chronic hepatitis B

A patient with two episodes of acute polyradiculoneuropathy (Guillain-Barré syndrome) that both occurred during exacerbation of chronic hepatitis B and separated by a 2-year asymptomatic interval is described. The possible causative relation between the neuropathy and the chronic hepatitis B is discussed.

A patient with two episodes of acute polyradiculoneuropathy (Guillain-Barré syndrome) that both occurred during exacerbation of chronic hepatitis B and separated by a 2-year asymptomatic interval is described. The possible causative relation between the neuropathy and the chronic hepatitis B is discussed.

Hepatitis B virus (HBV) RNA in serum has recently been linked to efficacy and prognosis of chronic hepatitis B (CHB) treatment. This study explored the nature, origin, underlying mechanisms, and potential clinical significance of serum HBV RNA. The levels of HBV DNA and RNA were determined in the supernatant of induced HepAD38, HBV-expressing HepG2.2.15 cells and primary human hepatocytes (PHH), and in the serum of transgenic mice and CHB patients. NP-40 and proteinase K treatment, sucrose density gradient centrifugation, electron microscopy, northern blot, multiple identification PCRs and 5' rapid-amplification of cDNA ends (5' RACE) were performed to identify the nature of serum HBV RNA. Although significantly lower than HBV DNA levels, abundant HBV RNA was present in the serum of CHB patients. A series of experiments demonstrated that serum HBV RNA was pregenome RNA (pgRNA) and present in virus-like particles. HBV pgRNA virion levels increased after blocking the reverse t...

Background/Aims. The fate of intrahepatic NK cell subsets in the course of HCV and HBV infections is not clearly understood. Methods. Blood and intrahepatic CD56 + NK cell subsets (expressing NKG2A, CD158a,h or CD158b,j receptors) from HCV or HBV patients were quantified by flow cytometry and localized by immunohistochemistry in liver biopsies. Results A significant reduction in NK cell frequency and a quantitative imbalance between CD56 bright and CD56 dim subsets were observed in chronic HCV patients as compared to HBV patients, underlining that the inflammatory environment is not the only cause of these phenomena. The proportions of intra-hepatic NK cells expressing either NKG2A, and/or CD158a,h, CD158b,j differed significantly between HCV and HBV patients. A higher frequency of perforin among intra-hepatic CD56 + CD3 -cells was observed in HCV compared to HBV patients. Double immunohistochemical staining showed that CD56 + CD3 -cells were localized within necrotic areas. Immune monitoring of circulating CD56 subsets revealed that CD3 -CD56 bright NKG2A + and CD3 -CD56 dim NKG2A + cells were positively correlated with the necro-inflammatory score and inversely correlated with viral load, respectively, in HCV patients. Conclusions. HCV and HBV affect NK cell subsets according to the status of the diseases, especially CD3 -CD56 dim NKG2A + and CD3 -CD56 bright NKG2A + cells, may be of interest for disease monitoring. * Median (Range) ** Number of cases / total (%) *** Note that for technical reasons (N° of cells avalaible), the entire set of experiments described could not be performed for every single patient ALT: Alanine AminoTransferase

Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) a and b and their receptor (LTbR) are upregulated in HBV-or HCV-induced hepatitis and HCC. Liver-specific LTab expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6 + oval cells, depends on lymphocytes and IKappa B kinase b expressed by hepatocytes but is independent of TNFR1. In vivo LTbR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTbR inhibition in LTab-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.

Chronic hepatitis B and C together with alcoholic and non-alcoholic fatty liver diseases represent the major causes of progressive liver disease that can eventually evolve into cirrhosis and its end-stage complications, including decompensation, bleeding and liver cancer. Formation and accumulation of fibrosis in the liver is the common pathway that leads to an evolutive liver disease. Precise definition of liver fibrosis stage is essential for management of the patient in clinical practice since the presence of bridging fibrosis represents a strong indication for antiviral therapy for chronic viral hepatitis, while cirrhosis requires a specific follow-up including screening for esophageal varices and hepatocellular carcinoma. Liver biopsy has always represented the standard of reference for assessment of hepatic fibrosis but it has some limitations being invasive, costly and prone to sampling errors. Recently, blood markers and instrumental methods have been proposed for the non-invasive assessment of liver fibrosis. However, there are still some doubts as to their implementation in clinical practice and a real consensus on how and when to use them is not still available. This is due to an unsatisfactory accuracy for some of them, and to an incomplete validation for others. Some studies suggest that performance of non-invasive methods for liver fibrosis assessment may increase when they are combined. Combination algorithms of non-invasive methods for assessing liver fibrosis may represent a rational and reliable approach to implement noninvasive assessment of liver fibrosis in clinical practice and to reduce rather than abolish liver biopsies.

Among possible causes of chronic hepatitis in adolescents most common are infections, autoimmune disorders and metabolic diseases. Thus, diagnostic procedures should be multidirectional. This study reports diagnosis and treatment difficulties in an 18-year-old male patient with hereditary hemochromatosis (HH), ulcerative colitis (UC), chronic hepatitis B (CHB) and Gilbert syndrome. The presented case illustrates problems in diagnostics related to the presence of numerous disease conditions in one patient. It should be taken into consideration that these diseases coexisting in one patient can mutually affect their symptoms creating specific diagnostic difficulties.

