Control Of Hepatitis B Virus Infection Research Articles

Small Interfering RNA Screening for the Small GTPase Rab Proteins Identifies Rab5B as a Major Regulator of Hepatitis B Virus Production.

Viruses are considered to use vesicular trafficking in infected cells, but the details of assembly/release pathways of hepatitis B virus (HBV) are still unknown. To identify key regulators of HBV production, we performed short interfering RNA (siRNA) screening for Rab proteins, which are considered to act as molecular switches in vesicular trafficking using HepG2.2.15 cells. Among 62 Rab proteins, the suppression of Rab5B most significantly increased HBV DNA in the culture supernatant. Surprisingly, 5 days after the transfection of Rab5B siRNA, HBV DNA in the supernatant was increased more than 30-fold, reflecting the increase of infectious HBV particles. Northern blotting showed that transcription of 2.4/2.1-kb mRNA coding envelope proteins containing large hepatitis B surface protein (LHBs) was increased. Analysis of hepatocyte nuclear factors (HNFs) showed that transcription of HNF4α, which is known to enhance 2.4-kb mRNA transcription, was regulated by Rab5B. Also, it was revealed that LHBs had accumulated in the endoplasmic reticulum (ER) after Rab5B depletion but not in the multivesicular body (MVB), which is thought to be an organelle utilized for HBV envelope formation. Therefore, it was considered that Rab5B is required for the transport of LHBs from the ER to MVB. Immunofluorescent microscopy showed that HBs proteins, including LHBs, colocalized with HBc in the ER of Rab5B-depleted cells, suggesting that HBV envelopment occurs not only in the MVB but also in the ER. In conclusion, Rab5B is a key regulator of HBV production and could be a target of antiviral therapy.IMPORTANCE HBV infection is a worldwide health problem, but the mechanisms of how HBV utilizes cellular machinery for its life cycle are poorly understood. In particular, it has been unclear how the viral components and virions are transported among the organelles. The HBV budding site has been reported to be the ER or MVB, but it has not been clearly determined. In this study, siRNA-based screening of Rab proteins using HBV-expressing cells showed that Rab5B, one of the Rab5 isoforms, has important roles in late steps of the HBV life cycle. Although Rab5 is known to work on early endosomes, this study showed that Rab5B plays a role in the transport of LHBs between the ER and MVB. Furthermore, it affects the transcription of LHBs. This is the first report on the mechanisms of HBV envelope protein transport among the organelles, and the results provide important insights into the therapeutic control of HBV infection.

Contribution of sex‑based immunological differences to the enhanced immune response in female mice following vaccination with hepatitisB vaccine.

HepatitisB virus (HBV) vaccination is regarded as the most economical and effective method for the prevention and control of HBV infection, a major global health problem. Previous studies have suggested that there may be sex‑specific differences regarding the immune response to the HBV vaccine in humans; however, the mechanisms associated with these sex‑specific differences are yet to be elucidated. In the present study, sex‑based immunological differences in mice following HBV vaccination were investigated to determine the mechanisms underlying sexual dimorphism, with the aim of identifying potential targets for clinical intervention. Balb/c mice (n=6) were vaccinated intramuscularly on 3different days (days0,14and28) with the HBV vaccine. Sera were analyzed via ELISA for the presence of HBV surface antigen (HBsAg)‑specific immunoglobulinG(IgG), and of different IgG subtypes, 3weeks following the third injection. Enzyme‑linked immunosorbent spot assays were conducted to determine interleukin‑4/interferon‑γ secretion. Immunological memory stimulated by the vaccine was detected via flow cytometry analysis and ELISA 1week following the booster immunization. The seroconversion of the treated female group was higher compared with the male group at one week following the second vaccination. Female mice exhibited significantly increased HBsAg antibody titers compared with males at 1‑5weeks following the third vaccination. Sera obtained from vaccinated female mice exhibited markedly increased titers of IgG1 and IgG2b compared with those from male mice. Furthermore, female mice exhibited elevated cytotoxic Tlymphocyte responses and immune memory. Collectively, the results of the present study indicated that sex‑based immunological differences affected the dynamics and characteristics of the immune response in mice immunized with the HBV vaccine.

