Chronic Hepatitis B Virus Carriers Research Articles

Lifetime Risk and Sex Difference of Hepatocellular Carcinoma Among Patients With Chronic Hepatitis B and C

Both hepatitis B (HBV) and C viruses (HCV) are causes of hepatocellular carcinoma (HCC), but lifetime risk and sex difference remain unclear. This study aimed to assess the lifetime risk and sex difference of HCC among patients with chronic HBV and/or HCV. A prospective cohort of 23,820 residents of Taiwan age 30 to 65 years were enrolled from 1991 to 1992, with 477 instances of HCC occurring subsequently. Serum samples collected at enrollment were tested for seromarkers and viral load of HBV and HCV. Newly developed HCC was ascertained through computerized data linkage with national cancer registry and death certification systems. The cumulative lifetime (age 30 to 75 years) incidences of HCC for men and women positive for both HBV surface antigen (HBsAg) and antibodies against HCV (anti-HCV) were 38.35% and 27.40%; for those positive for HBsAg only, 27.38% and 7.99%; for those positive for anti-HCV only, 23.73% and 16.71%; and for those positive for neither, 1.55% and 1.03%, respectively. There was a significant male predominance in incidence of HCC for chronic HBV carriers but not for chronic carriers of HCV or both. Multivariate adjusted hazard ratio of developing HCC decreased with age in HBsAg-seropositive men but increased with age in anti-HCV-seropositive women. Among dual-infected participants, there was an inverse association between HBV and HCV viral load. Risk of HCC increased significantly with increasing viral load of HBV and HCV. There exists a suppressive effect of HCV on HBV viral load. Individual and combined effects of the two viruses on HCC vary with sex and age.

Lack of association between FOS polymorphisms and clearance of HBV infection as well as HCC occurrence

Human v-Fos Finuel-Biskis-Jinkins (FBJ) murine osteosarcoma viral oncogene homolog (FOS) is located in 14q24.3. The FOS protein is a constituent of the activating protein-1 (AP-1) and its increased expression in the hepatocellular carcinoma (HCC) have been reported. In this study, the association of FOS polymorphisms with the HBV infection and HCC occurrence were evaluated in Korean patients. After re-sequencing in 24 unrelated healthy individuals, two common single nucleotide polymorphisms (SNPs) in regulatory regions that were selected based on linkage disequilibrium were genotyped in a total of 1,093 Korean subjects including 656 HBV chronic carriers, who were further stratified into chronic hepatitis/liver cirrhosis (CH/LC, n = 339) and HCC (n = 317) groups, and 437 spontaneously recovered (SR) controls. Logistic regression and Cox relative hazard analysis showed no significant association of regulatory polymorphisms and haplotypes in FOS with HBV clearance and HCC development (P > 0.05, respectively).

The G1613A Mutation in the HBV Genome Affects HBeAg Expression and Viral Replication through Altered Core Promoter Activity

Infection of hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we demonstrated that the G1613A mutation in the HBV negative regulatory element (NRE) is a hotspot mutation in HCC patients. In this study, we further investigated the functional consequences of this mutation in the context of the full length HBV genome and its replication. We showed that the G1613A mutation significantly suppresses the secretion of e antigen (HBeAg) and enhances the synthesis of viral DNA, which is in consistence to our clinical result that the G1613A mutation associates with high viral load in chronic HBV carriers. To further investigate the molecular mechanism of the mutation, we performed the electrophoretic mobility shift assay with the recombinant RFX1 protein, a trans-activator that was shown to interact with the NRE of HBV. Intriguingly, RFX1 binds to the G1613A mutant with higher affinity than the wild-type sequence, indicating that the mutation possesses the trans-activating effect to the core promoter via NRE. The trans-activating effect was further validated by the enhancement of the core promoter activity after overexpression of RFX1 in liver cell line. In summary, our results suggest the functional consequences of the hotspot G1613A mutation found in HBV. We also provide a possible molecular mechanism of this hotspot mutation to the increased viral load of HBV carriers, which increases the risk to HCC.

