A Model of Care Optimized for Marginalized Remote Population Unravels Migration Pattern in India.

BACKGROUND AND AIMS: Access to basic health needs remains a challenge for most of world's population. In this study, we developed a care model for preventive and disease-specific health care for an extremely remote and marginalized population in Arunachal Pradesh, the northeasternmost state of India. APPROACH AND RESULTS: We performed patient screenings, performed interviews, and obtained blood samples in remote villages of Arunachal Pradesh through a tablet-based data collection application, which was later synced to a cloud database for storage. Positive cases of hepatitis B virus (HBV) were confirmed and genotyped in our central laboratory. The blood tests performed included liver function tests, HBV serologies, and HBV genotyping. HBV vaccination was provided as appropriate. A total of 11,818 participants were interviewed, 11,572 samples collected, and 5,176 participants vaccinated from the 5 westernmost districts in Arunachal Pradesh. The overall hepatitis B surface antigen (HBsAg) prevalence was found to be 3.6% (n = 419). In total, 34.6% were hepatitis B e antigen positive (n = 145) and 25.5% had HBV DNA levels greater than 20,000 IU/mL (n = 107). Genotypic analysis showed that many patients were infected with HBV C/D recombinants. Certain tribes showed high seroprevalence, with rates of 9.8% and 6.3% in the Miji and Nishi tribes, respectively. The prevalence of HBsAg in individuals who reported medical injections was 3.5%, lower than the overall prevalence of HBV. CONCLUSIONS: Our unique, simplistic model of care was able to link a highly resource-limited population to screening, preventive vaccination, follow-up therapeutic care, and molecular epidemiology to define the migratory nature of the population and disease using an electronic platform. This model of care can be applied to other similar settings globally.

HBV infection-induced liver cirrhosis development in dual-humanised mice with human bone mesenchymal stem cell transplantation.

OBJECTIVE: Developing a small animal model that accurately delineates the natural history of hepatitis B virus (HBV) infection and immunopathophysiology is necessary to clarify the mechanisms of host-virus interactions and to identify intervention strategies for HBV-related liver diseases. This study aimed to develop an HBV-induced chronic hepatitis and cirrhosis mouse model through transplantation of human bone marrow mesenchymal stem cells (hBMSCs). DESIGN: Transplantation of hBMSCs into Fah-/-Rag2-/-IL-2Rγc-/- SCID (FRGS) mice with fulminant hepatic failure (FHF) induced by hamster-anti-mouse CD95 antibody JO2 generated a liver and immune cell dual-humanised (hBMSC-FRGS) mouse. The generated hBMSC-FRGS mice were subjected to assessments of sustained viremia, specific immune and inflammatory responses and liver pathophysiological injury to characterise the progression of chronic hepatitis and cirrhosis after HBV infection. RESULTS: The implantation of hBMSCs rescued FHF mice, as demonstrated by robust proliferation and transdifferentiation of functional human hepatocytes and multiple immune cell lineages, including B cells, T cells, natural killer cells, dendritic cells and macrophages. After HBV infection, the hBMSC-FRGS mice developed sustained viremia and specific immune and inflammatory responses and showed progression to chronic hepatitis and liver cirrhosis at a frequency of 55% after 54 weeks. CONCLUSION: This new humanised mouse model recapitulates the liver cirrhosis induced by human HBV infection, thus providing research opportunities for understanding viral immune pathophysiology and testing antiviral therapies in vivo.

Phenotype and function of HBV-specific T cells is determined by the targeted epitope in addition to the stage of infection.

