Detection of the hepatitis B surface antigen in patients with occult hepatitis B using an assay with enhanced sensitivity

Patients with occult hepatitis B infection (OBI) have undetectable hepatitis B surface antigen (HBsAg) by conventional assays but detectable hepatitis B virus (HBV) DNA in blood/liver. We evaluated the key performance characteristics of a sensitive HBsAg assay (ARCHITECT HBsAg Next Qualitative Assay, referred as NEXT) with respect to HBsAg detection. Assay precision, sample carryover and seroconversion sensitivity of NEXT were evaluated. HBsAg was measured by NEXT in 1,138 individuals, including 1,038 patients who attended liver clinics in a tertiary hospital (200 HBV DNA-positive blood donors whose HBsAg was undetectable by conventional assays, and 38 patients receiving immunosuppressive therapy, 800 chronic hepatitis B patients with HBsAg seroclearance) and 100 HBsAg-negative subjects recruited from a community project. The within-run and within-laboratory coefficients of variation were <6% for the positive sample pools. In 9 seroconversion panels tested, NEXT allowed an earlier HBsAg detection than conventional assays. NEXT detected HBsAg in 10/200 (5%) HBsAg-negative blood donors, 1/20 (5%) and 0/18 HBsAg-negative patients with and without HBV reactivation respectively, and 59/800 (7.3%) patients with HBsAg seroclearance. HBsAg was detectable by NEXT in 27.8%, 8.2%, 6.9%, 3.8% and 1.9% samples at <3, 3–5, >5–8, >8–11, and >11 years after HBsAg seroclearance, respectively. Seven out of 100 HBsAg-negative community identified subjects was tested positive by NEXT. Comparing with conventional HBsAg assays, NEXT demonstrated a higher sensitivity and conferred an increment of 5–7% detection rate in patients with OBI, thereby helping in identifying HBV carriers and prevention of OBI-associated HBV transmission and reactivation.

Switching from entecavir to tenofovir disoproxil fumarate for HBeAg-positive chronic hepatitis B patients: a phase 4, prospective study

Background Tenofovir disoproxil fumarate (TDF) is widely used and recommended as first-line treatment for patients infected with the hepatitis B virus (HBV). However, current data are limited regarding the efficacy and safety of switching to TDF for the treatment of chronic hepatitis B in hepatitis B e-antigen (HBeAg)-positive patients who are virologically suppressed with another nucleos(t)ide analogue. The primary objective of this study was to evaluate the hepatitis B surface antigen (HBsAg) reduction potential of switching from entecavir (ETV) to TDF at week 48 in HBeAg-positive chronic hepatitis B patients with undetectable serum HBV-DNA. Methods In this multicenter, single-arm, open-label, phase 4 clinical study, 75 participants currently treated with ETV 0.5 mg once daily were switched to TDF 300 mg once daily for 96 weeks. Results At week 48, 3/74 participants (4%) achieved 0.25 log10 reduction of HBsAg levels from baseline (the primary endpoint). Mean HBsAg reduction was −0.14 log10 IU/mL and 12% (9/74) achieved 0.25 log10 reduction by 96 weeks. No participants achieved HBsAg seroclearance. HBsAg reduction at weeks 48 and 96 was numerically greater in participants with higher alanine aminotransferase levels (≥ 60 U/L). Seventeen participants (25%) achieved HBeAg seroclearance up to week 96. No participants experienced viral breakthrough. All drug-related adverse events (18 participants [24%]) were mild in intensity, including an increase in urine beta-2-microglobulin (15 participants [20%]). Conclusions In conclusion, HBsAg reduction was limited after switching from ETV to TDF in this study population. Further investigation is warranted to better understand the clinical impact of switching from ETV to TDF. ClinicalTrials.gov: NCT03258710 registered August 21, 2017. https://clinicaltrials.gov/ct2/show/NCT03258710?term=NCT03258710&draw=2&rank=1

Incidence and Influencing Factors of New Hepatitis B Infections and Spontaneous Clearance: A Large-Scale, Community-Based Study in China

Background: Hepatitis B surface antigen (HBsAg) is widely used in hepatitis B screening, and HBsAg seroclearance indicates hepatitis B eradication. Few studies have explored the incidence of and determinants for spontaneous seroclearance using a long-term follow-up cohort study. Our research aimed to examine the incidence of and influencing factors for hepatitis B virus infection and spontaneous clearance of HBsAg from a large-scale cohort in China.Methods: A total of 151,926 resident individuals in Tongxiang underwent HBsAg screening at least thrice in a 7-year period. Serum samples collected at baseline and follow-up examinations were tested for HBsAg. Cox proportional hazard models were used to analyze determinants of HBsAg seroclearance and persistent HBsAg presence.Results: Among the 151,926 participants, new hepatitis B infections occurred in 4,497 participants, yielding an incidence rate of 571.38 per 100,000 person-years. The incidence rate for males was higher than that for females. In the multivariate Cox regression analysis, female gender, alcohol drinking history, hepatitis family history and middle-age group were predictors for persistent positive HBsAg status.Conclusions: The incidence rate of new hepatitis B infections was 571.38 per 100,000 person-years. Male and aged people in this community cohort have a higher infection rate. Alcohol drinking and hepatitis family history were risk factor leading to chronic infection. Female and middle-aged people were prone to persistent positive HBsAg status.

