Spontaneous Hepatitis B E Antigen Seroconversion Research Articles

Serum Hepatitis B Virus-DNA Levels Correlate With Long-term Adverse Outcomes in Spontaneous Hepatitis B e Antigen Seroconverters

Hepatitis B e antigen (HBeAg) status and serum hepatitis B virus (HBV) DNA levels are major factors affecting the prognosis of adult HBV carriers; however, the impact of viral load on long-term outcomes after spontaneous HBeAg seroconversion remains unclear. A total of 390 spontaneous HBeAg seroconverters with a long-term follow-up were enrolled. Serum HBV-DNA levels at 1 year after HBeAg seroconversion were determined, and their correlation with long-term adverse outcomes was explored. In a mean follow-up of 6.8 years, the average annual incidence rates were 4.4% and 1.9% for HBeAg-negative hepatitis and hepatitis flare, respectively. Compared with patients with HBV-DNA levels <200 IU/mL, the adjusted hazard ratios of HBeAg-negative hepatitis were 2.4 (95% confidence interval, 1.3-4.4), 3.6 (1.8-7.2), and 5.3 (2.8-10.0), respectively, for serum HBV-DNA level of 2000 -2 × 10(4), 2 × 10(4) -2 × 10(5), and ≥2 × 10(5) IU/mL. In addition, serum HBV-DNA levels were independently associated with HBeAg-negative hepatitis flare, which confirmed their impact on the immune active hepatitis after HBeAg seroconversion. HBeAg seroconversion may not always confer favorable outcomes. Serum HBV-DNA levels ≥2000 IU/mL at 1 year post HBeAg seroconversion correlate with increased risk of HBeAg-negative hepatitis and hepatitis flare.

Serial HBV DNA levels in patients with persistently normal transaminase over 10 years following spontaneous HBeAg seroconversion

Earlier studies addressing the hepatitis B virus (HBV) DNA cut-off level for inactive chronic HBV infection largely involved patients with normal alanine aminotransferase (ALT) for only 1-2 years and based on a single time HBV DNA assay. This study was conducted to address this issue using serial HBV DNA assays in patients with persistently normal ALT (PNALT) over 10 years following spontaneous hepatitis B e antigen (HBeAg) seroconversion. Serial serum specimens (mean 9 samples per patient) of 62 patients with PNALT and no disease progression over 10 years (median 18.1 years) after spontaneous HBeAg seroconversion were assayed for HBV DNA. Excluding assays within 1 year after HBeAg seroconversion, 21% and 82.3% of the patients with PNALT had HBV DNA levels persistently lower than 4 log(10) and 5 log(10) copies/mL, respectively, and only 8% had a level ≥ 5 log(10) copies/mL in at least two assays. Of the 27 patients with PNALT defined by ALT <30 U/L for male and <19 U/L for female, only 33% had serum HBV DNA level persistently <4 log(10) copies/mL. There was no significant difference in the serial HBV DNA changes among patients with different gender, HBV genotype or age at HBeAg seroconversion. Liver biopsy in nine patients invariably showed minimal necroinflammation and one showed Ishak fibrosis score 4. These results suggest that 5 log(10) copies/mL (20,000 IU/mL) is a more appropriate cut-off HBV DNA level for inactive chronic HBV infection in the setting of PNALT.

Human Interleukin-10 Genotypes Are Associated with Different Precore/Core Gene Mutation Patterns in Children with Chronic Hepatitis B Virus Infection