OBJECTIVE: Chronic HBV infection affects more than 250 million people worldwide and remains a global healthcare problem in part because we lack curative treatment. Sustained viral control requires HBV-specific T cells, but these become functionally impaired in chronic infection. Clinical evidence indicates that functional cure of HBV infection by the host immune response is feasible. Developing T cell-based therapies able to achieve functional cure will require identification of the requirements for a successful T cell response against HBV and the relative contribution of individual T cell specificities to HBV control. DESIGN: The phenotype and function of HBV-specific T cells were studied directly ex vivo using fluorochrome-labelled multimers. We studied multiple HBV-specific T cell specificities targeting different HBV proteins in individuals with either an acute self-limiting or chronic HBV infection. RESULTS: We detected strong T cell responses targeting multiple HBV viral proteins in acute self-limiting and low-frequency core and polymerase-specific T cells in chronic infection. Expression of the T cell inhibitory receptor PD-1, as well as T cell differentiation, T cell function and T cell regulation differed by stages and outcomes of infection. In addition, these features differed significantly between T cells targeting different HBV specificities. CONCLUSION: HBV-specific T cells with different target specificities are characterised by distinct phenotypical and functional profiles. These results have direct implications for the design of immunological studies in HBV infection, and are potentially relevant for informing immunotherapeutic approaches to induce functional cure.

Phenotypic and functional differences of HBV core-specific versus HBV polymerase-specific CD8+ T cells in chronically HBV-infected patients with low viral load.

OBJECTIVE: A hallmark of chronic HBV (cHBV) infection is the presence of impaired HBV-specific CD8+ T cell responses. Functional T cell exhaustion induced by persistent antigen stimulation is considered a major mechanism underlying this impairment. However, due to their low frequencies in chronic infection, it is currently unknown whether HBV-specific CD8+ T cells targeting different epitopes are similarly impaired and share molecular profiles indicative of T cell exhaustion. DESIGN: By applying peptide-loaded MHC I tetramer-based enrichment, we could detect HBV-specific CD8+ T cells targeting epitopes in the HBV core and the polymerase proteins in the majority of 85 tested cHBV patients with low viral loads. Lower detection rates were obtained for envelope-specific CD8+ T cells. Subsequently, we performed phenotypic and functional in-depth analyses. RESULTS: HBV-specific CD8+ T cells are not terminally exhausted but rather exhibit a memory-like phenotype in patients with low viral load possibly reflecting weak ongoing cognate antigen recognition. Moreover, HBV-specific CD8+ T cells targeting core versus polymerase epitopes significantly differed in frequency, phenotype and function. In particular, in comparison with core-specific CD8+ T cells, a higher frequency of polymerase-specific CD8+ T cells expressed CD38, KLRG1 and Eomes accompanied by low T-bet expression and downregulated CD127 indicative of a more severe T cell exhaustion. In addition, polymerase-specific CD8+ T cells exhibited a reduced expansion capacity that was linked to a dysbalanced TCF1/BCL2 expression. CONCLUSIONS: Overall, the molecular mechanisms underlying impaired T cell responses differ with respect to the targeted HBV antigens. These results have potential implications for immunotherapeutic approaches in HBV cure.

CD8+CD28- T cells: key cytotoxic players impacting disease pathogenesis in chronic HBV infection.

During chronic hepatitis B (CHB), CD8+ T cells down-regulate CD28, the primary co-stimulation molecule for T-cell activation. Diverse functional attributes of CD8+CD28- T cells are suggested in various disease contexts. The present study aimed to characterize CD8+CD28- T cells in different phases of chronic Hepatitis B virus (HBV) infection (CHI)- Immune-tolerance (IT), Hepatitis B e-antigen-positive CHB (EP-CHB), Inactive carriers (IC) and Hepatitis B e-antigen-negative CHB (EN-CHB), to appraise their contribution in HBV-related disease pathophysiology. Flow cytometry analysis of T cells in peripheral blood of study subjects revealed enhanced CD8+CD28- T-cell accumulation in EP-/EN-CHB, compared with IT/IC and they expanded equivalently in HBV-specific and non-specific CD8+ T-cell compartments. Profound increase in CD8+CD28- T cells expressing perforin/granzyme-B/CD57/IFN-γ/TNF-α and markers of terminal differentiation were observed exclusively in EP-/EN-CHB. Further, activation with anti-NKG2D resulted in heightened IFN-γ/TNF-α production selectively from CD8+CD28- T cells, suggesting NKG2D-mediated alternative co-stimulation. CD8+CD28- T cells sorted from CHB patients induced enhanced apoptosis of peripheral blood mononuclear cells (PBMC), including CD4+ T cells. However, NKG2D-ligand (major histocompatibility complex class I chain-related molecule A/B (MICA/B)) was preferentially expressed by HBV-specific CD4+ T cells of CHB patients, making these cells a potential target to NKG2D-dependent CD8+CD28- T-cell killing. Both CD28+ and CD28- T cells in CHB expressed CXCR3 at similar levels and thus capable of homing to the liver. A positive correlation was seen between CD8+CD28- T-cell frequency and serum-alanine transaminase (ALT) levels and CHB-derived CD8+CD28- T cells caused pronounced cell death in HBV-transfected Huh7 cells. Immunofluorescence staining identified greater intrahepatic incidence of CD8+CD28- T cells but decline in CD4+ T cells in CHB than IC. Collectively, CD8+CD28- T cells demonstrated differential distribution and phenotypic/functional skewing in different CHI phases and contribute to disease progression by Perforin-Granzyme- or IFN-γ-TNF-α-mediated cytotoxicity while restraining antiviral immunity through NKG2D-dependent HBV-specific CD4+ T-cell depletion.