The hepatitis B virus (HBV) genome exists in two forms: circular covalently closed DNA (cccDNA) and relaxed circular DNA (RCDNA). Here, we investigated the presence of differences in the sequences of both forms in paired samples of serum and liver tissue. The serum and liver biopsy samples were collected at the same time from 67 chronically infected patients. The genotyping of the RCDNA and cccDNA was performed using mass spectrometry analysis. The HBV mutations located in the HBV pol (P) and the HBV basal core promoter/pre-core (BCP/PC) regions were included. The BCP/PC and P sequences of the RCDNA extracted from liver and blood samples were different in 39% and 16% of patients, respectively. Differences were also found between RCDNA and cccDNA extracted from the same liver specimen. Moreover, the cccDNA BCP/PC region sequence had an impact on various virological and clinical parameters. We demonstrated that there are differences between the RCDNA and cccDNA sequences that were ext...

We characterized the early dynamics of hepatitis B virus (HBV) quasispecies evolution during the first weeks of antiviral therapy with low-to-moderate genetic barrier antiviral drugs and associated these data with antiviral response patterns. Fifteen chronic hepatitis B patients (men, 10; mean age, 34; HBeAg positive, 6) who received lamivudine or telbivudine for at least 52 weeks were included. HBV DNA was extracted from serum, and a 910-bp fragment covering domains A-F of the reverse transcriptase region was amplified, cloned and sequenced. Parameters of quasispecies heterogeneity, genetic diversity and complexity were calculated and were correlated with complete virologic response, defined as undetectable HBV DNA at week 52. Nine patients achieved complete virologic response during the observational period. While baseline HBV DNA levels and HBeAg status were associated with virologic response, baseline quasispecies complexity and diversity of responders showed no significant difference to those of nonresponders (P > 0.05). However, at week 4, quasispecies complexity of nonresponders was significantly higher compared with that of responders on the nucleotide level (P = 0.01) and the aa level (P = 0.04). The number of synonymous substitutions per synonymous site dropped significantly in responders at week 4 (P = 0.04), while there was no difference in nonresponders. The HBV quasispecies complexity at the early stage of antiviral therapy (week 4) with the low-to-moderate genetic barrier nucleoside analogs lamivudine or telbivudine was associated with subsequent virologic response. Further studies are needed to confirm HBV quasispecies evolution as additional predictive marker for beneficial treatment outcome.

Hepatitis B virus (HBV) infection is a global health problem, with more than 350 million people chronically infected worldwide. The chronic HBV infection in Poland is also an essential medical and social problem. Starting from 1993, a steady decline of the incidence of HBV has been observed, reaching the estimated rate of 4.5 per 100 000 in 2004. Nothing is known about the genetic variability of HBV in Poland, the occurrence and spreading of genetic variants and mutants of hepatitis B virus in the population of Polish patients during the course of the disease and in relation to antiviral treatment. It is very interesting to study the molecular epidemiology of the Polish population regarding hepatitis B virus infection as Poland is still ethnically a uniform country, with no more than 3 4% of ethnic minorities. The first results regarding distribution of HBV genotypes and serotypes in northern Poland have been published by our group in 2003 and 2004. This work was part of a scientific project supported by the Fifth Framework Prograxnme initiative of the European Union, entitled "Emerging variants of hepatitis B virus: new tools for epidemiological survey, diagnosis of infection, and monitoring of drug resistance". In the course of the project more than 200 hepatitis B infected patients from the northern part of Poland have been enrolled, diagnosed and if the viral load of HBV was suitable for analysis genotyped by sequencing of the HBV pol/S gene fragment. This review presents the main characteristics and some interesting aspects of the studied cohort of chronically infected patients from northern Poland as well as the molecular epidemiology.

ABSTRACTPolymorphisms along the hepatitis B virus (HBV) genome have an impact on disease outcome, sensitivity to antiviral treatment, escape from vaccination, and laboratory diagnosis. We have designed a diagnostic tool based on duplex amplification of the whole HBV genome and a high-density DNA chip designed to detect 245 mutations, 20 deletions, and 2 insertions at 151 positions and to determine the genotype of the virus in serum. Assay performances were evaluated with 170 samples, characterized by determination of viral load and sequencing of the Pol, S, and precore genes and the basal core promoter. One hundred fifty-three samples (90%) could be amplified and analyzed by the chip. Only two samples with more than 103genome copies/ml could not be analyzed. Genotype had no impact on analytical sensitivity. Reproducibility studies showed no difference between repeats for codon and genotype determination. Genotype determination by sequencing and the chip were concordant in 148 of 151...

Funded by National Institutes of Health grant RO1 46580 (to R.J.G.); RC1 Challenge-DK 087031 (to M.B. and M.C.); MERIT R37-DK-46071 (to M.C.); R01-DK-38652 (to M.C.), R01-DK-084139 (to M.B.), and the Department of Veterans Affairs: Merit Review Award (to M.C.

Background and study aims: Increased alanine aminotransferase (ALT) levels with negative hepatitis B virus (HBV) DNA by hybridization is a common problem in Turkey where is a mild endemic region. We aimed to evaluate the causes of elevated ALT levels in patients who are negative for hepatitis B e antigen (HBeAg) and HBV DNA (by hybridization) for at least 6 months. Patients-methods: Forty-nine patients were enrolled in this study. Histological changes [histological activity index (HAI), and the extent of fibrosis] were assessed according to the Knodell scoring system and steatosis were graded by Brunt's classification for NAFLD in all patients. Results: A mean age of the patients was 34.9 ± 12.1 years (16-70). 43 (87.8%) of them were male. Mean ALT level was 95 ± 39.7 IU/L (50-258). Hyperglycemia (>100 mg/dL) and hyperlipidemia were found in 12 and 24 patients, respectively. Hepatic steatosis (7 patients grade 1; 5 patients grade 2; and 7 patients grade 3), ground-glass hepatocyte,