Changes in Serum Levels of HBV DNA and Alanine Aminotransferase Determine Risk for Hepatocellular Carcinoma

It is not clear whether risk for hepatocellular carcinoma can be accurately determined from long-term changes in serum levels of hepatitis B virus (HBV) DNA or alanine aminotransferase (ALT). We measured serum levels of HBV DNA and ALT at enrollment and during follow-up analysis of 3160 participants in the REVEAL-HBV study. Development of hepatocellular carcinoma was determined from follow-up examinations and computerized linkage with National Cancer Registry and National Death Certification profiles. Multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models. During 38,330 person-years of follow-up, 81 participants developed hepatocellular carcinoma (incidence rate, 211.3/100,000 person-years). The risk for hepatocellular carcinoma was only slightly higher for participants whose follow-up levels of HBV DNA spontaneously decreased to <10,000 copies/mL compared with those with baseline levels of HBV DNA<10,000 copies/mL (control group; HR, 2.25; 95% CI, 0.68-7.37). Compared with the control group, the HRs (95% CI) for long-term levels of HBV DNA that persisted at 10,000 to 100,000 copies/mL, decreased to/persisted at 100,000 to 1,000,000 copies/mL, or decreased to/persisted at 1,000,000 to 10,000,000 copies/mL were 3.12 (1.09-8.89), 8.85 (3.85-20.35), and 16.78 (7.33-38.39), respectively. A gradient in ALT level was significantly associated with hepatocellular carcinoma risk: from all low-normal, to ever high-normal, to transient abnormal, to persistent abnormal (Ptrend<.001). Long-term changes in serum levels of HBV DNA and ALT are independent predictors of risk for hepatocellular carcinoma. Regular monitoring of levels of HBV DNA and ALT is important in clinical management of chronic carriers of HBV.

Hepatitis B virus nucleic acid testing in Chinese blood donors with normal and elevated alanine aminotransferase

Nucleic acid testing (NAT) is currently not a routine donor test in China. The aim of this study was to evaluate the current residual risk of hepatitis B virus (HBV) transmission and the value of ALT testing in preventing HBV infection. From January 2008 to September 2009, a total of 5521 qualified donations by routine screening and 5034 deferred donations due to elevated ALT alone were collected from five blood centers. Samples were tested for HBV DNA by triplex individual-donation (ID)-NAT (ULTRIO assay, on the TIGRIS system, Novartis Diagnostics). HBV NAT-reactive samples were further analyzed by HBV serology, alternative NAT, and viral load and were diluted to simulate if they could be detected in a minipool-NAT. There was no significant difference in the HBV NAT-yield rate between the qualified donations group (5/5521) and the deferred donations group (4/5034). Of these nine potential HBV-yield cases, one donor (11%) was a possible HBV window-period donor, one (11%) was a chronic HBV carrier, and seven (78%) had probable or confirmed occult HBV infections. Of seven potential HBV-yield cases quantified, the viral loads were less than or equal to 70.0 IU/mL. Minipool testing (minipools of 4, 8, and 16 donations) would miss 43% to 79% of the nine HBV-yield donations. Based on our findings in qualified donations, we estimate that the nationwide implementation of ID-NAT testing for HBV DNA in China would detect an additional 9964 viremic donations per year. ALT testing seems to have no significant value in preventing transfusion-transmitted HBV infection. ID-NAT versus simulated minipool-NAT using the ULTRIO test demonstrates the benefit to implement a more sensitive NAT strategy in regions of high HBV endemicity.