Chronic hepatitis B virus infection is associated with decreased serum 25(OH)D concentration in non-cirrhotic patients.

Aim of the studyRecent reports provide evidence for the immunomodulatory properties of vitamin D. Decreased vitamin D levels may contribute to the progression of liver disease in hepatitis B virus (HBV) infection. This study aims to assess serum 25(OH)D in patients with chronic HBeAg-negative HBV (CHB) infection at different phases of disease.Material and methodsFifty-eighty patients with CHB, 10 with a history of HBsAg/anti-HBs seroconversion, were enrolled. The control group consisted of 9 healthy volunteers. Serum 25(OH)D concentration was assessed by ELISA.ResultsSerum 25(OH)D concentration was significantly lower in the CHB group in comparison to the HC group. It did not differ across the consecutive phases of the HBeAg-negative HBV infection. Negative correlations between serum 25(OH)D and alanine aminotransferase (ALT) as well as frequency of peripheral blood monocytes were observed. Serum 25(OH)D in samples collected in winter was significantly lower in comparison to the pool of samples collected in the summer. Serum 25(OH)D concentration was not associated with the phases of HBV-infection, HBV viral load, APRI or liver histology.ConclusionsSerum 25(OH)D is significantly decreased in HBV infection irrespectively of the phase of the infection and negatively correlates with serum ALT level, which may reflect the deterioration of liver function. Based on our results, we can conclude that the role of vitamin D in the immune control of HBV infection is probably irrelevant.

Cell and Animal Models for Studying Hepatitis B Virus Infection and Drug Development

Many cell culture and animal models have been used to study hepatitis B virus (HBV) replication and its effects in the liver; these have facilitated development of strategies to control and clear chronic HBV infection. We discuss the advantages and limitations of systems for studying HBV and developing antiviral agents, along with recent advances. New and improved model systems are needed. Cell culture systems should be convenient, support efficient HBV infection, and reproduce responses of hepatocytes in the human body. We also need animals that are fully permissive to HBV infection, convenient for study, and recapitulate human immune responses to HBV and effects in the liver. High-throughput screening technologies could facilitate drug development based on findings from cell and animal models.

REP 2139: Antiviral Mechanisms and Applications in Achieving Functional Control of HBV and HDV Infection.

Nucleic acid polymers (NAPs) are broad spectrum antiviral agents whose antiviral activity in hepatitis B virus (HBV) infection is derived from their ability to block the release of the hepatitis B virus surface antigen (HBsAg). This pharmacological activity blocks replenishment of HBsAg in the circulation, allowing host mediated clearance. This effect has important clinical significance as the clearance of circulating HBsAg dramatically potentiates the ability of immunotherapies to restore functional control of HBV infection which persists after antiviral therapy is removed. These effects are reproducible in preclinical evaluations and in several clinical trials that have evaluated the activity of the lead NAP, REP 2139, in monotherapy and in combination with immunotherapy in hepatitis B e antigen (HBeAg) negative and HBeAg positive HBV infection and also in HBeAg negative HBV/hepatitis D virus (HDV) coinfection. These antiviral effects of REP 2139 are achieved in the absence of any direct immunostimulatory effect in the liver and also without any discernible direct interaction with viral components. The search for the host protein interaction with NAPs that drives their antiviral effects is ongoing, and the interaction targeted by REP 2139 within infected cells has not yet been elucidated. This article provides an updated review of available data on the effects of REP 2139 in HBV and HDV infection and the ability of REP 2139-based combination therapy to achieve functional control of HBV and HDV infection in patients.

Epidemiological study of hepatitis B and hepatitis C infections in Northeastern China and the beneficial effect of the vaccination strategy for hepatitis B: a cross-sectional study

