HBeAg-positive Hepatitis B Virus Research Articles

Evaluation of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients

ObjectivesMany studies have investigated the utility of hepatitis B virus (HBV) serological markers in HBV-infected patients. However, only a few studies have examined HBV serological markers in HBV-human immunodeficiency virus (HIV) co-infected patients. Here, we conducted a cross-sectional study to evaluate correlations of HBV serological markers in treatment-naïve HBV mono-infected patients and HBV-HIV co-infected patients. MethodsHBsAg, HBV DNA, HBV RNA, and HBcrAg were quantified in 51 HBV mono-infected patients and 33 HBV-HIV co-infected patients recruited at Tianjin Second People’s Hospital from 2016 to 2019. ResultsThere was no significant difference in serum levels of HBV DNA (P = 0.056), HBV RNA (P = 0.387), HBcrAg (P = 0.714) and HBsAg (P = 0.165) between the patient groups. In HBV mono-infected patients, strong positive correlations were confirmed between HBV RNA and HBV DNA (r=0.620, P < 0.01), HBcrAg and HBV DNA (r=0.802, P < 0.001), and HBcrAg and HBV RNA (r=0.727, P < 0.01). In HBV-HIV co-infected patients, serum HBsAg was very strongly correlated with HBcrAg (r=0.838, P < 0.001). In HBeAg-positive HBV mono-infected patients, all HBV serological markers correlated with each other, whereas only HBV RNA correlated with HBcrAg in HBeAg-negative HBV mono-infected patients (r=0.688, P = 0.007). In HBeAg-positive HBV-HIV co-infected patients, only HBsAg correlated with HBcrAg (r=0.725, P<0.001), whereas HBcrAg and HBV RNA correlated with each other in HBeAg-negative patients (r = 0.683, P=0.010). Moreover, CD4 T-cell counts were not significantly associated with HBsAg, HBV DNA, HBV RNA, and HBcrAg levels. ConclusionCompared with HBsAg and HBV DNA, which are widely used in clinical settings, our study confirmed that new HBV serological markers, such as HBV RNA and HBcrAg, have some utility in HBV mono-infected patients and HBV-HIV co-infected patients for monitoring the progression of liver disease.

Diagnostic and analytical performance of the hepatitis B core related antigen immunoassay in hepatitis B patients

BackgroundNovel serological markers for Hepatitis B virus (HBV) infection are needed for prognosis and guidance of therapy. ObjectiveWe evaluated the diagnostic performance of the Fujirebio Lumipulse G HBcrAg immunoassay on the Fujirebio LUMIPULSE G1200 analyzer. Study designAnalytical performance was examined using three HBeAg positive HBV samples. Diagnostic specificity was assessed using subpanels of 54 confirmed acute HAV, HCV, HEV, B19, CMV and EBV infections. Diagnostic sensitivity was investigated in well-defined HBV positive patient groups, both treated and untreated, including immunocompromised patients. ResultsThe Lumipulse G HBcrAg immunoassay provided a linear measurement at a dilution between 1:100 and1:10,000. Six out of 54 samples showed non-specific reactivity in sera from acute CMV, EBV and HEV infections, of which 2 of them >3 log U/ml. The highest levels of HBcrAg were measured in HBeAg positive patients, in both treated and untreated as well as in immunocompromised patients. Untreated patients had relatively low serum HBcrAg levels in the inactive carrier phase, which increased upon progression into the HBeAg-negative hepatitis phase. Also, we showed that the applicability of HBcrAg to distinguish between patients with resolved HBV infection and false-positive reactivity to solitary anti-HBc is limited. ConclusionsOur study demonstrated significant differences in HBcrAg levels depending on HBeAg status, the clinical phase, as well as the treatment status. Specificity of the assay is good; only 2 out of 54 samples showed reactivity above 3 log U/ml. Before implementing the assay in clinical practice, additional research in larger patient cohorts should be carried out.

