Positive CHB Research Articles

Expression Pattern of Cytokines in Patients with Chronic Hepatitis B Receiving PEGinterferon Therapy.

Chronic hepatitis B virus (CHB) infection is a worldwide health problem. Polyethylene glycol (PEG)ylated interferon (PEG-IFN) is an available therapy for CHB that has antiviral and immunomodulatory effects. However, PEG-IFN therapy is limited by the fact that only a subset of patients show a sustained response, its severe side effects, and high cost. The aim of this study was to explore novel biomarkers for the early prediction of PEG-IFN treatment response and to uncover its underlying mechanism. We enrolled 10 paired patients with Hepatitis B e antigen (HBeAg)-positive CHB who received PEG-IFN-α2a monotherapy. Patient serum samples were collected at 0, 4, 12, 24, and 48 weeks and serum samples were collected from eight healthy people as healthy controls. For confirmation, we enrolled 27 patients with HBeAg-positive CHB receiving PEG-IFN therapy and serum samples at 0 and 12 weeks were obtained. Serum samples were analyzed using Luminex technology. Among 27 assessed cytokines, 10 cytokines were identified to have high expression levels. Among them, six cytokines had significant differences in their levels between the patients with HBeAg-positive CHB and the healthy controls (P < 0.05). Potentially, treatment response could be predicted using the early time points of 4, 12, and 24 weeks. Moreover, after 12 weeks of PEG-IFN treatment, increased levels of pro-inflammatory cytokines and decreased levels of anti-inflammatory cytokines were observed. The fold change of IP-10 between 12 weeks and 0 weeks correlated with the decrease in ALT levels from 0 to 12 weeks (r = 0.2675, P = 0.0024). In patients with CHB, we observed a certain pattern in the levels of cytokines during treatment with PEG-IFN, and the cytokine IP-10 might be a potential biomarker for treatment response.

The Incidence and the Clinical Significance of the Gray Zone in the Clinical Phases of Chronic Hepatitis B Virus Infection

Background: five clinical phases were described in patients with chronic (HBV) infection: HBeAg- positive HBV infection, HBeAg- positive CHB, HBeAg negative HBV infection, HBeAg-negative CHB and occult HBV infection.&#x0D; Aim: This study aimed to determine the incidence of the unclassified phase (gray zone) in chronic hepatitis B patients and its significant in the clinical practice. &#x0D; Patients and methods: The study was conducted retrospectively on 109 patients' who have HBsAg positive for more than 6 months. The data recorded include; HbeAg and anti-HBe Ab, ultrasound of the abdomen, HBV DNA load and alanine aminotransferase (ALT), accordingly; we classify the patients to known clinical phases. Patients who were unfit one of these phases considered to be in the gray zone and subsequently sent for liver fibroscan to determine the fibrosis stage. &#x0D; Results: The mean age of our patients was 34.25 (±13.9) years with 54.12% being males. The mean viral load was 5,885,490 IU/ml and mean ALT was 56.22 (±89.88) U/L. eight patients (7.3%) were in the HBeAg+ve HBV infection, 13 patients (11.9%) were in HBeAg+ve CHB . Thirty four patients (31.1%) were in the HBeAg-ve HBV infection and 23 (21.1%) were in HBeAg-ve CHB phase, both were showed a significant statistical relationship with age&gt; 35 years. Thirty one (28.4%) further patients failed to identify with any of the four phases (normal ALT with HBV load &gt; 2000 IU/ml), this group also showed significant relation to age above 35 years and 12 patients (38.8%) had significant fibrosis on fibroscan.&#x0D; Conclusions: A considerable number of patients with chronic HBV infection have persistently normal ALT levels, despite elevated levels of viral load; this is known as the "grey zone" phase. These patients merit close follow up with short-interval measurement of liver enzymes, liver fibroscan and biopsy may be considered.

