A booster hepatitis B vaccine for children with maternal HBsAg positivity before 2 years of age could effectively prevent vaccine breakthrough infections.

BACKGROUND: The long-term protective effect of hepatitis B vaccine (HepB), the incidence of hepatitis B virus (HBV) vaccine breakthrough infections (VBIs), and whether a booster HepB is necessary remain to be clarified in children born to mothers with chronic HBV infection. METHODS: Based on a long-term follow-up prospective cohort of 1177 hepatitis B surface antigen (HBsAg)-positive mothers and their paired infants which was established from 2009 to 2011, total 454 children with immunoprophylaxis success as determined by postvaccination serologic testing (PVST) at 7 months old were included in this study. Among the 454 children, 246 never had a booster HepB, and 208 children received a booster HepB from 1 to 5 years of age. Multivariate logistic regression analysis was used to analyse the risk factors for HBV VBIs. RESULTS: The hepatitis B surface antibody (anti-HBs) levels declined sharply from 7 months to 2 years old, and the anti-HBs seronegative rate in the children increased significantly from 2 years old. A total of 31 (6.83%) of the 454 children experienced VBIs, of which 7 had overt and 7 had occult HBV infections. Notably, 14 (45.16%) of the 31 children with VBIs were diagnosed at 2 years old, and all of them had anti-HBs positivity (> 10 mIU/mL) at 1 year old. Maternal hepatitis B e antigen (HBeAg) positivity, higher HBV DNA and HBsAg levels, lower initial infant anti-HBs levels and not receiving a booster HepB were independent risk factors for VBIs. The incidence of VBIs was significantly lower in children with a booster HepB than in nonboosted children (0.50 vs. 11.90%, P < 0.001), and none of the boosted children developed overt or occult HBV infection. The anti-HBs levels of 76.67% for the children with VBIs in the nonboosted group indicated positivity before VBIs was detected. CONCLUSIONS: After the primary full immunization with HepB, children born to mothers with chronic HBV infection, especially the children with maternal HBeAg positivity, high HBV DNA levels, high HBsAg levels and/or low initial infant anti-HBs levels, were at a high risk of VBIs, and a booster HepB for these children before 2 years old, instead of when their anti-HBs level is < 10 mIU/mL, could reduce the incidence of VBIs.

The dynamic changes of HBV quasispecies diversity in infancy after immunoprophylaxis failure: a prospective cohort study.

BACKGROUND: Previous works have observed that younger infants with chronic hepatitis B virus (HBV) infection are more responsive to antiviral treatment. However, the underlying mechanism remains unclear. In this study, the dynamic changes of HBV quasispecies in infants with immunoprophylaxis failure were investigated to provide virological explanations for clinical management on infantile antiviral therapy. METHODS: Thirteen 7-month-old infants with immunoprophylaxis failure and their mothers were enrolled from a prospective cohort, and 8 of them were followed up to 3 years old. The sequences of HBV quasispecies were analyzed by the full-length genome clone-based sequencing, and compared among mothers and their infants at different ages. RESULTS: The results revealed that the complexity, mutation frequency and genetic distance of HBV quasispecies decreased significantly at full-length, partial open reading frames and regulatory regions of HBV genome at nucleotide level in 7-month-old infants comparing with their mothers, whereas increased significantly to near the maternal level when infants grew up to 3 years old. Furthermore, similar changes were also found in Core, PreS2, RT and P regions of HBV genome at amino acid level, especially for potential NAs-resistant mutants in RT region and immune-escape mutants in Core and PreS2 regions. CONCLUSIONS: This study uncovered the evolution of HBV quasispecies in infancy after mother-to-child transmission, which may provide the virological evidence for explaning that younger children are more responsive to antiviral therapy.

The role of caesarean section and nonbreastfeeding in preventing mother-to-child transmission of hepatitis B virus in HBsAg-and HBeAg-positive mothers: results from a prospective cohort study and a meta-analysis.

