Hepatitis B [keywords]
- High promoter methylation levels of glutathione-S-transferase M3 predict poor prognosis of acute-on-chronic hepatitis B liver failure. [JOURNAL ARTICLE]
- Hepatol Res 2016 Jul 21.
This study aimed to evaluate the prognostic value of glutathione-S-transferase M3 (GSTM3) gene promoter methylation in patients with acute-on-chronic hepatitis B liver failure (ACHBLF).A total of 119 patients with ACHBLF, 60 patients with chronic hepatitis B (CHB) and 30 healthy controls were enrolled. We used a quantitative methylation detection technique, MethyLight, to examine the methylation levels of GSTM3 in the peripheral blood mononuclear cells (PBMCs).GSTM3 methylation level was significantly higher in patients with ACHBLF than those in patients with CHB and healthy controls (P < 0.05, respectively). In patients with ACHBLF, GSTM3 methylation level [PMR (percentage of methylated reference)] positively correlated with total bilirubin, international normalized ratio and model for end-stage liver disease (MELD) score, and negatively correlated with prothrombin activity and albumin (P < 0.05, respectively). The PMR for GSTM3 of non-survivors was significantly increased than that of survivors (P < 0.05). Multivariate analysis indicated that GSTM3 methylation level was one of the independent prognostic factors for 3-month mortality of ACHBLF (P = 0.000). The area under the receiver operating characteristic curve (AUC) of PMR for GSTM3 in predicting 3-month mortality of ACHBLF was not statistically different from that of MELD score (0.798 vs 0.716, P = 0.152). However, the AUC of PMR for GSTM3 was significantly higher than that of MELD score in predicting 1-month mortality (0.887 vs 0.737, P = 0.020).Promoter methylation levels of GSTM3 in PBMCs closely correlated with disease severity and could be used to predict prognosis of patients with ACHBLF.
- Congenital and perinatally-acquired infections in resource-constrained settings. [JOURNAL ARTICLE]
- Expert Rev Anti Infect Ther 2016 Jul 21.
Congenital and perinatal infections are a leading cause of neonatal and infant morbidity and mortality. Maternal screening, vaccines or treatment where available, constitute effective prevention strategies to reduce the burden of these diseases. Data on the burden of congenital and perinatal infections are very limited for low and middle-income regions.This review aims to summarize the burden of congenital and perinatal infections and the main challenges for their control in resource-limited settings. Articles were identified through the main electronic databases and cover the period 1971- 2016. Expert commentary: Estimates from low and middle-income countries indicate that the burden of congenital infections may be higher in these regions than in industrialized countries. As preventive and curative strategies are available to tackle some of these infections, efforts at the international and national levels must be made to implement those and thus reduce their burden in resource-limited countries.
- A case of figurate urticaria by etanercept. [Journal Article]
- J Pharmacol Pharmacother 2016 Apr-Jun; 7(2):106-8.
Etanercept is a competitive inhibitor of tumor necrosis factor-alpha (TNF-α) a polypeptide hormone, involved in the development of the immune system, in host defense and immune surveillance. Even if the etanercept mechanism of action is not completely understood, it is supposed that it negatively modulates biological responses mediated by molecules (cytokines, adhesion molecules, or proteinases) induced or regulated by TNF. For this reason, it is widely used in the treatment of immunologicals diseases, such as rheumatoid and psoriatic arthritis, polyarticular juvenile idiopathic active, ankylosing spondylitis, and plaque psoriasis. Etanercept has a good tolerability profile. Adverse events related to skin are rare, arising usually in about 5% of patients treated with anti-TNF α. In this scenario, we describe a case of figurate urticaria arose after the re-administration of etanercept in a patient affected by psoriasis and hepatitis B. A 65-year-old man, affected by psoriasis, was hospitalized in September 2014 to the Regional Center for the treatment of psoriasis and Biological Drugs of Second University of Naples for progressive extension of psoriatic skin lesions. The laboratory analysis detected positivity for hepatitis B virus (HBV) antigens. For this reason, it was administered to him lamivudine 100 mg/die about 30 days before to start etanercept treatment. The etanercept therapy has resulted in a progressive improving of skin manifestations, and the patient decided individually to stop the therapy. Afterwards, for worsening of the psoriatic lesions, he was again hospitalized and treated with the same therapeutic schedule (lamivudine followed by etanercept). Ten days after the start of therapy, the patient showed the onset of urticarial rash. Due to this, the treatment with lamivudine and etanercept was suspended and the patient's clinical conditions improved. It is probably that immunological disorders due to etanercept therapy and HBV infection could explain the onset of figurate urticaria in our patient. In this contest, the post-marketing surveillance confirms its important role in the monitoring of drugs tolerability and effectiveness.
