Clinical characteristics of patients infected with hepatitis B virus genotypes A, B, and C

Background. The aim of the present study was to evaluate the clinical characteristics at first hospital consultation, according to the genotype of hepatitis B virus (HBV), in patients with chronic liver diseases and positivity for hepatitis B surface antigen (HBsAg) in metropolitan Tokyo. Methods. The subjects consisted of 1077 patients with chronic liver diseases who were HBsAg-positive. HBV genotype was determined by an enzyme-linked immunosorbent assay (ELISA), using PreS2 monoclonal antibody, which is specific for HBV genotypes in the PreS2 region. Results. The proportion of patients with genotype A was 2% (20 patients), genotype, B 9% (101 patients), and genotype C, 88% (945 patients), while 11 patients (1.0%) had other genotypes, including 2 (0.2%) each with genotypes D and F, and 7 (0.6%) that were untypeable. Patients with genotype A were significantly (P = 0.049) more likely to be positive for Hepatitis B envelope antigen (HBeAg) at the first consultation compared with those with genotype B. Patients with genotype B were significantly more likely to be HBeAg-negative at the first consultation compared with those with genotype A (P = 0.049) and genotype C (P = 0.001), significantly more likely to show minimal hepatic fibrosis (P = 0.003), and least likely to develop liver cirrhosis (P = 0.005). Patients with genotype C were likely to be HBeAg-positive (P = 0.001) and to have a positive family history of HBV infection (P = 0.0002). Conclusions. The clinical features of patients with HBV infection in metropolitan Tokyo varied depending on the HBV genotype. Received: April 7, 2001 / Accepted: July 20, 2001     

Mutations of pre-core and basal core promoter before and after hepatitis B e antigen seroconversion

AIM: To investigate the role of pre-core and basal core promoter(BCP) mutations before and after hepatitis Be antigen(HBe Ag) seroconversion.METHODS: The proportion of pre-core(G1896A) and basal core promoter(A1762T and G1764A) mutant viruses and serum levels of hepatitis B virus(HBV) DNA, hepatitis B surface antigen(HBs Ag), and HB core-related antigen were analyzed in chronic hepatitis B patients before and after HBe Ag seroconversion(n = 25), in those who were persistently HBe Ag positive(n = 18), and in those who were persistently anti-HBe positive(n = 43). All patients were infected with HBV genotype C and were followed for a median of 9 years.RESULTS: Although the pre-core mutant became predominant(24% to 65%, P = 0.022) in the HBe Ag seroconversion group during follow-up, the proportion of the basal core promoter mutation did not change. Median HBV viral markers were significantly higher in patients without the mutations in an HBe Ag positive status(HBV DNA: P = 0.003; HBs Ag: P < 0.001; HB core-related antigen: P = 0.001). In contrast, HBV DNA(P = 0.012) and HBs Ag(P = 0.041) levels were significantly higher in patients with the pre-core mutation in an anti-HBe positive status.CONCLUSION: There is an opposite association of the pre-core mutation with viral load before and after HBe Ag seroconversion in patients with HBV infection.     

Infection with hepatitis B virus genotype A in Tokyo, Japan during 1976 through 2001

Background Because genotype A of hepatitis B virus (HBV) is not indigenous, there have been only few data on infection with it in Japan.Methods We examined clinical and virological features of the 66 Japanese patients who admitted Toranomon Hospital in Tokyo, Japan, between 1976 and 2001, who were found to have HBV/A infection. HBV genotype A was classified into subtype A (European type) and A (South African type) by phylogenetic analysis of the preS1 and preS2 regions, and the S gene sequences.Results Of the 66 patients infected with HBV/A, 14 (21%) were asymptomatic carriers, 26 (39%) presented with acute hepatitis, 22 (33%) with chronic hepatitis, and 4 (6%) with liver cirrhosis. HBV/A infection persisted for more than 6 months in 5 of the 26 (19%) patients with acute hepatitis. The frequency of acute hepatitis in patients infected with HBV/A was higher after than before 1991 (2/22 [9%] vs 24/44 [55%]; P < 0.0001). The frequency of nucleotide 1858 of T was higher in asymptomatic carriers than in patients with acute hepatitis in whom infection was resolved (5/14 [36%] vs 0/21 [0%]; P = 0.008). Of the 57 patients for whom subtypes of genotype A were determined, subtype A was identified in 53 (93%) and subtype A in only 4 (7%). All patients infected with subtype A were persistently infected with HBV.Conclusions HBV/A infection has become more frequent during recent years, predominantly presenting as acute hepatitis, and subtype A is uncommon in the Tokyo metropolitan area.     