Hepatitis B genotypes/subgenotypes and MHR variants among Moroccan chronic carriers

The aim of this study was to determine the prevalence of Hepatitis B Virus (HBV) genotypes, subgenotypes, HBV surface antigen (HBsAg) subtypes and naturally occurring mutations in Major Hydrophilic region (MHR) of HBsAg among Moroccan patients with chronic HBV infection. The study included 200 patients chronically infected with HBV. The HBV genotypes, subgenotypes, HBsAg subtypes and MHR variants were determined by direct sequencing of the HBV surface (S) gene and phylogenetic analysis. The S gene was successfully amplified in 134 patients. The mean age was 40.6±12.2 years. Genotype D was predominant (90%, 120/134) and genotype A was less frequent (10%,14/134). Genotype D strains belonged to subgenotypes D7 (70.8%, 85/120), D1 (25.8%, 31/120) and D2 (0.9%, 1/120). Three strains (2.5%) could not be classified in any subgenotype of genotype D. All genotype A strains belonged to subgenotype A2. HBsAg subtypes found wereayw2 (82.1%, 110/134), adw2 (10.4%, 14/134), ayw3 (3%, 4/134) and ayw4 (3%, 4/134). The global prevalence of MHR variants was 15% (20/134) with substitution P120T/S the most frequent (3.7%, 5/134). The occurrence of MHR variants was significantly associated with advancing age (>40 years) (p=0.003) and independent of sex, HBeAg status, viral load, genotype, subgenotype and HBsAg subtype. This study provides the first description of predominance of HBV subgenotype D7/subtype ayw2 among Moroccan HBV chronic carriers. It also showed a significant prevalence of naturally occurring MHR variants in Morocco.

Geographical and Ethnic Distribution of the HBV C/D Recombinant on the Qinghai-Tibet Plateau

Two forms of hepatitis B virus (HBV) C/D recombinant have been identified in western China, but little is known about their geographical and ethnic distributions, and particularly the clinical significance and specific mutations in the pre-core region. To address these questions, a total of 624 chronic HBV carriers from four ethnic populations representing five provinces in western China were enrolled in this study. Genotypes were firstly determined by restriction fragment length polymorphism, and then confirmed by full or partial genome nucleotide sequencing. The distribution of HBV genotypes was as follows: HBV/B: 40 (6.4%); HBV/C: 221 (35.4%); HBV/D: 39 (6.3%); HBV/CD: 324 (51.9%). In the 324 HBV C/D recombinant infections, 244 (75.3%) were infected with the “CD1” and 80 (24.7%) were infected with the “CD2.” The distribution of HBV genotypes exhibited distinct patterns in different regions and ethnic populations. Geographically, the C/D recombinant was the most prevalent HBV strain on the Qinghai-Tibet Plateau. Ethnically, the C/D recombinant had a higher prevalence in Tibetan patients than in other populations. Clinically, patients with HBV/CD1 showed significantly lower levels of serum total bilirubin than patients with HBV/C2. The prevalence of HBeAg was comparable between patients with HBV/CD1 and HBV/C2 (63.3% vs 50.0%, P = 0.118) whether patients were taken together or stratified by age into three groups (65.6% vs 58.8% in <30 years, P = 0.758; 61.9% vs 48.0% in 30–50 years, P = 0.244; 64.3% vs 33.3%, P = 0.336). Virologically HBV/CD1 had a significantly lower frequency of G1896A than HBV/C2. In conclusion, the HBV C/D recombinant is restricted to the Qinghai-Tibet Plateau in western China and is found predominantly in Tibetans. The predominance of the premature pre-core stop mutation G1896A in patients with the HBV C/D recombinant may account for the higher prevalence of HBeAg in these patients.

