Hepatitis B Virus Breakthrough Research Articles

Effectiveness of zero dose HBV vaccine on prevention of HBV breakthrough infection among vaccinated Egyptian children

Hepatitis B virus (HBV) is a vaccine preventable disease. Sufficient post vaccination response is critical step to achieve infection eradication. Vaccine hypo-responsiveness is a major risk factor for HBV chronic infection. We aimed to evaluate the effectiveness of birth dose HBV vaccine in preventing perinatal HBV infection and to detect the rate of HBV surface antibody (HBs-Ab) seroconversion and its relation to interleukin-4 polymorphism (IL-4 PM) among a group of vaccinated Egyptian infants. This observational analytical study involved 77 infants aged 6 to 12 months who received 4 doses of HBV vaccine including a zero dose. We measured serum levels of HBV-DNA and hepatitis B surface antigen (HBsAg) as markers of infectivity, and the level of (HBsAb) to assess vaccine responsiveness. Cytokine gene analysis to detect IL-4 gene polymorphism and its association with vaccine un-responsiveness were investigated. We observed that none of the vaccinated infants acquired HBV infection. Of the included 77 infants, seroconversion against HBV was detected in 72 (93.5%), 28 (36.4%) had low response and 44 (57.1%) had high response. While 5 (6.5%) were non responders. There was significant association between IL-4 gene polymorphism and the poor seroconversion after HBV vaccination. (p=0.03). Furthermore, HBsAb titer was significantly lower in children who have IL-4 gene polymorphism (p=0.014). In conclusion, implementation of birth-dose HBV vaccination is effective for prevention of perinatal infection, but seroconversion rate may be insufficient to induce long term protection. IL-4 gene polymorphism is associated with poor response to HBV vaccine.

Hepatitis B prophylaxis among recipients of a hepatitis B core antibody positive liver transplant

ObjectiveUsing organs from donors with a history of hepatitis B virus (HBV) infection has expanded the pool for solid organ transplant. The purpose of this study was to assess the efficacy of HBV postexposure prophylaxis among recipients of a hepatitis B core antibody positive (HBcAb+) liver transplant and compare post-transplant outcomes with those who received a hepatitis B core antibody negative (HBcAb−) liver transplant. MethodsThis was a retrospective, single-center cohort analysis of liver transplant recipients at our institution. All adult liver transplant recipients between January 1, 2014, and August 30, 2020, were reviewed for inclusion. Recipients of an HBcAb+ organ who were administered antiviral therapy were matched 1:2 with recipients of an HBcAb− organ using propensity score matching. The primary outcome was breakthrough HBV infection. Secondary outcomes included graft survival, patient survival, and allograft rejection. Postexposure prophylaxis strategies for HBV were also assessed. Outcomes were analyzed for the first 12 months after transplant. ResultsTwenty-four HBcAb+ patients were matched to 48 HBcAb− patients. There were no documented cases of breakthrough HBV infection. Patient and graft survival was similar between both groups. Seven HBcAb+ patients (29%) experienced an episode of rejection within the first year compared with zero HBcAb− patients. ConclusionsResults of this study suggest that current strategies for HBV postexposure prophylaxis are effective. Patient and graft survival rates at 30 days after transplant were similar to institutional reported values. Rejection was more prominent in the HBcAb+ group.

Protective Effect of Neonatal Hepatitis B Vaccine Against HBV Breakthrough Infection in Children with Leukemia: A Real-world Study.

Background and AimsHepatitis B vaccine is the most effective preventive measure against hepatitis B virus (HBV) infection. However, the risk of HBV breakthrough infection in fully immunized children (neonatal hepatitis B immunization) who receive immunosuppressive therapy and transfusion of blood components is not well characterized. In this real-world study, we aimed to investigate the immune protection conferred by neonatal hepatitis B vaccine in children with acute lymphoblastic leukemia (ALL) who were treated with immunosuppressive therapy and blood component transfusions.MethodsChildren with ALL who had received all three doses of neonatal hepatitis B vaccine were included in this study. HBV seromarkers were detected before and after the initiation of immunosuppressive therapy.ResultsA total of 1,011 children with ALL who were fully vaccinated against hepatitis B in infancy before the initiation of immunosuppressive therapy were eligible for inclusion. HBV infection was detected in four of 410 children (0.98%) with an HBsAg test after the initiation of immunosuppressive therapy. The median interval from treatment initiation was 19 months.ConclusionsThree doses of neonatal hepatitis B vaccine conferred adequate protection. In endemic regions, there is a low risk of HBV breakthrough infection in fully immunized children with immunosuppressive therapy.

