Predictors of hepatitis B surface antigen loss, relapse and retreatment after discontinuation of effective oral antiviral therapy in noncirrhotic HBeAg‐negative chronic hepatitis B

International audienceReliable predictors of outcomes after treatment discontinuation in HBeAg-negative chronic hepatitis B (CHB) patients have not been established. We investigated the role of hepatitis B surface antigen (HBsAg), interferon-inducible protein-10 (IP10) and hepatitis B core-related antigen (HBcrAg) serum levels as predictors of HBsAg loss, relapse and retreatment in noncirrhotic HBeAg-negative CHB patients who discontinued long-term antiviral therapy. All HBsAg-positive (n = 57) patients of the prospective DARING-B study were included and followed monthly for 3 months, every 2/3 months until month-12 and every 3/6 months thereafter. HBsAg, IP10 and HBcrAg levels were measured by enzyme immunoassays, and SCALE-B score was calculated. Twelve patients achieved HBsAg loss before retreatment with 18-month cumulative incidence of 25%. Independent predictors of HBsAg loss were baseline HBsAg and month-1 IP10 levels. Of 10 patients with baseline HBsAg ≤100 IU/mL, 70% cleared HBsAg and 10% required retreatment. Of 23 patients with baseline HBsAg >1000 IU/mL, 4% cleared HBsAg and 43% required retreatment. Of 24 patients with intermediate baseline HBsAg (100-1000 IU/mL), 17% cleared HBsAg and 21% required retreatment; in this subgroup, month-1 IP10 was significantly associated with HBsAg loss, which occurred in 30% and 7% of cases with IP10 >150 and ≤150 pg/mL, respectively. Baseline HBcrAg was undetectable in all patients who cleared HBsAg and was associated with retreatment. SCALE-B was associated with HBsAg loss but not with relapse or retreatment. In conclusion, HBsAg, IP10 and HBcrAg serum levels can be useful for the decisions and management of treatment discontinuation in noncirrhotic Caucasian patients with HBeAg-negative CHB

Performance in Social Network and Revenue: Moderating Effect of Seasonality on Small Retailer

<p class="MsoNormal" style="margin-bottom: .0001pt; text-align: justify; line-height: normal;"><span style="font-size: 10.0pt; mso-bidi-font-size: 11.5pt; font-family: &quot;Times New Roman&quot;,serif; mso-ansi-language: EN-US;" lang="EN-US">Small business managers have resorted to strategies on social networking expecting that their relationship with consumers would lead to sales. However, identifying which actions on social networking relate to revenue has not been clarified in marketing studies. Moreover, these actions have influence the seasonality of demand, which causes fluctuations in sales. This research investigates the moderating effect of seasonality in the relation between the performance of a small business in a social networking and its revenue. A longitudinal study, using time series regressions, was carried out with dimensions of performance in social networking (involvement with the company&rsquo;s social networking, the company&rsquo;s virtual fans and reach and view of the company&rsquo;s page</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.5pt; font-family: &quot;Times New Roman&quot;,serif; mso-fareast-font-family: &quot;Times New Roman&quot;; mso-ansi-language: EN-US; mso-fareast-language: PT-BR;" lang="EN-US">)</span><span style="font-size: 10.0pt; mso-bidi-font-size: 11.5pt; font-family: &quot;Times New Roman&quot;,serif; mso-ansi-language: EN-US;" lang="EN-US"> as predictor variables, having the revenue as a predicted variable and the seasonalities as moderators. The result shows that the dimensions of involvement and company&rsquo;s virtual fans are predictors but at different period of times. The study identifies the timing to implement strategies on social networking that would lead to sales, confirming theories that claim to environmental interference in consumer relationships and sales.</span></p

Effect of multiple nucleic acid polymers treatments starting at the time of viral inoculation on HBV replication in HepaRG cells and primary human hepatocytes.