Quantitative analysis of HBV cccDNA from liver biopsy specimens in HBV carriers: correlation with serological makers and sera HBV DNA

To investigate the correlation of sera HBV DNA and serological makers with hepatic tissue HBVcccDNA in chronic HBV carriers. Real time fluorescence quantitative polymerase chain reaction (RT-PCR) were used to detect HBV covalently closed circular DNA (cccDNA) and total intrahepatic HBV DNA from 30 needle-biopsy specimens as well as HBV DNA in sera in chronic HBV carriers. Quantification of the HBsAg, HBeAg in sera were quantified using Chemiluminescence immunoassay. HBVcccDNA can be detected in chronic HBV carriers, which rang from 3.15 x 10(3) copies/mg to 1.06 x 10(7) copies/mg. There was a positive correlation between the cccDNA and HBVtDNA (r = 0.375, P < 0.05), but there was no correlation between the cccDNA and sera HBV DNA (P = 0.174). There was a positive correlation between cccDNA and sera HBsAg quantification (r = 0.562, P < 0.001) but no correlation with sera HBeAg qantification (r = 0.152, P > 0.05). HBV cccDNA can be replicated stably in hepatic tissue in all chronic HBV carriers. HBV DNA in sera can not be indicated hepatic tissue cccDNA level. While HBsAg quantification in sera can be used as a marker of cccDNA quantification in hepatic tissue to some extent.

Cancer risk in chronic hepatitis B: Do genome-wide association studies hit the mark?

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10(-18) ). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

Study on HBV antigens and IL-12 affecting T cell-mediated immunity in HBsAg carriers

To investigate the effect of HBV antigens and pathological mechanism of chronic HBV infection by analyzing the cellular immune function of peripheral blood mononuclear cells (PBMCs) from HBsAg carriers. PBMCs were prepared from individuals with chronic asymptomatic HBV infection and cultured in the presence of different antigens and/ or cytokines. The levels of cytokines in culture supernatants were detected by ELISA method. The phenotype of the cells was detected by FACS. The levels of IFN y secreted by PBMCs from HBsAg carriers were (48.3+/-19.8) pg/ml, significantly lower than that from healthy controls (t = 3.023, P less than 0.05); The IFN y produced by PBMCs from HBeAg positive patients due to HBsAg and HBcAg stimulation were (50.4+/-51.6) pg/ml and (63.2+/-36.9) pg/ml, significantly lower than that of HBeAg negative patients (t = 2.468 and 3.184, P less than 0.05, respectively). The IL-12p70 secreted by PBMCs from HBeAg positive patients was also significantly lower than that of HBeAg negative patients (P less than 0.05); Exogenous IL-12 promoted significantly PBMCs to secrete IFN y (P less than 0.01) and IL-12 combined with HBV antigens activated CD8+CD45RA+CCR7+ and CD8+CD45RA-CD62L+ cells. IL-12 secreted by PBMCs decreased in HBeAg positive patients, which may be the crucial reason of viral persistence in chronic HBV carriers. Exogenous IL-12 combined with specific HBV antigen could promote the central memory CD8+ T cells to produce IFN y.

The association of HBV-DNA change with cytokines levels in chronic HBV carriers superinfected with measles virus

Objective To investigate the HBV-DNA changes in HBV carriers superinfected with measles virus and its relation with cytokines. Methods HBV-DNA loads were detected by PCR in 23 chronic HBV carriers superinfected with measles virus (superinfection group), 27 chronic HBV carriers (HBV group), and 27 measles patients (measles group). Serum levels of cytokines (IL-2, 4, 5, and 10, IFN-r, TNF-a, and RANTES) were measured by Luminex Liquichip technology. Reaults The HBV-DNA loads were significantly lower in superinfection group than in HBV group (P＜0.05). There were significant differences in levels of IL-4, IL-5, IFN-r, and TNF-a between the three groups (P＜0.05); but there were no significant differences in IL-2, RANTES, and IL-10 (P＞0.05). The change of HBV-DNA loads were negatively related with levels of IFN-r and TNF-a, but positively related with levels of IL-4 and IL-5 (P＜0.05). Conclusions The elevated levels of IFN-r and TNF-a and the decreased levels of IL-4 and IL-5in chronic HBV carriers superinfected with measles virus can probably lead to the inhibition of HBV-DNA replication. Key words: Chronic hepatitis B; Measles virus; Cytokines; Viral interference