Hepatitis B virus (HBV) infection remains an important public health concern; approximately 400 million people are infected worldwide. 1 Chronic hepatitis B (CHB) has a wide clinical spectrum, ranging from asymptomatic carrier status to cirrhosis and hepatocellular carcinoma. Proper management of the disease is important to prevent mortality by reducing HBV-related complications. The predominant type of CHB infection is hepatitis B e antigen (HBeAg)-negative. This develops after the loss of HBeAg and can subsequently remain in a low/non-replicative phase (inactive chronic HBV carrier status) or progress to an active phase. The

ABSTRACTWe evaluated the efficacy of tenofovir disoproxil fumarate (TDF) in patients with lamivudine failure (LAM-F) in comparison with that in nucleoside/nucleotide analogue (NA)-naïve patients with chronic hepatitis B (CHB). The criteria for inclusion were being NA naïve or having previous LAM-F and receiving TDF therapy for at least 6 months. Biochemical and virological tests were performed at the baseline, at 3-month intervals in the first year, and every 6 months thereafter. The primary outcome measure for efficacy was a complete virological response (CVR), defined as an HBV DNA level of <20 IU/ml. CVR rates were calculated by Kaplan-Meier analysis, and a multivariate Cox proportional-hazard model was generated in order to find predictive factors independently associated with the time to a CVR. We included 197 patients in the study (136 males; mean age, 43 ± 12 years; 105 patients were NA naïve). Sixty-five patients had hepatitis B e antigen (HBeAg)-positive CHB. The median ...

To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBVtransfected HepG2.2.15 cells. H e p G 2 . 2 . 1 5 a n d H e p G 2 c e l l s w e r e stimulated with various concentrations of IFN-a2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16) with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-a could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-a in HepG2.2.15 compared to HepG2 cells. These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.

Activation of hepatitis B virus (HBV)-specific CD8 T cells by therapeutic vaccination may promote sustained control of viral replication by clearance of covalently closed circular DNA from infected hepatocytes. However, little is known about the exact targets of the CD8 T-cell response and whether HBV reproducibly evades CD8 T-cell immune pressure by mutation. The aim of this study was to address if HBV reproducibly selects substitutions in CD8 T-cell epitopes that functionally act as immune escape mutations. The HBV core gene was amplified and sequenced from 148 patients with chronic HBV infection, and the human leukocyte antigen (HLA) class I genotype (A and B loci) was determined. Residues under selection pressure in the presence of particular HLA class I alleles were identified by a statistical approach utilizing the novel analysis package SeqFeatR. With this approach we identified nine residues in HBV core under selection pressure in the presence of 10 different HLA class I all...

To characterize the IFN-response and its modulation by the antiviral compound lamivudine in HBVtransfected HepG2.2.15 cells. H e p G 2 . 2 . 1 5 a n d H e p G 2 c e l l s w e r e stimulated with various concentrations of IFN-a2a in the presence or absence of lamivudine. Then, total RNA was extracted and analysed by customised cDNA arrays and northern blot for interferon-inducible genes (ISGs). In addition, cellular proteins were extracted for EMSA and western blot. HBV replication was assessed by southern blot or ELISAs for HBsAg and HBeAg. Two genes (MxA, Cig5) with completely abolished and 4 genes (IFITM1, -2, -3, and 6-16) with partially reduced IFN-responses were identified in HepG2.2.15 cells. In 2 genes (IFITM1, 6-16), the response to IFN-a could be restored by treatment with lamivudine. This effect could not be explained by a direct modulation of the Jak/Stat signalling pathway since EMSA and western blot experiments revealed no suppression of Stat1 activation and ISGF3 formation after stimulation with IFN-a in HepG2.2.15 compared to HepG2 cells. These results are consistent with the assumption that chronic hepatitis B may specifically modulate the cellular response to IFN by a selective blockage of some ISGs. Antiviral treatment with lamivudine may partially restore ISG expression by reducing HBV gene expression and replication.

Serap A, Funda O, Bengu K, Mehmet K, Nazan C, Rasit Y, Savas K. Sustained seroconversion of chronic hepatitis B infection after stem cell transplantation.
Pediatr Transplantation 2011: 15: E92–E95. © 2010 John Wiley & Sons A/S.:  We present an 18‐yr‐old adolescent with acute lymphocytic leukemia, who underwent peripheral blood SCT with serologically and histologically documented chronic hepatitis B infection. Prior and during the transplant process, lamivudine was administered orally and he underwent SCT with a twofold decrease in viral load at the time of transplant from his HLA full matched, HBV natural immune (anti‐HBs and anti‐HBc positive) donor. Successful engraftment was achieved and three months after SCT, HBV seroconversion was documented accompanied with an ALT flare. Chronic graft‐versus‐host disease coincided after the transplantation, and he has been on immunosuppressive treatment for 25 months with sustained HBV seroconversion. We assume that adoptive immunity transfer...

Background. Tenofovir disoproxil fumarate (TDF) is an established nucleotide analogue in the treatment of chronic hepatitis B. Bone mineral density loss has been described in TDF-treated patients with human immunodeficiency virus infection, but limited data exist for patients with chronic hepatitis B. Dual X-ray absorptiometry (DEXA) was used to determine bone mineral density changes in TDF-exposed patients. We evaluated the accuracy of the Fracture Risk Assessment Tool (FRAX) as an alternative to DEXA in clinical practice. Methods. A total of 170 patients were studied: 122 were exposed to TDF, and 48 were controls. All patients underwent DEXA, and demographic details were recorded. FRAX scores (before and after DEXA) were calculated. Results. TDF was associated with a lower hip T score (P = .02). On univariate and multivariate analysis, advancing age, smoking, lower body mass index, and TDF exposure were independent predictors of low bone mineral density. In addition, the pre-DEXA FRAX score was an accurate predictor of the post-DEXA FRAX treatment recommendation (100% sensitivity and 83% specificity), area under the curve 0.93 (95% CI, .87-.97, P < .001). Conclusions. TDF-treated patients with chronic hepatitis B have reduced bone mineral density, but the reduction is limited to 1 anatomical site. Age and advanced liver disease are additional contributing factors, underlining the importance of multifactorial fracture risk assessment. FRAX can accurately identify those at greatest risk of osteoporotic fracture.