The combination therapy of Peginterferonα and entecavir for HBeAg-positive chronic hepatitis B with high HCC risk

The population of HBV infection with family history of hepatocellular carcinoma (HCC) is the high risk group for the development of HCC. The aim of this study was to evaluate the effect of the de novo combination therapy including pegylated-interferon α-2a (PEG-IFNα-2a) and entecavir (ETV) in this high risk population. The study recruited 58 Hepatitis B e Antigen (HBeAg)-Positive CHB patients patients with HBV-DNA > 107 IU/mL, genotype B or C and HCC family history and were treated for 48 weeks. Patients without HBeAg loss at the 48th week were 40 patients and extended the combination therapy to 96 weeks. All patients were followed up to 120 weeks. The rate of HBeAg loss and HBsAg loss was 12/40(30.0%) and 2/40(5.0%) at week 120 respectively. When logistic regression analysis was used to identify viables of HBeAg loss, HBV-DNA levels <20 IU/mL at week 48 was found to have a 6.02 fold increased probability (95% CI = 1.17–30.40, P = .03) of HBeAg loss. Patients with HBV-DNA levels <20 IU/mL at week 48 had a high probability of HBeAg loss 8/17(47.1%), HBsAg loss 2/17(11.8%), compared to 4/23(17.4%), 0/23(0%) in patients with HBV-DNA ≥ 20 IU/mL. Combination therapy for 96 weeks was well tolerated. During the combination therapy, low-level viremia during treatment is reversely associated with response. The combination therapy of PEG-IFNα and ETV was suggested to extend to 96 weeks when HBV-DNA was completed suppressed at week 48.

THU-103-HBEAG negative CHB patients is associated with more severe liver fibrosis than hbeag positive CHB patients: A propensity score matching analysis

THU-103-HBEAG negative CHB patients is associated with more severe liver fibrosis than hbeag positive CHB patients: A propensity score matching analysis

LBO‐02: Utility of a new HBV RNA assay in HBeAg positive and negative CHB and following HBsAg seroclearance in patients treated with ARC‐520, an RNAi drug targeting cccDNA derived HBV mRNA

Journal of Viral HepatitisVolume 25, Issue S2 p. 190-191 Abstract LBO-02: Utility of a new HBV RNA assay in HBeAg positive and negative CHB and following HBsAg seroclearance in patients treated with ARC-520, an RNAi drug targeting cccDNA derived HBV mRNA First published: 12 June 2018 https://doi.org/10.1111/jvh.01_12935Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume25, IssueS2Special Issue: 16th International Symposium on Viral Hepatitis and Liver Diseases (ISVHLD) held from June 14th to 17th, 2018, in Toronto, CanadaJune 2018Pages 190-191 RelatedInformation

Association between KIR Genes and Efficacy of Treatment of HBeAg-Positive Chronic Hepatitis B Patients with Entecavir.

To investigate whether the killer immunoglobulin-like receptor (KIR) genes were associated with seroconversion in HBeAg positive CHB responder patients treated with ETV. Polymerase chain reaction with sequence-specific primers (PCR-SSP) method was performed to genotype KIR genes in 200 healthy controls and 198 HBeAg-positive CHB patients which 59 were defined as the complete response group (CRG) to the treatment with ETV and 139 were defined as null or partial response group (NPRG). The frequencies of KIR2DS2 and KIR2DS3 were significantly higher (P=0.030, OR=1.57，95%CI=2.36-1.05 and P=0.018, OR=1.773，95%CI=2.77-1.13, respectively), while, the frequencies of KIR2DL3, KIR2DS1 and KIR3DS1 were significantly lower (P=0.038, OR=0.525, 95%CI=0.96-0.29,and P=0.031, OR=0.640, 95%CI =0.95-0.43, and P=0.035, OR=0.641, 95%CI=0.96-0.43, respectively) in HBeAg-positive CHB patients than those in healthy controls. The frequency of KIR2DS3 gene was significantly higher in NPRG than that in CRG (P=0.018, OR=0.402, 95%CI=0.83-0.20). The frequencies of KIR2DL3 and KIR3DS1 genes were significantly higher in CRG than those in NPRG (P=0.019, OR=3.625, 95%CI=10.83-1.21 and P=0.041, OR=1.949, 95%CI=3.65-1.04, respectively). Patients with KIR2DS3 might have negative responses to anti-HBV therapy with ETV and patients with KIR2DL3 and KIR3DS1 might have advantage in the therapy with ETV.