No associations of polymorphisms in ADPRT with hepatitis B virus clearance and hepatocellular carcinoma occurrence in a Korean population

The human adenosine diphosphate ribosyl transferase (ADPRT) gene might significantly affect cancer by encoding poly(ADP-ribose) polymerase 1 enzyme (PARP-1) and promoting an important role in cellular responses to DNA damage, genomic stabilization and regulation of tumor suppressor genes. We explored whether polymorphisms of ADPRT affect clearance of hepatitis B virus (HBV) infection or risk of hepatocellular carcinoma (HCC) occurrence in a Korean HBV cohort. Genotyping was performed in a total of 1066 subjects composed of 434 spontaneously recovered (SR) subjects as normal controls and 632 chronic carriers (CC) of HBV who were further classified into 325 patients with liver cirrhosis (LC)/chronic hepatitis (CH) and 307 patients with HCC. Logistic analyses of six common single nucleotide polymorphisms (SNP) and their haplotypes revealed that none of the polymorphisms were significantly associated with clearance of HBV infection and HCC occurrence, except for nominal evidence of association between haplotype 2 (ht2) with HBV clearance (P = 0.05). In the analysis of age of HCC occurrence which is an important factor in disease progression to HCC, results from Cox proportional hazards showed that none of the variants were significantly associated with onset age of HCC occurrence, although a nominal signal in ht4 (P = 0.03, but P(corr) > 0.05) was initially detected. Although ADPRT is an important gene for cellular responses and tumor regulations, our study provides evidence that ADPRT variations do not affect HBV clearance and HCC occurrence.

Presence of hepatitis B virus in oocytes and embryos: a risk of hepatitis B virus transmission during in vitro fertilization

To define the risk of hepatitis B virus (HBV) transmission through oocytes and embryos from chronic HBV carriers. Laboratory-based study. Research laboratory in a university hospital. Thirty-one couples with hepatitis B surface antigen (HBsAg)-negative women and HBsAg-positive men, 41 couples with HBsAg-positive women and HBsAg-negative men, and 39 seronegative couples. None. Hepatitis B virus DNA and RNA analyses in oocytes and embryos, and the location of virus particles containing HBsAgs. Hepatitis B virus DNA was detected in 3 of 18 male HBsAg-positive/female HBsAg-negative couples (and in 13 of 84 embryos) and 3 of 14 male HBsAg-negative/female HBsAg-positive couples (and in 15 of 71 oocytes and embryos). Hepatitis B virus RNA was detected in 9 of 13 male HBsAg-positive/female HBsAg-negative couples (and in 39 of 52 embryos) and 8 of 17 male HBsAg-negative/female HBsAg-positive couples (and in 30 of 63 oocytes and embryos). The HBsAg, which is present in the nuclei and cytoplasm of oocytes and embryos, was detected in 6 of 10 male HBsAg-negative/female HBsAg-positive couples (and in 13 of 20 oocytes and embryos). Hepatitis B virus DNA, HBV RNA, and HBsAg were not found in 135 oocytes and embryos from 39 seronegative couples. The presence of HBV in oocytes and embryos suggests the possibility of vertical transmission of HBV via the germ line.