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

Tenofovir alafenamide is a novel prodrug formulated to deliver the active metabolite to target cells more efficiently than tenofovir disoproxil fumarate at a lower dose, thereby reducing systemic exposure. In patients with HIV, tenofovir alafenamide was as efficacious as tenofovir disoproxil fumarate, with reduced bone and renal toxic effects. We compared the efficacy and safety of the two drugs in patients with HBeAg-positive chronic hepatitis B virus (HBV) infection in a non-inferiority study. We did this ongoing double-blind, non-inferiority study in 161 outpatient centres in 19 countries. Patients with chronic HBV infection who were positive for the hepatitis B e antigen (HBeAg) were randomly assigned (2:1) to receive either 25 mg tenofovir alafenamide or 300 mg tenofovir disoproxil fumarate with matching placebo. Randomisation was done by a computer-generated allocation sequence (block size six) stratified by plasma HBV DNA concentration and previous treatment experience. The primary efficacy endpoint was the proportion of patients with HBV DNA less than 29 IU/mL at week 48 in all patients who were randomly assigned and received at least one dose of study drug using a missing-equals-failed approach. The pre-specified non-inferiority margin was 10%. Key prespecified safety endpoints were bone and renal parameters at week 48. This study is registered with ClinicalTrials.gov, number NCT01940471. Of the 1473 patients screened from Sept 11, 2013, to Dec 20, 2014, 875 eligible patients were randomly assigned and 873 received treatment (581 with tenofovir alafenamide and 292 with tenofovir disoproxil fumarate). 371 (64%) patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48, which was non-inferior to the 195 (67%) of patients receiving tenofovir disoproxil fumarate who had HBV DNA less than 29 IU/mL (adjusted difference -3·6% [95% CI -9·8 to 2·6]; p=0·25). Patients given tenofovir alafenamide had a significantly smaller decrease in bone mineral density at hip (mean change -0·10% [95% CI -0·29 to 0·09] vs -1·72% [-2·02 to -1·41]; adjusted difference 1·62 [1·27 to 1·96]; p<0·0001) and at spine (mean change -0·42% [-0·66 to -0·17] vs -2·29% [-2·67 to -1·92]; adjusted difference 1·88 [1·44 to 2·31]; p<0·0001) as well as smaller mean increases in serum creatinine at week 48 (0·01 mg/dL [0·00-0·02] vs 0·03 mg/dL [0·02-0·04]; p=0·02). The most common adverse events overall were upper respiratory tract infection (51 [9%] of 581 patients receiving tenofovir alafenamide vs 22 [8%] of 292 patients receiving tenofovir disoproxil fumarate), nasopharyngitis (56 [10%] vs 16 [5%]), and headache (42 [7%] vs 22 [8%]). 22 (4%) patients receiving tenofovir alafenamide and 12 (4%) patients receiving tenofovir disoproxil fumarate experienced serious adverse events, none of which was deemed by the investigator to be related to study treatment. 187 (32%) of 581 patients in the tenofovir alafenamide group and 96 (33%) of 292 patients in the tenofovir disoproxil fumarate group had grade 3 or 4 laboratory abnormalities, the most common of which were elevations in ALT (62 [11%] of 577 patients receiving tenofovir alafenamide and 36 [13%] of 288 patients receiving tenofovir disoproxil fumarate) and AST (20 [3%] of 577 patients receiving tenofovir alafenamide and 19 [7%] of 288 patients receiving tenofovir disoproxil fumarate). In patients with HBeAg-positive HBV infection, tenofovir alafenamide was non-inferior to tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. Gilead Sciences.

Serum hepatitis B surface antigen quantification as a useful assessment for significant fibrosis in hepatitis B e antigen‐positive hepatitis B virus carriers

The role of serum quantitative hepatitis B surface antigen (qHBsAg) in identifying hepatitis B virus (HBV) carriers with significant fibrosis is unknown. This study aims to evaluate the diagnostic value of qHBsAg for hepatic fibrosis in hepatitis B e antigen (HBeAg)-positive HBV carriers. Consecutive biopsy-proven HBeAg-positive HBV carriers were prospectively recruited in our center from 2009 to 2011 and were randomly divided into training and validation set. Area under receiver-operator curve (AUC) was used to determine the diagnostic accuracy of simple tests for significant fibrosis (Scheuer stage, F ≥ 2). Overall, a total of 197 eligible patients (median age 31 years; 149 males) were enrolled. The median qHBsAg was 4.20 (log10 IU/mL). Significant fibrosis was confirmed in 112 (56.9%) patients. By logistical regression analysis, qHBsAg and γ-glutamyl transpeptidase were identified as predictors for significant fibrosis in training set (n = 124). Thus, qHBsAg index and γ-glutamyl transpeptidase to qHBsAg ratio (GqHBsR) were selected for the subsequent analysis. In the training set, an AUC of 0.762, 0.826, 0.749, and 0.771 was observed for qHBsAg index, GqHBsR, FIB-4, and aspartate aminotransferase to platelet ratio index, respectively (all P < 0.05). GqHBsR yielded a higher AUC than aspartate aminotransferase to platelet ratio index and FIB-4 (both P < 0.05). Using the optimal cut-off of 7.78, GqHBsR showed a sensitivity of 78.9% and a specificity of 73.6%. About 80% of liver biopsy could be avoided in the entire cohort. Serum qHBsAg-based simple tests, especially GqHBsR, can accurately and specifically identify significant fibrosis in treatment-naïve HBeAg-positive HBV carriers.