BackgroundViral hepatitis, mainly hepatitis B and C, is a serious public health problem worldwide. In China, the prevalence of hepatitis B virus (HBV) infection remains high, while that of hepatitis C virus (HCV) infection is controversial. This study investigated the epidemiology of HBV and HCV infections and assessed the beneficial effect of the vaccination strategy for hepatitis B in Northeastern China.MethodsFrom June 2016 to August 2016, 6541 residents of Changchun in Northeastern China were recruited for this cross-sectional study. Demographic characteristics as well as HBV and HCV serological test results were reviewed and analyzed.ResultsAmong all study participants, 3.8% and 0.36% tested positive for hepatitis B surface antigen (HBsAg) and anti-HCV, respectively. The HBsAg- and anti-HCV-positive rates were significantly higher in male participants (4.58% and 0.43%) than in female individuals (3.0% and 0.33%). Notably, among all age groups, the lowest rate of HBsAg positivity (0.2%) was found in children born after the implementation of the vaccination strategy for hepatitis B. Conversely, participants aged 40–49 years had significantly greater positive rates of HBsAg (5.9%) compared with those of other age groups. Furthermore, the highest rates of anti-HCV positivity (1.1%) were observed in participants aged 50–59 years.ConclusionsThe rate of HBsAg-positivity declined significantly following successful implementation of the policy on hepatitis B vaccination, indicating a beneficial impact on the control of HBV infection. However, only a slight decrease was observed in the anti-HCV–positivity rate, identifying an area in need of improvement within viral hepatitis prevention and control programs in China.

Pre-Activation of Toll-Like Receptor 2 Enhances CD8+ T-Cell Responses and Accelerates Hepatitis B Virus Clearance in the Mouse Models

Toll-like receptors (TLRs) play a crucial role in activation of innate immunity, which is essential for inducing effective adaptive immune responses. Our previous studies have shown that toll-like receptor 2 (TLR2) is required to induce effective virus-specific T-cell responses against hepatitis B virus (HBV) in vivo. However, the contribution of TLR2 activation to adaptive immunity and HBV clearance remains to be clarified. In this study, we explored the hydrodynamic injection (HI) mouse models for HBV infection and examined how the TLR2 agonist Pam3CSK (P3C) influences HBV control and modulates HBV-specific T-cell response if applied in vivo. We found that TLR2 activation by P3C injection leads to the rapid but transient production of serum proinflammatory factors interleukin-6 and tumor necrosis factor-α and activation of CD8+ T cells in vivo. Then, the anti-HBV effect and HBV-specific T-cell immunity were investigated by TLR2 activation in the mouse models for persistent or acute HBV infections using HBV plasmids pAAV-HBV1.2 and pSM2, respectively. Both P3C application at early stage and pre-activation promoted HBV clearance, while only TLR2 pre-activation enhanced HBV-specific T-cell response in the liver. In the mouse model for acute HBV infection, P3C application had no significant effect on HBV clearance though P3C significantly enhanced the HBV-specific T-cell response. Collectively, TLR2 pre-activation enhances HBV-specific T-cell responses and accelerates HBV clearance in HI mouse models. Thus, the modulation of host immune status by TLR2 agonists may be explored for immunotherapeutic strategies to control HBV infection.

Is it possible to stop nucleos(t)ide analogue treatment in chronic hepatitis B patients?

Chronic hepatitis B (CHB) remains a challenging global health problem, with nearly one million related deaths per year. Nucleos(t)ide analogue (NA) treatment suppresses viral replication but does not provide complete cure of the hepatitis B virus (HBV) infection. The accepted endpoint for therapy is the loss of hepatitis B surface antigen (HBsAg), but this is hardly ever achieved. Therefore, indefinite treatment is usually required. Many different studies have evaluated NA therapy discontinuation after several years of NA treatment and before HBsAg loss. The results have indicated that the majority of patients can remain off therapy, with some even reaching HBsAg seroconversion. Fortunately, this strategy has proved to be safe, but it is essential to consider the risk of liver damage and other comorbidities and to ensure a close follow-up of the candidates before considering this strategy. Unanswered questions remain, namely in which patients could this strategy be effective and what is the optimal time point at which to perform it. To solve this enigma, we should keep in mind that the outcome will ultimately depend on the equilibrium between HBV and the host’s immune system. Viral parameters that have been described as good predictors of response in HBeAg(+) cases, have proven useless in HBeAg(-) ones. Since antiviral immunity plays an essential role in the control of HBV infection, we sought to review and explain potential immunological biomarkers to predict safe NA discontinuation in both groups.

Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iVα7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection

Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iVα7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iVα7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA-4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iVα7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iVα7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1.