Hepatitis C Virus Infection May Lead to Slower Emergence of P. falciparum in Blood

BackgroundAreas endemic for Plasmodium falciparum, hepatitis B virus (HBV) and hepatitis C virus (HCV) overlap in many parts of sub-Saharan Africa. HBV and HCV infections develop in the liver, where takes place the first development stage of P. falciparum before its further spread in blood. The complex mechanisms involved in the development of hepatitis may potentially influence the development of the liver stage of malaria parasites. Understanding the molecular mechanisms of these interactions could provide new pathophysiological insights for treatment strategies in Malaria.MethodologyWe studied a cohort of 319 individuals living in a village where the three infections are prevalent. The patients were initially given a curative antimalarial treatment and were then monitored for the emergence of asexual P. falciparum forms in blood, fortnightly for one year, by microscopy and polymerase chain reaction.Principal FindingsAt inclusion, 65 (20.4%) subjects had detectable malaria parasites in blood, 36 (11.3%) were HBV chronic carriers, and 61 (18.9%) were HCV chronic carriers. During follow-up, asexual P. falciparum forms were detected in the blood of 203 patients. The median time to P. falciparum emergence in blood was respectively 140 and 120 days in HBV- and HBV+ individuals, and 135 and 224 days in HCV- and HCV+ individuals. HCV carriage was associated with delayed emergence of asexual P. falciparum forms in blood relative to patients without HCV infection.ConclusionsThis pilot study represents first tentative evidence of a potential epidemiological interaction between HBV, HCV and P. falciparum infections. Age is an important confounding factor in this setting however multivariate analysis points to an interaction between P. falciparum and HCV at the hepatic level with a slower emergence of P. falciparum in HCV chronic carriers. More in depth analysis are necessary to unravel the basis of hepatic interactions between these two pathogens, which could help in identifying new therapeutic approaches against malaria.

Strong influence of human leukocyte antigen (HLA)-DP gene variants on development of persistent chronic hepatitis B virus carriers in the Han Chinese population

Chronic hepatitis B virus (HBV) infection is a major health issue, especially in Asia. A recent genome-wide association study (GWAS) implicated genetic variants in the human leukocyte antigen (HLA)-DP locus associated with chronic hepatitis B in Japanese and Thai populations. To confirm whether the polymorphisms at the HLA-DP genes are associated with persistent chronic HBV infection in Han Chinese, we conducted an independent case-control study using 521 persistent chronic HBV carriers and 819 controls that included 571 persons with HBV natural clearance and 248 never HBV-infected (healthy) individuals. Eleven single nucleotide polymorphisms (SNPs) in a region including HLA-DPA and HLA-DPB and an adjacent SNP in strong linkage disequilibrium (LD) with a neighboring HLA-DR13 locus were genotyped using the TaqMan SNP genotyping assay. Eleven variants at HLA-DP showed a strong association with persistent chronic HBV carrier status (P = 1.82 × 10(-12) to 0.01). We also stratified the analysis by HBV clearance status to test the association between these polymorphisms and HBV natural clearance; similar results were obtained (P = 2.70 × 10(-11) to 0.003). Included SNPs define highly structured haplotypes that were also strongly associated with HBV chronic infection (block 1: odds ratio [OR] = 0.54, P = 8.73 × 10(-7) ; block 2: OR = 1.98, P = 1.37 × 10(-10) ). These results further confirm that genetic variants in the HLA-DP locus are strongly associated with persistent HBV infection in the Han Chinese population.

Hepatitis B Awareness and Education: A Failing Grade

Hepatitis B Awareness and Education: A Failing Grade

Subgenotype and Genetic Variability in the Precore/Core Regions of Hepatitis B Virus in Korean Patients with Chronic Liver Disease

Objective: The aim of this study was to determine the prevalence of hepatitis B virus (HBV) subgenotypes, the spectrum of mutations in the precore/core region through phylogenetic analysis, and the relevance of viral characteristics in disease progression in Korean patients. Methods: 133 patients with chronic HBV infection were enrolled. The precore and core region of HBV was amplified and sequenced. Phylogenetic analysis was performed for subgenotyping and the changes of nucleotides and amino acid were compared in liver disease stages. Results: HBV/C2 subgenotype was predominant in chronic HBV carriers (98.5%), followed by HBV/A2 (0.75%) and HBV/C7 (0.75%). The mutations of the precore region were not different between liver disease stages. However, amino acid changes in the cytotoxic T lymphocyte epitope (p < 0.020), CD4+ T cell epitope (p < 0.027), or B cell epitope (p < 0.029) were significantly higher in liver cirrhosis patients than in chronic hepatitis patients, but not in hepatocellular carcinoma patients. Conclusion: HBV/C2 is the most prevalent subgenotype in Korea, and HBV/C7 subgenotype found in the Philippines was first identified in the Korean population. Mutations in immune epitopes within the core gene were significantly associated with disease progression.