The study aimed to assess whether caesarean section and nonbreastfeeding can prevent mother-to-child transmission (MTCT) in HBsAg- and HBeAg-positive mothers via a cohort study and a meta-analysis. (1) Pregnant women who were positive for HBsAg and HBeAg and did not receive antiviral treatment during pregnancy were recruited from the First Hospital of Jilin University, Maternal and Child Health Care Center of Jiangsu and Henan from August 2009 to June 2015. Infants received active and passive immunity. (2) In addition, a systematic literature search was performed in the PubMed, Embase, Cochrane, China National Knowledge Infrastructure and Wanfang Chinese databases. The retrieval strategy was [("HBV" or "hepatitis b" or "hepatitis b virus") and ("mother-to-infant transmission" or "vertical transmission")]. Studies were screened, and data were extracted. The fixed-effect model was used to analyse the studies. A total of 852 mothers and 857 newborns were enrolled. At the age of 7 months, 41 infants (4.78%) were positive for HBsAg. Multivariate analysis showed that mothers with higher HBV DNA levels (>108  IU/mL; RR = 3.03, 95% CI: 1.41-6.52) were associated with an increased risk of infection. Although there was no statistical significance, caesarean section (RR = 0.61) and nonbreastfeeding (RR = 0.88) showed a tendency to reduce the risk of infection. (2) A total of 5726 studies were identified. Together with our study, 13 were included in the analysis of delivery mode, and 12 were included in the analysis of feeding mode. The risk of infection in the caesarean section group was lower than that in the vaginal delivery group (RR = 0.58, 95% CI: 0.46-0.74). In the analysis of feeding mode, the risk in the nonbreastfeeding group was significantly lower (RR = 0.74, 95% CI: 0.56-0.98). In conclusion, caesarean section and nonbreastfeeding reduced the risk of MTCT in infants of HBsAg- and HBeAg-positive mothers who did not receive antiviral therapy during pregnancy.

Hepatitis B virus infection and risk of non-alcoholic fatty liver disease: A population-based cohort study.

BACKGROUND & AIMS: Although non-alcoholic fatty liver disease (NAFLD) has been studied extensively, the potential risk factors for NAFLD among chronic hepatitis B (CHB) patients have not been fully known. METHODS: A population-based cohort of adult CHB patients without a history of alcohol drinking or NAFLD were recruited and followed up from October 2012 to January 2015 in Jiangsu province, China. Using Cox proportional hazards regression model, potential risk factors including viral and metabolic factors for NAFLD were evaluated. RESULTS: Two thousand three hundred and ninety-three adult CHB patients (mean age 50.7 ± 13.2 years) were included in the cohort. With 4429 person-years of follow-up, 283 individuals progressed to NAFLD with an incidence rate of 63.89/1000 person-years. Overweight and obese CHB patients had an increased risk of NAFLD (overweight adjusted hazard ratio [HR], 3.10; 95% CI, 2.29-4.18; obese HR, 8.52; 95%CI, 5.93-12.25) compared to normal weight carriers. The incidence of NAFLD was associated with concurrent type 2 diabetes mellitus (DM) (HR, 1.88; 95%CI, 1.15-3.08). However, no associations between viral factors with NAFLD incidence rate were identified. In a subgroup of participants with concurrent type 2 DM, detectable HBV DNA levels were negatively associated with the development of NAFLD (HR, 0.37; 95%CI, 0.14-0.98). There was super-multiplicative interaction between BMI and gender with respect to incidence of NAFLD, with an ROR of 2.08 (95%CI, 1.02-4.23). CONCLUSION: Metabolic factors play an important role in the presence of NAFLD among Chinese CHB patients. However, viral replication factors are not related to NAFLD except among those with concurrent type 2 DM.

Fine mapping the MHC region identified four independent variants modifying susceptibility to chronic hepatitis B in Han Chinese.

Several genome-wide association studies (GWAS) have demonstrated the association between genetic variants in the major histocompatibility complex (MHC) region and chronic hepatitis B (CHB) virus infection, but it is still unknown about the disease-causing loci and potential mechanisms owing to the complicated linkage disequilibrium for this region. To systematically characterize the MHC variations in relation to the CHB infection, we fine mapped the MHC region on our existing GWAS data with SNP2HLA taken the Pan-Asian panel as reference and finally identified four independent associations. The HLA-DPß1 amino acid positions 84-87, which drove the effect of reported single nucleotide polymorphisms rs9277535 and rs3077, showed the most significant association (OR = 0.65, P = 2.03 × 10(-8)). The Leu-15 of HLA-C, conferring the effect of rs3130542, increased the risk of CHB infection independently (OR = 1.61, P = 3.42 × 10(-7)). The HLA-DRß1*13, in perfect LD with glutamic at site 71, and rs400488, an expression quantitative trait locus for HLA-J, were newly identified to be associated with CHB infection independently (OR = 1.84, P = 3.84 × 10(-9); OR = 0.28, P = 6.27 × 10(-7), respectively). HLA-DPß1 positions 84-87 and HLA-DRß1 position 71 implicated the P1 and P4 in the antigen-binding groove, whereas HLA-C position 15 affected the signal peptide. These four independent loci together can explain ∼ 6% of the phenotypic variance for CHB infection, accounting for 72.94% of that explained by known genetic variations. We fine mapped the MHC region and identified four loci that independently drove the chronic HBV infection. The results provided a deeper understanding of the GWAS signals and identified additional susceptibility loci which were missed in previous association studies.