Hepatitis B virus (HBV) is mainly transmitted during birth or perinatal period, however, treatment is not usually recommended for pediatric patients with chronic hepatitis B (CHB). Twelve pediatric patients with CHB in Bangladesh were treated with both lamivudine and interferon. Lamivudine was given at a dose of 3 mg/kg, daily for 12 months. Two months after commencement of lamivudine therapy, all patents were given interferon-alpha (3 million IU/square meter of body surface area) three times weekly, subcutaneously for 10 months. Combination therapy was safe for all pediatric CHB patients. The levels of serum HBV DNA became undetectable (less than 500 copies/ml) in 8 patients and reduced in 4 patients after the end of therapy. Anti-HBe was detected in 10 of 12 patients at this time point. The levels of serum alanine aminotransferase (ALT) were significantly reduced in these patients (p less than 0.05) due to therapy. Neither flare of HBV DNA nor elevation of serum ALT were detected ...

Background/Aims: There is a lack of consensus about the currently accepted range of normal values for serum alanine aminotransferase (ALT) levels because some investigators have claimed that the true values are significantly lower than those listed by kit manufacturers. Methods: A total of 255 chronic hepatitis-B-virus (HBV)-infected patients with traditional, normal levels of ALT (≤42 U/l) were divided into 2 groups: (1) low normal ALT (men: ≤30 U/l; women: ≤19 U/l) and (2) high normal ALT (men: 31–42 U/l; women: 20–42 U/l). The extent of hepatic inflammation and fibrosis was evaluated in these patients by examining liver biopsy specimens. Results: The levels of HBV DNA were &gt;10,000 copies/ml in 58.4, 52.9 and 61.2% of the patients with traditional normal ALT, low normal ALT and high normal ALT values, respectively (p &gt; 0.05). Also, the moderate degrees of hepatic necroinflammation [histological activity index (HAI)-NI score of ≧9] and severe hepatic fibrosis (HAI-F score of ...

The objectives of this research were to investigate the leptin levels among Chronic Hepatitis B Virus (HBV), Chronic Hepatitis C Virus (HCV) and non-alcoholic steatosis hepatitis (NASH) diseases of Thai patients compared with controls. Twenty of each HBV, HCV and NASH patients compared with sixty people as the control group from the Outpatient Department at the Hospital for Tropical Diseases, Bangkok, Thailand were investigated. Fasting blood samples were collected for investigation of leptin concentration, liver enzyme function tests and hematological variables. The serum leptin concentration of liver patients was significantly higher than that of control subjects. It might be due to the accumulations of fat cells in liver disease patients. However, there is no relationship between leptin level and other parameters such as BMI, ALT, AST, ALP and hematological variables. Liver enzyme functions levels are much higher in patients groups. White blood cells counts, platelets and hematoc...

Entecavir (ETV) is a potent inhibitor of hepatitis B virus (HBV) replication. In patients adherent to treatment, virologic remission rates of &gt; 95 % can be maintained with entecavir at 3-5 years. A cohort study was performed, including all subjects who received ETV for chronic hepatitis B, in the South- Eastern Romania. We assessed viral response, HBeAg loss and seroconversion, HBsAg loss and seroconversion, biochemical response. Comparison of categorical data was performed by Chi2-test or Fisher´s exact where applicable. Data from 533 patients were available: predominantly males (64 %), 82.6 % nucleotide naive, 23.1 % HBe-Ag positive, 78.2 % with elevated ALT, 8 % with cirrhosis. The median follow up was 24 months (range 12-48 months). Rate of undetectable HBV DNA increased constantly from year 1 to 3, reaching 91.2 %. Positive predictive factors for virologic response were low score of fibrosis (p-0.006), low level of HBV DNA (p-0.003), while negative predictive factors were: H...

Summary.  Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; &gt;40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA &lt;20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA &lt;20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P &lt; 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0...

Arsenic in drinking water is associated with hepatomegaly and death from liver cancer. However, confounding factors related to liver diseases have not been carefully studied. We examined associations between exposure of arsenic in drinking water and risk of hepatitis and cirrhosis, and the interaction with chronic viral hepatitis, in people living in the Lanyang Basin of northeastern Taiwan, where well water has an arsenic content that ranges from undetectable to 3590 mg/L. We tested blood samples from 4387 people who lived in arseniasis-endemic areas in northeastern Taiwan from 1991 through 1994 for hepatitis B virus DNA, hepatitis B surface antigen (HBsAg), and antibodies against hepatitis C virus (anti-HCV). We measured arsenic concentrations in well water and collected information on residents' histories of major chronic diseases. Reports of chronic hepatitis or cirrhosis were ascertained using the Taiwan National Health Insurance database. Reports of liver cancer were ascertained using the Taiwan National Cancer Registry. Prevalence odds ratios in the overall study population for chronic hepatitis or cirrhosis for well water arsenic concentrations of £10 mg/L were 1.00 (reference), 0.93 for 10.1-49.9 mg/L (95% confidence interval [CI], 0.57-1.52), 1.24 for 50.0-99.9 mg/L (95% CI, 0.68-2.23), 0.98 for 100.0-299.9 (95% CI, 0.52-1.85), and 1.86 for ‡300.0 mg/L (95% CI, 1.08-3.20). Increasing levels of arsenic in drinking water were associated with increasing prevalence of chronic hepatitis or cirrhosis in residents who were seronegative for HBsAg and seronegative for anti-HCV, but not for seropositive for either HBsAg or anti-HCV. In individuals who were seropositive for HBsAg or anti-HCV, we observed an inverse association between hepatitis or cirrhosis and consumption of water with levels of arsenic ‡100.0 mg/L. Among participants who were seropositive for HBsAg or anti-HCV, consumption of water with levels of arsenic ‡100.0 mg/L was associated with a reduced risk of liver cancer (multivariate-adjusted hazard ratio, 0.29; 95% CI, 0.09-0.95; P < .05). A higher proportion of individuals exposed to cumulative arsenic level >14,000 mg/L 3year were carriers of inactive hepatitis B virus (DNA <10,000 copies/mL) and were positive for HBsAg (60%) than individuals exposed to water below this arsenic level (35%).

