HBeAg-negative Status Research Articles

HBeAg negative chronic hepatitis B in South Asia

Chronic Hepatitis B (CHB) infection has an intermediate prevalence rate in South Asian countries, except for Nepal and Sri Lanka where it has a low rate. HBeAg negative CHB infection has been found to be more pronounced in this part of the world. As described previously, CHB infection has two phases with HBeAg positive and HBeAg negative based on ALT, DNA & biopsy. The latter was previously described to have a benign course. The later guidelines have distinguished HBeAg negative status into two categories with an inactive phase and a reactivation one. In this review article we have highlighted HBeAg Negative status burden in South Asian countries and shown that HBeAg negative CHB infection may not be as benign as previously thought. Furthermore , mutations at precore and basal core promoter region may contribute to disease severity in HBeAg negative CHB infection.

A Retrospective- Prospective Study for the Efficacy and Safety of Entecavir in a Cohort of West Asian with Chronic HBV Infection

Aim: To assess the long-term efficacy and safety of Entecavir in the treatment of CHB. Patients and Methods: This study included 70 CHB consecutive patients on Entecavir for at least 36 months retrospectively, followed prospectively for 18 months. Results: twenty-three (32.8) were HBeAg +ve, 47.1% naive, 22 (31.4%) females, with a mean age of 42.9±13, 14 (20%) cirrhotic and 1 (1.4%) decompensated. There were no significant differences in the pre-treatment HBV-DNA level among HBeAg (+ve) and HBeAg-ve group, with a mean± SD log 10 of 7.9±5.4 and 7.4±5.0 respectively. (P= 0.237). There was a significant viral load reduction after 6 months Entecavir therapy that was more in the HBeAg –ve compared to HBeAg +ve group. In HBeAg +ve, 19 (82.61%) had HBV-DNA suppression after a median of 7 months, compared to 100% in HBeAg –ve with a median of 5 months (P <0.05). In the HBeAg-ve group; one (2.13%) had HBsAg loss at 45 months compared to none in HBeAg (+ve) group (P <0.001), while in the HBeAg (+ve) group; 5 (21.74%) showed HBeAg clearance after a median of 16 months. Multivariate analysis identified HBeAg negative status, as the only independent factor affecting viral suppression. The drug showed 100% safety. None showed hepatic decompensation, HCC or reported death. Conclusions: In real-life data; long term Entecavir treatment effectively sup-pressed HBV. Entecavir is considered an effective and safe treatment for CHB patients compared to 82% in HBeAg (+ve) group. Entecavir is considered an effective and safe choice on long term use for treatment CHB patients.

The hepatitis B virus reactivation after transarterial chemoembolization in Chinese hepatocellular carcinoma patients with low serum hepatitis B virus DNA level.

ObjectiveTo investigate the reactivation of the hepatitis B virus (HBV) following transarterial chemoembolization (TACE) in Chinese hepatocellular carcinoma (HCC) patients with low serum HBV DNA level, and to analyze the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.MethodsFrom November 2011 to January 2014, 109 patients newly diagnosed with HCC with an HBV DNA level less than 2,000 IU/mL were enrolled in the study. These patients underwent at least two TACE procedures and were followed-up for at least 3 months to assess the reactivation of HBV DNA. Ten variables were compared in patients with and without HBV reactivation to evaluate the factors related to HBV reactivation in HCC patients with low serum HBV DNA level.ResultsOf 109 HCC patients with low level HBV DNA, nine patients were HBeAg-positive, the other 100 patients were HBeAg-negative. Twenty-three of 109 (21.1%) patients developed HBV reactivation after TACE. Of nine HBeAg-positive patients, 55.6% (5/9) developed HBV reactivation, while in 100 HBeAg-negative patients, the rate of HBV reactivation was 18% (18/100) (P=0.019). Of ten variables of patients with low level HBV DNA, the levels of AFP and HBeAg status were found to be significantly correlated with HBV reactivation. Nevertheless, on binary logistic regression analysis, only HBeAg-positive status was the independent predictor of HBV reactivation in HCC patients with low serum HBV DNA level (odds ratio, 7.41; P=0.013).ConclusionHCC patients with low serum HBV DNA level still remain associated with risk of viral reactivation after TACE, and HBeAg-positive HCC patients have a higher risk than patients with HBeAg-negative status.