UBE2L3, a susceptibility gene that plays oncogenic role in hepatitis B-related hepatocellular carcinoma.

Previously, we identified UBE2L3 as a susceptibility gene for chronic hepatitis B virus (HBV) infection through genome-wide association study. Here, we analysed the association between genetic variants of UBE2L3 and the susceptibility to HBV-related hepatocellular carcinoma (HCC) and further explored its role in HCC. This case-control study included 1344 subjects who cleared HBV, 1560 HBV carriers and 1057 HBV-related HCC patients. Two single nucleotide polymorphisms (SNPs) were genotyped, including rs2266959 and rs4821116. Logistic regression analysis was performed to compute the odds ratio (OR) and 95% confidence interval (CI). We further analysed the expression of UBE2L3 and its association with pathological features based on The Cancer Genome Atlas (TCGA) data and our tissue microarray. Proliferation and migration assays were performed in hepatoma cell lines with or without UBE2L3 knockdown. Further RNA-seq analysis was performed to explore the underlying oncogenic mechanism. The variant genotypes of rs4821116 in UBE2L3 were associated with decreased risk for HCC and chronic HBV infection. Moreover, based on both TCGA and our tissue microarray data, higher levels of UBE2L3 expression were correlated with higher tumour grade, advanced tumour stage and poor survival. In vitro analysis revealed that UBE2L3 may promote hepatocyte proliferation and migration. RNA-seq analysis showed that UBE2L3 was inversely correlated with CDKN2B, a negative regulator of cell cycle, and CLDN1, loss of which may promote cancer metastasis. In conclusion, UBE2L3 may also be a susceptibility gene in HBV-related HCC, and it may promote HCC proliferation and migration by negatively regulating CDKN2B and CLDN1.

Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance and seroconversion in hepatitis B e antigen-negative chronic infection patients: A population-based prospective cohort.

Seroclearance of hepatitis B surface antigen (HBsAg) has been widely studied; however, seroconversion of HBsAg and characteristics of viral load among hepatitis B e antigen (HBeAg)-negative chronic infection patients after HBsAg lost is not clear. We performed a large-scale study in a HBeAg-negative chronic infection cohort to evaluate spontaneous HBsAg seroclearance incidence from October 2012 to April 2017 in Jiangsu province, China. We also elucidated the characteristics of HBsAg seroconversion and hepatitis B virus (HBV) DNA detectability among patients who cleared HBsAg. A total of 2997 HBeAg-negative chronic infection patients (mean age 52.3 ± 12.9 years at baseline) were included. With 10 519 person-years of follow-up, 348 patients successfully spontaneously cleared HBsAg, with an incidence rate of 3.31 per 100 person-years. Patients with HBV DNA detectable ~1999 IU/mL at baseline had a lower probability of HBsAg seroclearance relative to those with undetectable HBV DNA, with a hazard ratio of 0.31 (95% CI = 0.23, 0.41). HBsAg seroconversion occurred in 37.3% of those patients who cleared HBsAg. The geometric mean of anti-HBs among those with HBsAg conversion was 79.4 mIU/mL. Female had a higher HBsAg seroconversion rate (P = 0.011). Among those with HBsAg seroclearance, 11.2% still had HBV DNA levels of higher than 100 IU/mL. Patients with higher HBV DNA at baseline had a higher risk of detectable HBV DNA levels even after HBsAg seroclearance (P < 0.001). This study reveals HBsAg seroconversion rates and HBV DNA undetectability epidemiological characteristics of patients with HBsAg seroclearance and suggests that monitoring HBV DNA is needed when managing HBeAg-negative chronic patients, even after clearing HBsAg.

Expression quantitative trait loci for TNFRSF10 influence both HBV infection and hepatocellular carcinoma development.