Background. (Pegylated) Interferon ([Peg]IFN) therapy leads to response in a minority of chronic hepatitis B (CHB) patients. Host genetic determinants of response are therefore in demand. Methods. In this genome-wide association study (GWAS), CHB patients, treated with (Peg)IFN for at least 12 weeks ± nucleos(t)ide analogues within randomized trials or as standard of care, were recruited at 21 centers from Europe, Asia, and North America. Response at 24 weeks after (Peg)IFN treatment was defined as combined hepatitis B e antigen (HBeAg) loss with hepatitis B virus (HBV) DNA <2000 IU/mL, or an HBV DNA <2000 IU/mL for HBeAg-negative patients. Results. Of 1144 patients, 1058 (92%) patients were included in the GWAS analysis. In total, 282 (31%) patients achieved the response and 4% hepatitis B surface antigen (HBsAg) loss. GWAS analysis stratified by HBeAg status, adjusted for age, sex, and the 4 ancestry components identified PRELID2 rs371991 (B= -0.74, standard error [SE] = 0.16, P = 3.44 ×10 -6 ) for HBeAg-positive patients. Importantly, PRELID2 was cross-validated for long-term response in HBeAg-negative patients. G3BP2 rs3821977 (B = 1.13, SE = 0.24, P = 2.46 × 10 -6 ) was associated with response in HBeAg-negative patients. G3BP2 has a role in the interferon pathway and was further examined in peripheral blood mononuclear cells of healthy controls stimulated with IFNα and TLR8. After stimulation, less production of IP-10 and interleukin (IL)-10 proteins and more production of IL-8 were observed with the G3BP2 G-allele. Conclusions. Although no genome-wide significant hits were found, the current GWAS identified genetic variants associated with (Peg)IFN response in CHB. The current findings could pave the way for gene polymorphism-guided clinical counseling, both in the setting of (Peg)IFN and the natural history, and possibly for new immune-modulating therapies. clinical Trials Registation: NCT01401400.

Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg) in a novel nanoemulsion (NE) adjuvant (HBsAg-NE) could be effective with fewer administrations. Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/-17 nm) associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached &gt; or = 10(6) titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu). ...

Objective: The aim of this study was to define the cutoff values between compensated cirrhosis and non-cirrhotic patients with viral hepatitis B and C, using the criteria of the Doppler parameters of liver vascularity. Materials and methods: Seventy non-cirrhotic patients with viral hepatitis B and C and 30 cirrhotic patients were included in this prospective study. The diagnostic decisiveness properties of the Doppler values in the pre-determination of liver cirrhosis were evaluated using receiver operating characteristics curve analysis. Results: Taking the cutoff value for hepatic vein waveform index as 0.605, a sensitivity of 80% and a specificity of 77.1% were obtained. The sensitivity was 80%, and the specificity was 68.6% for a mean max portal velocity cutoff value of 18.25 cm/s. When the hepatic artery resistivity index cutoff value was taken as 0.705 for the diagnosis of cirrhosis, the sensitivity was 82.5% and the specificity 72.1%. For a hepatic artery pulsatility index cutoff value of 1.295, a sensitivity of 82.5% and a specificity of 72.1% were found.

Entecavir (ETV) is a potent nucleoside analogue against hepatitis B virus (HBV), and the emergence of drug resistance is rare in nucleoside-naive patients because development of ETV resistance (ETVr) requires at least three amino acid substitutions in HBV reverse transcriptase. We observed a case of genotypic ETVr with viral and biochemical breakthrough during ETV treatment of nucleoside-naive patients with chronic hepatitis B (CHB). A 57-years-old HBeAg-positive man received ETV 0.5 mg/day for 145 weeks. HBV DNA was 7.7 log10 copies/ ml at baseline, decreased to below 2 at week 48, declined to a nadir of 0 (negative) at week 72, and rebounded to 2.2 log10 copies/ ml at week 90 and remained this level until 109 weeks and increased to 6.8 log10 copies/ ml at week 145. Alanine aminotransferase (ALT) level increased to 440 IU/ L at week 145. The ETVr-related substitution (rtS202P) and lamivudine resistance-related substitutions (rtL180M + rtM204V) were detected by DNA sequencing analysis at week 145. The patient discontinued ETV therapy at week 145, and then received 245 mg of tenofovir disoproxil fumarate (TDF). Afterwards, HBV DNA level dropped to below 2.6 log10 copies/ml and ALT level was normalized after 19 weeks of TDF dosing. The three substitutions associated with ETV and lamivudine resistance developed after complete viral suppression in a nucleoside-naive CHB patient during ETV treatment. In spite of the extremely rare chance of viral mutation during ETV treatment, nucleoside-naive patients should be carefully monitored for resistance even if complete suppression is present.

