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It has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies. Responses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients. The HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients. This is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.

The human hepatitis B virus (HBV), that is causative for more than 240 million cases of chronic liver inflammation (hepatitis), is an enveloped virus with a partially double-stranded DNA genome. After virion uptake by receptor-mediated endocytosis, the viral nucleocapsid is transported towards the nuclear pore complex. In the nuclear basket, the nucleocapsid disassembles. The viral genome that is covalently linked to the viral polymerase, which harbors a bipartite NLS, is imported into the nucleus. Here, the partially double-stranded DNA genome is converted in a minichromosome-like structure, the covalently closed circular DNA (cccDNA). The DNA virus HBV replicates via a pregenomic RNA (pgRNA)-intermediate that is reverse transcribed into DNA. HBV-infected cells release apart from the infectious viral parrticle two forms of non-infectious subviral particles (spheres and filaments), which are assembled by the surface proteins but lack any capsid and nucleic acid. In addition, naked capsids are released by HBV replicating cells. Infectious viral particles and filaments are released via multivesicular bodies; spheres are secreted by the classic constitutive secretory pathway. The release of naked capsids is still not fully understood, autophagosomal processes are discussed. This review describes intracellular trafficking pathways involved in virus entry, morphogenesis and release of (sub)viral particles.

Chronic hepatitis B virus (HBV) infection is a major cause of liver disease and cancer worldwide for which there are no curative therapies. The major challenge in curing infection is eradicating or silencing the covalent closed circular DNA (cccDNA) form of the viral genome. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the liver transcriptome and yet their role in HBV replication is unknown. We establish a circadian cycling liver cell-model and demonstrate that REV-ERB directly regulates NTCP-dependent hepatitis B and delta virus particle entry. Importantly, we show that pharmacological activation of REV-ERB inhibits HBV infection in vitro and in human liver chimeric mice. We uncover a role for BMAL1 to bind HBV genomes and increase viral promoter activity. Pharmacological inhibition of BMAL1 through REV-ERB ligands reduces pre-genomic RNA and de novo particle secretion. The presence of conserved E-box motifs among members of the Hepadnaviridae family highlight an evolutionarily conserved role for BMAL1 in regulating this family of small DNA viruses. The circadian factors BMAL1/CLOCK and REV-ERB are master regulators of the human liver transcriptome but their role in hepatitis B virus infection is largely unknown. Here, Zhuang et al. show that REV-ERB regulates hepatitis B virus entry and BMAL1 directly binds HBV DNA and activates viral genome transcription.

In this randomized comparison of treatment with tenofovir disoproxil fumarate or adefovir dipivoxil for 48 weeks in patients with chronic hepatitis B, tenofovir was more likely to result in viral suppression. The follow-up period was not long enough to assess the resistance patterns, risks, and benefits of long-term treatment. In this randomized comparison of treatment with tenofovir disoproxil fumarate or adefovir dipivoxil for 48 weeks in patients with chronic hepatitis B, tenofovir was more likely to result in viral suppression. Chronic hepatitis B virus (HBV) infection is a major health problem. 1 – 3 Since most patients with chronic HBV infection require long-term therapy, 4 – 6 there is a need for new drugs with potent antiviral activity and established long-term safety, as well as a proven low rate of HBV antiviral resistance, a high genetic barrier (i.e., requiring more than one amino acid substitution to confer resistance to HBV treatment), or both. The ultimate goal of treatment of chronic HBV infection is to prevent liver complications. This goal is seldom achieved through hepatitis B surface antigen (HBsAg) loss and seroconversion, which are associated . . .

Glutamine cyclase, an enzyme involved in posttranslational modifications, is encoded by the glutaminyl-peptide cyclotransferase (QPCT) gene. Gene microarray analysis revealed that the QPCT gene was highly expressed in HepG2.2.15 cells compared with that in HepG2 cells. The serum expression level of the QPCT gene was detected by ELISA and was significantly greater in HBV-infected patients than in healthy controls. The mRNA and protein expression levels of the QPCT gene were markedly greater in the HBV-expressing cell lines (HepG2.2.15, and HepG2 and Huh7 cells transfected with the pBlu-HBV plasmid) than in the HepG2 and Huh7 cells. The levels of HBV pgRNA and HBV-DNA copy number, as well as the levels of HBeAg and HBsAg, also increased in the HepG2 and Huh7 cell lines cotransfected with the QPCT gene expression plasmid and the HBV 1.3-fold plasmid. Our study indicated that HBV can promote the expression of the QPCT gene, which in turn promotes the expression and replication of HBV.