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10) is a death domain-containing receptor for the apoptotic ligand TNFSF10, which involves multiple processes, including hepatocarcinogenesis and immune response against HBV infection. Several single nucleotide polymorphisms (SNPs) were identified as expression quantitative trait loci (eQTLs) for TNFRSF10. To assess the association of TNFRSF10 eQTL SNPs with the risk of hepatocellular carcinoma (HCC) and chronic HBV infection, we designed a case-control study that included 1,300 HBV-related HCC patients, 1,344 chronic HBV carriers, and 1,344 subjects with HBV natural clearance, and then genotyped two TNFRSF10 eQTL SNPs (rs79037040 and rs2055822). We found that rs79037040 GT/TT genotypes were associated with a decreased HCC risk (adjusted odds ratio [OR] = 0.83, 95% confidence intervals [CIs] = 0.71-0.97, P = 0.021) but an increased chronic HBV infection risk of borderline significance (adjusted OR = 1.14, 95%CIs = 0.98-1.33, P = 0.085). In contrast, the rs2055822 G allele was a risk factor for HCC (adjusted OR = 1.12, 95%CIs = 1.00-1.25, P = 0.041) but a protective factor for chronic HBV infection (adjusted OR = 0.89, 95%CIs = 0.80-0.99, P = 0.038). Furthermore, we observed a dose-dependent relationship between the number of alleles (rs79037040-T and rs2055822-A) and the risk of HCC and chronic HBV infection. In comparison with "0" alleles, having "1-4" alleles was significantly associated with decreased HCC risk and increased HBV infection risk. These findings suggest that eQTL SNPs for TNFRSF10 may be susceptibility markers for HCC and chronic HBV infection.

Expression quantitative trait loci in long non-coding RNA ZNRD1-AS1 influence both HBV infection and hepatocellular carcinoma development.

Zinc ribbon domain containing 1 (ZNRD1), cloned from human leukocyte antigen (HLA) region, may play integral roles in diverse processes including immune response against HBV infection and hepatocarcinogenesis. ZNRD1-AS1 (ZNRD1 antisense RNA 1) may be an important regulator of ZNRD1. By bioinformatics analyses, we identified that several single nucleotide polymorphisms (SNPs) in ZNRD1-AS1 may be expression quantitative trait loci (eQTLs) for ZNRD1. In this study, we hypothesized that these eQTLs SNPs in ZNRD1-AS1 may influence both chronic HBV infection and hepatocellular carcinoma (HCC) development. We designed a case-control study of 1300 HBV-positive HCC patients, 1344 HBV persistent carriers and, 1344 HBV natural clearance subjects to test the associations of three ZNRD1 eQTLs SNPs (rs3757328, rs6940552 and, rs9261204) in ZNRD1-AS1 with the risk of both chronic HBV infection and HCC. Logistic regression analyses in additive genetic model showed that variant alleles of all the three SNPs increased host HCC risk, whereas variant allele of rs3757328 was associated with HBV clearance. Moreover, the haplotype containing variant alleles of the three SNPs was significantly associated with both HCC development (adjusted OR = 1.18, 95% CI = 1.01-1.38, P = 0.035) and HBV clearance (adjusted OR = 0.83, 95% CI = 0.71-0.96, P = 0.013), when compared with the most frequent haplotype. In vitro experiments showed that ZNRD1 knockdown inhibited the expression of HBV mRNA and promoted proliferation of HepG2.2.15 cells. These findings suggest that ZNRD1 regulatory SNPs may be susceptibility makers for risk of both chronic HBV infection and HCC.

GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹9) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻4; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.

Potentially functional genetic variants in microRNA processing genes and risk of HBV-related hepatocellular carcinoma.