Cessation of Nucleos(t)ide Analogue Therapy in Non-Cirrhotic Hepatitis B Patients with Prior Severe Acute Exacerbation

Chronic hepatitis B (CHB) with severe acute exacerbation (SAE) is an urgent problem requiring nucleos(t)ide analogue (NA) therapy. We aim to evaluate the clinical relapse (CR) risk after discontinuing NA in patients with prior SAE. Methods: In this retrospective cohort study, CHB patients who discontinued NA therapy were screened between October, 2003 and January, 2019. A total of 78 non-cirrhotic patients who had received NA therapy for CHB with SAE, i.e., bilirubin ≥ 2 mg/dL and/or prothrombin time prolongation ≥3 s, (SAE group) were matched 1:2 with 156 controls without SAE (non-SAE group) by means of propensity scores (age, gender, NA categories, NA therapy duration, and HBeAg status). Results: The 5-year cumulative incidences of severe CR, i.e., ALT > 10X ULN, (42.78%, 95%CI: 27.84–57.73% vs. 25.42%, 95%CI: 16.26–34.58%; p = 0.045) and SAE recurrence (25.91%, 95%CI: 10.91–40.91% vs. 1.04%, 95%CI: 0–3.07%; p < 0.001) were significantly higher in the SAE group. Prior SAE history (HR 1.79, 95%CI: 1.04–3.06) was an independent factor for severe CR. The 5-year cumulative incidence of HBsAg seroclearance was significantly higher in the SAE group than that in the non-SAE group (16.82%, 95%CI: 2.34–31.30% vs. 6.02%, 95%CI: 0–13.23%; p = 0.049). Conclusions: Even though it creates a greater chance of HBsAg seroclearance, NA therapy cessation may result in a high risk of severe CR in non-cirrhotic CHB patients with prior SAE.

The Hepatitis B Virus Interactome: A Comprehensive Overview

Despite the availability of a prophylactic vaccine, chronic hepatitis B (CHB) caused by the hepatitis B virus (HBV) is a major health problem affecting an estimated 292 million people globally. Current therapeutic goals are to achieve functional cure characterized by HBsAg seroclearance and the absence of HBV-DNA after treatment cessation. However, at present, functional cure is thought to be complicated due to the presence of covalently closed circular DNA (cccDNA) and integrated HBV-DNA. Even if the episomal cccDNA is silenced or eliminated, it remains unclear how important the high level of HBsAg that is expressed from integrated HBV DNA is for the pathology. To identify therapies that could bring about high rates of functional cure, in-depth knowledge of the virus’ biology is imperative to pinpoint mechanisms for novel therapeutic targets. The viral proteins and the episomal cccDNA are considered integral for the control and maintenance of the HBV life cycle and through direct interaction with the host proteome they help create the most optimal environment for the virus whilst avoiding immune detection. New HBV-host protein interactions are continuously being identified. Unfortunately, a compendium of the most recent information is lacking and an interactome is unavailable. This article provides a comprehensive review of the virus-host relationship from viral entry to release, as well as an interactome of cccDNA, HBc, and HBx.

Usefulness of a Hepatitis B Surface Antigen-Based Model for the Prediction of Functional Cure in Patients with Chronic Hepatitis B Virus Infection Treated with Nucleos(t)ide Analogues: A Real-World Study

In patients with chronic hepatitis B (CHB) under long-term treatment with nucleso(t)ide analogues (NAs), the loss of hepatitis B surface antigen (HBsAg) is a rare event. A growing body of evidence supports the use of quantitative HBsAg for the prediction of functional cure, although these results are mainly derived from studies performed on Asian patients with hepatitis B e antigen (HBeAg)-positive CHB. Here, we investigated the clinical role of quantitative HBsAg in a real-life cohort of CHB patients under treatment with NAs in a tertiary care center from North-West Italy. A total of 101 CHB patients (HBeAg-negative, n = 86) undergoing NAs treatment were retrospectively enrolled. HBsAg was measured at baseline (T0), 6 months (T1), 12 months (T2) and at the last follow-up (FU). Median FU was 5.5 (3.2–8.3) years; at the end of FU, 11 patients lost the HBsAg (annual incidence rate = 1.8%). Baseline HBsAg levels were significantly different between patients with no HBsAg loss and those achieving a functional cure (3.46, 2.91–3.97 vs. 1.11, 0.45–1.98 Log IU/mL, p < 0.001). Similarly, the HBsAg decline (Δ) from T0 to T2 was significantly different between the two groups of patients (0.05, −0.04–0.13, vs. 0.38, 0.11–0.80 Log IU/mL, p = 0.002). By stratified cross-validation analysis, the combination of baseline HBsAg and ΔHBsAg T0–T2 showed an excellent accuracy for the prediction of HBsAg loss (C statistic = 0.966). These results corroborate the usefulness of quantitative HBsAg in Caucasian CHB patients treated with antivirals for the prediction of HBsAg seroclearance.