Long‐term effect of maternal HBeAg on delayed HBeAg seroconversion in offspring with chronic hepatitis B infection

Background and aims: This cohort study investigated the long‐term effect of maternal hepatitis B virus (HBV) sero‐status on the spontaneous HBeAg seroconversion in offspring with chronic HBV infection. Methods: A total of 185 HBeAg‐positive chronic HBV‐infected children, with maternal HBV seromarkers checked, were enrolled. The median age at enrolment and follow‐up duration was 5.7 years (range, neonate to 16.5 years) and 20.2 years (range, 4.2–31.0 years) respectively. These children were grouped according to the initial maternal HBsAg and HBeAg status: (i) children of non‐carrier mothers (n=48); (ii) children of HBeAg‐negative chronic HBV‐infected mothers (n=57); (iii) children of HBeAg‐positive chronic HBV‐infected mothers (n=80). HBV seromarkers and liver function profiles of these children were performed at 6‐month intervals. Results: One hundred and twenty‐one (65.4%) subjects had achieved spontaneous HBeAg seroconversion at the end of this follow‐up study. Spontaneous HBeAg seroconversion was achieved in 83.3% of children with non‐carrier mothers, 73.7% of children with HBeAg‐negative chronic HBV‐infected mothers and 48.8% of children with HBeAg‐positive mothers during similar duration (P<0.001). Positive maternal HBeAg and genotype C were associated with delayed spontaneous HBeAg seroconversion in multivariate analysis (P=0.01 and P=0.002 respectively). In children of HBeAg‐positive chronic HBV‐infected mothers, persistent presence of maternal HBeAg showed a trend of association with delayed HBeAg seroconversion in their offspring (P=0.06). Children of late maternal HBeAg seroconversion (>40 years old) had delayed HBeAg seroconversion compared with those of early HBeAg seroconversion mothers (P=0.06). Conclusions: Persistence of maternal HBeAg is an important risk factor for delayed spontaneous HBeAg seroconversion in children with chronic HBV infection.     

Natural history of chronic hepatitis B REVEALed

Chronic hepatitis B is a worldwide public health challenge. Knowledge of natural history of chronic hepatitis B is important for the management of the disease. A community-based prospective cohort study was carried out to evaluate the risk predictors of progression of chronic hepatitis B in Taiwan. A total of 23,820 participants were enrolled in 1991-1992 from seven townships in Taiwan. Their serum samples were collected at study entry and tested for hepatitis B surface antigen (HBsAg) and e antigen (HBeAg), antibodies against hepatitis C virus (anti-HCV), alanine aminotransferase (ALT), and α-fetoprotein (AFP). A subcohort of 3653 male and female participants who were seropositive for HBsAg and seronegative for anti-HCV was included in the Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-Hepatitis B Virus (REVEAL-HBV) study. Newly developed cases of cirrhosis and hepatocellular carcinoma (HCC) were ascertained through follow-up examination and data linkage with profiles of the National Cancer Registry, National Health Insurance Database and Death Certification System. The incidence of both HCC and cirrhosis were significantly associated with serum HBV DNA levels in a dose-response relationship from <300 (undetectable) to ≥1,000,000 copies/mL. The biological gradients remained significant (P<0.001) after adjustment for age, sex, habits of cigarette smoking and alcohol drinking, HBeAg serostatus, and serum ALT level at cohort entry. A significant association with risk of cirrhosis and HCC was also observed for HBV genotype, precore G1896A mutant and basal core promoter A1762T/G1764A double mutant. Nomograms have been developed for the long-term risk prediction of cirrhosis and HCC for patients with chronic hepatitis B. Inactive carriers of HBV have an increased HCC incidence and liver-related mortality than HBsAg-seronegative controls. Serum HBV DNA level at study entry is a major predictor of spontaneous seroclearance of HBeAg, HBV DNA and HBsAg. These findings may inform the effective and efficient management of chronic hepatitis B.     

Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus-related chronic liver disease

Background and Aim: Hepatitis E virus (HEV) has recently been implicated in episodes of acute decompensation in patients having underlying chronic liver disease (CLD) of varying etiology. However, HEV as a cause of acute exacerbation of previously asymptomatic and unrecognized hepatitis B virus (HBV)‐infected patients is less well described. The aim of the present study was to investigate the etiology of acute exacerbation of previously asymptomatic and unrecognized HBV‐infected patients and to evaluate the relative role of HEV. We also investigated the effect of superinfection on the clinical spectrum of underlying HBV infection. Methods: Forty‐three patients presented with the following were retrospectively analyzed: (i) clinical features suggestive of acute hepatitis; (ii) with hepatitis B surface antigen (HBsAg) (+); (iii) IgM hepatitis B core antibody (IgM anti‐HBc) (?); (iv) no previous history of liver disease; (v) no features suggestive of CLD at presentation; (vi) HBsAg remaining (+) for at least 12 months on follow up; and (vii) having a follow‐up biopsy during the convalescent phase showing evidence of chronic hepatitis B. Results: Of the 43 patients, 21 were hepatitis e antigen (HBeAg) (+) (Gr.1) and 22 HBeAg (?) (Gr.2) at presentation. In Gr.1, only two (9.5%) had superinfection (both with hepatitis A virus), whereas in Gr.2, 11 (50%) had superinfection (27.3% hepatitis E, 13.6% hepatitis A and 9.1% both) (P = 0.007). In Gr.1, the remaining 19 (90.5%) patients had spontaneous exacerbation (immune clearance with spontaneous seroconversion) whereas in Gr.2, the remaining 11 (50%) had spontaneous exacerbation (due to reactivation). Overall, HEV superinfection contributed to 20% of acute exacerbation episodes and, in particular, 36% of episodes in initially HBeAg (?) patients. Time to alanine aminotransferase normalization was longer in patients with superinfection (n = 13) as compared to spontaneous exacerbation (n = 30) (median [range] 36 [8–48]vs 16 [6–36] weeks, P = 0.001). During convalescence, there was no significant difference between histological activity index score (median [range] 8 [4–11]vs 8 [4–16] weeks, P = 0.629) and fibrosis scores (median [range] 3.5 [1–4]vs 2 [1–4] weeks, P = 0.099] on liver biopsy after recovery among patients with acute exacerbation due to superinfection and spontaneous exacerbation. Conclusions: Acute exacerbations in HBeAg (+) patients are most often due to spontaneous viral activation, while in HBeAg (?) patients, superinfection with non‐B hepatitis viruses and spontaneous viral activation are equally common. HEV is an important cause of acute exacerbation in previously asymptomatic and unrecognized patients with HBV‐related CLD.     

The change of the quantitative HBsAg level during the natural course of chronic hepatitis B

Background: There is insufficient information about HBsAg levels and their correlation with serum hepatitis B virus (HBV) DNA in chronic hepatitis B (CHB). Aims: We aimed to describe HBsAg levels during various phases of CHB and to investigate the correlation with serum HBV DNA levels. Methods: A total of 645 treatment‐naïve Korean CHB patients were included in this retrospective cross‐sectional study. They were categorized into immune tolerance (IT, n=56), HBeAg‐positive hepatitis (EPH, n=150), inactive carrier (IC, n=274) and HBeAg‐negative hepatitis (ENH, n=165). The baseline HBsAg and HBV DNA levels were measured. Results: The mean HBsAg titres (log IU/ml) differed (P<0.001): IT 4.29, EPH 3.64, IC 2.05 and ENH 3.23. In 645 patients, HBsAg and HBV DNA showed a significant correlation (r=0.693, P<0.001), and this was also observed in the IT, EPH and IC groups (r=0.664, r=0.541, r=0.505, respectively, all P<0.001), but not in the ENH group (r=0.093, P=0.321). Age had a negative correlation with HBsAg (r=?0.451, P<0.001). The cirrhotic patients had a significantly lower HBsAg level than the non‐cirrhotic patients (2.41 ± 1.36 vs. 3.02 ± 1.21 log IU/ml, P<0.001). Conclusions: The HBsAg level varied significantly in different phases of CHB and was correlated with HBV DNA during the IT, EPH and IC phases. These findings can provide additional information to understand the natural course and pathogenesis of CHB.     