- Hepatitis B virus polymerase localizes to the mitochondria and its terminal protein domain contains the mitochondrial-targeting signal. [JOURNAL ARTICLE]
- J Virol 2016 Jul 20.
To understand subcellular sites of hepatitis B virus (HBV) replication, we visualized core (Cp), polymerase (Pol) and pregenomic RNA (pgRNA) in infected cells. Interestingly, we found that majority of the Pol localizes to the mitochondria in cells undergoing viral replication. The mitochondrial localization of Pol was independent of both the cell-type and other viral components indicating that Pol contains an intrinsic mitochondrial targeting signal (MTS). Neither Cp nor pgRNA localized to the mitochondria during active replication, suggesting a role of Pol at the mitochondria other than DNA synthesis. The Pol of duck hepatitis B virus (DHBV) also localized to the mitochondria. This result indicates that localization of Pol to mitochondria is likely a feature of all hepadnaviruses. To map the MTS within HBV Pol, we generated a series of Pol-GFP fusions and found that a stretch spanning a.a.141-160 of Pol was sufficient to target GFP to the mitochondria. Surprisingly, deleting a.a.141-160 in full-length Pol did not fully ablate Pol's mitochondrial localization suggesting that additional sequences are involved in mitochondrial targeting. Only by deleting the N-terminal 160 amino acids in full length Pol was mitochondrial localization ablated. Crucial residues for pgRNA packaging are contained within a.a.141-160 indicating a multi-functional role of this region of Pol in the viral life cycle. Our studies show an unexpected Pol trafficking behavior that is uncoupled from its role in viral DNA synthesis.Chronic infection by HBV is a serious health concern. Existing therapies for chronically infected individuals are not curative, underscoring the need for a better understanding of the viral life cycle to develop better antiviral therapies. To date, the most thoroughly studied function of Pol is to package the pgRNA and reverse transcribe it to double-stranded DNA within capsids. This study provides evidence for mitochondrial localization of Pol and defines the MTS. Recent findings have implicated a non-reverse transcription role for Pol in evading host innate immune responses. Mitochondria play an important role in controlling cellular metabolism, apoptosis and innate immunity. Pol could be altering one or more of these host mitochondrial functions to gain a replicative advantage and persist in chronically infected individuals.
- Complementary effects of IL-15 and IFN-α induce immunity in HBV transgenic mice. [JOURNAL ARTICLE]
- J Virol 2016 Jul 20.
In chronic hepatitis B (CHB) failure of HBV control is associated with T cell dysfunction. HBV transgenic mice mirror many features of the human disease, including T-cell unresponsiveness, and thus represent an appropriate model to test novel therapeutic strategies. To date the tolerant state of CD8+ T cells in these animals could only be altered by strong immunogens or immunization with HBV antigen-pulsed dendritic cells, however, the induced effectors were unable to suppress viral gene expression or replication. Because of their known stimulatory properties, this study explored the therapeutic potential of a liver-directed gene transfer of IFN-α and IL-15 in a murine model of CHB using AAV delivery. Their combination resulted not only in a reduction of the viral load in the liver and the induction of an antibody response but gave rise to functional and specific CD8+ immunity. Furthermore, when transferring splenic and intrahepatic lymphocytes from IFN-α/IL-15-treated animals to new HBV carriers, partial antiviral immunity was achieved. Contrary to previous observations made using either cytokine alone, a markedly attenuated PD-L1 induction in hepatic tissue was observed upon co-administration. An initial study with CHB patient samples also gave promising results. Hence, synergizing the effects of two stimulating cytokines, IL-15 and IFN-α, demonstrated a potent approach to significantly enhance the CD8+ T cell response in a state of immune hyporesponsiveness and may be useful for treating chronic viral infections and neoplastic conditions.With 350 million people affected worldwide and 600,000 annual deaths due to HBV-induced liver cirrhosis and/or hepatocellular carcinoma, chronic hepatitis B (CHB) is a major health problem. However, current treatment options are costly, not very effective and/or need to be administered for life. The unprecedented efficacy of the strategy described in our paper may offer an alternative and is relevant for a broad spectrum of readers because of its clear translational importance to other chronic viral infections in which a hyporesponsive antigen-specific T cell repertoire prevents clearance of the pathogen.