Prevention of Vertical Transmission of Hepatitis B Within a North Carolina Hospital System

Hepatitis B virus (HBV) is a major contributor to liver-related disease globally. Vertical transmission of hepatitis B can lead to devastating outcomes in neonates, making prevention of transmission essential. Fortunately, prevention is possible with evidence-based interventions via guidelines from the American Association for the Study of Liver Diseases (AASLD). The purpose of this study was to assess compliance with AASLD guidelines at a tertiary referral hospital in North Carolina, and to suggest future quality improvement initiatives to improve care for this population. We performed a retrospective chart review, including data from all HBV-positive birthing persons at the tertiary referral hospital from April 1, 2014 through December 31, 2019. Data was then compared to AASLD guidelines. We identified 99 birthing persons who were hepatitis B positive at time of birth. Of the 99 birthing person/neonate dyads, nearly all infants received appropriate and timely HBV birth dose vaccination and HBIG administration. Risk status of HBV-infected birthing persons was completed in only 58% of this population. Of the individuals who were found to be high risk for vertical transmission of HBV, 75% received antiviral prophylaxis. This study provides a current assessment of prevention practices in vertical transmission of HBV compared to published guidelines. The tertiary hospital studied generally implemented AASLD recommendations for prevention of vertical transmission. However, our data revealed that appropriate risk status testing could be improved. With improvement in risk status testing, antiviral prophylaxis can be provided, decreasing the likelihood of breakthrough HBV vertical transmission. Follow-up for HBV-infected birthing persons and HBV-exposed neonates is also a priority. Achieving full compliance with AASLD guidelines to prevent vertical transmission of HBV is possible, and we provide structure for quality improvement initiatives that aim to accomplish this.

Genetic polymorphisms of chemokine (C-X-C motif) ligand 10 gene associated with hepatitis B virus infection in a Chinese Han population

Background and aimsChemokine (C-X-C motif) ligand 10 (CXCL10) has been recently shown to be associated with inflammatory diseases. However, the association between the genetic variation of this gene and the susceptibility to hepatitis B virus (HBV) infection remains unclear, especially in children. This study aimed to investigate the relationship between CXCL10 polymorphisms and the risk of chronic HBV infection in a Chinese Han population. MethodsA two-stage case-control study of 1048 adults and 627 children was performed. A total of 5 tagging SNPs in CXCL10 were genotyped. Dual-Luciferase Reporter Assay was used to assess the effect of the rs4508917 polymorphism on transcriptional activity of CXCL10. ResultsCXCL10 rs4508917 and rs4256246 polymorphisms were significantly associated with an increased risk of chronic HBV infection in Chinese Han adults (p = 0.036 and p = 0.033), of which rs4508917 AA genotype could increase the serum CXCL10 level (p = 0.014). In addition, the rs4508917 AA genotype was identified to facilitate HBV persistent infection (p = 0.017) and breakthrough infection (p = 0.013) in children. Subsequent functional analysis indicated that rs4508917 A allele could promote the transcriptional activity of CXCL10. Additionally, we observed that the rs4508917 A allele carriers (AA and AG genotypes) had a limited HBV viral load suppression in patients treated with nucleos(t)ide analogues (NAs). ConclusionThe A allele of the CXCL10 rs4508917 may be a risk factor of the persistent HBV infection both in adults and children, which may influence the response to NAs treatment.

Humoral Immune Memory to Hepatitis B Vaccine after Primary Vaccination of Children and Adolescents in Assiut, Egypt.