Quantification of hepatitis B surface antigen and E antigen: correlation between Elecsys and Architect assays

Quantification of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) and their change model during treatment are emerging as a useful tool for assessing the outcome of hepatitis B virus (HBV) infection and predicting the efficacy of antiviral therapy. The aim of this study was to compare the performance of the Elecsys and Architect assays for HBsAg and HBeAg quantification. Quantification of HBsAg and HBeAg, determined by these two assays, were assessed in 1292 sera from patients with chronic hepatitis B(CHB). HBeAg quantification in serum was performed by calibrating the results through HBeAg Paul‐Ehrlich international (PEI) reference standard. The HBV genotype was determined by direct sequencing and phylogenetic analysis. Of 1292 samples, the distribution of genotype was 514 (39.78%) genotype B, 776 (60.06%) genotype C, 2 (0.16%) genotype D. The results of HBsAg and HBeAg quantification between the Architect and Elecsys assays were significantly correlated (HBsAg: r = 0.939; HBeAg: r = 0.987), independent of HBV genotype and treatment phase. The mean differences between the two methods (the log₁₀ [Elecsys] ‐ the log₁₀ [Architect]) were 0.075 log₁₀ IU/mL and ?0.149 log₁₀PE IU/mL in quantifying HBsAg and HBeAg, respectively. This study demonstrates a high correlation between the Elecsys and the Architect assays in quantifying HBsAg and HBeAg, regardless of HBV genotype. Both the two assays can be used to monitor the HBsAg and HBeAg levels in patients with chronic hepatitis B.     

Association of on‐treatment serum hepatitis B surface antigen level with sustained virological response to nucleos(t)ide analog in patients with hepatitis B e‐antigen positive chronic hepatitis B

Aim: This study evaluated the on‐treatment serum hepatitis B surface antigen (HBsAg) level during nucleos(t)ide analog (NUC) therapy and the correlation with off‐treatment sustained virological response (SVR). Methods: Fifty‐one consecutive patients with hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B who achieved HBeAg loss/seroconversion after NUC therapy and completed 12 months or more of additional therapy were included. Serum HBsAg and hepatitis B virus (HBV) DNA levels were determined at baseline, 3, 6, 9 and 12 months, and at the end of treatment. SVR was defined as HBV DNA levels of less than 10 000 copies/mL until 6 or 12 months off‐treatment without reappearance of HBeAg. Results: Twenty‐two (43.1%) and 13 (25.5%) patients maintained SVR at 6 and 12 months off‐treatment, respectively. In univariate analyses, a decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months (P = 0.006) and 12 months (P = 0.013), the mean change in HBsAg level at 6 months (P = 0.024), and lamivudine or entecavir treatment (P = 0.019) were significant predictive factors for SVR at 6 months off‐treatment. A decline of HBsAg of 0.5 log₁₀ IU/mL or less at 6 months and lamivudine or entecavir treatment were independent factors on multivariate analyses (odds ratio [OR], 16.67; 95% confidence interval [CI], 1.86–142.86 [P = 0.012]; and OR, 14.83; 95% CI, 1.18–185.73 [P = 0.036]; respectively). Conclusion: On‐treatment serum HBsAg level predicted early off‐treatment SVR to NUC therapy in patients infected with genotype C.     