To elucidate the association between human interleukin-10 (IL-10) genotypes and hepatitis B virus (HBV) precore/core gene mutation in children with chronic HBV infection. The study group comprised of 21 children with chronic HBV infection with spontaneous hepatitis B e antigen (HBeAg) seroconversion who were followed for more than 10 years. Another nine children without HBeAg seroconversion served as the control subjects. Sera at the immune tolerance and inflammatory phase (alanine aminotransferase, >80 IU/L) were subjected to HBV precore/core sequence analysis. IL-10 -1082 polymorphism was also determined. HBV precore/core gene mutation increased significantly more in the inflammatory phase than in the tolerance phase (G1896A, 76.2% versus 4.8%; C1913A, 33.3% versus 0%; C2189A, 28.6% versus 4.8%; G2304A, 52.4% versus 14.3%) in study group (n = 21) but not the control group (n = 9). Subjects with the G/G genotype at the IL-10-1082 polymorphism site had higher C2189A mutation rate than the A allele carriers (P = .02). C2189A mutation carriers are associated with more viral load decrement from tolerance to inflammatory phase (P = .01) and earlier spontaneous HBeAg seroconversion (P = .01). The G/G genotype at the IL-10 -1082 polymorphism is associated with higher C2189A mutations, lower HBV viral load at immune inflammatory phase, and earlier spontaneous HBeAg seroconversion than A allele carriers.

Age-Specific Prognosis Following Spontaneous Hepatitis B E Antigen Seroconversion in Chronic Hepatitis B

Hepatitis B e antigen (HBeAg) seroconversion in chronic hepatitis B virus infection confers a favorable prognosis, but untoward outcomes may develop in some patients. The impact of the age of HBeAg seroconversion on prognosis is not clearly known. HBeAg-positive patients with biopsy-proven chronic hepatitis B were followed up long-term. Follow-up studies included liver biochemistry, alpha-fetoprotein, and ultrasonography every 3 to 6 months or more frequently if clinically indicated. Of the patients who underwent spontaneous HBeAg seroconversion, the incidences of HBeAg-negative hepatitis, cirrhosis, hepatocellular carcinoma (HCC), and hepatitis B surface antigen seroclearance were compared between patient groups with different ages at the time of HBeAg seroconversion using Kaplan-Meier survival analysis and Poisson regression model. Spontaneous HBeAg seroconversion was documented in 508 patients. Of the 483 patients who had no evidence of cirrhosis or HCC at the time of HBeAg seroconversion, HBeAg seroconversion occurred before age 30 in 218 patients (group A), between age 31 and 40 in 199 patients (group B), and after age 40 in 66 patients (group C). The 15-year cumulative incidences of HBeAg-negative hepatitis, cirrhosis, and HCC increased with increasing age of HBeAg seroconversion, the lowest being in group A (31.2%, 3.7%, and 2.1%, respectively) and highest being in group C (66.7% [P < 0.0001], 42.9% [P <0.0001], and 7.7% [P = 0.29], respectively). The hazard ratio of HBeAg-negative hepatitis, cirrhosis, and HCC was 2.95, 17.6, and 5.22, respectively, in group C compared with group A. Patients with HBeAg seroconversion before age 30 have excellent prognosis, whereas patients with delayed HBeAg seroconversion after age 40 have significantly higher incidences of HBeAg-negative hepatitis, cirrhosis, and HCC.

Serum Levels of Interleukin-10 and Interleukin-12 Predict Early, Spontaneous Hepatitis B Virus e Antigen Seroconversion

This prospective cohort study aimed to determine the effect of cytokines on spontaneous hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) infection. Polymorphisms in interleukin (IL)-2, IL-4, IL-10, IL-12beta, and interferon-gamma were evaluated in 288 HBeAg-positive chronic HBV patients (median initial age, 8.6 years; median follow-up duration, 19.3 years). Serum cytokine levels were determined in 154 subjects (53.5%) before and after HBeAg seroconversion by enzyme-linked immunosorbent assay analysis. Peripheral blood mononuclear cells (PBMC) were isolated from patients with chronic HBV infection and stimulated with HBV core antigen (HBcAg); data on cytokine genotypes and phenotypes were compared. The IL-10-1082 G/G and IL-12beta -10993C/G genotypes predicted early, spontaneous HBeAg seroconversion (hazard ratio [HRs] = 3.43 and 1.54; P < .001, and P < .004, respectively), based on multivariate survival analysis. The IL-10 -1082 G/G genotype was associated with higher serum levels of IL-10 and IL-12; the IL-12beta -10993 C/G genotype predicted higher levels of IL-12 secretion by PBMC after in vitro HBcAg stimulation (P = .04). Higher levels of serum IL-12 (>45 pg/mL) and IL-10 (>70 pg/mL) were associated with early, spontaneous HBeAg seroconversion (HR = 1.52 and 1.48; P = .04 and .02, respectively). The IL-10-1082 G/G is associated with higher serum IL-10 and IL-12 levels and IL-12beta -10993 C/G is associated with increased secretion of IL-12 in response to HBcAg stimulation of PBMC. Both genotypes are associated with early, spontaneous HBeAg seroconversion. Higher serum levels of IL-10 and IL-12 in HBeAg-positive patients are correlated with early, spontaneous HBeAg seroconversion.

HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B

During the natural history of chronic hepatitis B virus (HBV) infection, the loss of serum hepatitis B e antigen (HBeAg) and the development of anti-HBe antibodies (HBeAg seroconversion) mark a transition from the immune-active phase of disease to the inactive carrier state. This review examines the evidence from natural history and cohort studies on the relationship between HBeAg seroconversion and disease progression. The role of HBeAg seroconversion as an important milestone in the management of HBeAg-positive patients with chronic hepatitis B (CHB), as well as the advantages and disadvantages of administering a finite course of therapy for HBeAg-positive CHB, is also discussed. The evidence from natural history and cohort studies indicates that spontaneous or treatment-induced HBeAg seroconversion is associated with lower rates of disease progression to cirrhosis and hepatocellular carcinoma, a potential of hepatitis B surface antigen seroconversion, and improved survival rates. Updated guidelines developed by major liver associations recommend stopping oral therapy for HBeAg-positive patients who achieve sustained HBeAg seroconversion with polymerase chain reaction-undetectable HBV-DNA on two separate occasions for 6 or more months apart, taking into consideration the individual's clinical and virologic response to therapy, as well as the severity of liver disease. Thus, early induction of HBeAg seroconversion with interferon-based therapy or oral nucleos(t)ide analogues has important clinical and socioeconomic implications for the management of CHB.

Influence of a single nucleotide polymorphism in the P1 promoter of the furin gene on transcription activity and hepatitis B virus infection #

Hepatitis B e antigen (HBeAg) is a viral strategy of immune response evasion associated with hepatitis B virus (HBV) persistence. Spontaneous HBeAg seroconversion is usually accompanied by liver disease remission. Unfortunately, this goal is difficult to achieve and requires expensive and time-consuming treatment. Furin, a proprotein convertase, is involved in HBeAg maturation and is therefore a potential therapeutic target or indicator for predicting disease progression and antiviral response. Here we demonstrate that healthy Han Chinese from southern China (an endemic area of HBV infection) harbor a common single nucleotide polymorphism (SNP; -229 C/T) in a 1268-bp region of the P1 promoter of the furin gene [FES upstream region (Fur)]. A luciferase reporter gene assay showed that transcription activity is about 3 times higher in allele T carriers than in allele C carriers of this SNP. Allele T includes a suboptimal transcription factor NF-E2 [i.e., nuclear factor (erythroid-derived 2)]-binding motif according to bioinformatics and studies using site-directed mutagenesis. We also observed that individuals carrying allele T were more likely to become persistently infected. When persistently infected patients were divided into subgroups according to recent guidelines and HBeAg-defective virus infection was taken into account, patients with allele T or genotype TT had a decreased likelihood of HBeAg seroconversion or an increased likelihood of progressing to HBeAg-negative chronic hepatitis B or liver cirrhosis if accompanied by HBeAg-defective virus infection. The common SNP in the P1 promoter of the Fur gene affects furin transcription activity and HBV infection outcome, possibly by increasing furin messenger RNA expression, and this suggests that furin is a potential therapeutic target and that this SNP is a potential predictor of disease progression or therapeutic response.