MAGT1-mediated disturbance of Mg2+ homeostasis lead to exhausted of HBV-infected NK and CD8+ T cells

The magnesium transporter 1 (MAGT1) is a critical regulator of basal intracellular free magnesium ([Mg2+]i) levels. It has been shown that MAGT1 was involved in the disorder in Mg2+ homeostasis after Epstein-Barr virus (EBV) infection. Here, we identified the effects of MAGT1-mediated disturbance of Mg2+ homeostasis on chronic hepatitis B virus (HBV)-infected natural killer (NK) and CD8+ T cells. The expression of MAGT1 was gradually decreased with the increase of infected time in CD8+ T cells, but not with that in NK cells, of the patients. Decreased level of intracellular free Mg2+ ([Mg2+]i) leads to defective expression of programmed cell death 1 (PD-1) and the NK activating receptor (NKG2D) in NK and CD8+ T cells. Our data illustrate that [Mg2+]i plays a key role in control of HBV infection.

Safety and efficacy of REP 2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial

REP 2139 clears circulating hepatitis B virus (HBV) surface antigen (HBsAg), enhancing the restoration of functional control of HBV infection by immunotherapy. We assessed the safety and efficacy of REP 2139 and pegylated interferon alfa-2a in patients with chronic HBV and hepatitis D virus (HDV) co-infection. In this open-label, non-randomised, phase 2 trial, patients aged 18-55 years, who were treatment naive, hepatitis B e antigen [HBeAg] negative, anti-hepatitis D antigen [HDAg] positive, and HDV RNA positive, with serum HBsAg concentrations of more than 1000 IU/mL, and a history of HDV infection for 6 months or more before treatment, were recruited at Toma Ciorbă Hospital of Infectious Diseases in Chișinău, Moldova. Patients were excluded if they had HDV superinfection, liver infections other than HBV and HDV, or liver cirrhosis. Patients received 500 mg intravenous REP 2139 once per week for 15 weeks, followed by combined therapy with 250 mg intravenous REP 2139 and 180 μg subcutaneous pegylated interferon alfa-2a once per week for 15 weeks, then monotherapy with 180 μg pegylated interferon alfa-2a once per week for 33 weeks. The primary endpoints assessed at the end of treatment were the safety and tolerability of the treatment regimen, analysed in the intention-to-treat population. Secondary outcomes included the proportion of patients with serum HBsAg less than 50 IU/mL, the proportion of patients with suppressed HBV DNA, and the proportion of patients who maintained these responses through follow-up. The REP 301 trial is registered with ClinicalTrials.gov, number NCT02233075. We also did an additional follow-up at 1 year after the end of treatment, as an interim analysis of the REP 301-LTF trial (planned duration 3 years), registered with ClinicalTrials.gov, number NCT02876419, which is ongoing but not recruiting patients. Between Sept 8, 2014, and Jan 27, 2015, we enrolled 12 patients into the REP 301 study. All 12 patients experienced at least one adverse event during treatment: two (17%) patients experienced anaemia, eight (67%) neutropenia, and ten (83%) thrombocytopenia. Five (42%) patients had raised alanine aminotransferase levels, four (33%) had raised aspartate aminotransferase levels, and two (17%) had increased bilirubin concentrations. Four (33%) patients had a serious adverse event, and 12 (100%) patients had treatment-emergent lab abnormalities. Six patients had HBsAg levels less than 50 IU/mL by the end of treatment (all <0·05 IU/mL); five maintained this level of suppression at the end of 1 year follow-up. Six patients had hepatitis B surface antibody (anti-HBs) titres above 10 mIU/mL at the end of treatment (five had maximum anti-HBs concentrations of 7681-86 532 mIU/mL during treatment), which were maintained at the end of 1 year follow-up in these five patients. Elevated alanine and aspartate aminotransferase concentrations and profound elevations of anti-HBs titres were restricted to patients who had HBsAg levels of less than <1 IU/mL before the introduction of pegylated interferon alfa-2a. Nine patients had suppressed HBV DNA (<10 IU/mL]) at the end of treatment, which was maintained by seven patients and newly established in an eighth patient at the end of 1 year follow-up. 11 patients became HDV RNA negative during treatment, with nine remaining HDV RNA negative at the end of treatment; seven of these patients remained HDV RNA negative by the end of 1 year follow-up. By the end of 1 year follow-up, normalisation of serum aminotransferases occurred in nine of 12 patients. Combined REP 2139 and pegylated interferon alfa-2a therapy is safe, well tolerated, and establishes functional control of HBV and HDV co-infection and normalisation of serum aminotransferases in a high proportion of patients 1 year after therapy. This combination therapy approach might provide a new treatment option for patients with HBV and HDV co-infection. Replicor.