Toll-like receptors, long non-coding RNA NEAT1, and RIG-I expression are associated with HBeAg-positive chronic hepatitis B patients in the active phase.

BACKGROUND: Innate immunity plays a crucial role in host-virus interactions and greatly influences viral replication including HBV infection. However, few studies have investigated the possible antiviral immune roles played by TLRs, RIG-I, and long no-coding RNA NEAT1 in chronic HBV infection (CHB) patients in clinical samples and their relationships among immune responses. In this study, we sought to investigate the mRNA expression levels of TLR1-10, RIG-I, and NEAT1 expression in HBeAg-positive CHB treatment-naïve patients with the active phase. METHODS: The expression levels of TLR1-10, RIG-I, and NEAT1 of CHB patients with the active phase and healthy controls were measured by qPCR. Serum HBV DNA and routine liver biochemistry including ALT, etc were also measured to evaluate the impaired physiological function of the liver affected by CHB. RESULTS: The expression levels of TLR1 and TLR6 in CHB with active phase were remarkably lower than that in healthy controls. The levels of TLR3 in CHB patients with active phase were remarkably higher than that in healthy controls. The total NEAT1 expression was abnormally decreased in CHB patients as compared with healthy controls. The levels of RIG-I were significantly decreased in CHB patients in the active phase when compared to healthy controls. The expression of TLR6 and RIG-I was closely correlated with NEAT1 expression. TLR6 level was positively correlated with RIG-I level. CONCLUSION: Chronic HBV infection can alter the innate immune response by downregulating functional expression of TLR1, TLR6, NEAT1.

Psoriatic patients with chronic viral hepatitis do not have an increased risk of liver cirrhosis despite long-term methotrexate use: Real-world data from a nationwide cohort study in Taiwan.

BACKGROUND: Methotrexate (MTX) is commonly used in the treatment of patients with moderate-to-severe psoriasis. OBJECTIVE: We conducted a nationwide population-based cohort study to investigate the impact of long-term MTX use on the risk of chronic viral hepatitis-related cirrhosis among psoriatic patients in Taiwan. METHODS: This study obtained data from the National Health Insurance Research Database in Taiwan. We identified 2417 psoriatic patients with chronic hepatitis B (CHB) (370 MTX users and 2047 nonusers of MTX) and 1127 psoriatic patients with chronic hepatitis C (CHC) (174 MTX users and 953 nonusers of MTX) from January 1, 2000, to December 31, 2010. RESULTS: After a mean follow-up of more than 9 years since the diagnosis of chronic viral hepatitis, a total of 125 patients with CHB (5%) and 120 patients with CHC (11%) developed liver cirrhosis. Comparable proportions of MTX users and nonusers of MTX developed liver cirrhosis (4% vs 5% in patients with CHB and 11% vs 11% in patients with CHC [both P >.05]). LIMITATIONS: There is possible selection bias and medication nonadherence. CONCLUSION: Our real-world data show that long-term MTX use may not be associated with an increased risk of liver cirrhosis among psoriatic patients with chronic viral hepatitis.

Interleukin-35 Level Is Elevated in Patients with Chronic Hepatitis B Virus Infection.