Associations between hepatitis B virus basal core promoter/pre-core region mutations and the risk of acute-on-chronic liver failure: a meta-analysis.

BackgroundSeveral studies have suggested a relationship between hepatitis B virus (HBV) basal core promoter/pre-core mutations and HBV-induced acute-on-chronic liver failure (ACLF). Therefore, we evaluated this potential relationship using a meta-analysis.MethodsChinese or English studies from 1966 to January 31, 2014 were included in the analysis. A random or fixed-effects model was used to merge the odds ratios (ORs).ResultsWe identified 31 case–control studies containing a total population of 1995 ACLF and 3822 chronic hepatitis B (CHB) patients. Several mutations were significantly correlated with ACLF: T1753V (1.889, 95 % confidence interval (CI) [1.357–2.631]), A1762T (2.696 [2.265–3.207]), G1764A (3.005 [2.077–4.347]), A1762T/G1764A (2.379 [1.519–3.727]), C1766T (1.849 [1.403–2.437]), T1768A (2.440 [1.405–3.494]), A1846T (3.163 [2.157–4.639]), G1896A (2.181 [1.800–2.642]), G1899A (3.569 [2.906–4.385]) and G1896A/A1762T/G1764A (1.575 [1.172–2.116]). Additionally, HBeAg-negative status was also statistically significant for the progression to ACLF (OR = 2.813, 95 % CI = 2.240–3.533, p < 0.001). However, there was no association between ACLF development and HBV genotype.ConclusionsThe HBV basal core promoter/pre-core mutations T1753V, A1762T, G1764A, C1766T, T1768A, A1846T, G1896A and G1899A, and an HBeAg-negative status correlate with an increased risk of HBV-ACLF.Electronic supplementary materialThe online version of this article (doi:10.1186/s12985-015-0313-5) contains supplementary material, which is available to authorized users.

Seroclearance rate of hepatitis B surface antigen in 2,112 patients with chronic hepatitis in Japan during long-term follow-up

Rate of hepatitis B surface antigen (HBsAg) seroclearance was determined in 2,112 Japanese patients with chronic hepatitis B who were followed up for at least 15 years. Patients had a median age of 37 years and included 1,431 (67.8 %) men. Median values were AST/ALT, 43/62 IU/L; platelet counts, 182 × 10(3)/mm(3); HBsAg, 3,400 IU/mL; and hepatitis B virus (HBV) DNA, 6.2 log copies/mL. Factors influencing HBsAg seroclearance were evaluated by the Cox proportional model and annual rate of HBsAg seroclearance by the Kaplan-Meier life table method. The overall annual rate of HBsAg seroclearance was 1.75 % in 2,112 patients; it was 1.65 % in 1,130 untreated and 2.05 % in 982 treated patients (p = 0.289). In untreated patients, seroclearance was influenced by age, no HBV infections in third-degree or closer relatives, and HBsAg levels in univariate analysis. Seroclearance was influenced by a median age ≥50 years [relative risk (RR) 1.61 (p = 0.018)] and HBsAg ≤2,000 IU/mL [RR 1.77 (p = 0.014)] in multivariate analysis. In treated patients, age, male gender, no HBV infections in third-degree or closer relatives, interferon therapy, chronic hepatitis, high AST and γ-GTP levels, low platelet counts, hepatitis B e antigen (HBeAg)-negative status, low HBsAg levels and the wild-type precore sequence significantly influenced HBsAg seroclearance. In multivariate analysis, no family history [RR 2.22 (p = 0.006)], interferon treatment [RR 3.15 (p < 0.001)], and HBeAg-negative status [RR 3.75 (p < 0.001)] significantly influenced HBsAg seroclearance. In this retrospective cohort study, the annual rate of HBsAg seroclearance was 1.65 % in untreated patients and 2.05 % in treated patients.

