Despite significant improvement in the management of chronic hepatitis B virus (HBV) it remains a public health problem, affecting more than 350 million people worldwide. The natural course of the infection is dynamic and involves a complex interplay between the virus and the host's immune system. Currently the approved therapeutic regimens include pegylated-interferon (IFN)-α and monotherapy with five nucleos(t)ide analogues (NAs). Both antiviral treatments are not capable to eliminate the virus and do not establish long-term control of infection after treatment withdrawal. IFN therapy is of finite duration and associates with low response rates, liver decompensating and numerous side effects. NAs are well-tolerated therapies but have a high risk of drug resistance development that limits their prolonged use. The imperative for the development of new approaches for the treatment of chronic HBV infection is a challenging issue that cannot be over-sided. Research efforts are focusing on the identification and evaluation of various viral replication inhibitors that target viral replication and a number of immunomodulators that aim to restore the HBV specific immune hyporesponsiveness without inducing liver damage. This review brings together our current knowledge on the available treatment and discusses potential therapeutic approaches in the battle against chronic HBV infection.

Epigenetic modifications are stable alterations in gene expression that do not involve mutations of the genetic sequence itself. It has become increasingly clear that epigenetic factors contribute to the outcome of chronic hepatitis B virus (HBV) infection by affecting cellular and virion gene expression, viral replication and the development of hepatocellular carcinoma. HBV persists in the nucleus of infected hepatocytes as a stable non-integrated covalently closed circular DNA (cccDNA) which functions as a minichromosome. There are two major forms of HBV epigenetic regulation: posttranslational modification of histone proteins associated with the cccDNA minichromosome and DNA methylation of viral and host genomes. This review explores how HBV can interphase with host epigenetic regulation in order to evade host defences and to promote its own survival and persistence. We focus on the effect of cccDNA bound-histone modifications and the methylation status of HBV DNA in regulating viral replication. Investigation of HBV epigenetic control has important clinical correlates with regards to the development of potential therapeutic regimens that will successfully eradicate HBV infection and deal with HBV reactivation in those undergoing treatment with demethylating agents.

Liver cancer is the third leading cause of cancer mortality worldwide with hepatocellular carcinoma (HCC) representing more than 90% of primary liver cancers. Most HCC patients are also suffering from chronic liver disease (CLD). Evidence is emerging that the composition of diet plays an important role in HCC and CLD development and may also have a chemoprotective role. In contrast to other types of cancer, there are few studies investigating the role of diet in hepatocarcinogenesis. From the available data it is evident that high intakes of red meat and dietary sugar positively correlate with HCC occurrence. On the contrary, high consumption of white meat, fish, vegetables, fruits and cereals are inversely associated with HCC risk. This letter discusses the potential role of dietary interventions in the prevention of hepatocarcinogenesis. The increasing HCC incidence and its high fatality are making HCC prevention an urgent matter. Dietary modifications are found to offer protection against HCC, however, new studies from well-designed and large prospective trials are required to confirm these results.

Vertically transmitted hepatitis B virus (HBV) usually causes chronic infection. While combined active–passive immunoprophylaxis in neonates of hepatitis B surface antigen-positive (HBsAg⁺) mothers at birth prevents vertical transmission, it is not yet clear whether neonates encounter the virus or its products in the absence of hepatitis B e antigen (HBeAg). This study was undertaken to investigate HBV antigen-specific T-cell responses in vaccinated neonates of HBsAg⁺/HBeAg⁻ mothers. Blood was collected from 46 HBsAg⁺ mothers and their neonates (subjects) as well as 24 age-matched controls. All neonates of HBsAg⁺ mothers received appropriate immunoprophylaxis, and HBsAg and hepatitis B surface antibody (anti-HBs) antibody titers were determined after completion of the vaccination course. Peripheral blood mononuclear cells (PBMCs) from infants at birth, 1 and 6 months of age were stimulated with recombinant HBsAg, hepatitis B core antigen (HBcAg) and mitogen, and interferon (IFN)-γ concentrations were determined by ELISA. HBsAg-induced production of IL-2, IL-5, IL-6 and IL-10 was assessed using a cytometric bead array kit on cells from 6-month-old neonates post-vaccination. All neonates were HBsAg⁻ and responded to vaccination. Increased IFN-γ production following HBcAg stimulation was seen in 30.4% of neonates born to HBsAg⁺/HBeAg⁻ mothers. Subjects demonstrated significantly higher IL-2 production post-HBsAg stimulation, whereas IL-5, IL-6 and IL-10 cytokine responses were not significantly different. Almost one-third of uninfected neonates developed viral antigen-induced IFN-γ production, suggesting that they had been exposed to virions or viral derivatives. This encounter, however, did not impair their T-cell responses to vaccination.

Plasmacytoid dendritic cells (pDCs) play a central role in antiviral immunity, detecting viruses via Toll-like receptors (TLR) and producing in response vast amounts of type I interferons (IFNs). Hepatitis B virus (HBV) causes chronic infection after vertical transmission. This study investigated whether an HBV-infected maternal environment might influence DC numbers and pDC function in uninfected infants. Blood was collected from inactive HBsAg carrier and control mothers and their infants at birth and 1 and 6 months of age. HBV DNA was measured in maternal and neonatal perinatal sera using real-time PCR. The circulating frequencies of myeloid DCs (mDCs) and pDCs were determined in the babies by flow cytometry. Peripheral blood mononuclear cells (PBMCs) and cord blood pDCs were stimulated with resiquimod, and alpha interferon (IFN-α) production and the pDC phenotype were assessed. The effect of the common-cold virus, rhinovirus (RV), on resiquimod stimulation was also determined. HBV DNA was detected in 62.3% of the mothers and 41% of their infants. DC numbers and pDC functions were similar between subjects and controls and were not correlated with maternal or neonatal viremia. RV infection did not induce pDC maturation until the age of 6 months, and it reduced TLR7-dependent resiquimod-induced IFN-α production similarly in both groups. Although the DC system is immature at birth, DCs of uninfected neonates of HBV-positive mothers are competent to initiate and maintain T-cell responses. RV is a weak inducer of IFN-α production until the age of 6 months and inhibits IFN-α responses triggered by the TLR7 pathway.

Asthma is a complex chronic inflammatory disorder. Diet’s impact on asthma symptoms is controversial. The objective of this pilot crossover, randomized, two-period study was to examine the effect of dietary histamine intake on asthma symptoms in twenty-one children with mild intermittent asthma. Children were randomly assigned to either a high- or low-histamine diet, based on the Mediterranean pattern, for 4 weeks. After a 2-week washout period, patients crossed to the alternative diet for 4 additional weeks. Asthma symptoms were assessed at baseline and after the completion of each diet period by a clinician. Daily symptoms and peak flow were recorded throughout the intervention. Adherence to the dietary intervention was assessed via analysis of four random 24-h recalls, for each intervention period. Eighteen children completed the study. Significantly higher mean air flow obstruction was recorded and a trend for prolonged and more severe symptoms was observed during the high-histamine period. Diet may have an active and direct impact on asthma symptoms. Food choice is affected and/or may affect symptoms in children with mild asthma. Diet intervention is promising yet challenging, for asthma control.