Backgrounds: As one of the major public health problems, the hepatitis B virus (HBV) infection would activate the immune system. The outcome of HBV infection was affect significantly by the interactions between HBV and host immune response. Interleukins play important role in anti-viral immunity. Here we investigated the role of interleukin-35 (IL-35) in chronic HBV infection patients. Methods/Results: Serum IL-35 in 72 chronic hepatitis B virus infection patients and 41 healthy control subjects were analyzed by ELISA assay. The mRNA level of IL-35 in PBMCs was determined by RT-qPCR. In this study, we found that both protein and mRNA levels of IL-35 were significantly decreased in chronic HBV patients compared to the healthy controls. Furthermore, the statistical analysis found that serum IL-35 was significantly associated with HBV DNA (P =0.0158), ALT (P =0.0003), AST (P =0.0216), TB (P =0.0270) and AFP (P =0.0369). Importantly, correlation analysis also found that serum IL-35 level was negatively correlated with HBV DNA copies, ALT, AST, TB and AFP. Meanwhile, IL-35 treatment inhibited the level of HBV DNA, HBsAg and HBeAg in HepAD38 cells. Conclusion: Our study identified that IL-35 may be a novel marker associated with HBV infection and hepatocytes injury. These data suggested the potential use of IL-35 in the HBV treatment.

A novel mutation in TAP1 gene leading to MHC class I deficiency: Report of two cases and review of the literature.

Major histocompatibility complex (MHC) class I deficiency syndrome is a rare primary immunodeficiency caused by mutations in the peptide transporter complex associated with antigen presentation (TAP) gene which plays a crucial role in intracellular peptide antigen presentation. A few cases have been reported to date. Recurrent sinopulmonary infections and skin ulcers are the main characteristics of the syndrome. Here we report two siblings diagnosed with TAP1 deficiency syndrome associated only with recurrent sinopulmonary infections with the description of a novel mutation leading to a premature stop codon in TAP1 gene and review of the relevant literature. Both of the siblings had recurrent sinopulmonary infections since childhood, responded to antibiotherapy well, neither of them had hospitalization history because of infections. One had chronic hepatitis B infection which may possibly be related to TAP1 gene defect.

RNA helicase DEAD box protein 5 regulates Polycomb repressive complex 2/Hox transcript antisense intergenic RNA function in hepatitis B virus infection and hepatocarcinogenesis.

UNLABELLED: Chronic hepatitis B virus (HBV) infection is a major factor in hepatocellular carcinoma (HCC) pathogenesis by a mechanism not yet understood. Elucidating mechanisms of HBV-mediated hepatocarcinogenesis is needed to gain insights into classification and treatment of HCC. In HBV replicating cells, including virus-associated HCCs, suppressor of zeste 12 homolog (SUZ12), a core subunit of Polycomb repressive complex2 (PRC2), undergoes proteasomal degradation. This process requires the long noncoding RNA, Hox transcript antisense intergenic RNA (HOTAIR). Intriguingly, HOTAIR interacts with PRC2 and also binds RNA-binding E3 ligases, serving as a ubiquitination scaffold. Herein, we identified the RNA helicase, DEAD box protein 5 (DDX5), as a regulator of SUZ12 stability and PRC2-mediated gene repression, acting by regulating RNA-protein complexes formed with HOTAIR. Specifically, knockdown of DDX5 and/or HOTAIR enabled reexpression of PRC2-repressed genes epithelial cell adhesion molecule (EpCAM) and pluripotency genes. Also, knockdown of DDX5 enhanced transcription from the HBV minichromosome. The helicase activity of DDX5 stabilized SUZ12- and PRC2-mediated gene silencing, by displacing the RNA-binding E3 ligase, Mex-3 RNA-binding family member B (Mex3b), from HOTAIR. Conversely, ectopic expression of Mex3b ubiquitinated SUZ12, displaced DDX5 from HOTAIR, and induced SUZ12 down-regulation. In G2 phase of cells expressing the HBV X protein (HBx), SUZ12 preferentially associated with Mex3b, but not DDX5, resulting in de-repression of PRC2 targets, including EpCAM and pluripotency genes. Significantly, liver tumors from HBx/c-myc bitransgenic mice and chronically HBV-infected patients exhibited a strong negative correlation between DDX5 messenger RNA levels, pluripotency gene expression, and liver tumor differentiation. Notably, chronically infected HBV patients with HCC expressing reduced DDX5 exhibited poor prognosis after tumor resection, identifying DDX5 as an important player in poor prognosis HCC. CONCLUSION: The RNA helicase DDX5, and E3 ligase Mex3b, are important cellular targets for the design of novel, epigenetic therapies to combat HBV infection and poor prognosis HBV-associated liver cancer. (Hepatology 2016;64:1033-1048).