Mutations of T-Cell Epitopes in the Hepatitis B Virus Surface Gene in Children With Chronic Infection and Hepatocellular Carcinoma

Hepatitis B virus (HBV) infection induces an interaction of host immune responses against virus antigen-presenting hepatocytes. The emergence of mutants is a strategy through which the virus can escape host attacks and produce chronic infection. In this study, we aimed to investigate mutations of the human leukocyte antigen-A2-restricted T-cell epitope (TCE) in chronic HBV-infected children. In total, 441 chronic HBV-infected children were longitudinally followed-up every 6 months. They were divided into hepatitis B e antigen (HBeAg) (-) (N = 60) and HBeAg (+) (N = 381) groups according to this seromarker at their enrollment. The HBeAg (+) group was further divided into HBeAg (+/-) (N = 229) and HBeAg (+/+) (N = 152) groups, depending on the occurrence of spontaneous HBeAg seroconversion. Twenty-five children with HBV-related hepatocellular carcinoma (HCC) were also recruited. TCE mutations were examined using the latest serum samples, and serum samples at enrollment were used if TCE mutations were present in the latest serum samples in the seroconverters. HBV genotypes and liver enzymes were also analyzed. The HBeAg (+/+) group had a lower TCE mutation rate (7.9%) than that of the HBeAg (+/-) (29.2%), HBeAg (-) (26.7%), and HCC (28.0%) groups. In the HBeAg (+/-) group, TCE mutations were present before HBeAg seroconversion in 11.9% of the subjects. Those with TCE mutations showed HBeAg seroconversion at an older age (16.1 +/- 5.3 yr vs 12.7 +/- 5.7 yr, P < 0.001) and with higher peak alanine aminotransferase (ALT) levels (median 175 U/L vs 119 U/L, P = 0.03) than those without TCE mutations. TCE mutations tended to be positively associated with HBeAg seroconversion and higher ALT levels in chronic HBV-infected children.

Pre-S Deletion and Complex Mutations of Hepatitis B Virus Related to Advanced Liver Disease in HBeAg-Negative Patients

This longitudinal study investigated the interactions and roles of hepatitis B virus (HBV) genotypes, pre-S deletions, and core promoter and precore mutations on the progression of liver disease in hepatitis B e antigen (HBeAg)-negative patients. A total of 141 HBeAg-negative patients without liver cirrhosis or hepatocellular carcinoma at study entry were recruited for this study, including 45 inactive HBV carriers and 96 patients with HBeAg-negative chronic hepatitis B. The HBV genotypes and the sequences of pre-S, core promoter, and precore regions were determined. Compared with patients without developing liver cirrhosis, patients with the development of liver cirrhosis had higher rates of genotype C; pre-S deletions; C or G1753, T1762/A1764, T1766, and/or A1768 mutants; and G1799 variant. Cox regression analysis showed that older age, higher total bilirubin and HBV DNA levels, pre-S deletions, and T1766 and/or A1768 mutants were significantly associated with the development of liver cirrhosis. HBV with a complex mutation pattern (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutants) rather than a single mutation was associated with the development of liver cirrhosis, and the patterns of mutation combinations differed between HBV genotype B and C. Moreover, pre-S deletion was a significant risk factor for hepatocellular carcinoma. This study indicated that pre-S deletion and combined mutations of HBV are useful molecular markers for predicting the clinical outcomes of HBeAg-negative patients.

Long-term outcome of chronic hepatitis B in Caucasian patients: mortality after 25 years

Objective:To assess risk factors for liver-related death, we re-evaluated, after a median follow-up of 25 years, a cohort of 70 Caucasian patients with hepatitis B e antigen (HBeAg) positive chronic...