A 24-week, parallel-group, open-label, randomized clinical trial comparing the early antiviral efficacy of telbivudine and entecavir in the treatment of hepatitis B e antigen-positive chronic hepatitis B virus infection in adult Chinese patients

Background: Because drug-resistant strains of hepatitis B virus (HBV) have developed, and because serum HBV-DNA levels may rebound in patients who receive treatment with nucleoside/nucleotide analogues for up to 2 years, there remains a largely unmet clinical need for agents to induce potent virologic suppression in the initial stage of the disease course of HBV infection. Objective: The aim of this work was to compare the early antiviral effectiveness of telbivudine and entecavir in the treatment of patients with hepatitis B e antigen (HBeAg)-positive HBV. Methods: In this parallel-group, open-label trial, adult Chinese patients with previously untreated HBeAg-positive HBV (HBV-DNA concentration: ≥6 log 10 copies/mL; alanine aminotransferase [ALT] level: ≥2 times the upper limit of normal) were randomized to receive telbivudine 600 mg or entecavir 0.5 mg daily for 24 weeks. Blood samples were collected at the baseline and at 12 and 24 weeks after the treatment. The primary end point was the mean reduction from baseline in serum HBV-DNA concentration at week 24. Secondary end points included mean reduction from baseline in serum HBV-DNA concentration at week 12, the absence of serum HBV-DNA, absence of serum HBeAg, HBeAg seroconversion at week 24, the normalization of serum ALT at week 24, and occurrence of adverse events through week 24. Results: A total of 131 patients were enrolled in the study: 91 men and 40 women, with a mean (SD) age of 32.5 (8.9) years. All patients were ethnic Han Chinese. The baseline demographic characteristics and serum HBV-DNA concentrations in the 2 treatment groups were well matched. Sixty-five patients were randomized to receive telbivudine and 66 to receive entecavir. The mean reductions from baseline in serum HBV-DNA were 4.99 and 4.69 log 10 copies/mL at week 12, respectively, and 6.00 and 5.80 log 10 copies/mL at week 24 (both time points, P = NS between groups). At week 12, HBV-DNA was undetectable in 43.1% (28/65) of the telbivudine group and 34.8% (23/66) of the entecavir group ( P = NS); at week 24, it was undetectable in 67.7% (44/65) of the telbivudine group and 57.6% (38/66) of the entecavir group ( P = NS). At week 12, HBeAg absence and seroconversion rates were significantly greater in the telbivudine group than the entecavir group (absence: 20.0% [13/65] vs 3.0% [2/66], respectively [ P = 0.002]; seroconversion: 13.8% [9/65] vs 3.0% [2/66] [ P = 0.030]). However, at week 24, HBeAg absence and seroconversion rates were comparable between the telbivudine and entecavir groups (absence: 36.9% [24/65] vs 28.8% [19/66] [ P = NS]; seroconversion: 24.6% [16/65] vs 13.6% [9/66] [ P = NS]). In addition, the normalization of ALT levels was observed in 78.5% (51/65) and 74.2% (49/66) of patients treated with telbivudine and entecavir, respectively, at week 24 ( P = NS). The adverse events were upper respiratory tract infection (12.3% of telbivudine patients vs 9.1% of entecavir patients), fatigue (6.2% vs 7.6%), diarrhea (1.5% vs 3.0%), and coughing (0% vs 1.5%), most of which were mild to moderate. Elevated creatinine phosphokinase was noted in 8 telbivudine-treated patients (12.3%). There were no statistically significant differences in rates of adverse events between groups except for creatinine phosphokinase. Conclusion: In this study of ethnic Han Chinese adults with previously untreated HBeAg-positive HBV infection, there were no statistically significant differences in effectiveness or tolerability between telbivudine 600 mg and entecavir 0.5 mg at the end of 24 weeks of treatment.

