers. The retrospective design enrolled 320 subjects, including 189 patients in the training cohort and 131 patients in the validation cohort.Results: By logistic regression, a simple-to-use scoring system integrating baseline HBsAg level < 1000 IU/mL, HBsAg decline > 0.5 log at week 12 and ALT flare at week 12 was developed in the training cohort and high performance for predicting HBsAg < 100 IU/mL, HBsAg < 10 IU/mL and HBsAg loss at the end of 48-week treatment. The area under receiver operating characteristics curve was 0.84, 0.80 and 0.76 in the training cohort and 0.88, 0.87 and 0.84 in the validation cohort, respectively.Conclusions: Our simple-to-use scoring system can guide clinicians to decide whether to continue peginterferon treatment in CHB patients in order to achieve low HBsAg levels or HBsAg loss at the end of treatment, which might greatly improve the opportunity to reach a functional cure in these patients and lead more cost-effective treatment decision.

Quantitative HBsAg and Qualitative HBeAg Predicts Intrauterine Placental Infection and Umbilical Blood Cord in Pregnant Women

Objective: To know the correlation between quantitative HBsAg and maternal HBeAg with hepatitis B intrauterine transmission via placental infection. Hepatitis B in pregnancy causes a mother to child transmission (MTCT) via transplacental route started with placental infection. HBV DNA viral load and HBeAg are the independent risk factors for MTCT, but it rarely available in developing country. Materials and methods: A cross-sectional study in 33 pregnant women with HBsAg positive in 4 referral hospital in East Java, Indonesia. Quantitative HBsAg and HBeAg status were determined serologically from a peripheral venous blood sample. Placental Hepatitis B infection was detected by immunohistochemistry of HBsAg from placental tissues. The intrauterine transmission was diagnosed by positive HBsAg in cord blood sampling after deliveries. Results: Serum quantitative HBsAg level has a good sensitivity and spesificity to predict placental infection (90% and 83%), with a cut off value of 3.14 Log10 IU/mL (AUC 0.87; 95% CI: 0.74-0.99). Quantitative HBsAg level also has a good sensitivity and spesificity to predict HBV transmission in umbilical blood cord (81.8% and 95.5%) with a cut off value of 3.62 log10 IU/ml (AUC: 0.925, 95% CI: 0.813-1; p = 0.000). Placental infection is significantly related with intrauterine transmission with OR 4.6 (95% CI 2.29-9.4; p = 0.002). Conclusion: The study reveals that maternal serum quantitative HBsAg level can be used as an alternative test to substitute HBeAg or HBV DNA as a marker to predict the placental infection and intrauterine transmission, especially in low-middle income countries.

Dynamics of Hepatitis B Virus Surface Antigen Level with Peripheral Blood Lymphocytes in Chronic Hepatitis B Infection

Background: Peripheral blood mononuclear cells containing an aggregate of immune competent cells, such as T lymphocytes, B cells and natural killer cells, play an important role in control or persistence of the hepatitis B virus (HBV) infection. Similarly, the expression of hepatitis B viral antigens on the surface of infected hepatocytes can invoke a cytotoxic T–cell response. Objective: To investigate the dynamic changes in hepatitis B surface antigen (HBsAg) and peripheral lymphocyte subsets of healthy donors and chronic hepatitis B patients. Methodology: Serum HBsAg was quantified by enzyme-linked immunosorbent assay according to the manufacturer’s guidelines. Peripheral blood lymphocyte cell phenotyping was carried out by flow cytometry for all chronic hepatitis B patients and healthy blood donors. Results: The results of this study showed a significant correlation between HBsAg level and percentage of T and NK cells (r=0.366; P=0.01, r=-0.462; P=0.01, respectively). On the other hand, significance variation in peripheral blood lymphocyte percentage of T lymphocyte subsets in patients were found to be directly proportional to T cell subsets CD4+and CD8+ (P=0.001) compared with healthy blood donor controls. Conclusion: In conclusion this study highlighted the role of the HBsAg level in supressing the immune cells of the innate and adaptive immune system. Understanding the interactions between HBsAg and peripheral blood cells serves as a basis for development of HBV therapeutic vaccines and a prognostic biomarker in persistent HBV infection.