Estimating the Prevalence of Hepatitis B Virus Infection and Exposure Among General Population in Iran

Context: Accurate and updated data describing hepatitis B virus (HBV) epidemiology is crucial for development of national policies to control HBV infection in each country. This study was conducted to estimate the prevalence of HBV infection and exposure in Iran, using the available provincial data. Methods: MEDLINE, Web of Science, Scopus, Google Scholar, and Scientific Information Database were searched for studies assessing the prevalence of hepatitis B surface antigen (HBs Ag) or hepatitis B core antibody (anti-HBc Ab) among the general population between 2006 and 2016 in at least one city of Iran. National prevalence was estimated by two methods. Method 1 used only prevalence estimates of provinces with available survey data. In method 2, all provinces were classified based on the risk of HBV infection among blood donors. HBV prevalence in provinces with missing data was extrapolated from the provinces with available data, and with comparable risk of HBV infection among blood donors. In both methods, national prevalence was estimated using pooled provincial prevalence estimates, weighted by the province population size. Results: Thirteen studies from 12 provinces were included. The prevalence of HBs Ag and anti-HBc Ab varied markedly across provinces. Provincial HBs Ag prevalence ranged from 0.76% to 5.10% (I-square = 91.7%) and provincial anti-HBc Ab prevalence ranged from 4.17% to 36.90% (I-square = 99.3%). Using method 1, the national prevalence of HBs Ag and anti-HBc Ab was estimated as 1.84% (95%CI: 1.61%, 2.09%), and 13.59% (95%CI: 12.92%, 14.29%), respectively. Using method 2, the national prevalence of HBs Ag was estimated as 1.79% (95% uncertainty range: 1.67%, 1.91%), equating to 1,347,000 (1,253,000 - 1,434,000) individuals living with chronic HBV infection in Iran. The prevalence of HBs Ag and anti-HBc Ab was higher among men compared to women. Conclusions: HBV prevalence in Iran is low, and has decreased over past decades. However, the risk of HBV infection varies across provinces with some provinces having high HBV prevalence. More detailed data of the HBV epidemiology and transmission in provinces where HBV infection is endemic could support designing the appropriate interventions to control HBV epidemics.

Immune response to hepatitis B vaccine among north Iranian healthcare workers and its related factors.

Hepatitis B virus (HBV) is an important occupational risk among healthcare workers (HCWs). Vaccination is the most cost-effective method of preventing and controlling HBV infection. Several factors have been suggested to effect response to the vaccine. The present study aimed to evaluate vaccine response among north Iranian HCWs and to determine the factors influencing vaccine response. Response to the standard three-dose vaccination regimen was evaluated in term of anti-hepatitis B surface antigen level among 1,010 HCWs using an enzyme-linked immunosorbent assay (ELISA) method. Logistic regression was applied to predict antibody response, with related factors including sex, age, years of working experience, marital status, history of transfusion, smoking, history of needle stick injury, rheumatic disease, steroid use, and elapsed time from vaccination measurement. Of the 1,010 HCWs, 898 (88.9%) acquired protective levels of antibody (> 10 IU/mL). Compared with those < 30 years of age, HCWs older than 50 years and between 40 and 50 years of age were more likely to have non-protective anti-HBs levels (odds ratio = 4.48; p = 0.001 and odds ratio = 1.85; p = 0.03, respectively). HBV vaccine efficacy and immune response were satisfactory among north Iranian HCWs. Since it is predicted that anti-HBs levels decrease with aging, testing for anti-HBs titer is desirable for HCWs older than 50 years of age.

IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection.

The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-betloEomesloBlimp-1hiHobitlo T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69+CD103+ CXCR6+CXCR3+). These tissue-resident memory T cells (TRM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFβ induces liver-adapted TRM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFNγ production, equip liver CD8 TRM to survive while exerting local noncytolytic hepatic immunosurveillance.