Genetic variations in miRNA processing genes may affect the biogenesis of miRNA, hence risk of HBV infection and hepatocellular carcinoma (HCC) development. In the present study, we hypothesized that potentially functional polymorphisms in 3'-untranslated region (UTR) of miRNA processing genes might contribute to susceptibility of HBV infection and HCC development. To test the hypothesis, we genotyped three selected SNPs (rs1057035 in DICER1, rs3803012 in RAN, and rs10773771 in PIWIL1) in a case-control study of 1300 HBV-positive HCC cancer cases, 1344 HBV persistent carriers, and 1344 HBV natural clearance subjects in Chinese. We observed that DICER1 rs1057035 CT/CC variant genotypes were associated with a significant decreased risk of HCC (adjusted OR = 0.79, 95% CI = 0.64-0.96) compared with wild-type TT and RAN rs3803012 AG/GG variant genotypes increased the risk of HBV persistent infection compared with AA genotype (adjusted OR = 1.35, 95% CI = 1.03-1.77). However, PIWIL1 rs10773771 CT/CC variant genotypes were associated with an approaching decreased risk of HCC (adjusted OR = 0.86, 95% CI = 0.73-1.01) and similar with RAN rs3803012 AG/GG (adjusted OR = 0.80, 95% CI = 0.61-1.06). Furthermore, reporter gene assays indicated that the three SNPs (rs1057035, rs3803012, and rs10773771) might change the binding ability of miRNAs to the 3'UTR of the three genes (DICER1, RAN, and PIWIL1), respectively. These findings indicated that DICER1 rs1057035, RAN rs3803012, and PIWIL1 rs10773771 might contribute to the risk of HBV-related HCC.

Genetic variants in human leukocyte antigen/DP-DQ influence both hepatitis B virus clearance and hepatocellular carcinoma development.

Recent genome-wide association studies showed that four single-nucleotide polymorphisms (SNPs) in human leukocyte antigen (HLA)-DP (rs3077 and rs9277535) and HLA-DQ (rs2856718 and rs7453920) were associated with chronic hepatitis B virus (HBV) infection in Japanese populations. More than 75% of hepatocellular carcinoma (HCC) patients are attributable to persistent infection of hepatitis B virus (HBV), especially in China. We genotyped these four SNPs in 1,300 HBV-positive HCC patients, 1,344 persistent HBV carriers, and 1,344 persons with HBV natural clearance from Southeast China to further test the associations of HLA-DP/DQ variants and with risk of both HBV clearance and HCC development. Logistic regression analyses showed that HLA-DQ rs2856718 significantly decreased host HCC risk, whereas three SNPs were associated with HBV clearance (HLA-DP rs9277535 as well as HLA-DQ rs7453920 and rs2856718). In addition, HLA-DP rs3077 showed an approaching significant effect on susceptibility to HBV persistent infection and HCC development when considering multiple testing adjustments. Taken together, we report, for the first time, that genetic variants in the HLA-DP and HLA-DQ loci may be marker SNPs for risk of both HBV clearance and HCC development.

Cumulative effects of temperature on blood pressure during pregnancy: A cohort study of differing effects in three trimesters.

BACKGROUND: Little is known about the non-linear cumulative effects of temperature on blood pressure (BP) during pregnancy. We investigated the differing effects of daily ambient temperature on BP for up to 30 days in three trimesters. METHODS: The first, second, and third trimester analyses included 2547, 2299, and 2011 pregnant women, respectively, from a prospective cohort in Nanjing from January 2017 to January 2020. BP was measured at each follow-up visit. The individual daily temperature exposures were calculated for 30 days prior to the follow-up date. The Distributed Lag Non-linear Model was used to investigate the relationship between temperature and BP in each trimester. RESULTS: Temperatures under 15 °C elevate systolic, diastolic BP, and mean arterial pressure (SBP, DBP, and MAP) in the first trimester, while temperatures above 15 °C reduce SBP in the second and third trimesters. By using Distributed Lag Linear Models, we estimated that with a 1 °C decrease in daily temperature, the SBP and DBP increased by 0.32 (95 % CI: 0.12, 0.52) and 0.23 (95 % CI: 0.07, 0.39) mmHg, respectively, in the first trimester with a 20-day cumulative lag, while with a 1 °C increase in daily temperature, the SBP decreased by 0.23 (0.35, 0.10) mmHg in the third trimester with a 30-day cumulative lag. The significant effects of temperature mainly manifested between 2 and 4 weeks of exposure. CONCLUSIONS: Temperature has different effects on BP over three trimesters. Protective measures to reduce cold-related BP rise will help reduce the risk of hypertensive disorders of pregnancy.

Booster Vaccination in Infancy Reduces the Incidence of Occult HBV Infection in Maternal HBsAg-positive Children.