Virological and clinical implication of core promoter C1752/V1753 and T1764/G1766 mutations in hepatitis B virus genotype D infection in Mongolia

Background and Aim: The aim of the present study was to reveal virological and clinical features of hepatitis B virus (HBV) genotype D infection. Methods: One hundred and twenty‐two Mongolian chronic liver disease (CLD) patients infected with HBV were subjected for serological HBV‐markers screening and HBV‐enzyme immunoassay (EIA) genotyping. Nucleotide sequences were analyzed for 48 HBV/D strains (23 isolated from hepatocellular carcinoma (HCC) and 25 from CLD patients). Results: Prevalence of hepatitis B e antigen (HBeAg) positivity was low (25.9%) in young patients (≤30 years old) indicating early HBeAg seroclearance in HBV/D carriers. The T1764/G1766 double mutation was the most common basal core promoter (BCP) mutation (29.2%) and was frequent in HBeAg‐negative patients (39.3%). Patients harboring T1764/G1766 mutants exhibited lower HBV‐DNA and HBV core antigen (HBcAg) levels than those with wild‐type BCP strains (P = 0.024, 0.049, respectively). C1752 and/or V (not T) 1753 mutation was significantly prevalent in HCC patients (HCC vs CLD; 52.2% vs 20%, P = 0.033). T1762/A1764 mutation was detected in 75.0% of HCC patients with high viral load (≥5 log copies/mL). Precore stop codon mutation A1896 was detected in (70.8%) of HBV/D‐infected patients. Conclusions: In Mongolians infected with HBV/D, C1752 and/or V1753 mutation was associated with HCC.     

Changes of serum aminotransferase activities in relation to serum hepatitis Be antigen levels in chronic type B hepatitis

The purpose of this study was to determine the level of serum hepatitis Be antigen (HBeAg) during hepatitis B virus carriage and its clinical significance. The mean level of serum HBeAg, quantitated by solid-phase enzyme immunoassay, was 5924 units in asymptomatic carriers (s.d. = 5534, n= 100), 3044 units in patients with chronic persistent hepatitis (s.d. = 4826, n= 34), 3599 units in chronic active hepatitis (s.d. = 4953, n= 45) 1348 units in liver cirrhosis (s.d. = 2379, n= 25) and 766 units in hepatocellular carcinoma (s.d. = 1257, n= 18). In the 10 HBeAg-positive patients with chronic active hepatitis, the fluctuation in HBeAg level was followed by changes in alanine aminotransferase (ALT) activity. Among the 36 peaks of HBeAg and ALT, HBeAg peaks preceded ALT peaks in 22 and simultaneous peaks were present in 14. The changes of HBeAg level were closely related to increase in disease activity as estimated by ALT activities; therefore, HBeAg quantitation can be a useful predictor of disease activity in chronic hepatitis B.     

A new core promoter mutation and premature stop codon in the S gene in HBV strains from Iranian patients with cirrhosis

Summary. In order to define hepatitis B virus (HBV) mutational patterns in Iran, nucleotide sequences obtained from 91 patients and encompassing the precore, basal core promoter (BCP) and surface (S) regions, were compared. The patients were grouped as asymptomatic carriers, chronic active hepatitis or cirrhotic patients. Genotypes and mutations were determined by sequencing and phylogenetic analysis. All strains belonged to genotype D, and most of them to subgenotype D1. All but two strains specified ayw2, one ayw3 and one adw2 determinants. Two deletions of 8‐ or 20‐bp were found in the X region in eight strains, six from patients with chronic active hepatitis. Eight of 21 strains from patients with cirrhosis harboured unusual mutations such as a stop codon at position 69 in the S region or a previously not described mutation in the BCP region (¹⁷⁶¹TC/ATTTG¹⁷⁶⁶). All patients infected by strains with the stop codon mutation had detectable HBsAg and high viral load. The accumulation of mutations found in the BCP and S regions in HBV strains from patients with chronic active hepatitis and cirrhosis may predict disease progression in Iranian HBsAg carriers.     