ObjectivesWe sought to assess the prevalence of hepatitis B virus (HBV) seroprotection among vaccinated children in the Assiut governorate, Egypt, and assess a booster dose immune memory response among non-seroprotected children.MethodsUsing a multistage cluster sample, 566 children were recruited from three clusters: one urban and two rural. Children were aged from nine months to 16 years old. All participants received the full three doses of the compulsory HBV vaccine during infancy. Serum hepatitis B surface antigen (HBsAg), total anti-hepatitis B core (anti-HBc) antibodies, and quantitative detection of anti-HBs were measured using enzyme-linked immunosorbent assay. Repeatedly positive samples for HBsAg/anti-HBc were submitted for quantitative HBV DNA detection using real-time polymerase chain reaction. Non-seroprotective participants (anti-HBs < 10 IU/L) were given a booster dose of HBV vaccine. Two weeks later, a blood sample was taken from each child to assess an anamnestic response.ResultsThe seroprotection rate was 53.2%, and only two children had HBV breakthrough infection (0.4%) with positive serum anti-HBc and HBV DNA. Age was the only significant predictor for non-seroprotection with an adjusted odds ratio (OR) of 3.2, 9.4, and 9.9 among children aged 5–10, 11–15, and > 15 years, respectively, compared to younger children (p < 0.001). About 85% of non-seroprotected children developed an anamnestic response after receiving the booster dose, and 84.3% of responders had a good response (3 100 IU/L). Undetectable pre-booster titer was found to be the only risk factor for non-response to booster with OR = 3.2 (p < 0.010). About 95.7% of children who were not responding to booster dose developed immune response after receiving the three doses of HBV vaccine.ConclusionsOlder age of children was the only significant predictor for HBV non-seroprotection. High anamnestic response rate signifies the presence of immune memory with long-term protection despite the waning of anti-HBs over time. However, some children with pre-booster undetectable anti-HBs titers may be unable to develop anamnestic response, and a second vaccination series might be necessary for HBV protection for these children.

High Risk of HBV Infection Among Vaccinated Polytransfused Children With Malignancy.

The national Egyptian hepatitis B virus (HBV) vaccination program coverage of all infants started in 1992. The study aimed to assess immunity against HBV and occurrence of HBV breakthrough infections in vaccinated polytransfused children with malignancies. Eighty-nine polytransfused children with malignancies were recruited; 37 were on chemotherapy (male:female 20:17; mean age 7.7±4.0 y), and there were 52 naive patients (male:female 31:21; mean age 7.6±3.2 y). In addition, 162 age-matched and sex-matched healthy controls were recruited. Patients' sera were tested for quantitative anti-hepatitis B surface (HBs) (enzyme-linked immunoassays technique), hepatitis B surface antigen (HBsAg), total anti-hepatitis B core, and HBV-DNA (nested polymerase chain reaction for surface, core, and x-regions). There was a significant lower percentage of having protective anti-HBs (10 to 100 IU/L) level among those receiving chemotherapy (13.5%) than those without (44.2%) and controls (32.1%). Twenty-one (67.7%) of those on chemotherapy were HBsAg positive compared with 10 (32.2%) of those without. Overall, 46 patients were HBV-DNA positive; 38 were c-region positive, 5 were s-region positive, 2 positive for the c-region and the s-region, and 1 tested positive for the c-region and the x-region. Of 46 patients, 20 were also positive for HBsAg (overt infection), while 26 had occult HBV infection (HBsAg-negative). Anti-HBs ≥10 IU/L co-existed among 45% of patients with overt infection and in 50% of those with occult infection. There was nonsignificant impact of receiving chemotherapy on the level of HBV-DNA. Vaccinated children with malignancies, especially those under chemotherapy, are at a significant risk of HBV infection. The co-existence of anti-HBs with HBsAg and/or HBV-DNA may represent a possible residual transfusion-transmission risk with mutant HBV strains.

The Risk of HBV Breakthrough Infection in Immunosuppressive Patients with High Ratio of HBcAb-Positive Blood Components Transfusion