Sustained disease remission after spontaneous HBeAg seroconversion is associated with reduction in fibrosis progression in chronic hepatitis B Chinese patients

Recently, controversies have arisen about whether hepatitis B e antigen (HBeAg) seroconversion can result in regression of fibrosis, thus improving the clinical outcome of Chinese patients with chronic hepatitis B. In this study, we determined if spontaneous HBeAg seroconversion is associated with regression of fibrosis in Chinese chronic hepatitis B patients. We evaluated the histology of liver samples from 128 HBeAg-positive treatment-naive Chinese patients who had undergone 2 liver biopsies over the years. Regression of fibrosis was defined as a decrease in fibrosis stage of at least 1 point. Sustained disease remission was defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA < 10(4) copies/ml at follow-up liver biopsy. The mean duration (+/- standard error of the mean) between the initial and follow-up liver biopsies was 43.9 +/- 3.4 months. Regression of fibrosis was higher in patients with sustained disease remission (5 of 13 [38.5%] versus 22 of 115 [19.1%], P < 0.00005), patients who were younger (20-29 years old) at initial liver biopsy (17 of 54 [31.5%] versus 10 of 74 [13.5%], P = 0.0004), and patients with genotype B (17 of 43 [39.5%] versus 10 of 85 [11.8%], P = 0.004). On multivariate analysis, sustained disease remission (relative risk [RR] 3.00, 95% confidence interval [95% CI] 1.29-7.01, P = 0.01) and being 20-29 years old at initial liver biopsy (RR 2.94, 95% CI 1.01-8.62, P = 0.04) were independently associated with regression of fibrosis. The rate of fibrosis progression was lower in patients with sustained disease remission than in those who remained HBeAg positive (median 0 fibrosis units/year, range -2.00 to -0.70 fibrosis units/year, versus median 0.51 fibrosis units/year, range 0 to +2.03 fibrosis units/year, P = 0.02). Spontaneous sustained remission of disease is associated not only with little progression of fibrosis but also with regression of fibrosis.

Characterization of viral kinetics in patients with hepatitis B e antigen‐positive chronic hepatitis B

A study was conducted during a 1 year follow-up to characterize the viral kinetics in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and to develop a model of predicting the probability of spontaneous HBeAg seroconversion. Fifty-seven patients with HBeAg-positive chronic hepatitis B were enrolled with monthly follow-ups from three Phase III clinical trial placebo groups. According to serial viral loads, 30 patients (52.6%) with the stationary pattern maintained stable HBV DNA levels with fluctuations of less than 1.5 log copies/ml. Twenty patients (35.1%) with the declining pattern exhibited a spontaneous decline of more than 1.5 log copies/ml without a following rebound of at least 1.5 log copies/ml. The remaining seven patients (12.3%) had the wavering pattern. Both declining and wavering patterns, when compared with the stationary pattern, had significantly higher hepatic necroinflammation in terms of ALT and Knodell scores at the baseline and peak ALT levels during the follow-up period. The declining pattern had a significantly better clinical outcome in terms of the lowest final HBV DNA and a reduction in the necroinflammatory score after 1 year. Furthermore, the declining pattern had a favorable HBeAg seroconversion rate (40%) compared with the wavering (14.3%) and stationary patterns (0%). A regression equation, incorporating simultaneous serum bilirubin, ALT, and HBV DNA levels, predicted the probability of HBeAg seroconversion with a sensitivity of 76.8% and a specificity of 74.7%. In conclusion, different viral kinetic patterns in patients with chronic hepatitis B implicate distinct clinical significance and immunologic perspective.

Viremia Profiles in Children With Chronic Hepatitis B Virus Infection and Spontaneous e Antigen Seroconversion