Prognosis and predictors of hepatocellular carcinoma in elderly patients infected with hepatitis B virus.

With rapidly aging population in the world, many elderly patients present with hepatitis B virus (HBV) infection. We conducted a retrospective cohort study involving 359 untreated HBV patients aged 60 and older who were free of hepatocellular carcinoma (HCC) and acute hepatitis at the initial visit, and examined the incidence of HCC and liver-related mortality rate. During the follow-up period of 7.9 years (range, 0-25 years), 26 patients (7.2% of patients) developed HCC, 20 patients died from liver-related diseases (61% of total deaths), including HCC, liver failure, and gastrointestinal bleeding. The cumulative rates of HCC at years 5, 10, and 15 were 6.5%, 15.6%, and 15.6%, respectively. The cumulative rates of mortality from liver-related diseases at years 5, 10, 15 were 3.3%, 12.3%, and 15.7%, respectively. Multivariate analysis identified HBV DNA (≥5.0 Log IU/mL), male gender, and FIB4-Index (≥3.6) as significant independent risk factors for HCC, and alpha-fetoprotein (≥10 ng/mL) as significant independent predictors of liver-related mortality. We conclude that high levels of HBV DNA, progression of liver fibrosis, and male gender are independent risk factors of HCC in untreated patients infected with HBV aged 60 and older.

Comparing the Clinical Features and Outcomes of Acute Hepatitis E Viral Infections with Those of Acute Hepatitis A, B, and C Infections in Korea.

OBJECTIVES: This study investigated the etiology of acute viral hepatitis and compared the clinical features of hepatitis E virus (HEV) infections with those of other acute viral hepatitis infections in Korea. METHODS: This study included 2,357 consecutive patients who were diagnosed with acute hepatitis, based on acute illness with jaundice or elevated alanine aminotransferase levels (>100 IU/L), between January 2007 and January 2016. Acute viral infections were observed in 23 (19.8%) patients with HEV, 49 (42.2%) patients with hepatitis A virus, 28 (24.1%) patients with hepatitis B virus, and 16 (13.8%) patients with hepatitis C virus. RESULTS: The incidence of acute HEV infection was higher among older patients (median age: 49 years) and male patients (69.6%), and was associated with the consumption of undercooked or uncooked meat (43.5%). Half of the acute HEV infections involved underlying liver disease, such as alcoholic liver disease, chronic hepatitis B, common bile duct stones, and autoimmune hepatitis. Two HEV-infected patients were diagnosed with Guillain-Barré syndrome, although no patients developed fulminant hepatitis. CONCLUSION: Our findings indicate that HEV infection in Korea is frequently transmitted through the consumption of raw meat and may cause acute or chronic liver disease.

[Clinical and morphological correlations in occult hepatitis B]. / Kliniko-morfologicheskie sopostavleniia pri okkul'tnom gepatite B.