Background & Aims: Immunosuppressive therapy may cause hepatitis B virus (HBV) reactivation in patients with HBcAb-positive, but the impact of HBcAb-positive blood components transfusion is poorly defined. This study aimed to evaluate the risk of HBV breakthrough infection in immunosuppressed children patients with a high HBcAb-positive blood components transfusion in HBV highly endemic areas. Methods: Children patients with acute lymphoblastic leukemia (ALL) will undergo routine blood transfusions. Cohort study was conducted in ALL children receiving blood components transfusion during chemotherapy from Sep, 2012 to Aug, 2018. Eligible children were hepatitis B surface antigen (HBsAg) and HBcAb-negative pre-transfusion. The main outcome was HBsAg or HBV DNA detected during immunosuppressive therapy. Findings: HBV breakthrough infection was identified in 0.98% (4/410) of children during immunosuppressive therapy. Among the four breakthrough patients, there were both one family with HBV infection history and one without. The appearance of HBcAb-positive was transient after blood transfusion (from 6.3% to 37.7%, eventually dropped to 0.67%). Meanwhile, HBsAb levels had significantly decreased during immunosuppressive therapy (from 63.0% to 37.4%). Interpretation: The risk of HBV breakthrough infection in immunosuppressive children patients is relatively low, even with the high radio of HBcAb-positive blood components transfusion. The patients should be paid special attention who with the existing occult HBV infection or have a family HBV infection history. Clinically, there is no need to worry about the sudden rising of HBcAb after blood transfusion. Funding Info: This study was supported by the National Natural Science Foundation of China (No.81371876), National Clinical Research Center for Child Health and Disorders General Project (No. NCRCCHD-2019-GP-04), Outstanding Youth Foundation of Children's Hospital of Chongqing Medical University. Declaration of Interests: We declare no competing interests. Ethical Statement: This study was approved by the Ethics Review Committee of Children’s Hospital of Chongqing Medical University.

Detection of Single Nucleotide Polymorphisms in IL-1B gene in Iraqi Patients with Hepatitis B

Host genetic factors play an important role in the pathogenesis of hepatitis B virus (HBV) infection. However, the role of interleukin 1 receptor, type I (IL-1B) gene in HBV infection and breakthrough infection in people remains unclear. The aim of this study was to detect a SNP in IL-1B in HBV infection in Iraqi people.

Single Nucleotide Polymorphisms in IFN-γ Signaling Pathway Associated with Risk of Hepatitis B Virus Infection in Chinese Children.

Hepatitis B virus (HBV) infection is a challenging public health problem in China and worldwide. Mother-to-child transmission is one of the main transmission routes of HBV in highly endemic regions. However, the mechanisms of HBV perinatal transmission in children have not been clearly defined. The aim of this study was to demonstrate the association between single-nucleotide polymorphisms (SNPs) in IFN-γ signaling pathway and HBV infection or breakthrough infection in children. Two hundred and seventy-four HBV-infected children defined as test positive for hepatitis B surface antigen (HBsAg) and 353 controls defined as negative for HBsAg in China were recruited from October 2013 to May 2015. SNPs in IFN-γ signaling pathway including IFNG, IFNGR1, IFNGR2, and IL12B were genotyped. Rs2234711 in IFNGR1 was significantly associated with HBV infection in children (OR = 0.641, 95% CI: 0.450–0.913). In addition, rs2234711 was also significantly associated with HBV breakthrough infection in children born to HBsAg-positive mothers (OR = 0.452, 95% CI: 0.205–0.998). Our study confirmed that genetic variants in IFN-γ signaling pathway have significant associations with HBV infection, especially with HBV breakthrough in children. This study provides insight into HBV infection in children and could be used to help design effective strategies for reducing immunoprophylaxis failure.

Will Infant Hepatitis B Immunization Protect Adults?

Globally, infant hepatitis B virus (HBV) immunization programs are markedly reducing the rate of chronic HBV infections among children <5 years of age. Desirable improvements include increased birth dose coverage and better prevention of perinatal HBV transmission. Follow-up studies show that by the teenage years most of those immunized as infants have lost circulating anti-HBs antibody and some fail to respond to challenge HBV vaccination, implying loss of protection from infection. With high exposure to HBV, such individuals can develop breakthrough HBV infection but this rarely leads to chronic infection, the main goal of prevention programs. While longer-term follow-up studies into adulthood are needed, current evidence does not support a need for booster immunization of otherwise healthy teens or young adults.

Breakthrough HBV Infection in Children with Acute Lymphocyte Leukemia During Chemotherapy: A Prospective Study