<p>(A) Treatments procedure: HBV infected HepaRG cells and primary human hepatocytes were treated every two days starting at the time of inoculation. Supernatants and cell lysates were harvested for extracellular HBsAg, HBeAg and intracellular total HBV RNA analysis at day 4 (data not shown) and day 8 post-inoculation. The antiviral effect of (B) REP 2055 at 0.1 μM, 1 μM and 5 μM final concentrations and (C) REP 2006, REP 2139, REP 2165, REP 2031 and REP 2138 at 5 μM final concentration was assessed on differentiated HepaRG cells at day 8 post-inoculation by measuring secreted HBsAg, HBeAg and total HBV RNA. The antiviral effect of (D) REP 2055 and (E) REP 2139 at 0.1 μM, 1 μM and 5 μM final concentrations was assessed on primary human hepatocytes at day 8 post-inoculation by measuring secreted HBsAg, HBeAg and total HBV RNA. The solvent of NAP compounds was used as a non-treated condition. Heparin (HEP) was used as a positive control for entry inhibition at a concentration of 300 μg/ml. All data, expressed as means ± standard deviation, were independently reproduced three to four times, except for the effect of REP 2055 and REP 2139 on HBV RNA in HepaRG which was reproduced two times. Statistical analysis was conducted with R software using an ordinary one-way ANOVA with random effect for comparison to non-treated sample; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.</p

Effect of a single nucleic acid polymers treatment at the time of viral inoculation on HBV replication in HepaRG cells and primary human hepatocytes.

<p>(A) Treatments procedure: HBV infected cells were treated at the time of inoculation for the duration of inoculation with REP 2055 at 0.1 μM, 1 μM and 5 μM final concentrations in (B) differentiated HepaRG cells and (C) primary human hepatocytes at day 8 post-inoculation by measuring secreted HBsAg, HBeAg and total HBV RNA. (D) In primary human hepatocytes, in a side by side experiment with 5 μM REP 2055, heparin (HEP) was used as a positive control for entry inhibition at a concentration of 300 μg/ml (See legend to <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0179697#pone.0179697.g001" target="_blank">Fig 1</a>. for experimental details). All data originate from three independent experiments except in (D) where two independent experiments have been performed. Results are expressed as means ± standard deviation. Statistical analysis was conducted with R software using an (B, C) ordinary one-way ANOVA with random effect for comparison to non-treated sample and (D) unpaired, 2-tailed t-tests for comparison of specific samples using GraphPadPrism6 software; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001.</p

Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B patients

International audienceBACKGROUND & AIMS: Hepatitis B virus (HBV) persistence and the pathobiology of chronic HBV (CHB) infections result from the interplay between viral replication and host immune responses. We aimed to comprehensively analyse the expression of intrahepatic host genes as well as serum and liver HBV markers in a large cohort of untreated CHB patients. METHODS: One-hundred and five CHB patients untreated at the time of liver biopsy (34 HBeAg[+] and 71 HBeAg[-]) were analysed for the intrahepatic expression profile of 67 genes belonging to multiple innate immunity pathways. Results were correlated to serological (quantification of HBsAg [qHBsAg] and HBV DNA) and intrahepatic viral markers (total HBV DNA, pre-genomic RNA and covalently closed circular HBV DNA). RESULTS: Intrahepatic gene expression profiling revealed a strong downregulation of antiviral effectors, interferon stimulated genes, Toll-like and pathogen recognition receptor pathways in CHB patients as compared to non-infected controls, which was not directly correlated to HBV replication. A subset of genes [CXCL10, GBP1, IFITM1, IFNB1, IL10, IL6, ISG15, TLR3, SOCS1, SOCS3] was more repressed in HBeAg(-) respect to HBeAg(+) patients (median of serum HBV DNA 7.9x103vs. 7.9x107IU/ml, respectively). Notably, HBeAg(-) patients with lower qHBsAg (\textless5x103IU/ml) showed a relief of repression of genes belonging to multiple pathways. CONCLUSIONS: Our results show a strong impairment of innate immune responses in the liver of CHB patients. The association of low levels of qHBsAg with gene repression, if confirmed, might prove useful for the identification of patients who would most benefit from immune-modulators and/or HBsAg targeting agents as strategies to restore immune responsiveness. LAY SUMMARY: Chronic hepatitis B virus (HBV) infections represent a major public health problem worldwide. Over 200 million people are chronically infected and at risk of developing chronic hepatitis, liver cirrhosis and cancer. Our work aimed to understand the molecular consequences of chronic hepatitis B in the infected liver. It was conducted in a large cohort of untreated chronically infected HBV patients and analysed the expression of immunity and liver disease-related genes in the liver, with respect to markers of viral replication and persistence. Our results indicate that chronic HBV infection has a suppressive effect on immune responses, which was more pronounced with high levels of hepatitis B virus surface antigen (HBsAg). These data provide novel insight into the mechanisms of HBV persistence in the liver and suggest that approaches aimed at reducing HBsAg levels, may restore immune responsiveness against the viru

Chemical characteristics of the different NAPs used in this study.