Hepatitis B virus (HBV) has been classified into seven genotypes, designated A–G. The HBV genotype has a characteristic geographical distribution. The Republic of Uzbekistan is located in the heart of Asia and has been considered to be a region with high endemicity of hepatitis viruses. However, the present distribution of hepatitis virus infection in this region is unknown. The aim of this study was to investigate the distribution of HBV genotypes and to elucidate the validity of two genotyping systems in Uzbekistan. Fifty‐four patients with hepatitis B surface antigen were investigated. HBV genotypes were determined by two methods: one based on restriction fragment length polymorphism (RFLP) targeting to S region, and another on enzyme‐linked immunosorbent assay (ELISA), using monoclonal antibodies to pre‐S2 region. Seven (13%) and 47 (87%) of the 54 subjects were classified into genotypes A and D, respectively. Dual infection of two viral populations of the same genotype was obse...

Background. HBV/HCV coinfection is a common finding among hemodialysis patients. However, there is scarce information concerning the impact of HBV coinfection on the response to treatment of HCV-infected patients on hemodialysis. Aim. We aimed to compare the rate of sustained virologic response (SVR) to treatment with interferon-alfa (IFN) between hemodialysis patients with HBV/HCV coinfection and those with HCV-monoinfection. Material and methods. HCV-infected patients on hemodialysis treated with IFN were included. Patients coinfected by HBV/HCV were compared to HCV-monoinfected patients, regarding clinical and biochemical features and rates of SVR. Results. One hundred and eleven patients were treated. HBV/HCV coinfection was observed in 18/111 patients (16%). Coinfected patients were younger (p = 002), had more time on dialysis (p = 0.05) and showed a tendency to present a higher prevalence of septal fibrosis (p = 0.06). The analysis by intention to treat showed SVR of 56% among coinfected patients and 18% in HCV-monoinfected patients (p = 0.004). Conclusion. In conclusion, end-stage renal disease patients with HBV/HCV coinfection exhibit higher rate of SVR to HCV treatment than HCV-monoinfected patients. It is possible that factors related to the host immune response and viral interaction could explain the better response observed among coinfected patients.

Information is very scarce on the prevalence of hepatitis-B virus (HBV) infection among blood donors and patients with human immunodeficiency virus (HIV) infection in Nigeria. Hepatitis-B surface antigen (HBsAg) ELISA was used to determined the prevalence of HBsAg among 175 blood donors (aged 20-40 years) and 490 HIV-infected patients (aged 17-60 years) in Jos, Nigeria. Twenty-five (14.3%) of the blood donors and 127 (25.9%) of the HIVinfected individuals were HBsAg seropositive, indicating a higher HBV infection among HIV-infected persons than among healthy blood donors. A slightly higher HBsAg seroprevalence was recorded in the males (14.6%) than females (12.9%) of the blood donors. Among the HIV-infected patients, the males had considerably higher HBsAg seroprevalence than the females (31.8 vs 22.1%) with the highest prevalence of HBsAg occurring in the 51-60 years age group (44%), followed by those of 31-40 years (28.2%). Results confirmed the high endemicity of HBV infection in Jos, Nigeria and the significantly greater prevalence of HBV infection among HIV -infected patients than among blood donors.

Background: Primary defects in innate immunity in chronic hepatitis-C and-B may shift towards dysregulated adaptive immunity. Cytokines are critical immune regulators. Aim: To clarify cytokines and chemokines in chronic hepatitis-C and-B to investigate the innate and adaptive immunity. Methods: Twenty-seven serum cytokines were evaluated in 27 patients with chronic hepatitis-C (genotype 1 [n=20], genotype 2 [n=7], hepatitis-C virus. RNA 5.72 ± 3.17 Log IU/ mL),12 patients with chronic hepatitis-B (e-antigen [+] [n=5], e-Ag [-] [n=7], genotype B [n=2], genotype C [n=9], hepatitis-B virus. DNA 6.19 ± 1.31 Log-copies/mL) and controls (n=5). Results: Th1 and Th2 cytokines levels were significantly higher (p< 0.05) in chronic hepatitis-B than those in chronic hepatitis-C. Interleukin-12 and-15 levels were significantly higher (p < 0.05) in chronic hepatitis-B than those in chronic hepatitis C. CXCL8 and-10 were significantly higher (p < 0.05) in chronic hepatitis-C and-B than those in controls. Immune responses were stronger in patients with chronic hepatitis-C (genotype 2) than in those with chronic hepatitis-C (genotype1). The results showed a distinct state of immunity among chronic hepatitis-B and-C. Conclusions: Skewing immunity was observed in chronic hepatitis-B and-C as well as impairments to induce innate immunity linked to adaptive immunity. Augmenting immunological strategies are necessary for the treatment and management of chronic hepatitis-B and-C with a high viral load.

Earlier studies of both chronic hepatitis B and C virus (HBV and HCV) patients have shown a strong correlation between the soluble membrane Fas (sFas) and Fas protein expression on hepatocytes. The serum concentrations of sFas and soluble Fas ligand (sFasL) was examined in both healthy and HBV-infected Vietnamese patients to determine their relationship with the outcome of HBV infection. Patients with chronic rather than acute HBV had significantly higher amounts of sFas and sFasL, whilst the highest concentrations of both molecules were detected in those with malignant forms of HBV infection. sFas and sFasL concentrations tended to increase with a profile that paralleled the progression from asymptomatic to acute through chronic to malignant states, most markedly in the case of sFas. The sFas:sFasL ratio highlighted the relative predominance of sFas in those with acute and chronic HBV compared with asymptomatic or severe forms. In patients with hepatocellular carcinoma (HCC) a significant correlation was also observed between sFasL and alpha-feto protein (AFP) levels. The results indicate that sFas and to a lesser extent sFasL levels are to some degree associated with clinical progression in HBV infection.