Background: Acute lymphocyte leukemia (ALL) is the most common cancer in children, and chemotherapy is the most effective treatment in clinical practice. The risk of occult hepatitis B virus (HBV) reactivation in adults patients undergoing immunosuppressive therapy has become more and more prominent. However, there were no study about the happening of HBV infection in ALL patients. In this study, we tried to explore the occurrence of HBV infection in child patients with ALL during chemotherapy. Methods: Seven hundred and thirty one child patients were involved in this study, who were diagnosed with ALL and receiving chemotherapy between August 2012 to December 2017. Demographic characteristics, clinical profile and changes of HBV seromarker in subjects pre- and during-chemotherapy were collected. Findings: Breakthrough HBV infection was identified in four subjects between 397 to 560 days after chemotherapy. During chemotherapy, high proportions of anti-HBc and anti-HBe seroconversion were found in child patients with ALL. Significantly low anti-HBs titers was detected in the HBV breakthrough patients. Interpretation: Breakthrough HBV infections could occur in ALL children during immunosuppressive therapy. The reactivation of occult HBV infection and transmit by blood transfusion should be take more attention. For the ALL child patients, the better time point for HBV infection test are between one and two years after chemotherapy. Younger child patients with significantly lower titers of protective anti-HBs during chemotherapy might have higher risk of breakthrough HBV infection. Funding Statement: This study was supported by the National Natural Science Foundation of China (No.81371876), Health and Family Planning Commission of Chongqing [2013] 39-2013-1-025 and Chongqing Municipal Colleges and Universities Outstanding Talent Support Program and Outstanding Youth Foundation of Children's Hospital of Chongqing Medical University. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Ethics Review Committee of Children’s Hospital of Chongqing Medical University.

Immunogenicity of compulsory and booster doses of hepatitis B vaccine among children in Cairo, Egypt.

Although Egypt had adopted implementation of routine infant hepatitis B virus (HBV) vaccination in 1992, its effectiveness is not evaluated on a national scale. Assessment of early and long-term seroprotection after compulsory vaccination is an important measure for monitoring the success of the vaccination program. The aim of this study was to assess HBV seroprotection and immune memory in children and adolescents who were vaccinated during infancy in Cairo Governorate. The study was carried out in two phases. The first phase was a cross-sectional study carried out in five districts in Cairo Governorate, recruiting 819 children in the age range of 9 months to 16 years. All children had received full doses of the compulsory HBV vaccination. Serum samples were taken from each child and assessed for antibody against hepatitis B virus surface antigen (anti-HBs) titer; total antibodies against HBV core antigen, and HBV surface antigen. HBV DNA was investigated by real-time PCR for those who were HBV core antigen or HBV surface antigen positive. In the second phase, nonseroprotected children (anti-HBs <10 IU/I) received HBV booster dose. AntiHBs titer was reassessed after 4 weeks to identify anamnestic response. Individuals showing antibody concentrations ofless than 10 IU/l were then given an additional complete course of vaccination. Four out of 819 children had HBV breakthrough infection. The seroprotection rate was 60.7%, and was significantly higher among children aged less than 5 years compared to the older age groups and among boys compared to girls. Multivariate logistic analysis showed age as the only independent predictor of low anti-HBs titer. About 95% of nonseroprotected children developed anamnestic response postbooster. Anti-HBs geometric mean titer (GMT) increased significantly from pre-booster (13.8±16.9IU/L) compared to post-booster (307±6.0IU/L, P<0.001). Anti-HBs GMT was significantly higher among children with prebooster anti-HBs level ≥1 IU/l (424.9±4.4 IU/l) compared to children with undetectable level (178.3±8.3). Despite waning of anti-HBs over time, long-term protection still exists. The high anamnestic response rate signifies the existence of immune memory and giving a booster dose is not recommended. However, we suggest that prolonged follow up and surveillance of vaccinees immunized at an early age should be continued.

Chronologic changes in serum hepatitis B virus DNA, genotypes, surface antigen mutants and reverse transcriptase mutants during 25-year nationwide immunization in Taiwan.

We investigated breakthrough infection and hepatitis B virus (HBV) genetic changes in immunized subjects after 25years of a universal infant immunization. Specifically, serum HBV DNA, genotypes, surface antigen mutants and nucleoside analog-resistant (NAr) mutants were assessed in 2853 subjects (<25years old) surveyed in 2009, and these data were compared with the data from previous serosurveys. A comparison across different age-stratified groups using the 2009 data revealed a significant increase in the seropositive rate of anti-HBc (5.51% vs 12.38%, P=.001) and HBV DNA (1.13% vs 3.96%, P=.007) between those 17-22 and 23-24years of age, possibly due to selective infant immunization in 1984-1986. Well-characterized NAr mutants, potential NAr mutants and surface "a" determinant mutants were detected in none, 15 (45.5%) and nine (27.3%) of 33 HBV DNA-positive subjects, respectively. Of 15 immunized, HBV DNA-positive young adults (18-24years), three (20%) carried "a" determinant mutants. Amongst 1176 HBsAg-negative subjects evaluated for occult HBV infection, those seropositive for anti-HBc had a higher seropositive rate for HBV DNA (10/110, 9.1% vs 7/1066, 0.66%; P<.001) and "a" determinant mutants (4/110, 3.6% vs 0/1066; P<.001) than those seronegative for anti-HBc. Overall, the HBsAg-positive subjects in six serosurveys showed no significant increase in genotype C frequency in the comparison between the vaccinated and unvaccinated cohorts (25/98, 25.5% versus 14/79, 17.7%, P=.188). Over the 25-year programme, there was no increase in the prevalence of genotype C in HBsAg carriers and no increase in breakthrough HBV infection or surface mutant prevalence beyond adolescence. Nucleic acid amplification should still be considered the primary screening method for occult hepatitis B detection in high-risk recipients.