This study investigated the viremia profiles in children with chronic hepatitis B virus (HBV) infection and spontaneous hepatitis B e antigen (HBeAg) seroconversion. Fifty-eight children with chronic HBV infection met the following criteria: normal alanine aminotransferase (ALT) level at enrollment, followed up for more than 10 years, no antiviral treatment, and having undergone spontaneous HBeAg seroconversion during follow-up evaluation. They were grouped according to the post-HBeAg seroconversion HBV-DNA levels: (1) low viremia: transient or never 10(4) copies/mL or greater (n=35) (2) fluctuating high viremia: 10(4) copies/mL or greater at least twice at intervals more than 1 year apart (n=23). Abdominal sonography, ALT, and HBV-DNA levels were assessed annually. Another 14 nonseroconverted children served as controls. The precore mutant (nt1896) and genotypes were examined. The initial HBV-DNA level of the 58 seroconverters was 10(8.4+/-1.0) copies/mL and decreased to 10(2.9+/-2.0) copies/mL at the end of follow-up period. Their mean ages at enrollment, at peak HBV-DNA, at peak ALT, at HBeAg seroconversion, and at final follow-up were 7.0 +/- 3.7, 13.4 +/- 5.8, 16.3 +/- 6.0, 17.2 +/- 5.8, and 23.7 +/- 4.1 years, respectively. The precore mutant appeared more often in the fluctuating-high-viremia group than in the low-viremia group (60.9% vs 22.9%, P=.004). HBV genotypes had no effect on the viremia profiles. After HBeAg seroconversion, none had persistent abnormal ALT levels. Generally, these young seroconverters had decreased viral loads, normal ALT levels, and uneventful courses after HBeAg seroconversion. A longer follow-up period is necessary to elucidate the significance of HBeAg seroconversion occurring in childhood and young adulthood.

HLA typing associated with hepatitis B E antigen seroconversion in children with chronic hepatitis B virus infection: A long-term prospective sibling cohort study in Taiwan

To conduct a prospective cohort study to clarify the relationship between human leukocyte antigen (HLA) polymorphisms and the seroconversion of hepatitis B e antigen (HBeAg). In the prospective cohort study, 81 HBeAg-positive children with chronic hepatitis B virus (HBV) infection from 40 unrelated families were recruited and followed-up regularly for a mean period of 17.70 +/- 3.23 years. The association between HLA antigen and the age at HBeAg seroconversion was analyzed using Cox regression model with shared frailties under left truncation and right censorship. HLA-B61 and HLA-DQB1*0503 antigens predicted a higher HBeAg seroconversion rate (relative incidence = 6.17 and 3.22, P = .024 and .017, respectively). Within-family frailty in our sibling cohort study demonstrated a negligible or a low degree of within-family correlation with spontaneous HBeAg seroconversion in each HLA antigen. HLA class I antigen B61 and class II antigen DQB1*0503 are associated with earlier HBeAg seroconversion in Taiwanese children with chronic HBV infection.

Chronic Hepatitis B: A Critical Appraisal of Current Approaches to Therapy

Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. With the exception of 2 statements, the experts' responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree.

Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma

The aim of this study was to investigate the influence of hepatitis B virus (HBV) genotypes on the clinical outcome of chronic childhood HBV infection and hepatocellular carcinoma (HCC). A total of 460 HBV carrier children were followed-up for 15 years and 26 children with HBV-related HCC were recruited. HBV genotyping was examined at enrollment and the latest follow-up of these carrier children and at diagnosis in HCC children. Viral load was checked at enrollment for the carrier children. These carriers were grouped based on their initial hepatitis B e antigen (HBeAg) and antibody to hepatitis B e antigen (anti-HBe) status. The HBeAg positive (+) group was divided further into an HBeAg(+/+) group and HBeAg(+/-) group, depending on whether spontaneous HBeAg seroconversion occurred during the follow-up period. Genotype B constituted 73%, 86%, and 76% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) groups, respectively. Genotype C was found in 27%, 8%, and 6% in the HBeAg(+/+), HBeAg(+/-), and anti-HBe(+) group, respectively. Genotype C carriers were more prevalent in the HBeAg(+/+) group than the other 2 groups (P = .01), and had a delayed HBeAg seroconversion compared with the genotype B carriers (P < .001). Changes of genotype during the follow-up period were rare (2.8%). In those with HCC, genotype B was also the major type (74%). There was no difference in the baseline viral load between genotypes B and C. Although HBV genotype B dominates in children with chronic HBV infection and HCC in Taiwan, genotype C delays HBeAg seroconversion in pediatric chronic HBV infection.

Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C

Background & Aims: Recent studies suggest that hepatitis B virus (HBV) genotype B is associated with less active liver disease than HBV genotype C. The aim of our study was to determine if HBV genotype B is associated with higher rates of spontaneous hepatitis B e antigen (HBeAg) seroconversion compared with genotype C. Methods: A retrospective study using stored sera from 332 Chinese patients with chronic HBV infection followed for a mean of 48 months (range, 12–98) were tested for HBV genotype using a line-probe assay. Results: HBV DNA was detected in 273 patients, 122 had HBV genotype B and 147 genotype C. Patients with genotype B had a significantly lower prevalence of HBeAg at presentation and significantly higher rates of spontaneous HBeAg seroconversion during follow-up. HBV genotype B patients who were HBeAg positive were significantly younger, and spontaneous HBeAg seroconversion occurred approximately 1 decade earlier compared with HBV genotype C patients. Multivariate analyses identified high alanine aminotransferase (baseline and follow-up), age >30 years, and genotype B as independent factors associated with spontaneous HBeAg seroconversion. Conclusions: HBV genotype B is associated with earlier HBeAg seroconversion than genotype C. This finding may explain the less active/progressive liver disease in patients with genotype B.GASTROENTEROLOGY 2002;122:1756-1762

Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B

During the course of chronic hepatitis B virus (HBV) infection, hepatitis B e antigen (HBeAg) seroconversion to its antibody (anti-HBe) often coincides with normalization of liver biochemical test and clinical remission, but data regarding long-term outcome after spontaneous seroconversion are still scarce. Excluding patients with other virus(es) concurrent infection, 283 patients with chronic HBV infection were followed up for at least 1 year after spontaneous HBeAg seroconversion to anti-HBe. Follow-up studies included clinical, biochemical, and virologic evaluation and hepatocellular carcinoma (HCC) screening with ultrasonography and α-fetoprotein assay. During a median follow-up period of 8.6 years (range, 1 to 18.4 years) after HBeAg seroconversion in 283 patients, 189 (66.8%) showed sustained remission, whereas the remaining 94 (33.2%) experienced alanine aminotransferase (ALT) elevation over twice the upper limit of normal: 12 (4.2%) associated with HBeAg reversion, 68 (24%) with detectable serum HBV DNA but HBeAg negative, and 14 (4.9%) of undetermined causes. Of the 269 patients without evidence of cirrhosis at the time of HBeAg seroconversion, 21 (7.8%) developed cirrhosis with a cumulative incidence and relative risk significantly higher in patients developing active hepatitis than in patients with sustained remission ( P < .05). HCC developed in 6 (2.2%) of the 283 patients, also with a significantly higher cumulative incidence in patients developing active hepatitis after HBeAg seroconversion ( P < .005). In conclusion, the results suggest that spontaneous HBeAg seroconversion confers favorable long-term outcomes. However, active hepatitis still may develop and lead to cirrhosis and HCC. (H EPATOLOGY 2002;35:1522-1527.)

Why treat chronic hepatitis B in childhood with interferon α?

See article on page 715 Advances in the understanding of hepatitis B viral infection are a major accomplishment in modern hepatology. In three decades we have progressed from rather vague...

Natural history of hepatitis B virus infection in children.

Hepatitis B virus (HBV) infection during childhood can cause acute, fulminant or chronic hepatitis, liver cirrhosis, and liver cancer. Approximately 90% of the infants of hepatitis B e antigen (HBeAg) seropositive mothers become hepatitis B surface antigen (HBsAg) carriers. Children chronically infected are mostly asymptomatic. Although liver damage is usually mild during childhood, severe liver disease, including cirrhosis and hepatocellular carcinoma, may develop insidiously for 2-7 years. Spontaneous HBeAg seroconversion occurs gradually as the age of the child increases. Viral replication is reduced during this process, which is usually preceded by an elevation of aminotransferases. In a long-term follow-up study, the annual HBeAg seroconversion rate was 4-5% in children older than 3 years of age and less than 2% in children under 3 years. The annual seroconversion rate of HBsAg was very low (0.56%). Age at infection, maternal HBsAg and HBeAg status, host immune status, and possibly the HBV strain are the main factors determining the course of HBV infection in children.