High Frequency of Genotype D and Spontaneous Hepatitis B Virus Genomic Mutations Among Haitians in a Multiethnic North American Population

The importance of hepatitis B virus (HBV) genotype and mutations has been increasingly recognized. We aimed to determine HBV genotype, precore (PC), and basal core promoter region (BCP) mutations in a HBV multiethnic South Florida population. Samples from 213 patients were tested for HBV-DNA using Abbott RealTime HBV IUO assay, and for mutations using INNO-LiPA assay. Patients were predominantly male (67%); 61 (31%) were African American, 60 (28%) Hispanic, 37 (17%) Haitian, 27 (19%) white non-Hispanic, and 14 (6.6%) Asian. Genotype A was found in 101 (69%), D in 25 (17%), F in 9 (6%), G in 7 (5%), C and E in 6 (4%) each, B in 4 (3%), and H in 2 (1%) patients. Mixed genotypes were detected in 11 patients. Genotype A was more prevalent in all ethnicities except for Asian. Among hepatitis B e antigen (HBeAg)-negative patients (59%), BCP, PC, and combined BCP/PC mutations were found in 30 (37.5%), 13 (16.3%), and 14 (17.5%), respectively. Genotype D was associated with higher frequency of HBeAg-negative status [18/24 (75%) vs. 62/121 (51%) P=0.03] and mutations [16/19 (84%) vs. 40/67 (60%) P=0.04] compared with others. Genotype A was negatively associated with mutations [26/31 (84%) vs. 30/55 (55%), P=0.009]. PC mutations were more common in genotype D (14/19, 73%) compared with genotype A (7/54, 13%, P<0.0001). One-hundred percent and 79% of Asians and Haitians had spontaneous mutations, respectively. All Haitians with genotype D had PC mutations and 3 (50%) had BCP/PC. The present study shows that HBeAg-negative status and spontaneous mutations were more common with genotype D; the presence of genotype D in Haitians was always associated with spontaneous mutations.

Quantitation of HBsAg predicts response to entecavir therapy in HBV genotype C patients

To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus (HBV) genotype C. Fifty patients [hepatitis B e antigen (HBeAg)-negative:HBeAg-positive = 26:24] with HBV genotype C, who received naïve entecavir therapy for > 2 years, were analyzed. Patients who showed HBV DNA levels ≥ 3.0 log viral copies/mL after 2 years of entecavir therapy were designated as slow-responders, while those that showed < 3.0 log copies/mL were termed rapid-responders. Quantitative hepatitis B surface antigen (HBsAg) levels (qHBsAg) were determined by the Architect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction (PCR). Drug-resistance mutations were detected by the PCR-Invader method. At year 2, HBV DNA levels in all patients in the HBeAg-negative group were < 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow- and rapid-responders; the median qHBsAg in the slow-responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid-responders (P < 0.01). When the pretreatment factors predictive of HBV DNA-negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were significant (P < 0.01). Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor (P = 0.03). Quantitation of HBsAg could be a useful indicator to predict response to entecavir therapy.

Evaluation of normal or minimally elevated alanine transaminase, age and DNA level in predicting liver histological changes in chronic hepatitis B