Adolescent booster with hepatitis B virus vaccines decreases HBV infection in high-risk adults

BackgroundNeutralizing antibodies (anti-HBs) after immunization with hepatitis B virus (HBV) vaccines against HBV surface antigen (HBsAg) wane after 10–15years. We analyzed the effect of an adolescent booster given to vaccination-protected children born to mothers with different HBsAg-carrying status against HBV infection in their mature adulthood. MethodsA total of 9793 individuals, who were HBsAg-negative at childhood (baseline) and donated blood samples, both during childhood and adulthood, from the vaccination group in “Qidong Hepatitis B Intervention Study”, were enrolled. Among them 7414 received a one-dose, 10μg-recombinant HBV vaccine booster at 10–14years of age. At endpoint (23–28years of age), we determined the HBV serological markers and quantified their serum HBV-DNA in each of the chronic HBV-infected adults. ResultsFifty-seven adults were identified as chronic HBV infection, indicated by HBsAg(+)&anti-HBc(+) for more than 6months. The individuals who were born to HBsAg-positive mothers (high-risk adults) had significantly increased risk of developing chronic HBV infections in adulthood compared with those who were born to HBsAg-negative mothers; the adjusted odds ratio (OR) was 12.56, 95%CI:7.14–22.08. The seronegative status of anti-HBs at 10–11years of age significantly increased the risk of HBV infections among the high-risk adults. When HBsAg(−)&anti-HBc(+) children who were born to HBsAg-positive mothers 70% of them remained as the status and 10% of them developed HBsAg(+)&anti-HBc(+). While when they were born to HBsAg-negative mothers 1.05% HBsAg(−)&anti-HBc(+) children developed HBsAg(+)&anti-HBc(+) and 24.74% of them remained as the status in 12–18years. One dose of adolescent booster showed significant protection on high-risk adults from chronic HBV infection; P for trend was 0.015. ConclusionsMaternal HBsAg-positive status was an independent risk factor for vaccination-protected children to develop HBV breakthrough infection in adulthood. Adolescent boosters might be appropriate for high-risk individuals who were born to HBsAg-positive mothers when their serum anti-HBs<10mIU/ml.

Variations in IL-1R1 Gene Influence Risk for Hepatitis B Virus Infection of Children in a Han Chinese population

Background/AimsHost genetic factors play an important role in the pathogenesis of hepatitis B virus (HBV) infection. However, the role of Interleukin1Receptor, Type I (IL-1R1) gene in HBV infection and breakthrough infection in children remains unclear. The aim of this study was to investigate the association between SNPs in IL-1 family and HBV infection and breakthrough infection in children. Patients and MethodsA total of 627 Chinese children (274 HBV infected children and 353 controls) ages 6 months to 12 years were recruited from October 2013 to May 2015.Six SNPs were genotyped in IL-1R1, Interleukin-1beta (IL-1B) and Interleukin-18 (IL-18) genes. ResultsA statistically significant association was found between genotype AA in rs3917267 (IL-1R1) and HBV infection in children (OR, 1.740; 95%CI, 1.091–2.774; p=0.020), which was also found at allele A (OR, 1.316;95%CI, 1.050–1.648; p=0.017). Furthermore, rs3917267 was also significantly associated with breakthrough infection of HBV in children born of hepatitis B surface antigen (HBsAg) positive mothers (OR,3.675; 95%CI, 1.160-11.646; P=0.027). ConclusionOur study confirmed that genetic variant in IL-1R1(rs3917267) has significant association with HBV infection and HBV breakthrough infection in children, which provides new clues for the study of pathogenesis of chronic HBV infection in children.