Occult hepatitis B (ОHB) characterized by the absence of blood HBsAg attracts the attention of specialists of different profiles; however, its clinical morphological aspects have not been practically studied. AIM: to estimate the proportion of OHB in the structure of fatal outcomes in chronic viral hepatitis (CVH) and to characterize its clinical course and structural changes on autopsy materials. MATERIAL AND METHODS: A total of 455 autopsy cases of CVH were examined for its etiology in the S.P. Botkin Clinical Hospital of Infectious Diseases in 2014-2016. An in-depth prospective clinical analysis was made to investigate 28 cases of OHB in the stage of decompensated liver cirrhosis, which had subsequently culminated in death. The criteria of inclusion were history data and clinical symptoms of CVH in the detection of markers for hepatitis A, C, and D and HIV in serum HBcAb in the absence of HBsAg. HBsAbs were also determined. Along with the traditional morphological examination, immunohistochemistry (IHC) for HBsAg and HBcAg was carried out. RESULTS: There were 108 CVHB cases (23.7% of the total cases of CVH), including 77 OHB cases (71.3% of those of CVHB) while HBsAg was not determined. HBsAb-negative patients were more often observed to have clinical signs of jaundice (p<0.05) and skin itching (p<0.05). Dyspepsia and hemorrhagic manifestations prevailed in patients with HBsAb (more than 10 IU/l) (p<0.05). All the cases were found to have characteristic morphological signs of CVH, including intranuclear inclusions and nuclear polymorphism in 10.7% of deaths. There was an IHC-positive reaction to VHB antigens in 28.6% of the patients and a doubtful reaction in 25.0%. CONCLUSION: Serum НВсAb may serve as a diagnostic marker for HBV infection. Clinical and morphological correlations enabled the authors to state that CVHB was present in all cases in the absence of serum HBsAg in the patients.

The long-term efficacy of combining nucleos(t)ide analog and low-dose hepatitis B immunoglobulin on post-transplant hepatitis B virus recurrence.

BACKGROUND: The aim of this study was to determine the long-term efficacy of nucleos(t)ide analog (NA) and low-dose hepatitis B immunoglobulin (HBIG) combination treatment for preventing post-transplant hepatitis B virus (HBV) recurrence. METHODS: A total of 296 patients with HBV-associated liver disease who underwent liver transplantation (LT) were enrolled. A combination of a daily NA and low-dose HBIG was used after LT. RESULTS: The median follow-up period was 46 months. HBV recurrence occurred in eight patients. The cumulative probability of HBV recurrence at 1, 3, 5, and 7 years was 1%, 3%, 3%, and 4%, respectively. Seven were on lamivudine (LMV) or adefovir dipivoxil (ADV), or LMV and ADV and HBIG combination treatment and one entecavir (ETV) and HBIG. With Cox regression analysis, HBV recurrence was determined to be associated with the presence of hepatocellular cancer (HCC) prior to LT (HR: 12.3, P=.02). Overall, 44 patients died. Survival was significantly better in the ETV or tenofovir disoproxil fumarate (TDF) and HBIG group than the other group (P<.001). CONCLUSION: The combination of ETV or TDF and low-dose HBIG achieved a more favorable prophylaxis against HBV recurrence after LT. The presence of HCC prior to LT was associated with post-transplant HBV recurrence.

Relevance of serum interleukin-33 and ST2 levels and the natural course of chronic hepatitis B virus infection.

BACKGROUND: Interleukin-33 (IL-33) and ST2 have been demonstrated to be associated with liver damage. However, their potential value in hepatitis B virus (HBV) infection remains unknown. This study was designed to investigate the change of serum IL-33 and ST2 levels in the natural course of chronic HBV infection. METHODS: A total of 120 patients with chronic hepatitis B (CHB), 20 chronic hepatitis B virus carriers in immunotolerant phase and 28 healthy controls were enrolled in this study. All patients with CHB were divided into four groups according to their serum ALT levels. The serum levels of IL-33 and ST2 of all participants were determined by enzyme-linked immunosorbent assay, and compared between each two out of those six groups. RESULTS: No significant differences were found in serum levels of IL-33 and ST2 between the group of CHB with ALT 1-2 upper limit of normal and the healthy controls (P = 0.354 for IL-33 and P = 0.815 for ST2). Other than that, there were significant differences when serum levels of IL-33 and ST2 were compared between any other two out of those six groups (P < 0.05, respectively). The overall correlation analysis indicated that changes of serum IL-33 and ST2 levels were positively associated with ALT levels in patients with chronic HBV infection (rs = 0.879, P < 0.001 for IL-33 and rs = 0.923, P < 0.001 for ST2). No significant differences were found when the serum levels of ALT, IL-33 and ST2 were compared between patients with HBeAg-positive CHB and HBeAg-negative CHB. CONCLUSIONS: Our study revealed that the serum levels of IL-33 and ST2 varied in different courses of chronic hepatitis B virus infection. The serum levels of IL-33 and ST2 elevated as serum ALT levels increased in patients with CHB. They might indicate liver damage for patients with CHB, just like ALT.