Serum alanine transaminase (ALT), hepatitis B virus (HBV) DNA level and age are used in the evaluation of chronic hepatitis B (CHB). We designed this study to evaluate liver histology with ALT and its relation with age and HBV DNA. During the period of October 2006 to July 2009, 499 CHB patients were included in this study with detectable HBV DNA at PCR. Of these, 181 had normal ALT, 200 had ALT [>(1 × ULN) < (2 ULN)] and 118 had ALT ≥ 2 ULN and were labelled as Group 1, 2 and 3 respectively. A strong positive correlation was found between ALT and histological activity index (HAI) and fibrosis. However, 29 (52.7%) and five (9.1%) in Group 1 with positive HBeAg status had HAI ≥4 and fibrosis ≥2 respectively. Among those with HBeAg-negative status, 66 (23.1%) had HAI >4 and 31 (10.8%) had fibrosis ≥2. In Group 2, 14 (15.7%) had moderate-to-severe HAI and 19 (21.2%) had fibrosis ≥2 when HBeAg was positive, in those with HBeAg negative 34 (30.6%) had moderate-to-severe HAI and 38 (34.2%) had fibrosis ≥2. An ALT value of ≥58.5 U/l had higher sensitivity than that of 80 U/l in predicting significant histological changes. Further, HAI and fibrosis were significantly greater in the age of >30 years. We recommend liver biopsy in HBeAg-negative CHB over 30 years of age regardless of ALT level and starting treatment at ALT 1.5 × ULN instead of 2 × ULN.

Hepatitis B virus in Buenos Aires, Argentina: genotypes, virological characteristics and clinical outcomes

Hepatitis B virus (HBV) is classified into eight major genotypes, A-H, which are geographically distributed worldwide. The aim of this work was to describe the clinical characteristics associated with the HBV genotypes circulating in Buenos Aires city. The study included 139 patients infected with HBV, whose clinical courses were classified as acute symptomatic self-limiting hepatitis, inactive carrier state and chronic active hepatitis (HBV e-antigen (HBeAg)-positive and HBeAg-negative). The HBV genotypes were determined in 128 patients by PCR–restriction fragment length polymorphism and phylogenetic analysis. Biochemical, virological, clinical and histological features were analysed. A differential distribution of genotypes between acute symptomatic and chronic infections was found. Among the acute cases, genotype F was predominant (65.2%, 30/46) and genotype D was rare (4.3%, 2/46), whereas among the chronic infections, a homogeneous distribution of genotypes A (26.8%, 22/82), D (31.7%, 26/82) and F (36.6%, 30/82), with an unusual presence of genotypes B (1.2%, 1/82) and C (3.7%, 3/82), was observed. Regarding the liver histology of chronically infected patients, genotype F tended to display higher histological activity indexes. Mutations related to HBV surface antigen immunoreactivity, antiviral resistance and HBeAg-negative status were studied. This work constitutes, to our knowledge, the first description of the clinical characteristics related to HBV genotypes in Argentina, where the distribution of genotypes in patients with acute infection has not been reported previously. Finally, it was established that genotype F is the prevalent genotype among the acute symptomatic infections in Buenos Aires city, and that it shows a tendency to cause an adverse disease outcome among the chronic cases.

Treatment of Chronic Hepatitis B in Asia-Pacific Countries: Is the Asia-Pacific Consensus Statement being followed?

The Asia-Pacific consensus guidelines for the management of chronic hepatitis B state that the principal indicators for starting therapy are increased HBV DNA levels (> or =20,000 IU/ml for hepatitis B e antigen [HBeAg]-positive status and >2,000 IU/ml for HBeAg-negative status) and alanine aminotransferase (ALT) levels >2x the upper limit of normal. We aimed to determine whether clinicians in the Asia-Pacific region are treating patients with chronic hepatitis B according to the Asia-Pacific consensus statement on the management of chronic hepatitis B. An online survey of chronic hepatitis B treatment practices was prepared, consisting of 14 questions grouped into seven categories: patient statistics, treatment statistics, treatment decision, first-choice treatment, treatment duration, future directions and patient preference. In total, 124 respondents from 12 countries completed the survey. Most respondents indicated that detectable HBV DNA was either the first or second most important factor when deciding whether to initiate therapy. Many physicians were unsure about initiation of treatment in patients >40 years of age when ALT levels were within the normal range. Oral antiviral drugs were the most frequently used medication because of their effectiveness, safety and ability to provide sustained viral suppression. Conversely, the most important reasons for selecting interferon therapy were effectiveness, fixed duration of treatment and lack of drug resistance. Criteria for stopping treatment generally followed the recommendations included in the guidelines. These data suggest that clinicians from the Asia-Pacific region use criteria beyond those advocated in treatment guidelines when deciding whether to initiate treatment in HBV-infected patients.