Host Genetic Variants in HLA Loci Influence Risk for Hepatitis B Virus Infection in Children.

BackgroundHepatitis B virus (HBV) infection is a serious public health problem in China and worldwide. Mother-to-child transmission is one of HBV’s main transmission routes in highly endemic regions. Genome-wide association studies (GWAS) identify single nucleotide polymorphisms (SNPs) at HLA loci as associated with HBV infection. However, the mechanisms of HBV perinatal transmission and breakthrough in children have not yet been clearly defined.ObjectivesWe aimed to explore the association between SNPs at HLA loci and HBV infection and breakthrough in children.MethodsA total of 274 HBV-infected children and 353 controls were selected among children aged between 6 months and 12 years in China. Seven SNPs at HLA-DP and HLA-DQ loci were genotyped to analyze their association with HBV infection in children.ResultsAlleles G in both HLA-DPA1 rs3077 and HLA-DPB1 rs9277535 were found to be significantly associated with HBV infection in children with odds ratios (OR) of 1.309 (95% CI 1.046 to 1.639) and 1.411 (95% CI 1.125 to 1.771), respectively. In addition, overdominant analysis found that the rs2281388 (HLA-DPB1) GA genotype and the rs9366816 (HLA-DPB2) TC genotype were related to HBV infection (rs2281388, OR = 1.422, 95% CI: 1.032-1.961; rs9366816, OR = 1.444, 95% CI: 1.045-1.994). Furthermore, this study highlighted that rs9277535 was also significantly associated with HBV breakthrough infection in children whose mothers were positive for hepatitis B surface antigen (HBsAg).ConclusionsOur study confirmed that genetic variants in HLA-DPA1 and HLA-DPB1 loci have significant associations with HBV infection, especially with HBV breakthrough in children. This study provides insight into HBV infection in children and is valuable for the targeted management of, and control strategies for, this disease.

Occult hepatitis B virus infection and S gene escape mutants in HIV-infected patients after hepatitis B virus vaccination.

Hepatitis B virus (HBV) vaccination is recommended for HIV patients. Despite the relative success of HBV vaccination, breakthrough infections can occur infrequently in patients, and it can be due to occult HBV infection, vaccine unresponsiveness and/or emergence of escape mutants. This study assessed the presence of occult HBV infection and S gene escape mutants in HIV-positive patients after HBV vaccination. Ninety-two HIV-positive patients were enrolled in this study, including 52 responders to HBV vaccine and 40 non-responders. All of the cases received HBV vaccine according to routine HBV vaccination protocols. The presence of HBV-DNA was determined by real-time polymerase chain reaction (PCR). In HBV-DNA positive samples, the most conserved regions of S gene sequences were amplified by nested PCR and PCR products were sequenced. Occult HBV infection was detected in two cases. Glycine to arginine mutation at residue 145 (G145R) within the 'a' region of the S gene was detected in one of the occult HBV infection cases who was in the non-responder group. This study showed that the prevalence of occult HBV infection and vaccine escape mutants was low in our HBV-vaccinated HIV-positive patients in both responder and non-responder groups, so there was no alarming evidence indicating breakthrough HBV infection in our vaccinated HIV-positive cases.

A Longitudinal Hepatitis B Vaccine Cohort Demonstrates Long-lasting Hepatitis B Virus (HBV) Cellular Immunity Despite Loss of Antibody Against HBV Surface Antigen.

Long-lasting protection resulting from hepatitis B vaccine, despite loss of antibody against hepatitis B virus (HBV) surface antigen (anti-HBs), is undetermined. We recruited persons from a cohort vaccinated with plasma-derived hepatitis B vaccine in 1981 who have been followed periodically since. We performed serological testing for anti-HBs and microRNA-155 and assessed HBV-specific T-cell responses by enzyme-linked immunospot and cytometric bead array. Study subgroups were defined 32 years after vaccination as having an anti-HBs level of either ≥10 mIU/mL (group 1; n = 13) or <10 mIU/mL (group 2; n = 31). All 44 participants, regardless of anti-HBs level, tested positive for tumor necrosis factor α, interleukin 10, or interleukin 6 production by HBV surface antigen-specific T cells. The frequency of natural killer T cells correlated with the level of anti-HBs (P = .008). The proportion of participants who demonstrated T-cell responses to HBV core antigen varied among the cytokines measured, suggesting some natural exposure to HBV in the study group. No participant had evidence of breakthrough HBV infection. Evidence of long-lasting cellular immunity, regardless of anti-HBs level, suggests that protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 32 years.

