BACKGROUND/AIMS: The efficacy of tenofovir disoproxil fumarate (TDF) for the treatment of chronic hepatitis B (CHB) patients following prior treatment failure with multiple nucleos(t)ide analogues (NAs) is not well defined, especially in Asian populations. In this study we investigated the efficacy and safety of TDF rescue therapy in CHB patients after multiple NA treatment failure. METHODS: The study retrospectively analyzed 52 CHB patients who experienced failure with two or more NAs and who were switched to regimens containing TDF. The efficacy and safety assessments included hepatitis B virus (HBV) DNA undetectability, hepatitis B envelop antigen (HBeAg) seroclearance, alanine transaminase (ALT) normalization and changes in serum creatinine and phosphorus levels. RESULTS: The mean HBV DNA level at baseline was 5.4 +/- 1.76 log10 IU/mL. At a median duration of 34.5 months of TDF treatment, the cumulative probabilities of achieving complete virological response (CVR) were 25.0%, 51.8%, 74.2%, and 96.7% at 6, 12, 24, and 48 months, respectively. HBeAg seroclearance occurred in seven of 48 patients (14.6%). ALT levels were normalized in 27 of 31 patients (87.1%) with elevated ALT at baseline. Lower levels of HBV DNA at baseline were significantly associated with increased CVR rates (p < 0.001). However, CVR rates did not differ between TDF monotherapy or combination therapy with other NAs, and were not affected by mutations associated with resistance to NAs. No significant adverse events were observed. CONCLUSIONS: TDF is an efficient and safe rescue therapy for CHB patients after treatment failure with multiple NAs.
Adenine/adverse effects/*analogs & derivatives/therapeutic use ; Adult ; Aged ; Alanine Transaminase/blood ; Antiviral Agents/adverse effects/*therapeutic use ; Biological Markers/blood ; Creatinine/blood ; DNA, Viral/blood ; Drug Resistance, Viral/genetics ; Drug Substitution ; Female ; Genotype ; Hepatitis B e Antigens/blood ; Hepatitis B virus/*drug effects/genetics/immunology/pathogenicity ; Hepatitis B, Chronic/blood/diagnosis/*drug therapy ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Mutation ; Phosphorous Acids/adverse effects/*therapeutic use ; Phosphorus/blood ; Retrospective Studies ; Time Factors ; Treatment Failure ; Viral Load ; Young Adult

BACKGROUND/AIMS: The aims of the present study were to determine the outcomes of inactive hepatitis B virus (HBV) surface antigen (HBsAg) carriers over a 10-year study period and to elucidate the HBV serological profile of their family members. METHODS: We retrospectively analyzed the medical files of inactive HBsAg carriers followed up at the Department of Infectious Diseases of Kocatepe University Medical Faculty Hospital between March 2001 and January 2011. RESULTS: In total, 438 inactive HBsAg carriers were enrolled in this trial. The follow-up period was 33.7+/-22.5 months (mean+/-SD). Anti-hepatitis-B surface antibody seroconversion occurred in 0.7% of cases, while chronic hepatitis B was found in 0.5%. The anti-hepatitis-D virus (HDV) status was evaluated in 400 patients and anti-hepatitis C virus (HCV) in 430. It was found that 1% and 0.2% were positive for anti-HDV and anti-HCV, respectively. HBV serology was investigated in at least 1 family member of 334/438 (76.3%) patients. The HBsAg positivity rate was 34.6% in 625 family members of 334 patients. A comparison of the HBsAg positivity rates in terms of HBV DNA levels in index cases revealed that HBsAg seropositivity rates were higher in family members of HBV DNA-negative patients than in family members of HBV DNA-positive cases (P=0.0001). CONCLUSIONS: The HBsAg positivity rate was higher in family members of inactive HBsAg carriers than in the general population; these family members therefore have a higher risk of HBV transmission. Furthermore, despite negative HBV DNA levels, transmission risk was not reduced in these patients, and horizontal transmission seems to be independent of the HBV DNA value.
Adult ; Antibodies/blood ; Carrier State ; DNA, Viral/analysis ; Family Health ; Female ; Follow-Up Studies ; Hepatitis B Antibodies/blood ; Hepatitis B Surface Antigens/*blood ; Hepatitis B virus/genetics/immunology ; Hepatitis B, Chronic/*diagnosis/transmission/virology ; Hepatitis Delta Virus/immunology ; Humans ; Male ; Middle Aged ; Retrospective Studies

<b>OBJECTIVEb>To investigate the clinical value of serum anti-Ku86 in early detection of hepatocellular carcinoma (HCC).