Hepatitis B virus: molecular genotypes and HBeAg serological status among HBV-infected patients in the southeast of Brazil.

BackgroundKnowledge of HBV genotype is very important for clinical treatment. Studies have suggested possible pathogenic and therapeutic differences among HBV genotypes. The aim of this study was to determine HBV subtypes and genotypes in HBV-infected patients in our region (southeast Brazil) and to correlate results with clinical and histopathological data.MethodsOne hundred and thirty-nine HBsAg-positive patients were included in the study. All patients were anti-HCV and anti-HIV negative (64% male; mean age 42 ± 14.5 years; range 7-80 years; 84% Caucasian) and were followed up at the University Hospital. A method for genotyping and subtyping HBV by partial HBsAg gene sequencing with primers common to all known genotypes was used. The viral load was measured by Amplicor Monitor assay (Roche).ResultsHBV genotype A was the most prevalent (55%), while genotypes C, D and F were found in 3%, 38% and 4% of HBV-infected patients, respectively. Among the patients infected by genotype A, 18.3% (14/76) were African descendents and, among the patients infected by genotype D, 11.3% (6/53) were also African descendents. In the four patients infected with genotype C, 2 were Asian descendents and 2 were Caucasians. All (7) genotype F infected patients were Caucasians. Seventy percent of our HBsAg-positive patients were HBeAg negative (62% genotypes A; 26.2% D; 7.1% C and 4.7%F). The viral load of HBV-DNA was about 5 times higher in HBeAg-positive than in HBeAg-negative patients. About 40% of these patients had alanine aminotransferase of up to 1.5 times the normal level. The mean stage of fibrosis in genotype A patients (2.8) was significantly higher than the mean stage of fibrosis in genotype D patients (2.0) (P = 0.0179).ConclusionThe genotypes encountered in our HBV-infected patients were apparently a consequence of the types of immigration that occurred in our region, where European and African descendents predominate. The HBeAg-negative status predominated, possibly due to the length of time of infection. The viral load in HBeAg-positive patients was higher than in HBeAg-negative individuals. The fibrosis grade in genotype A-infected patients was more advanced than genotype D-infected patients.

The Role of Viral‐specific Immune Responses on the Outcome of Chronic Hepatitis B (HBV) Infection in Children: New Insights Into Immunopathology

The Role of Viral‐specific Immune Responses on the Outcome of Chronic Hepatitis B (HBV) Infection in Children: New Insights Into Immunopathology

Epidemiology of chronic hepatitis B infection in France: risk factors for significant fibrosis – results of a nationwide survey

Epidemiological data concerning hepatitis B are scarce in France. To describe epidemiological, clinical, virological and histological features of HBsAg-positive patients followed at non-academic hospitals in France. Clinical, biological, virological and histological data of all HBsAg-positive consecutive patients observed from April 1, 2001 to May 31, 2002 in participating centres were recorded prospectively. Multivariate analyses of factors associated with significant fibrosis and cirrhosis were performed. Nearly 1166 HBsAg-positive patients were seen in the 58 centres: 671 males and 495 females from metropolitan France (32%) and from outside metropolitan France (68%); mean age 41 +/- 15 years. Twenty-nine percent of patients were probable HBsAg inactive carriers, while 50% had chronic hepatitis; 43% of these were HBeAg-positive and 57% HBeAg-negative. Liver biopsy had been performed in 558 (51%) patients; 205 (17.6%) patients had cirrhosis. By multivariate analysis, factors associated with significant fibrosis were: age >40 years (P < 0.05), HBeAg-negative status (P < 0.02) and histological activity (P < 0.0001). Factors associated with cirrhosis: age (P < 0.0001), platelet count <150 000/mm(3) (P < 0.0001) and viral co-infection (P < 0.03). HBV infection represents a significant workload for hepatogastroenterologists at non-academic hospitals in France.