Low Ratio of Treg to Th17 Cells After 36 Weeks of Telbivudine Therapy Predict HBeAg Seroconversion.

Changes of Treg/Th17 cells ratio and their associated cytokines have some correlations with an immune modulatory effect of Telbivudine treatment. The aim of our study was to investigate the role of the dynamic ratio of Treg/Th17 cells in the mechanism of LdT therapy and their relationships with the clinical responses. We detected the frequency and cytokines production of Treg and Th17 cells in 28 hepatitis B envelope antigen (HBeAg)-positive CHB patients at 0, 12, 24, 36, 48, and 96 weeks after initial LdT therapy. LdT could upregulate the frequency of Th17 cells and Th17 cells associated cytokines, downregulated the frequency of Treg cells and level of TGF-β, which leads to the decrease of Treg/Th17 ratio in HBeAg-positive CHB patients. Treg/Th17 ratio at treatment week 36 could independently predict HBeAg seroconversion in the first 2 years of Telbivudine treatment. Telbivudine therapy can decrease Treg/Th17 ratio, which may predict HBeAg seroconversion during treatment.

HBsAg seroclearance or seroconversion induced by peg-interferon alpha and lamivudine or adefovir combination therapy in chronic hepatitis B treatment: a meta-analysis and systematic review.

Seroclearance or seroconversion of hepatitis B surface antigen (HBsAg) is generally considered as the clinical endpoint. The purpose of the present meta-analysis was to evaluate pegylated interferon alpha (PEG-IFNα) with or without lamivudine (LAM) or adefovir (ADV) combination treatment in HBsAg seroclearance or seroconversion with CHB. Randomized controlled trials of adults with CHB prior to May 30th 2015, with 48-52 weeks of PEG-IFNα and LAM or ADV combination therapy or monotherapy, were included. Review Manager Software 5.2.0 was used for meta-analysis. No statistical difference was noticed in HBsAg seroclearance (9.9% vs 7.1%, OR = 1.47, 95% CI 0.75, 2.90; p = 0.26) or observed in HBsAg seroconversion (4.2% vs 3.7%, OR = 1.17, 95% CI 0.57, 2.37; p = 0.67) between PEG-IFNα + LAM and PEG-IFNα + placebo for 24-26 weeks follow-up after treatment on hepatitis B e antigen (HBeAg)-positive CHB. Statistical difference was not showed in HBsAg disappearance (10.5% vs 6.4%, OR = 1.68, 95% CI 0.75, 3.76; p = 0.21) but was demonstrated in HBsAg seroconversion (6.3% vs 0%, OR = 7.22, 95% CI 1.23, 42.40; p = 0.03) between PEG-IFNα + ADV and PEG-IFNα for 48-52 weeks treatment on HBeAg-positive CHB By systematical evaluation, there were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM for 48-52 weeks treatment on HBeAg-positive CHB. There were no differences in HBsAg disappearance and seroconversion between PEG-IFNα + placebo and PEG-IFNα + LAM during 24 weeks to 3 years follow-up after treatment on HBeAg-negative CHB by systematical evaluation. The combination between PEG-IFNα and LAM or ADV was not superior to monotherapy of PEG-IFNα in terms of HBsAg seroclearance or seroconversion.