<b>METHODSb>Expression levels of Ku86 protein in HCC and adjacent normal liver tissues were detected by Western blotting. Serum anti-Ku86 level in 83 patients with early HCC and 124 patients with liver cirrhosis were detected by enzyme-linked immunosorbent assay (ELISA). Chemiluminescence was used to measure the serum level of α-fetoprotein (AFP).

<b>RESULTSb>Expression of Ku86 protein in HCC was increased when compared with the adjacent normal liver tissues (0.21 ± 0.05 vs. 0.08 ± 0.02, P < 0.01). Serum anti-Ku86 level was significantly elevated in HCC patients compared with that in liver cirrhosis patients (0.47 ± 0.22 vs. 0.22 ± 0.06 Abs at 450 nm, P < 0.01), but there was no significant difference between HBV infection and HCV infection in HCC patients (0.51 ± 0.19 vs. 0.47 ± 0.24, P = 0.267). Of note, serum anti-Ku86 level was significantly decreased after surgical resection of the tumors in the 30 HCC cases tested (P < 0.01). The results of ROC analysis indicated a better performance of anti-Ku86 (0.857) than AFP (0.739) for early detection of HCC. In 83 HCC patients, the positive rate of anti-Ku86 was 61.4% (51/83), significantly higher than that of the AFP positive rate (27.7%, 23/83). The anti-Ku86 level was positive in 37 of 60 HCC cases with negative AFP. Combination assay of AFP and anti-Ku86 could detect 60 of 83 HCC cases (72.3%, 60/83). There was no significant correlation of anti-Ku86 and AFP (r = 0.156, P = 0.161).

<b>CONCLUSIONSb>Serum anti-Ku86 level is significantly elevated and is not related to HBV and HCV infection in HCC patients. Serum anti-Ku86 antibody may be a potential biomarker for early detection of HCC, and can be used in combination with AFP in clinics.

Adult ; Aged ; Antigens, Nuclear ; immunology ; Autoantibodies ; blood ; Biomarkers, Tumor ; blood ; Carcinoma, Hepatocellular ; blood ; diagnosis ; virology ; DNA-Binding Proteins ; immunology ; Early Detection of Cancer ; Female ; Hepatitis B ; blood ; Hepatitis C ; blood ; Humans ; Ku Autoantigen ; Liver Cirrhosis ; blood ; Liver Neoplasms ; blood ; diagnosis ; virology ; Male ; Middle Aged ; ROC Curve ; alpha-Fetoproteins ; metabolism

<b>OBJECTIVEb>To investigate the role ofCD4+CD25+ T regulatory (Treg) cells, T helper (Th)17cells and interleukin (IL)-6 in the progression of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) and determine their value as prognostic markers.

<b>METHODSb>The Chinese National Knowledge Infrastructure (CNKI), WanFang, Chinese Scientific Journals (VIP), PubMed, Embase and Web of Science databases were searched for English language case-control studies on the relationship between regulatory T lymphocytes and ACLF.The quality of included studies was assessed using the Newcastle-Ottawa scale. The meta-analysis was designed according to the PICOS approach recommended by the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. RevMan software, version 5.1, was used to perform the meta-analysis.

<b>RESULTSb>Nine case-cohort studies were selected for inclusion in the metaanalysis.The results of the meta-analyses showed that the level of CD4+CD25+ Treg cells was not significantly different between patients with HBV-related ACLF and patients with chronic hepatitis B (CHB) (mean difference (MD)=0.59, 95% confidence interval (CI)-1.68, 2.85, P=0.61) nor between patients with HBVrelated ACLF and healthy controls (MD=1.12, 95% CI:-1.42, 3.66, P=0.39). Thus, it appears that ACLF patients do not have a higher level of CD4+CD25+ Treg cells than CHB patients or healthy controls. However, the ACLF patients did appear to have a significantly higher level of Th17 cells than both the CHB patients (MD=1.73, 95% CI:0.21, 3.26, P=0.03) and the healthy controls (MD=1.62, 95% CI:(0.52, 2.72, P=0.004). In addition, the ACLF patients also had significantly higher level than both the CHB patients (MD=11.69, 95%CI:1.98, 21.40, P=0.02) and the healthy controls (MD=13.17, 95% CI:1.38, 24.95, P=0.03).

<b>CONCLUSIONb>CD4+CD25+ Treg cells may be an important protective factor in the progression and prognosis of HBV-related ACLF, while Thl7 cells and IL-6 may be risk factors for further progression and worsened prognosis.