Emergence of lamivudine-resistant hepatitis B virus during combination antiretroviral therapy that includes lamivudine for patients co-infected with HIV and hepatitis B virus in China: a 2-year pilot cohort study

BackgroundIn China, more than 10% of individuals infected with HIV are carriers of hepatitis B virus (HBV). Patients infected with HIV-1 are usually given combination antiretroviral therapy that includes lamivudine (ART-3TC) as a reverse-transcriptase inhibitor. Previous studies from some developed counties showed that, in ART-3TC, 3TC-resistant HBV progressively emerges at a rate of 15–20% per year in patients co-infected with HIV-1 and HBV. We investigated the occurrence of 3TC-resistant HBV during ART-3TC for double infections and tested the use of tenofovir disoproxil fumarate (TDF) as an additional reverse-transcriptase inhibitor (ART-3TC/TDF) in a 2-year cohort study in China. Methods172 plasma samples from 43 Chinese patients co-infected with HIV-1 and HBV (from 134 cases positive for HBsAg) were examined for the prevalence of 3TC-resistant HBV by direct sequencing of PCR products covering the HBV reverse transcriptase gene. The patients were randomised (7:1), using a randomised number table, to receive either ART-3TC or ART-3TC/TDF (because ART-3TC/TDF was not a standard first-line treatment in China at that time). HIV-1 RNA and HBV DNA loads were detected at baseline, 12 weeks, 48 weeks, and 96 weeks from plasma samples. All samples were tested for HIV and HBV drug resistance against 3TC. The efficacy of viral suppression and incidence of drug-resistance mutation were compared between the two groups. This study was approved by the ethics committee at Peking Union Medical College Hospital, Beijing, China, and registered at ClinicalTrials.gov (identifiers NCT00618176 and NCT00872417). Patients were enrolled in Chinese cohort studies (National Key Technologies R&D Program for the tenth and 11th Five-year Plans). FindingsMedian HIV-1 RNA loads of the ART-3TC group and the ART-3TC/TDF group significantly decreased from 26 205 copies/mL (IQR 917; p<0·0001) to fewer than 20 copies/mL (<20; p=0·0278) and from 58 972 copies/mL (3395; p<0·0001) to fewer than 20 copies/mL (<20; p=0·0207), respectively, after 96 weeks of treatment. Median HBV DNA loads also significantly decreased from 3·4 × 106 IU/mL (IQR <20; p<0·0001) to less than 20 IU/mL (<20; p<0·0001) in the ART-3TC group and from 2·7×105 IU/mL (399; p<0·;0001) to less than 20 IU/mL (<20; p=0·0152) in the ART-3TC/TDF group after 96 weeks of treatment. Although median HIV-1 viral load did not differ significantly (p>0·05) between the two groups after 96 weeks, the rate of HIV-1 RNA decline in the ART-3TC/TDF group was slightly lower than that in the ART-3TC group (RNA load range <20–905 copies/mL vs <20–4932 copies/mL at 12 weeks, <20–157 copies/mL vs <20–398 copies/mL at 48 weeks). ART-3TC/TDF had a higher efficacy than ART-3TC in controlling amounts of HBV. At 96 weeks, the median HBV DNA load was less than 20 IU/mL (IQR <20–1·2 × 108) in the ART-3TC group, suggesting that some patients had rebound or uncontrolled HBV DNA loads, but no such case was reported in the ART-3TC/TDF group, the median HBV DNA load of which was <20 IU/mL (<20; p=0<0119). Ten (23%) of 43 patients, all from the ART-3TC group, had HBV breakthrough after 96 weeks of treatment, and eight of these patients were resistant to ART-3TC (60% tr204 mutation and 80% rt180 mutation; appendix). InterpretationAlthough both regimens were able to control replication of HIV and HBV during the 2-year treatment, our findings showed that, in China, ART-3TC is likely to lead to the emergence of 3TC-resistant HBV, lending support to the benefit of the inclusion of TDF for patients co-infected with HIV-1 and HBV.