Correlation between HBsAg Quantitation Assay, Histopathology and Viral - DNA Level in Chronic HBV Patients

Background and study aim : Hepatitis B is a serious and common infectious disease of the liver, affecting millions of peoplethroughout the world. In this regard, Egypt has an intermediate HBV seroprevalence. Quantitation of hepatitis B surface antigen (HBsAg) by automated chemiluminescent micro-particle immunoassay has been proposed to be a surrogate marker. The aim of this study was to evaluate correlation between HBsAg quantitation assay, histo-pathology and viral-DNA level in chronic hepatitis BeAg negative patients. Patients and methods: This study carried on 50 HBV-DNA positive naive CHB patients. All the studied patients wereHBeAg negative. HBV DNA was measured by real-time polymerase chain reaction, and serum HBsAg was quantified by electrochemiluminescence assay (Roche Diagnostic). Liver biopsy done to all patients in this study for histopathological grading and staging of hepatic fibrosis by experienced pathologist using METAVER scoring. Results: A significant correlation between serum HBsAg quantitation level and HBV DNA levels was revealed in all studied HBeAg negative patients (r =0.748, P= 0.05). Conclusion: All the studied patients were tested for assess correlation between HBsAg quantitation, HBV-DNA level and histo-pathology grading and staging. There is strong positive correlation between HBsAg quantation level and HBV-DNA and between HBsAg quantation level and stages of fibrosis. No correlation between HBV DNA levels and histopathology.

Study on Post-Treatment Relapse in HBeAg Positive CHB Patients.

BackgroundMany factors are associated with post-treatment relapse in CHB patients, and there are no effective factors to predict relapse. In this study, we investigate the influence factors associated with post-treatment relapse and their predictive value in HBeAg positive CHB (eP-CHB).MethodsThe factors associated with post-treatment relapse were analyzed firstly by a retrospective study in eP-CHB. Variables included age, sex, regimen, baseline HBeAg and HBV DNA level, total course of treatment as well as duration of consolidation therapy after HBeAg seroconversion. The predictive effects of the influence factors were evaluated in an eP-CHB prospective cohort.Results89 patients were enrolled in the retrospective study, 42(47.2%) relapsed after discontinuation of treatment. Factors related to post-treatment relapse were total course of treatment, duration of consolidation therapy and baseline HBV DNA level. Relapse rates in patients with total course >36 months, consolidation duration >12 months and baseline HBV DNA level < 1.0E+5IU/ml were lower than those of total course <24 months (P = 0.002), consolidation duration≤12 months (P = 0.011) and baseline HBV DNA level > 1.0E+7IU/ml (P = 0.01) respectively. Patients with HBV DNA≥1.0E+7IU/ml plus HBeAg<200COI at baseline had the highest relapse rate and cumulative relapse rate than the other three arms (P = 0.048 and 0.008 respectively). Logistic regression analysis demonstrated that baseline HBV DNA level, duration of consolidation therapy and combination of baseline HBV DNA and HBeAg (IgDNA/IgHBeAg) were independent factors to predict post-treatment relapse. The model based on baseline IgDNA/IgHBeAg and consolidation duration worked well in predicting post-treatment relapse in the prospective study and the accuracy, specificity, sensitivity, PPV and NPV for prediction were 80.3%, 81.1%, 79.2%, 73.1% and 85.7% respectively.ConclusionsVirological factors including baseline HBV DNA, HBeAg and treatment course were major influence factors associated with post-treatment relapse in eP-CHB. Patients with higher HBV DNA and lower HBeAg levels at baseline, shorter total course as well as consolidation therapy were more likely to develop relapse after discontinuation of therapy. The antiviral therapy in eP-CHB patients should be individually managed at different levels. It is better to treat those with higher viral load and lower HBeAg levels at baseline for a longer course, especially longer consolidation duration so as to decrease the relapse rate.

P057: Efficacy and safety of Peginterferon alfa‐2b (40 kD, Y Shape) (Pegberon) in HBeAg‐ positive CHB patients — a phase III, randomized, multicenter, positive‐controlled, open‐label clinical study

P057: Efficacy and safety of Peginterferon alfa‐2b (40 kD, Y Shape) (Pegberon) in HBeAg‐ positive CHB patients — a phase III, randomized, multicenter, positive‐controlled, open‐label clinical study

Distinct quasispecies characteristics and positive selection within the core gene in chronic hepatitis B virus infected child and adult patients.