<p>Chemical characteristics of the different NAPs used in this study.</p

Hepatitis C virus genotypes in a northeastern area of Brazil.

Submitted by Ana Maria Fiscina Sampaio ([email protected]) on 2014-05-02T17:51:10Z No. of bitstreams: 1 Silva LK Hepatitis C virus genotypes....pdf: 44851 bytes, checksum: fca0a98c8d5466e0d87b0d663bb37fe7 (MD5)Made available in DSpace on 2014-05-02T17:51:10Z (GMT). No. of bitstreams: 1 Silva LK Hepatitis C virus genotypes....pdf: 44851 bytes, checksum: fca0a98c8d5466e0d87b0d663bb37fe7 (MD5) Previous issue date: 2000Fundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilHospital Universitário Professor Edgard Santos. ,Laboratório Gastroenterologia e Hepatologia. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilInstitut National de la Santé et de la Recherche Médicale Unité. Lyon, FranceInstitut National de la Santé et de la Recherche Médicale Unité. Lyon, FranceInstitut National de la Santé et de la Recherche Médicale Unité. Lyon, FranceHospital Universitário Professor Edgard Santos. ,Laboratório Gastroenterologia e Hepatologia. Salvador, BA, BrasilHospital Universitário Professor Edgard Santos. ,Laboratório Gastroenterologia e Hepatologia. Salvador, BA, BrasilHospital Universitário Professor Edgard Santos. ,Laboratório Gastroenterologia e Hepatologia. Salvador, BA, BrasilFundação Oswaldo Cruz. Centro de Pesquisa Gonçalo Moniz. Salvador, BA, BrasilWe used a reverse transcription-polymerase chain reaction (RT-PCR) to obtain the genotypes of circulating hepatitis C virus (HCV) in patients from a Gastro-Hepatology Unit in the city of Salvador (Bahia State) in northeastern Brazil. Viral RNA was detected in 83 (65.4%) of 127 anti-HCV seropositive serum samples. Positivity was significantly associated with alterations in levels of aspartate aminotransferase and alanine aminotransferase (P < 0.05). Genotyping of HCV was performed by RT-PCR using genotype-specific primers from the core region: 24.1% were infected with subtype 1a, 38.6% with 1b, 3.6% with 2, 21.7% with 3a, and 12.0% with a mixed genotype. There was no difference in genotype distribution when compared with results from other Brazilian locations. Surprisingly, the high frequency of genotype 3 in Brazilian samples continues to be different from that reported around the world and warrants further investigatio

Relationship between NAPs sequence, amphipathicity, chemical modification and anti-HBV antiviral activity.

<p>(A) Treatments procedure: HBV infected HepaRG cells were treated at the time of inoculation for the duration of inoculation. Supernatants and cell lysates were harvested for extracellular HBsAg, HBeAg and intracellular total HBV RNA analysis at day 4 (data not shown) and day 8 post-inoculation. (B) To determine the effect of different NAPs chemical modifications on antiviral activity, HepaRG cells were treated once at the time of viral inoculation with REP 2172, REP 2147, REP 2006, REP 2107, REP 2055 and REP 2139 NAP compounds containing or not PS (phosphorothioation), 2’-OMe (2’O-methyl ribose) and 5-MeC (5-methylcytidine) at a 5 μM concentration and secreted HBsAg, HBeAg and total HBV RNA were measured at day 8 post-inoculation. The solvent of NAP compounds was used as a non-treated condition. All data originating from two independent experiments are expressed as means ± standard deviation. Statistical analysis was conducted with unpaired, 2-tailed t-tests, for comparison of specific samples; *, p < 0.05; **, p < 0.01; ***, p < 0.001; ****, p < 0.0001, ns; non-significant.</p