Frequent Occurrence of Chronic Hepatitis B Virus Infection among West African HIV Type-1--Infected Children

The aim of this study, conducted in Ivory Coast, was to evaluate the prevalence and evolution of viral hepatitis in children coinfected with human immunodeficiency virus type 1 (HIV-1). Hepatitis B virus (HBV) and hepatitis C virus (HCV) markers were retrospectively and longitudinally assessed among 280 HIV-1-infected children enrolled in the Agence Nationale de Recherches sur le SIDA et les Hépatites Virales B et C 1244/1278 cohort. Among these, 173 (61.8%) received highly active antiretroviral therapy (HAART), including lamivudine (3TC) for 122 children. Detection of the hepatitis B s antigen (HBsAg) was performed on specimens collected at inclusion and 6 months later. If results of both tests were positive, hepatitis B e antigen (HBeAg)/hepatitis B e antibody (HBeAb) and HBV DNA levels were measured at inclusion and during follow-up. A fourth-generation HCV enzyme immunoassay was used for HCV screening at inclusion. In our pediatric cohort, no patients were infected with HCV, but the prevalence of HBsAg at inclusion was 12.1% (34 of 280; 95% confidence interval [CI], 8.6-16.6). Among the HBV-HIV-1-coinfected children, a high rate of positive HBeAg chronic hepatitis B (CHB) was noted at inclusion (82.4% [ 28 of 34]; 95% CI, 65.5%-93.2%) and after a median follow-up of 18 months (78.3%; 95% CI, 45.5%-92.7%), with no significant difference between children treated with HAART (with or without 3TC) and untreated ones. These children showed high HBV DNA levels (usually >8.0 log(10) copies/mL) and viral population consisting of nearly exclusively wild-type HBeAg-positive HBV strains, strongly suggesting that most of them were in the initial immunotolerant phase of chronic hepatitis B. In sub-Saharan Africa, children with chronic hepatitis B and who are treated with 3TC-based HAART are at risk of developing 3TC resistance. Further studies are required to guide the management of HBV-HIV-1-coinfected children.

Evaluation of the cost-effectiveness of entecavir versus lamivudine in hepatitis BeAg-positive chronic hepatitis B patients.

As new treatment options for chronic hepatitis B virus (HBV) become available, evaluations of cost-effectiveness become important. Entecavir is a deoxyguanine nucleoside analogue approved by the U.S. Food and Drug Administration in March 2005 for HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (alanine aminotransferase or aspartate aminotransferase) or histologically active disease. Entecavir has demonstrated greater suppression of viral replication compared with lamivudine, but also has a relatively higher drug acquisition cost in the United States. To estimate the long-term health and economic impact of treating HBV with entecavir versus lamivudine in patients who are positive for hepatitis B e antigen (HBeAg) based on the efficacy and safety results of the Phase 3, double-blind, randomized controlled trial, Benefits of Entecavir for Hepatitis B Liver Disease (BEHoLD). A decision tree model was developed to evaluate the cost-effectiveness of entecavir compared with lamuvidine in suppressing HBV DNA to an undetectable level. Risks for compensated cirrhosis (CC), decompensated cirrhosis (DC), and hepatocellular carcinoma (HCC) were derived from the published Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV, 2006) study, a longitudinal (mean follow-up: 11.4 years) cohort study of community residents who were seropositive for the hepatitis B surface antigen; 85% of REVEAL-HBV participants were HBeAg-negative. To estimate future risks of CC, DC, and HCC, the REVEAL-HBV study's multivariate-adjusted relative risks of CC, DC, and HCC for 5 HBV DNA (viral load level) categories were applied to posttreatment HBV DNA levels obtained from the BEHoLD trial of 709 HBeAg-positive HBV patients treated with entecavir (n = 354) or lamivudine (n = 355). Entecavir and lamivudine were assigned annual costs of $7,365 and $2,604, respectively, based on the wholesale acquisition cost. Life expectancy for DC and HCC was estimated by the declining exponential approximation of life expectancy method. Other model parameter values, such as utilities and event medical costs, were derived from published sources. The joint uncertainty of projected event time distribution and treatment failure rates beyond the trial period were considered using probabilistic sensitivity analyses (PSA) with 1,000 replicates. The analytic perspective was that of a U.S. third-party payer responsible for all direct health care expenditures. In the BEHoLD clinical trial (AI463022), subjects were predominantly male (75%), Asian (57%), or white (40%) with a mean age of 35 years. Entecavir was superior to lamivudine in the proportion of subjects who achieved undetectable HBV DNA (< 300 copies per mL) by polymerase- chain reaction assay at week 48 (69.1% vs. 39.8%, respectively) (P < 0.001). In the REVEAL-HBV study after statistical adjustment for age, gender, cigarette smoking, and alcohol consumption, rates of CC, DC, and HCC were associated with higher HBV DNA levels (e.g., compared with the reference category [< 300 copies per mL], adjusted hazard ratios for HCC were 1.2, 2.9, 9.5, and 15.2 for serum HBV DNA levels of 300-9,999, 10,000-99,999, 100,000-999,999, and e > or = 1 million copies per mL, respectively). In the reference case, for a hypothetical cohort of 1,000 HBV patients aged 35 years, 52 weeks of entecavir treatment compared with lamivudine treatment avoided 71 cases of CC, 8 DC cases, and 42 HCC cases within 10 years, resulting in a 0.728 quality-adjusted life-year (QALY) gain at an incremental cost of $2,350, with a 3% annual discount. The incremental cost of using entecavir was $3,230 per QALY gained (95% confidence interval [CI], $2,312-$4,528), with 99.3% of PSA-derived estimates below $5,000 per QALY. Results were robust and most sensitive to efficacy, drug cost, and treatment duration. Assuming that (1) the efficacy of entecavir after 1 year is sustainable and (2) liver disease risk levels from the REVEAL-HBV study population (a primarily HBeAg-negative group) adequately represent risk for a treated HBeAg-positive patient group, entecavir given for up to 10 years would be highly cost-effective in HBeAg-positive patients.