Acute-On-Chronic Liver Failure ; diagnosis ; immunology ; CD8-Positive T-Lymphocytes ; Case-Control Studies ; Disease Progression ; Hepatitis B virus ; Hepatitis B, Chronic ; complications ; Humans ; Interleukin-6 ; immunology ; Prognosis ; T-Lymphocytes, Regulatory ; immunology ; Th17 Cells ; immunology

BACKGROUND/AIMS: The Ministry of Health and Welfare and the Korea Centers for Disease Control and Prevention in South Korea have been organizing hepatitis B virus (HBV) vertical infection prevention projects since July 2002. In this single-institute study, the results of surveys conducted in target mothers who delivered babies in a tertiary hospital were investigated and analyzed. METHODS: Of the 9,281 mothers and their 9,824 neonates born between July 2002 and December 2012, 308 hepatitis B surface antigen (HBsAg)-positive mothers and their 319 neonates were selected for this study, and their records were analyzed retrospectively. RESULTS: A total of 308 mothers were HBsAg-positive, with an HBV prevalence of 3.32% (308/9,281). There were 319 neonates born to these HBsAg-positive mothers, and 252 were confirmed to as either HBsAg-positive or -negative. Four were confirmed as HBsAg-positive, with a 1.59% (4/252) HBV vertical infection rate. All the mothers of neonates who had an HBV vertical infection were hepatitis B e antigen (HBeAg)-positive. Among the HBsAg-positive neonates, three were HBeAg-positive and had an HBV DNA titer of 1.0 x 10(8) copies/mL. CONCLUSIONS: The HBV prevalence of mothers was 3.32% (308/9,281), and their vertical infection rate was 1.59% (4/252). Thus, the South Korean HBV vertical infection prevention projects are effective, and, accordingly, HBV prevalence in South Korea is expected to decrease continuously.
Adult ; Biological Markers/blood ; DNA, Viral/blood ; Female ; Health Surveys ; Hepatitis B/blood/diagnosis/epidemiology/prevention & control/*transmission/virology ; Hepatitis B Surface Antigens/blood ; Hepatitis B e Antigens/blood ; Hepatitis B virus/genetics/immunology ; Humans ; Infant, Newborn ; *Infectious Disease Transmission, Vertical/prevention & control ; *National Health Programs ; Pregnancy ; Prevalence ; Republic of Korea/epidemiology ; Retrospective Studies ; *Tertiary Care Centers ; Viral Load

BACKGROUND/AIMS: Programmed death-1 (PD-1) expression was investigated in CD4+ and CD8+ T cells from hepatitis B virus (HBV)-infected patients at the chronic hepatitis B (CHB) infection, liver cirrhosis (LC), and hepatocellular carcinoma (HCC) stages. METHODS: PD-1 expression in circulating CD4+ and CD8+ T cells was detected by flow cytometry. The correlations between PD-1 expression and HBV viral load, alanine aminotransaminase (ALT) levels and aspartate aminotransferase (AST) levels were analyzed using GraphPad Prism 5.0. RESULTS: PD-1 expression in CD4+ and CD8+ T cells was significantly increased in both the CHB group and advanced-stage group (LC plus HCC). In the CHB group, PD-1 expression in both CD4+ and CD8+ T cells was positively correlated with the HBV viral load, ALT, and AST levels. However, in the LC plus HCC group, significant correlations between PD-1 expression and the clinical parameters were nearly absent. CONCLUSIONS: PD-1 expression in peripheral CD4+ and CD8+ T cells is dynamic, changes with HBV infection progression, and is related to HBV viral load and liver function, especially in CHB. PD-1 expression could be utilized as a potential clinical indicator to determine the extent of virus replication and liver injury.
Adult ; CD4-Positive T-Lymphocytes/*metabolism ; CD8-Positive T-Lymphocytes/*metabolism ; Carcinoma, Hepatocellular ; Disease Progression ; Female ; Hepatitis B, Chronic/*diagnosis/immunology ; Humans ; Liver Cirrhosis ; Liver Neoplasms ; Male ; Programmed Cell Death 1 Receptor/*metabolism ; Viral Load

BACKGROUND/AIMS: The prevalence of occult HBV infection depends on the prevalence of HBV infection in the general population. Hemodialysis patients are at increased risk for HBV infection. The aim of this study was to determine the prevalence of occult HBV infection in hemodialysis patients. METHODS: Total of 98 patients undergoing hemodialysis in CHA Bundang Medical Center (Seongnam, Korea) were included. Liver function tests and analysis of HBsAg, anti-HBs, anti-HBc and anti-HCV were performed. HBV DNA testing was conducted by using two specific quantitative methods. RESULTS: HBsAg was detected in 4 of 98 patients (4.1%), and they were excluded. Among 94 patients with HBsAg negative and anti-HCV negative, one (1.1%) patient with the TaqMan PCR test and 3 (3.2%) patients with the COBAS Amplicor HBV test were positive for HBV DNA. One patient was positive in both methods. Two patients were positive for both anti-HBs and anti-HBc and one patient was negative for both anti-HBs and anti-HBc. CONCLUSIONS: The present study showed the prevalence of occult HBV infection in HBsAg negative and anti-HCV negative patients on hemodialysis at our center was 3.2%. Because there is possibility of HBV transmission in HBsAg negative patients on hemodialysis, more attention should be given to prevent HBV transmission.
Adult ; Aged ; Aged, 80 and over ; Antibodies/blood ; DNA, Viral/analysis ; Feces/*virology ; Female ; Hepatitis B/complications/*epidemiology/transmission ; Hepatitis B Core Antigens/immunology ; Hepatitis B virus/genetics/immunology ; Hepatitis C Antibodies/blood ; Humans ; Kidney Failure, Chronic/*complications/diagnosis ; Male ; Middle Aged ; Polymerase Chain Reaction ; Prevalence ; Renal Dialysis ; Risk Factors