Hepatitis B Virus Immunopathology, Model Systems, and Current Therapies.

Most people develop acute hepatitis B virus (HBV)-related hepatitis that is controlled by both humoral and cellular immune responses following acute infection. However, a number of individuals in HBV-endemic areas fail to resolve the infection and consequently become chronic carriers. While a vaccine is available and new antiviral drugs are being developed, elimination of persistently infected cells is still a major issue. Standard treatment in HBV infection includes IFN-α, nucleoside, or nucleotide analogs, which has direct antiviral activity and immune modulatory capacities. However, immunological control of the virus is often not durable. A robust T-cell response is associated with control of HBV infection and liver damage; however, HBV-specific T cells are deleted, dysfunctional, or become exhausted in chronic hepatitis patients. As a result, efforts to restore virus-specific T-cell immunity in chronic HBV patients using antiviral therapy, immunomodulatory cytokines, or therapeutic vaccination have had little success. Adoptive cell transfer of T cells with specificity for HBV antigen+ cells represents an approach aiming to ultimately eliminate residual hepatocytes carrying HBV covalently closed circular DNA (cccDNA). Here, we discuss recent findings describing HBV immunopathology, model systems, and current therapies.

Challenges in warranting access to prophylaxis and therapy for hepatitis B virus infection.

Despite an available vaccine and efficient treatment for hepatitis B virus (HBV) infection, chronic HBV infection still remains a major global threat, and one of the top 20 causes of human mortality worldwide. One of the major challenges in controlling HBV infection is the high number of undiagnosed chronic carriers and the lack of access to prophylaxis and treatment in several parts of the world. We discuss relevant barriers that need to be overcome to achieve global control of HBV infection and make eradication possible. Most important, vaccination must be scaled-up to lower the risk of vertical transmission and decrease the number of new infections, and comprehensive screening programs must be linked to care to obtain a better rate of diagnosis and treatment. This can probably only be achieved if sustainable funding is available. We therefore emphasize the importance of making the management of viral hepatitis a global health priority.

Prevalence and predictors of hepatitis B in Jeddah City, Saudi Arabia: a population-based seroprevalence study.

Despite solid preventive strategies to reduce the risk of hepatitis B virus (HBV) infection, recent reports about its prevalence and predictors are lacking in several Saudi cities at the community level. This study aimed to assess the seroprevalence of HBV and to identify the most important predictors among the Saudi population in Jeddah city, Saudi Arabia. A cross-sectional study was conducted among 5,584 Saudi people attending primary health-care centers in Jeddah city during 2012/2013. Sociodemographic and hepatitis-related data were collected. HBV was diagnosed by ELISA test. The seroprevalence of HBV was estimated, and appropriate statistical analyses were performed, including univariate and multivariable regression analyses. The seroprevalence of HBV was 2.2% (95% CI = 1.82-2.58) in the studied participants. The prevalence was higher among non-governmental workers (3.5%), male participants (3.4%) and those aged ≥ 25 years (2.4%). The most important predictors for increasing the risk of HBV in this study were HBV contacts, male sex, history of dental procedures and blood transfusion. The significant positive risks associated with these predictors were 3.3, 2.5, 2.0 and 1.65, respectively. HBV vaccination, on the other hand, was associated with a significant risk reduction of 88% (OR = 0.12; 95% CI = 0.03-0.51). The seroprevalence of HBV was relatively low among the Saudi population in Jeddah city reflecting the actions taken by health authorities to control HBV infection. However, more efforts, particularly in relation to health education programmes, strict control of blood banks and dental clinics, are still needed.

Complete hepatitis B virus prophylaxis withdrawal in hepatitis B surface antigen-positive liver transplant recipients after longterm minimal immunosuppression.