Background and Aims: Occult HBV infection (OBI) in children has proven to be associated with their immune response to hepatitis B vaccine (HepB). This study aimed to investigate the effect of a booster HepB on OBI, which is rarely investigated. Methods: This study enrolled 236 maternal HBsAg-positive children who were followed up annually until 8 years of age and were hepatitis B surface antigen (HBsAg) negative. Of those 100 received a booster HepB between 1 and 3 years of age (booster group), and 136 were never boosted (non-booster group). Serial follow-up data of children and baseline data of their mothers were collected and between-group differences were analyzed. Results: The incidence of OBI varied dynamically during follow-up, with 37.14% (78/210), 19.09% (42/220), 20.85% (44/211), 31.61% (61/193), 8.65% (18/208) and 12.71% (30/236) at 7 months, 1, 2, 3, 4, and 8 years of age. At 8 years of age, the negative conversion rate of HBV DNA in the booster group was significantly higher than that in non-booster group [57.89% (11/19) vs. 30.51% (18/59), p=0.032]. For children without OBI at 7 months old, the incidence of OBI in booster group was significantly lower than that in non-booster group [25.64% (10/39) vs. 67.74% (63/93), p<0.001]. Conclusions: The incidence of OBI in maternal HBsAg-positive children was high, serum HBV DNA in children with OBI was intermittently positive at low levels, and a booster HepB in infancy reduced the incidence of OBI in children with HBsAg-positive mothers.

Maternal hepatitis B e antigen can be an indicator for antiviral prophylaxis of perinatal transmission of hepatitis B virus.

As a high-risk factor of perinatal HBV transmission, the potential role of maternal hepatitis B e antigen (HBeAg) to guide antiviral prophylaxis has not yet been fully reported. This large prospective cohort study enrolled 1177 hepatitis B surface antigen (HBsAg)-positive pregnant women without antiviral treatment and their newborns. HBeAg, HBsAg, and viral load in maternal serum collected before delivery were measured. All the newborns were given standard passive-active immunoprophylaxis within 12 h after birth, and post-vaccination serologic testing was performed at 7 (±7d) months of age. The results revealed that 20 of the 1177 infants (1.70%) were immunoprophylaxis failure, and all their mothers were HBeAg positive. Maternal quantitative HBeAg was positively correlated with viral load (r = 0.83; P < .0001) and quantitative HBsAg (r = 0.68; P < .0001). The area under the receiver operating characteristic curve (AUC) for predicting immunoprophylaxis failure by maternal HBeAg was comparable to that by maternal viral load (0.871 vs 0.893; P = .441) and HBsAg (0.871 vs 0.871; P = .965). The optimal cutoff value of maternal quantitative HBeAg to predict perinatal infection was 2.21 log10 PEI U/mL, and the sensitivity and specificity was 100.0% and 74.5%, respectively. According to maternal viral load >2 × 105 IU/mL, the sensitivity and specificity of maternal qualitative HBeAg to identify the risk of HBV MTCT for pregnant women and determine the necessity for antiviral prophylaxis was 95.5% and 92.6%, respectively. This study showed that maternal HBeAg can be a surrogate marker of HBV DNA for monitoring and evaluating whether antiviral prophylaxis is necessary for preventing perinatal HBV transmission.

Functional polymorphisms of matrix metallopeptidase-9 and risk of coronary artery disease in a Chinese population.

Matrix metallopeptidase-9 (MMP-9) plays a pivotal role in vascular remodeling and development of atherosclerotic lesion. The potentially functional MMP-9 polymorphisms may contribute to the susceptibility of coronary artery disease (CAD). A case-control study composed of 762 CAD cases and 555 CAD-free controls was conducted in a Chinese population to investigate the association between the MMP-9 -1562 C>T, R279Q, P574R and R668Q polymorphisms and CAD risk. It was found that the variant genotypes of R279Q, P574R and R668Q were associated with a non-significant decreased risk of CAD when compared with their wild-type genotypes, respectively, Furthermore, compared with those without any variant genotypes for these four nonsynonymouse loci, individuals carrying all four variant genotypes (-1562 CT/TT, 279 RQ/QQ, 574 PR/RR and 668 RQ/QQ) had a 51% decreased risk of CAD (adjusted OR = 0.49; 95% CI = 0.26-0.95, P = 0.033). Although no significant main effects were observed for MMP-9 -1562 C>T locus on CAD risk, variant genotypes of -1562 C>T were associated with a 2.53 increased risk of CAD in subjects with diabetes mellitus (DM) (95% CI = 1.18-5.45, P = 0.018). In CAD cases, variant genotypes of -1562 C>T were associated with a significantly increased risk of MI (adjusted OR, 1.48, 95% CI, 1.01-2.20, P = 0.048). These findings suggest that MMP-9 R279Q, P574R and R668Q may have combined effect in the occurrence of CAD and -1562 CT/TT genotypes may contribute to CAD in diabetics and MI in CAD patients.