There are significant differences in clinical characteristics between chronic hepatitis B virus infected (CHB) child and adult patients. Viral quasispecies characteristics are associated with its pathogenic properties. For hepatitis B virus (HBV), its core region is the main immune recognition region for its enriched epitopes. In our study, we discuss the quasispecies characteristics and positive selection within core gene within chronic HBV infected child and adult patients. By analyzing 170 core gene sequences from child CHB patients and 121 core genes sequences from adult CHB patients, quasispecies characteristics were described by sequence complexity, diversity, non-synonymous substitution ratio (dN) and synonymous substitution ratios (dS). In addition, positive selection sites were also determined by bioinformatics tools. Then, all these parameters were compared between child and adult CHB patient groups. Compared with child patients, adult patients with CHB showed distinct quasispecies characteristics within the core region, had a higher sequence complexity and diversity and more positive selection sites, suggesting that the adult CHB patients had a higher immune selection pressure on the HBV core gene. Reduced selection pressure on the HBV core gene in hepatitis B e antigen (HBeAg)-positive CHB patients than HBeAg negative CHB patients were observed in both adult and child patient groups. The majority of the screened positive selection sites lay within human leukocyte antigens (HLA)-restricted epitopes. In conclusion, this study analyzed the quasispecies characteristics discrepancy between child and adult patients with CHB, and revealed the possible reason for the distinct clinical characteristics in the perspective of population genetics.

O116 : Predictive value of baseline and on-treatment qHBsAg level in HBeAg positive CHB patients who switched from NUCs to pegylated interferon A-2A: A further analysis from new switch study

O116 : Predictive value of baseline and on-treatment qHBsAg level in HBeAg positive CHB patients who switched from NUCs to pegylated interferon A-2A: A further analysis from new switch study

Comparison of histology activity index scores in patients with HBeAg positive and HBeAg negative CHB to see difference in severity of liver injury

The aim of this study is to compare histology activity index (HAI) scores in patients with HBeAg positive and HBeAg negative CHB to see if there is any difference in severity of liver injury between these two types of HBV. We did percutaneous liver biopsies of 77 CHB patients. Serum HBeAg status were assessed in all study subjects. Of them, 37.66% patients (29/77) had HBeAg positive HBV infection, while the rest 62.33% (48/77) had HBeAg negative HBV infection. 22/48 (27.78%) patients with HBeAg negative CHB had mild to moderate CH (HAI score 4-12) and 26/48 (72.22%) patients had minimal CH (HAI score 1-3). In contrast, mild to moderate CH was seen in 19/29(72.23%) patients with HBeAg positive CHB. The study shows there is no correlation between the necro-inflammatory activity in the liver and HBeAg status in the ser um in patients with CHB. DOI: http://dx.doi.org/10.3329/bmj.v42i1.18970 Bangladesh Med J. 2013 Jan; 42 (1): 7-10

Expansion of circulating TFH cells and their associated molecules: involvement in the immune landscape in patients with chronic HBV infection

BackgroundBlood CXCR5+CD4+ T cells are defined as circulating T follicular helper (TFH) cells, which is required for effective humoral immunity. This study aimed to investigate the role of circulating TFH cells in patients with chronic hepatitis B virus (CHB) infection.MethodsThe frequency and phenotype of circulating TFH cells were monitored by flow cytometry in CHB patients and in healthy controls (HC). The expression of BCL-6, IL-21, IL-4, CXCR5, and IL-6R mRNA was analyzed using real-time PCR. Serum HBsAg, HBeAg, HBeAb, HBV DNA loads, ALT and AST were determined. The potential association of the frequency of TFH cells and their surface markers with clinical parameters was assessed.ResultsThe frequency of CXCR5+CD4+ T cells was increased in CHB patients and positively correlated with ALT and AST but not with HBV DNA loads. Moreover, an expansion of ICOS-, PD-1-, CD40L-, and IL-21R-expressing TFH cells occurred in CHB patients, but failed to correlate with ALT, AST and HBV DNA loads. Interestingly, the frequency of CXCR5+CD4+ T cells and ICOS+CXCR5+CD4+ T cells was significantly higher in HBeAg positive CHB patients than in HC. Additionally, the percentages of CXCR5+CD4+ T cells were positively correlated with AST, and ICOS-expressing CXCR5+CD4+ T cells were negatively correlated with HBV DNA loads. No significant differences in the frequency of CXCR5+CD4+ T cells were observed between inactive carrier (IC) patients and healthy controls. However, ICOS-, PD-1-, CD40L-expressing TFH cells were increased in IC patients and positively correlated with AST. Furthermore, the expression of BCL-6, IL-21, IL-4, CXCR5, and IL-6R mRNA in TFH cells was higher in CHB patients than in HC.ConclusionsThese data demonstrate that circulating TFH cells may participate in HBV-related immune responses. In addition to the frequency of TFH cells, the phenotype of these cells plays an important role in CHB patients.