- Methylation of CAR is involved in the Suppression of CYP2C19 in HBV-associated Hepatocellular Carcinoma. [JOURNAL ARTICLE]
- Drug Metab Dispos 2016 Jul 20.
Hepatocellular carcinoma (HCC) is one of the most dangerous malignancies, which represents a major international health problem due to its increasing incidence and high mortality rate. It has been known that the progression of HCC involves a genome-wide alteration of epigenetic modifications, which leads to aberrant gene expression patterns. CYP2C19, which catalyzes the metabolism of a number of xenobiotics, is one of the most important members of the CYP450 superfamily. The activity of CYP2C19 was reported to be compromised in HCC, but the underlying mechanism remains unclear. In the present study, we evaluated the expression levels of CYP2C19 and its transcriptional factors by quantitative real-time PCR using mRNA extracted from both primary hepatocytes treated with 5-aza- 2'-deoxycytidine (5-aza-dC) and paired tumor and non-tumor liver tissues from hepatitis B virus (HBV)-infected patients. DNA methylation was examined by bisulfite sequencing (BSP) and methylation specific PCR (MSP). Results indicated that CYP2C19 could be regulated by e-box methylation of constitutive androstane receptor (CAR). The decreased expression of CYP2C19 in tumorouos tissues of HBV infected HCC patients is highly related with the down-regulated expression and promoter hypermethylation of CAR. Our study demonstrated that aberrant CAR methylation is involved in the regulation of CYP2C19 in HBV-related HCC and it may play a role during liver tumorigenesis.
- Localization of immunodominant epitopes within the "a" determinant of hepatitis B surface antigen using monoclonal antibodies. [JOURNAL ARTICLE]
- Arch Virol 2016 Jul 20.
The common "a" determinant is the major immunodominant region of hepatitis B surface antigen (HBsAg) shared by all serotypes and genotypes of hepatitis B virus (HBV). Antibodies against this region are thought to confer protection against HBV and are essential for viral clearance. Mutations within the "a" determinant may lead to conformational changes in this region, which can affect the binding of neutralizing antibodies. There is an increasing concern about identification and control of mutant viruses which is possible by comprehensive structural investigation of the epitopes located within this region. Anti-HBs monoclonal antibodies (mAbs) against different epitopes of HBsAg are a promising tool to meet this goal. In the present study, 19 anti-HBs mAbs were employed to map epitopes localized within the "a" determinant, using a panel of recombinant mutant HBsAgs. The topology of the epitopes was analyzed by competitive enzyme-linked immunosorbent assay (ELISA). Our results indicate that all of the mAbs seem to recognize epitopes within or in the vicinity of the "a" determinant of HBsAg. Different patterns of binding with mutant forms were observed with different mAbs. Amino acid substitutions at positions 123, 126, 129, 144, and 145 dramatically reduced the reactivity of antibodies with HBsAg. The T123N mutation had the largest impact on antibody binding to HBsAg. The reactivity pattern of our panel of mAbs with mutant forms of HBsAg could have important clinical implications for immunoscreening, diagnosis of HBV infection, design of a new generation of recombinant HB vaccines, and immunoprophylaxis of HBV infection as an alternative to therapy with hepatitis B immune globulin (HBIG).
- Disparities in HIV clinic care across Europe: findings from the EuroSIDA clinic survey. [Journal Article]
- BMC Infect Dis 2016.:335.