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion.

The evolution of precore stop codon mutation (A1896) and dinucleotide mutation (T1762/A1764) in the basic core promoter (BCP) of hepatitis B virus (HBV) genome during transient seroconversion and seroreversion of hepatitis B e antigen (HBeAg) remains unclarified. Five HBeAg-positive HBV carriers who experienced transient seroconversion followed by seroreversion of HBeAg (Group I, 3.3%) and 3 HBeAg-negative HBV carriers with documented reversion of HBeAg (Group II, 2.5%) in a prospective cohort of 272 patients with chronic hepatitis B were thus identified. The sequential changes at the precore nucleotide 1896 and BCP dinucleotide 1762/1764 were determined by polymerase chain reaction and direct sequencing. At enrollement, precore A1896 and BCP T1762/A1764 were noted in 4 (50%) and 1 (13%) of the eight patients. During a median follow-up period of 58 months (range: 31-76 months), 12 episodes of transient HBeAg seroconversion followed by seroreversion were encountered in Group I patients and 3 episodes of HBeAg seroreversion in Group II patients. Accompanying acute exacerbations were found in two-thirds of patients with either HBeAg seroconversion or seroreversion. Overall, precore nucleotide A1896 remained identical in 73% and 83% of the seroconversion and seroreversion events, respectively. BCP dinucleotide T1762/A1764 remained unchanged in 94% and 92% of the seroconversion and seroreversion events, respectively. At the end of follow-up, only one had both precore and BCP mutations. In conclusion, these data suggested that HBeAg seroreversion might be due to the lack of sustained precore and BCP mutations after HBeAg seroconversion. Although uncommon, HBeAg seroreversion can be associated with hepatitis exacerbation.

Association between frequency of amino acid changes in core region of hepatitis B virus (HBV) and the presence of precore mutation in Japanese HBV carriers.

To elucidate the relationship between the frequency of core mutations and precore mutation of hepatitis B virus (HBV) in Japanese HBV carriers, we investigated the nucleotide sequence of the precore/core region of HBV in 26 Japanese HBV carriers [15 who were HBe antigen-negative (HBeAg-) and 11 who were HBeAg-positive (HBeAg+)]. The number of amino acid changes (5.9 +/- 3.8) in the core region of HBV in HBeAg-carriers was significantly greater than that in the HBeAg+ carriers (1.5 +/- 1.0; P < 0.005). The precore stop codon mutation was found in 93.3% of HBeAg-negative HBV carriers, while no precore mutation was found in the HBeAg-positive HBV carriers, suggesting that the frequency of core mutations may be associated with the presence of the precore stop codon mutation. However, there was no significant difference in the frequency of amino acid changes among HBeAg-HBV carriers. The mean number of core amino acid changes of liver cirrhosis patients, chronic active hepatitis patients, chronic persistent hepatitis patients, and asymptomatic carriers were 2.7 +/- 1.5, 6.0 +/- 2.2, 4.7 +/- 1.2, and 8.4 +/- 5.3, respectively. We detected hot spots for core mutations, which showed characteristic localizations and specific substitutions: Gly-87, Leu-97, and Thr-130 were detected exclusively in patients with chronic liver disease with or without HBeAg. To address further the relationship between frequency of core mutations and the presence of the precore stop codon mutation, we investigated the precore/core nucleotide sequence serially along with seroconversion in three patients with chronic hepatitis B in whom the hepatitis either became inactive or remained active after the seroconversion. Emergence of the precore stop codon mutation and a significant increase in core amino-acid changes after seroconversion were noted in all three patients. Our results suggest a close association between the frequency of core amino acid changes and the presence of the precore stop codon mutation; some characteristic core mutations may be associated with the clinical course of chronic hepatitis B in Japanese patients.