Sex differences in relation to serum hepatitis B e antigen and alanine aminotransferase levels among asymptomatic hepatitis B surface antigen carriers

This study aimed to investigate sex differences in relation to hepatitis B e antigen (HBeAg) and serum alanine aminotransferase (ALT) levels in chronic asymptomatic hepatitis B virus (HBV) infection. HBeAg and ALT level were determined in 636 asymptomatic hepatitis B surface antigen carriers. There was no significant sex differences in the age-adjusted prevalence of HBeAg. Abnormal ALT level (>45 IU/l) was more frequent in carriers with HBeAg (17.5% vs 7.6%; P = 0.001). Multivariate analysis indicated that male sex (odds ratio, 2.0; 95% confidence interval, 1.1–3.6) and HBeAg (odds ratio, 2.6; 95% confidence interval, 1.6–4.3) were independent risk factors for abnormal ALT levels. Male sex and HBeAg-positivity are independent risk factors for abnormal ALT activity in chronic HBV infection. This observation may be related to sex differences in chronic HBV infection. Received: June 7, 1999 / Accepted: April 28, 2000     

Hepatitis B virus: prevalence of precore/core promoter mutants in different clinical categories of Indian patients

Summary. To determine the association of precore (Pre-C)/basal core promoter (BCP) mutants with clinical outcome of hepatitis B in Western India, 192 hepatitis B virus (HBV) infected individuals were investigated. HBV-DNA PCR positivity among asymptomatic hepatitis B surface antigen (HBsAg) positive carriers (61/100) was lower ( P  < 0.0001) than chronic hepatitis B (CHB), acute ( P  = 0.0001), and fulminant hepatitis B patients ( P  = 0.047). Pre-C status was based on restriction fragment length polymorphism (RFLP, n  = 153) and sequencing ( n  = 118). Prevalence of Pre-C mutants was higher among carriers (23/61) than CHB (10/62, P  = 0.0071) or acute (3/22; P  = 0.037) patients. Children from carrier and CHB categories showed significantly higher circulation of Pre-C-wild than mutant HBV. Clinical manifestations were independent of BCP mutations (1762/64-T/A). Hepatitis B e antigen (HBeAg) negative CHB patients [62.5% (15/24)] were circulating wild HBV. Higher HBV-DNA levels were associated with chronic hepatitis and HBeAg positivity, whilst Pre-C mutant positives had lower levels. BCP mutations did not affect HBV-DNA levels. Multivariate regression analysis identified HBeAg (OR = 4.3) and Pre-C mutants (OR = 3.1) to be associated with chronic hepatitis and carriers respectively. In a separate sub-set analysis ( n  = 59), HBV-DNA level was identified as the only variable. In conclusion, chronic or fulminant hepatitis B was not associated with Pre-C or BCP mutants and switching over to Pre-C mutant was beneficial for the infected individual in maintaining disease free status for extended periods.     

Sequence analysis of the S gene region in HBV DNA from patients positive for both HBsAg and HBsAb tests

Aims: To study the characteristics of mutation in the amino acids coded by the S gene region in the HBV DNA sequence and to comprehensively explore and analyze the cause of the double positive result phenomena in both HBsAg and HBsAb tests. Methods: Specimens collected from 43 cases of chronic hepatitis B patients with positive results for both HBsAg and HBsAb tests were used as the experimental group; specimens collected from 43 cases randomly picked from all patients with chronic hepatitis B with a single positive result for HBsAg test were used as the control group. In HBV DNA, the S gene region was amplified and sequenced. Amino acid sequences were grouped, and mutations were analyzed based on the sequencing results. Results: The patients were infected with HBV of the genotype B and C and those who with genotype C show more mutations than genotype B carriers. Compared with the control group, the experimental group had a marked increase in S gene amino acid mutations; a higher amino acid mutation rate was observed in the first loop (aa124–137) of the a‐determinant (aa124–147) and there was a statistical difference (genotype B: 2.68% vs. 0.00%, P = 0.041; genotype C: 7.14% vs. 2.01%, P < 0.001). Conclusion: The first loop in a‐determinant of S gene sequence possesses a large numbers of mutated amino acids, leading to changes of antigenicity and simultaneous positive results in both HBsAg and HBsAb tests finally.     

Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha-2a and adefovir

Background and Aim: We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg‐interferon and adefovir for 48 weeks. Methods: Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment. Results: Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA < 2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow‐up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg ≤ 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%. Conclusions: At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of < 7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR.     