Persistent HBV replication and serological response during up to fifteen years of tenofovir-based antiretroviral therapy in HIV-hepatitis B coinfected patients: a multicenter prospective cohort study

Objectives To determine the extent of hepatitis B virus (HBV) suppression and its association with hepatitis "e" antigen (HBeAg) and hepatitis B surface antigen (HBsAg)-seroclearance in HIV-HBV-coinfected patients undergoing long-term tenofovir (TDF)-based antiretroviral therapy (ART). Methods We prospectively followed 165 HIV-HBV-coinfected patients undergoing TDF-based ART. Serum HBV-DNA viral loads, HBeAg and HBsAg were obtained at TDF-initiation and every 6-12 months. We calculated the proportion achieving virological response (VR, <60 IU/mL) during follow-up. We also calculated rates of HBeAg- and HBsAg-seroclearance, which were compared between those who achieved versus never achieved VR during follow-up using an exact binomial test. Results During a median 8.1 years (IQR=4.0-13.2) of TDF-treatment, 152 (92.1%) patients were able to achieve VR and 13 (7.9%) never achieved VR (median HBV-DNA at the end of follow-up=608 IU/mL, range=67-52,400,000). The prevalence of individuals with detectable HBV-DNA (≥60 IU/mL) decreased during TDF-treatment: 15.1% (n=14/93) at 5-years, 3.2% (n=2/62) at 10-years and, 3.2% (n=1/31) at 15-years. 44/96 HBeAg-positive patients (6.15/100 person-years) had HBeAg-seroclearance and 13/165 patients overall (0.87/100 person-years) had HBsAg-seroclearance. No difference in HBeAg-seroclearance was observed between those who achieved versus never achieved VR (7.4 versus 3.7/100 person-years, p=0.33), while HBsAg-seroclearance was only observed in those with VR (1.0 versus 0/100 person-years, p=0.49; respectively). Individuals with VR also had a higher frequency of undetectable HIV-RNA during treatment (p<0.001). Conclusions During long-term TDF-based ART for HIV-HBV coinfection, persistent HBV viremia is apparent, but becomes less frequent over time. HBsAg-seroclearance only occurred in those with full HBV and relatively high HIV suppression.

Risk of hepatocellular carcinoma after spontaneous and nucleos(t)ide analogue induced hepatitis B surface antigen seroclearance.

e16162 Background: Despite a favorable clinical course, the risk of hepatocellular carcinoma (HCC) still exists in patients achieving HBsAg seroclearance. Therefore, we investigated the incidence of HCC after spontaneous and nucleos(t)ide analogue (NA) induced HBsAg seroclearance in real-life clinical practice. Methods: A cohort study was conducted using data from Gangnam Severance Hospital. We identified all subjects with positive HBsAg between January 1, 2001 and March 21, 2018. NA use, liver biochemistries, serial HBsAg and anti-HBs results were retrieved. The primary endpoint was the incidence of HCC after naturally and NA induced HBsAg seroclearance. Results: Among the 5,609 HBsAg-positive patients, 83 chronic hepatitis B (CHB) patients achieved HBsAg seroclearance during 19 years. The cumulative incidence of HBsAg seroclearance was 0.024% at 2 years to 32.4% at 19 years. Of the 83 patients with HBsAg seroclearance, 52 patients achieved spontaneous HBsAg seroclearance and 31 patients achieved NA-induced HBsAg seroclearance. Of 52 patients with spontaneous HBsAg seroclearance, only one patient (2%) developed HCC 6 months after HBsAg seroclearance. On the other hands, there was no development of HCC in patients with NA-induced HBsAg seroclearance. No significant difference was observed in the cumulative incidence of HCC between two groups ( P=0.443). All patients had sustained HBsAg seroclearance and there was no HBsAg seroreversion. Conclusions: The incidence of HCC was extremely rare after spontaneous and NA induced HBsAg seroclearance in real-life clinical practice. NA-induced HBsAg seroclearance is also as durable as spontaenous HBsAg seroclearance.

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 &lt; 0.05). In subgroup analysis, we found that the significant difference still existed in patients with high baseline HBsAg level (&gt;3 log IU/mL). Additionally, the proportion of patients who achieved on-treatment HBsAg decline &gt;1 log IU/mL in TDF and ETV group was 33.3 and 17.1% (p &lt; 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 (&gt;3 log IU/mL), TDF might be a superior therapeutic regimen combining with its relatively safety.