412 PREVALENCE, VIROLOGICAL AND CLINICAL CHARACTERISTICS OF CHRONIC HEPATITIS DELTA VIRUS INFECTION (CHD) IN ROMANIA

receiving anti-viral therapy could be used as a response marker at baseline (BL), or early during treatment to predict treatment outcome. Methods: A prototype array-based assay served (IMPACT – Immunological Multi-Parameter Chip Technology, Roche Diagnostics) to determine HBsAg, anti-HBs and complex levels. We tested a panel of serum samples of 40 HBeAg-positive and 44 HBeAg negative patients who received pegylated interferon and adefovir for 48 weeks and were followed subsequently for 2 years. Results: HBsAg loss occurred in 4 of 40 HBeAg positive and 7 of 44 HBeAg negative patients. Sixteen of 40 HBeAg positive patients lost HBeAg and 13 of them formed anti-HBe. At BL complexes were present in 83 (99%) patients, whereas free anti-HBs levels were only detectable in 5 patients. Complex levels at BL and WK 12 were higher in HBeAg positive patients with HBeAg loss, compared to patients who retained HBeAg (p =0.0046 and p=0.026 respectively). ROC analysis for HBeAg loss in HBeAg positive patients at BL and WK 12 showed AUC 0.77 (p =0.004) and AUC 0.73 (p =0.026) for complex levels and AUC 0.57 (non significant) and AUC 0.61 (non significant) for HBsAg levels. We saw no correlation in either HBeAg-positive or -negative patients between complex levels and HBsAg loss. Nor did we find any correlation between complex and HBsAg or anti-HBs levels. Discussion: We demonstrated for the first time that before and during treatment HBsAg/anti-HBs immune complex levels can predict HBeAg loss in HBeAg positive CHB patients treated with peg-interferon and adefovir. Complexes were present in almost all patients at BL and were higher in patients that lost HBeAg. In conclusion, determining HBsAg/anti-HBs immune complex levels before and early during treatment could select CHB patients with an optimal chance to achieve HBeAg loss.

Pegylated interferon α modulates innate immunity in eAg positive chronic hepatitis B and determines changes in HBsAg quantification

IntroductionPegylated-Interferon a (PEG-IFNα) therapy provides sustained immune control and is associated with HBsAg loss and improved survival. Despite this, the immune mechanisms and timing of immunomodulatory effects remain ill-defined. Recent...

70 PEGYLATED INTERFERON ALPHA MODULATES INNATE IMMUNITY IN EAG POSITIVE CHRONIC HEPATITIS B AND DETERMINES CHANGES IN HBSAG QUANTIFICATION