Association of Ephrin receptor A3 gene polymorphism with susceptibility to chronic severe hepatitis B

Aim: Previous research has suggested that Ephrin receptor A3 (EphA3) plays signaling roles in the processes of inflammation by regulating lymphocyte migration and proliferation. In this study, we investigated whether the EphA3 gene polymorphism was associated with disease progression of chronic hepatitis B virus (HBV) infection. Methods: The EphA3 variant rs9310117 was genotyped in 1245 unrelated Han Chinese HBV carriers including 800 cases and 445 controls. χ² test was used to examine the difference in allele frequencies and genotype distributions between groups. The association between the polymorphism and disease progression of HBV infection was conducted by unconditional logistic regression analysis. Results: Statistical analysis revealed that the genetic variant was significantly associated with the occurrence of chronic severe hepatitis B (CSHB). We observed that subjects bearing at least one T allele (C/T or T/T genotype) had a decreased susceptibility to chronic severe hepatitis B compared with those bearing C/C genotype (P = 0.003, odds ratio = 0.560; 95% confidence interval, 0.381–0.824, recessive model). Genotype C/T had also been confirmed to protect subjects from suffering chronic severe hepatitis B (P = 0.001, odds ratio = 0.498; 95% confidence interval, 0.330–0.752, additive model). Conclusion: Our results suggest that the genetic alteration at EphA3 locus plays a role in the occurrence of chronic severe hepatitis B.     

Correlation of hepatocyte expression of hepatitis B viral antigens with histological activity and viral titer in chronic hepatitis B virus infection: an immunohistochemical study

Background and Aim: The localization of hepatitis B virus (HBV) core antigen to the nucleus or cytoplasm of hepatocytes has biological implications for viral packaging and persistence. This study examined the relationship between the localization of hepatitis B virus antigens, histological activity, and viral titer in patients with chronic HBV infection. Methods: Liver biopsies from 110 patients with chronic HBV infection were studied. Ishak's scoring system was used for the histological analysis. The localization of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) and the percentage of hepatocytes stained positive by immunohistochemistry were correlated with viral titer, histological activity, and fibrosis indices using Spearman rank correlation. Results: In 88 hepatitis B e‐antigen (HBeAg)‐positive individuals, the nuclear localization of HBcAg correlated significantly with DNA titer (r = 0.435, P = 0.001) and negatively with fibrosis (r = ?0.297, P = 0.005). The cytoplasmic localization correlated significantly with histological activity (r = 0.211, P = 0.049). In 22 HBeAg‐negative individuals, the nuclear localization of HBcAg correlated significantly with histological activity (r = 0.625, P = 0.002), DNA titer (r = 0.651, P = 0.009), and fibrosis (r = 0.447, P = 0.042). The cytoplasmic localization correlated significantly with DNA titer (r = 0.524, P = 0.045) and fibrosis (r = 0.528, P = 0.012). There was no correlation of HBsAg expression with DNA titer, histological activity index, or fibrosis in both groups. HBeAg‐positive patients presented at a younger age. Conclusion: In HBeAg‐positive individuals, nuclear core antigen correlated with DNA titer, and cytoplasmic localization with histological activity, whereas in HBeAg‐negative individuals, nuclear localization correlated with DNA titer, histological activity, and fibrosis, and cytoplasmic localization correlated with DNA titer and fibrosis, but not with histological activity. These observations suggest biological differences between HBeAg‐positive and ‐negative disease.     

乙型肝炎慢性化机制的研究现状

感染HBV后出现不同的结局:(1)急性自限性肝炎;(2)慢性肝炎;(3)慢性HBV携带者或HBsAg携带者;(4)隐匿性慢性乙型肝炎;(5)乙型肝炎肝硬化;(6)重型肝炎。除急性自限性肝炎和重型肝炎外,其余四种都可以成为慢性HBV感染。慢性乙型肝炎是一个慢性过程,肝硬化、肝细胞癌与之呈正相关。因此,治愈乙型肝炎、预防肝硬化与肝癌的发生是我们研究的重点和努力的方向。要解决乙型肝炎这个问题,必须了解乙型肝炎慢性化的形成机制。近些年,对乙型肝炎慢性化的形成机制有了不少新的研究成果,其中主要与病毒载量、基因型和宿主免疫状态等有关,作者查找了近年有关这方面的研究,现作一综述。     

Diagnosis and management of pre-core mutant chronic hepatitis B

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.