Background/Aims: We determined the diagnostic significance of IgM anti-HBc by a rapid, fully automated microparticle enzyme immunoassay (IMx CORE-M) in acute HBsAg positive hepatitis. Methods: We studied prospectively for at least 6 months 100 patients with acute self-limited hepatitis B (group A) and 40 patients with acute hepatitis superimposed on histologically confirmed chronic hepatitis B (group B). On admission, all patients in group A were positive and those in group B were negative for IgM anti-HBc by a commercially available enzyme immunoassay. Results: Based on the assay criteria, the rates of IMx CORE-M (>1.2) positive serum samples on admission, 4,12 and 24 weeks later were: in group A: lOO%, 95%, 72%, 44% and in group B: 20%, 27.5%, 17.5%, and 15%, respectively. Misclassiflcation was observed in 20-27.5% of the acute on chronic hepatitis B cases. However, the mean IMx CORE-M index value was found to be significantly higher in group A during the whole follow-up. In EPATITIS B surface antigen (HBsAg) is usually de-H tected in serum in acute and chronic hepatitis B virus (HBV) infection. However, IgM antibody to hepatitis B core antigen (IgM anti-HBc) is considered to be a specific marker for the diagnosis of acute type B hepatitis (l-4). A high titer of IgM anti-HBc has been found to be diagnostic for acute type B hep-

dialysis and HCV Ab positivity. All the patients, except for one had accumulation of iron. Transaminase levels were CH in 5, IH in 9 and CN in 3 patients. HAI in the group with CH transaminase levels (10.4 4-1.67) was significantly higher than IH (7.33 4-1.87) and CN (5.67 4-1.15) transaminase level groups (p < 0.05). The degree of fibrosis and hemosiderosis was significantly higher in the patients with CH transaminase levels than the other groups. In the CH transaminase group, the degree of periportal necrosis, fibrosis and hemosiderosis is significantly higher than IN and CN transaminase groups. Changes consistent with chronic hepatitis C is observed in all the patients who are HCV-RNA positive.

Hepatitis B virus (HBV) and high liver iron deposits have both been associated with the development of cirrhosis. Among HBV factors, genotype and mutations in the basal core promoter (BCP) and precore regions have been most frequently studied but the evidence for a positive association with cirrhosis has been inconsistent. In this study, sera from persons with chronic HBV infection with and without cirrhosis were used for whole HBV genome analysis and for the estimation of serum iron marker (serum iron or ferritin) levels. Single codon analysis showed that the precore wild-type, TGG (nt 1,895-1,897), gave the highest accuracy (77.5%) for the identification of cirrhosis compared to other codons. When TGG was analyzed together with the precore start codon wild-type, ATG (nt 1,814-1,816), the accuracy was improved to 80.0% (odds ratio ¼ 35.29; 95% confidence interval ¼ 3.87-321.93; Phi ¼ 0.629; P < 0.001). When the serum iron marker was included for analysis, it was clear that a combination of a precore wild-type and high serum iron marker gave a better accuracy (90.0%) (odds ratio ¼ 107.67; 95% confidence interval ¼ 10.21-1,135.59; Phi ¼ 0.804; P < 0.001) for the identification of cirrhosis than either biomarker alone. It appeared that a combined use of both these biomarkers might help to predict the development of cirrhosis in a person with chronic HBV infection, but longitudinal studies are required to test this hypothesis.

To evaluate the cost-effectiveness of different drug therapies for chronic hepatitis B in adult patients. METHODS: Using a Markov model, a hypothetical cohort of 40 years for HBeAg-positive or HBeAg-negative patients was constructed. Adefovir, entecavir, tenofovir and lamivudine (with rescue therapy in cases of viral resistance) were compared for treating adult patients with chronic hepatitis B undergoing treatment for the first time, with high levels of alanine aminotransferase, no evidence of cirrhosis and without HIV co-infection. Values for cost and effect were obtained from the literature, and expressed in effect on life years (LY). A discount rate of 5% was applied. Univariate sensitivity analysis was conducted to assess model uncertainties. Initial treatment with entecavir or tenofovir showed better clinical outcomes. The lowest cost-effectiveness ratio was for entecavir in HBeAgpositive patients (R$ 4,010.84/LY) and lamivudine for HBeAg-negative patients (R$ 6,205.08/LY). For HBeAg-negative patients, the incremental cost-effectiveness ratio of entecavir (R$ 14,101.05/LY) is below the threshold recommended by the World Health Organization. Sensitivity analysis showed that variation in the cost of drugs may make tenofovir a cost-effective alternative for both HBeAg-positive and HBeAg-negative patients. Entecavir is the recommended alternative to start treating patients with chronic hepatitis B in Brazil. However, if there is a reduction in the cost of tenofovir, it can become a cost-effective alternative.

OBJETIVO Avaliar o custo-efetividade de diferentes tratamentos medicamentosos para hepatite B crônica entre pacientes adultos. MÉTODOS Utilizando modelo de Markov, construiu-se coorte hipotética de 40 anos para pacientes HBeAg-positivo ou HBeAg-negativo. Foram comparados os usos de adefovir, entecavir, tenofovir e lamivudina (com terapia de resgate em caso de resistência viral) para tratamento de pacientes adultos com hepatite B crônica, virgens de tratamento, com elevados níveis de alanina aminotransferase, sem evidência de cirrose e sem coinfecção por HIV. Valores para custo e efeito foram obtidos da literatura. A medida do efeito foi expressa em anos de vida ganhos (AVG). Taxa de desconto de 5% foi aplicada. Análise de sensibilidade univariada foi conduzida para avaliar incertezas do modelo. RESULTADOS O tratamento inicial com entecavir ou tenofovir apresentou melhores resultados clínicos. As menores razões custo-efetividade foram de entecavir para pacientes HBeAg-positivo (R$ 4....