Although advances in HIV medicine have yielded increasingly better treatment outcomes in recent years, HIV-positive people with access to antiretroviral therapy (ART) still face complex health challenges. The EuroSIDA Study Group surveyed its clinics to explore regional differences in clinic services.The EuroSIDA study is a prospective observational cohort study that began enrolling patients in 1994. In early 2014, we conducted a 59-item survey of the 98 then-active EuroSIDA clinics. The survey covered HIV clinical care and other aspects of patient care. The EuroSIDA East Europe study region (Belarus, Estonia, Lithuania, the Russian Federation and Ukraine) was compared to a "non-East Europe" study region comprised of all other EuroSIDA countries.A larger proportion of clinics in the East Europe group reported deferring ART in asymptomatic patients until the CD4 cell count dropped below 350 cells/mm(3) (75 % versus 25 %, p = 0.0032). Considerably smaller proportions of East Europe clinics reported that resistance testing was provided before ART initiation (17 % versus 86 %, p < 0.0001) and that it was provided upon treatment failure (58 % versus 90 %, p = 0.0040). Only 33 % of East Europe clinics reported providing hepatitis B vaccination, compared to 88 % of other clinics (p < 0.0001). Only 50 % of East Europe clinics reported having access to direct-acting antivirals for hepatitis C treatment, compared to 89 % of other clinics (p = 0.0036). There was significantly less tuberculosis/HIV treatment integration in the East Europe group (27 % versus 84 % p < 0.0001) as well as significantly less screening for cardiovascular disease (58 % versus 90 %, p = 0.014); tobacco use (50 % versus 93 %, p < 0.0001); alcohol consumption (50 % versus 93 %, p < 0.0001); and drug use (58 % versus 87 %, p = 0.029).Study findings demonstrate how specific features of HIV clinics differ across Europe. Significantly more East Europe clinics deferred ART in asymptomatic patients for longer, and significantly fewer East Europe clinics provided resistance testing before initiating ART or upon ART failure. The East Europe group of clinics also differed in regard to hepatitis B vaccination, direct-acting antiviral access, tuberculosis/HIV treatment integration and screening for other health issues. There is a need for further research to guide setting-specific decision-making regarding the optimal array of services at HIV clinics in Europe and worldwide.
- PREVALENCE OF OCCULT HEPATITIS B INFECTION IN IRANIAN CANCER PATIENTS BEFORE CHEMOTHERAPY TREATMENT. [Journal Article]
- Arq Gastroenterol 2016 Jul-Sep; 53(3):175-9.
Occult hepatitis B infection is characterized by negative hepatitis B surface antigen (HBsAg) and also detectable hepatitis B virus (HBV) -DNA, with or without hepatitis B core antibody (anti-HBc). HBV reactivation in individuals under immunosuppressive therapy is critical, occurring in occult HBV.In this study, we aimed to determine the prevalence of occult HBV infection among hepatitis B surface antigen negative in cancer patients before receiving chemotherapy.Sera from 204 cancer patients who were negative for HBsAg, were tested for anti-HBc antibodies. The samples that were negative for HBsAg but positive for anti-HBc also examined for HBV-DNA by polymerase chain reaction (PCR).Of the 204 HBsAg negative blood samples, 11 (5.4%) samples were positive for anti-HBc antibodies. HBV-DNA was detected in 9/11 (81%) of anti-HBc positive samples. Occult HBV infection in hematological cancers was more than solid cancers, 4.8% and 4.3% respectively. There was no significant difference in HBc antibody positivity based on vaccination, previous blood transfusions, history of familial hepatitis or biochemical parameters (ALT, AST, total and direct bilirubin levels) (P>0.05).Screening of occult HBV infection by HBsAg, HBV DNA and anti HB core antibody should be suggested as a routine investigation in cancer patients before receiving chemotherapy.
- Splenic diffuse red-pulp small B-cell lymphoma associated with hepatitis B virus: a report of two cases. [Journal Article]
- Sao Paulo Med J 2016 Jul 18.:0.
Splenic diffuse red-pulp small B-cell lymphoma is a rare disease, representing less than 1% of all non-Hodgkin lymphomas (NHL). This entity is characterized by involvement of bone marrow sinusoids and peripheral blood. The majority of cases are at an advanced stage when diagnosed. Its pathogenesis is still poorly understood.We report on two patients with chronic non-replicating hepatitis B virus (HBV) who developed splenic diffuse red-pulp small B-cell lymphoma. Both of them were in stage IV at diagnosis and evolved with aggressive disease. Both of them achieved a complete response through chemotherapy, but one of them died due to infectious complications during bone marrow transplantation. The other decided not to undergo transplantation and continues not to show any evidence of disease today (three years after treatment). Some studies have shown a possible association between B-cell NHL and HBV. Nonetheless, the mechanism through which this oncogenic virus interacts with B-cell NHL is still poorly understood. HBV is lymphotropic and may insert into the host's genome, thus causing overexpression of oncogenes and downregulation of tumor suppressor genes. Therefore, chronic stimulation by HBV can increase B-cell proliferation, which promotes monoclonal expansion of these cells and results in malignancy.HBV may be implicated in the pathogenesis of this lymphoma, although no direct association between these two entities could be proved in the present study. Further investigations are necessary.