Introduction Pegylated-Interferon a (PEG-IFNα) therapy provides sustained immune control and is associated with HBsAg loss and improved survival. Despite this, the immune mechanisms and timing of immunomodulatory effects remain ill-defined. Recent data has reported changes in a subset of NK cells in HBeAg negative disease which may predict response. This study evaluated the effects of PEG-IFNα on the innate immune response in eAg positive patients, a cohort known to respond favourably to interferon. Methods Paired PBMC samples were compared pre and during PEG-IFNα therapy from 16 patients. Changes in innate immune responses were evaluated at two on-treatment intervals, 12 and 24 weeks. The number, phenotype and function of NK cell populations were assessed. The expression of TNF related apoptosis inducing ligand (TRAIL) and the production of interferon γ (IFNγ) on the NK cell population was determined with flow cytometry. Changes in the innate response were correlated with HBsAg quantification (Abbott ARCHITECT). Results PEG-IFNα increased the CD56 bright NK cell population (CD56/CD16) by threefold (mean fold change; MFC 3.02, p=0.01) in all patients. This was associated with an overall decline in HBsAg 0.42 log and HBV DNA 2.5 log. Further increase in CD56 bright NK cells was noted from 12 to 24 weeks (MFC 2.3 vs 3.7). Consistent with this, HBsAg decline was also more marked at 24 weeks (mean decline log 0.13 vs 0.70). In the absence of HBsAg decline, there was no upregulation of CD56 bright NK cells. Upregulation of TRAIL expression was noted on this CD56 bright NK subset by more than twofold (MFC 2.44, p=0.009), this effect was more dramatic at 12 weeks (MFC 2.12 vs 2.72). A twofold increase in IFNγ producing CD56 bright NK cells was observed, (MFC 2.39, p=0.03); again this effect was more marked at 12 weeks (MFC 2.61 vs 2.01). Conclusion These data highlight the effects of PEG-IFNα on the innate immune response in eAg positive CHB. An upregulation of CD56 bright NK cells, their expression of TRAIL and IFNγ production presage a decline in HBsAg and HBV DNA. These changes observed at 12 weeks, are not reflected in concurrent HBsAg decline, but may predict sustained immune control in the longer term with a more marked HBsAg decline at 24 weeks.

Hyper-Activated Pro-Inflammatory CD16+ Monocytes Correlate with the Severity of Liver Injury and Fibrosis in Patients with Chronic Hepatitis B

BackgroundExtensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages.Methodology/Principal FindingsThe frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16+ subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16+ monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16− monocytes/macrophages. Furthermore, peripheral blood CD16+ monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores.ConclusionsThese distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease.

Combination Therapy of Pegylated Interferon alpha 2b (PegIFN) and Adefovir Dipivoxil (ADV) in Chronic Hepatitis B (CH-B) Patients Reduces the Reservoir of Transcriptionally Active cccDNA and Hepatitis B Surface Antigen (HBsAg)

Introduction: We previously demonstrated that 48 weeks of ADV therapy resulted in a significant median 73% reduction of serum HBsAg (Werle, Gastroenterology 2004). Changes in HBsAg were significantly and positively correlated with changes in intrahepatic cccDNA, total intrahepatocellular HBV DNA and serum HBV DNA. The number of HBcAg positive hepatocytes remained stable. Aim: To determine the reduction of serum HBsAg titer from baseline to end-of- treatment in CH-B patients undergoing antiviral combination therapy. Methods: 21/26 patients with HBeAg positive and negative CH-B completed a 48-week course of treatment with ADV and PegIFN in a single center pilot study as of September 2004. HBsAg was quantified in patient sera by ELISA using the Monolisa® AgHBs Ultra Kit (Biorad, France) with purified HBsAg as the standard (Hytest, Finland). Intrahepatic ccc- and HBV DNA was quantified as described earlier. Results: At baseline, median serum HBsAg titer was 257µg/ml. After 48 weeks of combination therapy median serum HBsAg titer decreased to 136µg/ml, a 47% reduction. cccDNA decreased from median 6 copies/hepatocyte to 0.2 copies/hepatocyte (–1.46log). Total intrahepatocellular HBV DNA was reduced by –2.1log10, serum HBV DNA decreased by–4.7log10. Changes in HBsAg were positively correlated with changes in total intracellular HBV DNA and serum HBV DNA. Conclusions: 48 weeks of combination therapy with PegIFN and ADV results in an approx. 50% decrease in serum HBsAg in chronic hepatitis B patients. Earlier studies suggested the decline in HBsAg titer during antiviral therapy with a nucleotide analogue due to the reduced reservoir of transcriptionally active cccDNA rather than to the loss of infected hepatocytes. Further analysis of this non-cytolytical mechanism for the clearance of HBV-infection is currently under way.