Tailored approaches have been attempted to prevent hepatitis B virus (HBV) reinfection in antibodies against hepatitis B surface antigen (HBsAg)-positive liver transplantation (LT) recipients in order to minimize the use of hepatitis B immune globulin (HBIG) and nucleoside analogues (NAs). We report the results of complete HBV prophylaxis withdrawal after a follow-up of at least 6 years in LT recipients with undetectable serum HBV DNA and intrahepatic total HBV DNA and covalently closed circular DNA at LT. We included 30 HBsAg positive, hepatitis B e antigen-negative recipients, 6 with hepatitis C virus and 7 with hepatitis D virus coinfection, who had received HBIG plus NA for at least 5 years after LT. Stepwise HBIG and NA withdrawal was performed in two 6-month periods under strict monitoring of HBV virology. All patients underwent a clinical, biochemical, and virological follow-up at 3-6 month intervals. HBV recurrence (HBsAg seroreversion ± detectable HBV DNA) occurred in 6 patients: in 1 patient after HBIG interruption and in 5 after both HBIG and NA cessation. Only 3 patients required reinstitution of HBV prophylaxis because of persistent HBV replication, and all achieved optimal control of HBV infection and did not experience clinical events. The other who recurred showed only short-lasting HBsAg positivity, with undetectable HBV DNA, followed by spontaneous anti-HBs seroconversion. An additional 15 patients mounted an anti-HBs titer, without previous serum HBsAg detectability. At the end of follow-up, 90% of patients were still prophylaxis-free, 93.3% were HBsAg negative, and 100% were HBV DNA negative; 60% had anti-HBs titers >10 IU/L (median, 143; range, 13-1000). This small series shows that complete prophylaxis withdrawal is safe in patients transplanted for HBV-related disease at low risk of recurrence and is often followed by spontaneous anti-HBs seroconversion. Further studies are needed to confirm this finding. Liver Transplantation 22 1205-1213 2016 AASLD.

Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection.

Hepatitis B virus (HBV) is a major human pathogen, and about one third of the global population will be exposed to the virus in their lifetime. HBV infects hepatocytes, where it replicates its DNA and infection can lead to acute and chronic hepatitis with a high risk of liver cirrhosis and hepatocellular carcinoma. Despite this, there is limited understanding of how HBV establishes chronic infections. In recent years it has emerged that foreign DNA potently stimulates the innate immune response, particularly type 1 interferon (IFN) production; and this occurs through a pathway dependent on the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate synthase and the downstream adaptor protein stimulator of IFN genes (STING). In this work we describe that human and murine hepatocytes do not express STING. Consequently, hepatocytes do not produce type 1 IFN in response to foreign DNA or HBV infection and mice lacking STING or cyclic guanosine monophosphate-adenosine monophosphate synthase exhibit unaltered ability to control infection in an adenovirus-HBV model. Stimulation of IFN production in the murine liver by administration of synthetic RNA decreases virus infection, thus demonstrating that IFN possesses anti-HBV activity in the liver. Importantly, introduction of STING expression specifically in hepatocytes reconstitutes the DNA sensing pathway, which leads to improved control of HBV in vivo. The lack of a functional innate DNA-sensing pathway in hepatocytes hampers efficient innate control of HBV infection; this may explain why HBV has adapted to specifically replicate in hepatocytes and could contribute to the weak capacity of this cell type to clear HBV infection. (Hepatology 2016;64:746-759).

Hepatitis B virus dampens autophagy maturation via negative regulation of Rab7 expression

Hepatitis B virus (HBV) infection brings a huge challenge for medical health practitioners. It has been reported that invaded HBV escapes autophagic degradation through inhibiting lysosome maturation following enhanced autophagy formation, which putatively contributes to HBV replication and infection. However, the underlying mechanism by which HBV escapes from autophagic degradation remains elusive. In this study, we monitored the autophagic process using HepG2 cells and mice without or with transient HBV DNA plasmid transfection (pHepG2) or stable HBV infection (HepG2.2.15 cells) in vitro and in vivo. The results of Western blot, transmission electron microscopy and confocal microscopy, confirmed that HBV induced autophagy, while the fusion of autophagosomes with lysosomes was arrested. Furthermore, Rab7, a small GTPase that functions as a molecular switch responsible for the autophagosome-lysosome fusion, was inhibited, suggesting a potential mechanism for HBV-induced inhibition of autophagic degradation. In conclusion, our study proposes a potential mechanism for how HBV escapes autophagic degradation, which might be a novel therapeutic target for controlling HBV infection.