Viral genotype and baseline load predict the response to adefovir treatment in lamivudine-resistant chronic hepatitis B patients

To determine the factors associated with virological response (VR), HBeAg loss or the emergence of adefovir (ADV)-related mutations in ADV-treated chronic hepatitis B (CHB) patients with lamivudine (LAM) resistance. Fifty-four LAM-resistant CHB patients (46% HBeAg-positive) were treated with ADV monotherapy (n=28) or ADV plus LAM (n=26) for a mean of 30.4 months. Thirty-eight patients (70.4%) achieved VR defined as HBV-DNA levels <10(4)copies/ml within the first 12 months of treatment. Six (24%) of 25 HBeAg-positive patients exhibited HBeAg loss and 20% seroconverted to anti-HBe. Eight patients (14.8%) developed ADV-related mutations. In the multivariate analysis, female gender (HR=0.20, 95% CI: 0.05-0.76, p=0.018), HBeAg-negative (HR=0.37, 95% CI: 0.14-0.96, p=0.040) and low baseline HBV-DNA levels (HR=0.65, 95% CI: 0.45-0.95, p=0.027) were independent predictors of VR, whereas low HBV-DNA levels (HR=0.36, 95% CI: 0.11-1.20, p=0.095) and HBV-genotype D (HR=0.06, 95% CI: 0.004-0.84, p=0.037) independently predicted HBeAg loss. ADV therapy suppresses viral replication in more than 70% of LAM-R patients. Factors associated with virologic response are female gender, HBeAg-negative status and low baseline serum HBV-DNA levels. Genotype D HBV infection and low baseline HBV-DNA levels independently predict HBeAg loss.

Clinical Significance of Hepatitis B Virus (HBV) Genotypes and Precore and Core Promoter Mutations Affecting HBV e Antigen Expression in Taiwan

To assess the prevalence and clinical significance of hepatitis B virus (HBV) genotypes and precore and core promoter mutations in Taiwan, a cohort of 200 Taiwanese chronic hepatitis B patients was analyzed. The HBV genotypes and sequences of the precore and the core promoter regions were determined in 66 asymptomatic carriers and 134 patients who had liver biopsy-verified chronic hepatitis and liver cirrhosis. The HBV e-antigen (HBeAg)-negative patients had a higher frequency of mutations at core promoter nucleotides 1753 and 1773 and precore nucleotides 1846, 1896, and 1899 than HBeAg-positive patients. Among the 200 patients, the frequencies of genotype C, T1762 and A1764, C1753, T1766 and A1768, and A1896 mutations increased and the frequencies of T or G1752, T1773, G1799, and C1858 mutations decreased with advancing liver diseases. These factors were different between those with HBeAg-positive status and those with HBeAg-negative status. Based on multiple logistic regression analysis, the risk factors of liver cirrhosis for 200 patients were the presence of T1762 and A1764 mutations (odds ratio [OR] = 11.11; 95% confidence interval [CI] = 3.91 to 31.25; P < 0.001), age > or =35 years (OR = 3.42; 95% CI = 1.33 to 8.77; P = 0.011), and genotype C (OR = 2.87; 95% CI = 1.21 to 6.81; P = 0.017). Further categorical analysis found that 62.1% of patients with genotype C, T1762 and A1764 mutations and age > or =35 years had liver cirrhosis. None of the 55 patients infected with the genotype B, A1762 and G1764 wild type and age <35 years showed liver cirrhosis. In conclusion, our data suggest that pathogenic differences between HBeAg-positive and -negative patients may exist. In Taiwan, HBV genotype C and the T1762 and A1764 mutations may play a role in HBV-related liver cirrhosis, and these could serve as molecular markers for prediction of the clinical outcomes of chronic HBV patients.