Three automated immunoassay kits for anti-Hepatitis A Virus (HAV) IgM-Architect, (Abbott Laboratories, USA), Elecsys (Roche Diagnostics, Germany), and ADVIA Centaur (Siemens Healthcare Diagnostics Inc., USA)-were compared. We included 178 consecutive samples, for which an anti-HAV IgM test was requested at Seoul National University Hospital from September 2009 to January 2010. Reviewing of medical records, reverse transcription (RT)-PCR for HAV RNA, or total anti-HAV assay were performed on 16 (9.0%) samples with discrepant results. The percent agreements (kappas) of the Architect and ADVIA Centaur, Architect and Elecsys, and ADVIA Centaur and Elecsys kits were 96.6% (0.91), 96.6% (0.92), and 97.8% (0.94), respectively. Eight out of 16 discrepant samples showed gray-zone values in Architect but were nonreactive in the others. Slightly earlier seroconversion was suspected in Elecsys. The 3 assays showed comparable performances with excellent agreements in a tertiary care hospital setting.
Hepatitis A virus/genetics/*immunology ; Hepatitis B/*diagnosis ; Hospitals, University ; Humans ; Immunoassay/*methods ; Immunoglobulin M/*analysis ; RNA, Viral/analysis ; Reagent Kits, Diagnostic ; Retrospective Studies ; Reverse Transcriptase Polymerase Chain Reaction ; Tertiary Healthcare

Occult HBV infection (OBI) is defined as presence of HBV DNA in the liver tissue in patients with serologically undetectable HBsAg. There are differences in virologic and serological profiles of OBI. Majority of OBI are positive for anti-HBs and/or anti-HBc and minor portion are negative for all HBV markers. However, there are no HBV mutations in the surface and its regulatory regions. HBV infection persists by the presence of covalently closed circular DNA (cccDNA) within the infected hepatocytes, which serves as a reservoir for future infection. OBI increases the risk of HBV transmission through transfusion, hemodialysis, and organ transplantation. Therefore effective measures should be employed to screen OBI. Antiviral therapy is needed in HBsAg-negative transplant patients who are anti-HBc positive to prevent the recurrence of HBV infection. Since HBV replication is strongly suppressed by immune surveillance system in OBI patients, immunosuppression results in massive HBV replication. This leads to acute hepatitis and sometimes mortality when immune surveillance is recovered after stopping immunosuppressive drugs/anticancer chemotherapy. Therefore, narrow surveillance is required to recognize the viral reactivation and start antiviral agents during immunosuppressive therapy/anticancer chemotherapy in patients with OBI.
Blood Transfusion ; DNA, Viral/analysis ; Hepatitis B/*diagnosis/transmission ; Hepatitis B Core Antigens/immunology ; Hepatitis B virus/genetics/*physiology ; Humans ; Liver Transplantation ; Renal Dialysis ; Virus Activation

Occult HBV infection is characterized by the absence of serum HBsAg with persistence of low level of intrahepatic HBV DNA. Several suggested mechanisms for the origin of occult HBV infection include strong suppression of viral replication and gene expression, mutation in the regulatory regions of HBV genome, formation of immunoglobulin-bound HBsAg, viral interference, and blockage of HBsAg secretion from infected hepatocytes. Standardized assays are not yet available, and sensitive HBV DNA amplification assay is necessary for the diagnosis of cryptic infection. Detection rate of HBV DNA is highest in IgG anti-HBc positive population. However, neither anti-HBc nor anti-HBs can be detected in a significant proportion of infected persons. Occult HBV infection occurs in a number of clinical settings and is highly prevalent in HCV-infected patients as well as in patients with cryptogenic chronic liver disease including hepatocellular carcinoma.
DNA, Viral/analysis ; Hepatitis B/*diagnosis/*epidemiology/metabolism ; Hepatitis B Antibodies/blood ; Hepatitis B Core Antigens/immunology ; Hepatitis B Surface Antigens/blood ; Humans