Background: Hepatocellular carcinoma (HCC) incidence is increasing in the United States. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC. Hepatitis infection in patients with HCC is generally diagnosed by serology, which is not always consistent with the presence of HBV and HCV in the liver. The relationship of liver viral status to serostatus in hepatocarcinogenesis is not fully understood. Methods: HBV and HCV were evaluated in formalin-fixed, paraffin-embedded liver tissue specimens in a retrospective study of 61 U.S. HCC cases of known serologic status. HBV DNA and HCV RNA were detected by PCR, reverse transcription PCR (RT-PCR), and pyrosequencing, and HBsAg and HBcAg were evaluated by immunohistochemistry. Results: Viral markers were detected in the liver tissue of 25 of 61 (41%) HCC cases. Tissue viral and serologic status were discordant in 27 (44%) cases, including those with apparent “occult” infection. Specifically, HBV DNA was detected in tiss...

The oral TLR7 agonist GS-9620 has anti-viral effects in woodchuck and chimpanzee models of chronic hepatitis B virus (HBV) infection. We investigated in a clinical trial the capacity of this agent to reconstitute protective immunity in patients with chronic HBV infection. We performed a prospective study of 28 patients with suppression of HBV infection by nucleos(t)ide analogue therapy who tested negative for HB e antigen at 4 medical centers in Italy. Patients were randomly assigned (1:3:3:3) to groups given placebo or different doses of GS-9620 (1, 2, and 4 mg, weekly for 12 weeks). We added data from 8 patients receiving nucleos(t)ide analogue therapy to the placebo group (controls); 13 treatment-naive patients with chronic HBV infection and 15 subjects who spontaneously recovered from an acute HBV infection served as additional controls. Peripheral blood mononuclear cells were collected at baseline, during administration of GS-9620 or placebo, and 12 weeks afterward. Phenotype a...

Hepatitis B reactivation has been observed in HIV-infected patients with isolated anti-HBc. However, the impact of isolated anti-HBc on liver fibrosis is not known in this population. We investigated liver stiffness values (LSV) in a population of HIV-infected patients with isolated anti-HBc, and attempted to identify risk factors for high values. Fifty-one out of 69 patients (74%) had low LSV (≤7.1 kPa). In univariate analysis, high LSV (&gt;7.1 kPa) were associated with HCV coinfection, the duration of HIV infection, the duration of antiretroviral therapy and lipodystrophy. In age-adjusted multivariate analysis, HCV coinfection (OR 11.5; 95% CI, 3.0-62.9; P=0.001) and lipodystrophy (OR 4.6; 95% CI, 1.1-20.7; P=0.031) remained associated with high liver stiffness values. Lipodystrophy was the only factor associated with high liver stiffness values in our population of HIV-infected patients with isolated anti-Hbc and extensive exposure to antiretroviral drugs active on HBV, apart fr...

The aim of this study was to determine hepatitis B surface antigen (HBsAg) seroclearance rate among patients treated with lamivudine at a specialized tertiary care referral hospital in Tehran, Iran. Methods: All patients on lamivudine (biovudin®) therapy at a dose of 100 mg/day, who showed seroclearnace between March 2001 and September 2011 were recruited. The main evaluation parameters were duration of HBsAg seroclearance and duration of HBsAg seroconversion. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were evaluated using standard methods. HBsAg seroclearance was defined as two consecutive negative serums HBsAg at least 6 months apart, whereas HBsAg seroconversion was defined as the disappearance of serum HBsAg and the presence of anti-HBs for >6 months. Results: A total of 203 chronic HBV patients treated with lamivudine at a dose of 100 mg/day were included in the study. HBsAg seroclearance and seroconversion were observed in 11 patients after the initiation of the lamivudine therapy. Overall, in lamivudine responder patients, the mean time to HBsAg seroclearance was 26.90±10.93 months (range: 12-48 months). Furthermore, the responders showed seroconversion after a mean time of 26.90±11.08 months from the initiation of lamivudine therapy. When comparing the characteristics of those who have responded to lamivudine and those who have not responded, baseline HBV-DNA levels was significantly lower in responder than non responder patients (p<0.001). Meantime, there was no difference in age, sex, baseline ALT, AST and liver biopsy score between lamivudine responder and lamivudine non-responder patients. Despite introduction of tenofovir and entecavir as first line treatment for chronic HBV infection, lamivudine remains to be a low cost, safe and effective drug for HBsAg seroclearnace.

Host and viral factors are important determinants in the pathogenesis of chronic HBV infection. To date, polymorphisms in several genes such as tumor necrosis factor-alpha, tripartite motif-containing 22, have been found to contribute to the risk of developing chronic HBV infection. The polymorphism in P2X7 gene has recently been demonstrated to be associated with susceptibility or resistance to infectious diseases. However, still no clear association between P2X7 gene and chronic HBV infection has been reported in the literature. Hence, this study aimed to investigate whether two polymorphisms of P2X7 (1513 and -762) genes confer susceptibility to chronic HBV infection. In a case control study, single nucleotide polymorphisms (SNPs) in P2X7 (1513, -762) genes were assessed using allele-specific PCR and PCR-RFLP. Thereafter, frequency of the genotypes and alleles in patients and control groups were compared and analyzed. For the 1513 loci, the heterozygosity (AC) was higher in patients (73; 50.0%) than controls (14; 23.3%) [P = 0.001, OR 3.286, 95% CI 1.587-6885]. Furthermore, we found that the C allele was a risk factor for predisposition to chronic HBV infection (P = 0.006, OR 2.247, 95% CI 1.207-4.231). For the -762 loci, there were no significant statistical differences between the case and control groups in the genotype and allele frequencies (P > 0.05). In conclusion, in our study population, the P2X7 gene polymorphisms could be associated with susceptibility to chronic HBV infection.