Identification of GRP75 as a novel PreS1 binding protein using a proteomics strategy.

The PreS1 region of the L protein is important in cell attachment and consequently in hepatitis B virus (HBV) infectivity. To identify novel PreS1 interacting protein, we performed Glutathione-S-transferase (GST) pull-down, two-dimensional gel electrophoresis (2-DE) and mass spectrometry assays. Glucose-regulated proteins (GRP) 78 and 75 were found to bind PreS1. The interactions between PreS1 and GRP75 were confirmed by a co-immunoprecipitation experiment. GRP78 and GRP75 may play important roles in mediating HBV virion entering into hepatocyte and regulating proper folding of the L protein due to their critical functions in protein folding and trafficking. The finding of novel PreS1 binding protein enriches our knowledge about molecular mechanism of HBV infection.

Virological activity in treatment-naïve HBeAg-negative HBV-infected adult patients: A community-based study in Jiangsu, China.

Nowadays most of the hepatitis B virus (HBV) infected population are adults, among which hepatitis B e antigen (HBeAg) negative infection occupied the largest proportion of HBV infection in China. HBeAg-negative patients are heterogeneous, and the corresponding interventions are different. Therefore, it is worth researching the infection characteristics of HBeAg-negative patients to help guide the interventions.A total of 11,738 treatment-naïve HBeAg-negative adult patients were randomly selected, and their demographic and medical history information were collected. The liver biochemistry, and HBV infection biomarkers including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), HBeAg, hepatitis B e antibody (anti-HBe), hepatitis B core antibody (anti-HBc), and hepatitis B virus deoxyribonucleic acid (HBV-DNA) levels were tested. The infection characteristics and their influencing factors were explored.Sixty percent of the patients presented HBV-DNA-positive, of which 31.2% had HBV-DNA level higher than 2000 IU/mL, and 16.5% had HBV-DNA level higher than 20,000 IU/mL. HBV-DNA levels tended to increase along with the increasing of age, and the male patients had significant higher HBV-DNA levels than the female patients. Twenty-four percent of the patients had abnormal transaminase. The male patients were more vulnerable to abnormal transaminase (30.0%) than the female patients (18.4%). Fifty-five percent patients with HBV-DNA ≥20,000 IU/mL presented abnormal alanine aminotransferase (ALT) or aspartate transaminase (AST), which was significantly higher than that of patients with HBV-DNA levels below 20,000 IU/mL (19.0-21.7%). Multivariate logistic regression analyses revealed that the male patients and the patients with higher viral load had higher risk of having abnormal liver function.A considerable number of HBeAg-negative patients were virological active and had liver damage. It is necessary and urgent to carry out regular active interventions for the chronic HBV-infected patients.

Reduction of the occurrence of occult HBV infection in infants by increasing the dose of hepatitis B vaccine: a large prospective cohort study.

Occult hepatitis B virus (HBV) infection (OBI) has been observed among infants born to hepatitis B surface antigen (HBsAg)-positive mothers despite successful immunoprophylaxis. This study enrolled 549 infants [349 infants received a 10µg/dose of hepatitis B vaccine (HepB), and 200 infants received 20µg/dose HepB] born to HBsAg-positive mothers with HBV DNA load >6log10IU/mL. The anti-HBs levels in the 10µg group were significantly lower than that in the 20µg group both at 7 [652.48 (564.05-754.82) vs. 1541.72 (1268.69-1873.51) mIU/mL, P<0.001] and 12 months old [257.44 (220.29-300.88) vs. 1073.41 (839.27-1372.78) mIU/mL, P<0.001]. The OBI incidence in the 10µg group was significantly higher than that in the 20µg group at both 7 [21.55% (25/116) vs. 7.56% (9/119), P=0.002] and 12 months old [17.07% (14/82) vs. 6.90% (6/87), P=0.041]. OBI incidence in infants with anti-HBs levels <100mIU/mL was higher than that of those with anti-HBs ≥100mIU/mL [35.71% (5/14) vs. 13.12% (29/221), P=0.036]. This study showed that increasing the immunisation dose from 10µg to 20µg significantly improved anti-HBs levels and decreased OBI incidence in infants with a high maternal viral load. We recommend 20µg HepB to treat this high-risk population.