Changes of HBV DNA After Chemoembolization for Hepatocellular Carcinoma and the Efficacy of Antiviral Treatment.

Unlike systemic chemotherapy for hematological malignancies with hepatitis B virus (HBV) infection, transarterial chemoembolization (TACE) for HBV-related hepatocellular carcinoma (HCC) has only recently been reported to cause HBV reactivation and subsequent hepatitis. Most patients with HBV-related HCC have an underlying disease with liver fibrosis or cirrhosis, and TACE may potentially induce HBV reactivation and liver decompensation. Currently, there are no clinical guidelines for managing TACE-caused HBV reactivation. In this review, we summarize the changes of HBV status and liver function after TACE and the effect of antiviral treatment before, during, or after TACE.

First description of past Hepatitis B Virus infection acute reactivation occurring in a Human Immunodeficiency Virus infected patient as manifestation of immune reconstitution inflammatory syndrome.

We report the case of an acute, self-resolving HBV-related hepatitis occurring in a HIV-infected patient carrying isolated anti-HBc antibodies. This acute HBV hepatitis may be considered as a clinical manifestation of a reactivation of HBV during an immune reconstitution inflammatory syndrome. Other hypotheses, even unlikely, are discussed.

Meta-analysis of prophylactic entecavir or lamivudine against hepatitis B virus reactivation.

UNLABELLED:  Introduction and aim. Studies suggest that entecavir and lamivudine are useful as prophylactics against hepatitis B virus (HBV) reactivation in patients undergoing chemotherapy or immunosuppressive therapy, but which drug is more effective is unclear. Here we meta-analyzed available evidence on relative efficacy of prophylactic entecavir or lamivudine therapy in patients with chronic or resolved hepatitis B infection who were undergoing chemotherapy or immunosuppressive therapy. MATERIAL AND METHODS: Two reviewers searched PubMed, EMBASE and Google Scholar as well as reference lists in relevant articles to find studies published between January 2005 and May 2015 that met inclusion and exclusion criteria. Data on HBV reactivation, HBV-related hepatitis and all-cause mortality were extracted from the studies and meta-analyzed. RESULTS: A total of eight studies involving 593 patients were included in the meta-analysis, which was performed using a fixed-effect model since no significant heterogeneity was found. Entecavir was associated with significantly lower risk of HBV reactivation than lamivudine (RR 0.29, 95% CI 0.17 to 0.52) as well as lower risk of HBV-related hepatitis (RR 0.11, 95% CI 0.03 to 0.40). The two drugs were associated with similar risk of all-cause mortality (RR 1.12, 95% CI 0.54 to 2.35). Egger's test suggested no significant publication bias in the meta-analysis. CONCLUSIONS: The available evidence suggests that entecavir is more effective than lamivudine for preventing HBV reactivation and HBVrelated hepatitis in patients with chronic or resolved HBV infection who are undergoing chemotherapy or immunosuppressive therapy.

TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy.

Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.

Role of scavenger receptors in the pathophysiology of chronic liver diseases.

Scavenger receptors comprise a large family of structurally diverse proteins that are involved in many homeostatic functions. They recognize a wide range of ligands, from pathogen-associated molecular patterns (PAMPs) to endogenous, as well as modified host-derived molecules (DAMPs). The liver deals with blood micro-organisms and DAMPs released from injured organs, thus performing vital metabolic and clearance functions that require the uptake of nutrients and toxins. Many liver cell types, including hepatocytes and Kupffer cells, express scavenger receptors that play key roles in hepatitis C virus entry, lipid uptake, and macrophage activation, among others. Chronic liver disease causes high morbidity and mortality worldwide. Hepatitis virus infection, alcohol abuse, and non-alcoholic fatty liver are the main etiologies associated with this disease. In this context, continuous inflammation as a result of liver damage leads to hepatic fibrosis, which frequently brings about cirrhosis and ultimately hepatocellular carcinoma. In this review, we will summarize the role of scavenger receptors in the pathophysiology of chronic liver diseases. We will also emphasize their potential as biomarkers of advanced liver disease, including cirrhosis and cancer.