Power play: Scoring our goals for liver cancer with better GWAS study design

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome Ip36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1962 individuals with HCC, 1430 control subjects, and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 x 10(―18)). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B-, or PGD-related pathways might be involved in the pathogenesis of this malignancy.

National survey of hepatitis B virus (HBV) polymorphism in asymptomatic HBV blood donors from 1999 to 2007 in France

Hepatitis B virus (HBV) diversity is characterized by eight genotypes correlated to eight hepatitis B surface antigen (HBsAg) subtypes, which differ in their geographical distribution. To establish virologic characteristics and the evolution of HBV diversity, we carried out a study over a 9-year period in HBV-infected French blood donors. HBsAg subtyping based on specific antibody method concerned 2901 donors, from whom 940 have been analyzed by an S-gene sequencing to determine genotypes and S-gene mutations. HBsAg subtypes were distributed as follows: ayw2, 34.4%; adw2, 25.7%; ayw1, 10.2%; ayw4, 14.9%; adr, 7.8%; ayw3, 6.4%; and adw4, 0.7%. Ayw4 (Genotype E) proportion increased over time in correlation with an increased proportion of subjects originated from sub-Saharan Africa. The genotype observed with the highest proportion was D (43.0%), then A (26.2%), E (17.5%), B (6.5%), C (6.4%), and F (0.4%). Genotype B had the highest proportion of hepatitis B e antigen (39.2%) and the highest viral loads (VLs). Forty-three (5.5%) isolates presented one (n=35) or multiple (n=8) amino acid envelope substitutions. Donors infected with mutated isolates had lowest VLs. rtA181T/sW172 stop mutation associated with resistance to nucleos(t)ide analogs was detected in two donors suggesting a transmission of these isolates. This extensive study shows that HBV genotype evolution is closely linked to the geographical origin of subjects and that the occurrence of viral envelope mutants is not an exceptional event in healthy HBV chronic carriers. Blood donors rarely recruited in HBV studies provide further relevant information on the characteristics of HBV diversity.

Hepatitis D virus: an update

Hepatitis D virus (HDV) infection involves a distinct subgroup of individuals simultaneously infected with the hepatitis B virus (HBV) and characterized by an often severe chronic liver disease. HDV is a defective RNA agent needing the presence of HBV for its life cycle. HDV is present worldwide, but the distribution pattern is not uniform. Different strains are classified into eight genotypes represented in specific regions and associated with peculiar disease outcome. Two major specific patterns of infection can occur, i.e. co-infection with HDV and HBV or HDV superinfection of a chronic HBV carrier. Co-infection often leads to eradication of both agents, whereas superinfection mostly evolves to HDV chronicity. HDV-associated chronic liver disease (chronic hepatitis D) is characterized by necro-inflammation and relentless deposition of fibrosis, which may, over decades, result in the development of cirrhosis. HDV has a single-stranded, circular RNA genome. The virion is composed of an envelope, provided by the helper HBV and surrounding the RNA genome and the HDV antigen (HDAg). Replication occurs in the hepatocyte nucleus using cellular polymerases and via a rolling circle process, during which the RNA genome is copied into a full-length, complementary RNA. HDV infection can be diagnosed by the presence of antibodies directed against HDAg (anti-HD) and HDV RNA in serum. Treatment involves the administration of pegylated interferon-α and is effective in only about 20% of patients. Liver transplantation is indicated in case of liver failure.