Objective Treatment with peginterferon α-2a (PegIFN) for 48 weeks is the standard of care for selected HBeAg-negative patients chronically infected with hepatitis B virus (HBV), but with limited treatment efficacy. A study was undertaken to investigate whether treatment extension to 96 weeks improves the outcome in this patient population. Methods 128 HBeAg-negative patients (120 genotype D) were randomised to weekly 180 μg PegIFN for 48 weeks (group A, n=51), 180 μg PegIFN for 48 weeks followed by 135 μg weekly for an additional 48 weeks (group B, n=52) or 180 μg PegIFN plus lamivudine (100 mg/day) for 48 weeks then 135 μg PegIFN for 48 weeks (group C, n=25). Endpoints were alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (primary), HBV DNA <2000 IU/ml and HBsAg clearance at 48 weeks after treatment. Results Forty-eight weeks after treatment, six patients in group A and 13 in group B achieved alanine aminotransferase normalisation plus HBV DNA <3400 IU/ml (11.8% vs 25.0%, p=0.08), 6 vs 15 patients had HBV DNA <2000 IU/ml (11.8% vs 28.8%, p=0.03), 0 vs 3 achieved HBsAg clearance (0% vs 5.8%, p=0.24) and 0 vs 5 had HBsAg <10 IU/ml (0% vs 9.6%, p=0.06). While extended PegIFN treatment was the strongest independent predictor of response, the combination with lamivudine did not improve responses. Discontinuation rates were similar among the groups (19.6%, 23.1%, 32.0%, p=0.81) and were mostly due to PegIFN-related adverse events. Conclusions In HBeAg-negative genotype D patients with chronic hepatitis B, PegIFN treatment for 96 weeks was well tolerated and the post-treatment virological response improved significantly compared with 48 weeks of treatment. Trial registration number http://ClinicalTrials.gov registration number: NCT01095835.

Hepatitis B Virus (HBV) is one of the most common human infectious agents, and the mutations in its genome may cause chronic hepatitis (CH), liver cirrhosis (LC), and hepatocellular carcinoma (HCC). This study was designed to characterize the enhancer-II (Enh-II) region of X gene in HBV positive patients to assess the association of such mutations with CH, LC, and HCC. HBV positive samples (N = 200) with patients' demographic and clinical data were collected from different regions of Khyber Pakhtunkhwa (KP), Pakistan. The Enh-II region of the HBx gene was sequenced and zanalyzed for polymorphism associated with advanced liver disease. Univariate and logistic regression analyses were performed to evaluate potent mutations associated with a risk for LC and HCC. HBV Enh-II region sequences analysis revealed 25 different mutations. The highest frequency of mutations S101F (62.2%), A102V/R/G/I (56.25%), M103L/A (68.75%)were found in HCC, followed in LC and CH patients as 57.1%, 42.8%, 28.52% 16%, 15.2% and 18.4% respectively. H94 deletion in the α-box of the Enh-II region, associated with a high risk of HCC was found in half of the HCC patients. This deletion was present in 28.5% of LC and 6.5% of CH patients. Importantly, the high frequency of some notable mutations such as E109A/Y, A110S/K, Y111D/E, and F112L was first time reported in the entire study population. The frequencies of these mutations were high in HCC (43.75%, 37.5%, 50% and 43.75% respectively) as compared to LC (14.28%, 14.28%, 28.2% and 42.8%) and CH patients (12.8%, 15.2%, 16.8% and 16% respectively). Mutations associated with LC and HCC are prevalent in the Enh-II region in Pakistani HBV isolates. The mutations found are alarming in CH patients as these may progress to LC and HCC in a large number of patients.

Small interfering RNA (siRNA) constitutes a promising therapeutic modality supporting the potential functional cure of hepatitis B. A novel ionizable lipidoid nanoparticle (RBP131) and a state-of-the-art lyophilization technology were developed in this study, enabling to deliver siRNA targeting apolipoprotein B (APOB) into the hepatocytes with an ED 50 of 0.05 mg/kg after intravenous injection. In addition, according to the requirements of Investigational New Drug (IND) application, a potent siRNA targeting hepatitis B virus (HBV) was selected and encapsulated with RBP131 to fabricate a therapeutic formulation termed RB-HBV008. Efficacy investigations in transient and transgenic mouse models revealed that the expressions of viral RNAs and antigens (HBsAg and HBeAg), as well as viral DNA, were repressed, dose-dependently and time-dependently at multilog decreasing amplitude, in both circulation and liver tissue. In contrast, entecavir (ETV), the first-line clinically-employed nucleoside analog drug, barely recused the antigen expression, although it triggered as high as 3.50 log reduction of viral DNA, in line with clinical observations. Moreover, the toxicity profiles suggested satisfactory safety outcomes with ten times the therapeutic window. Therefore, this study provides an effective nucleic acid delivery system and a promising RNAi agent for the treatment of hepatitis B.

The selection pressure imposed by the host immune system impacts on hepatitis B virus (HBV) variability. This study evaluates HBV genetic diversity, nucleos(t)ide analogs resistance and HBsAg escape mutations in HBV patients under distinct selective pressures. One hundred and thirteen individuals in different phases of HBV infection were included: 13 HBeAg-positive chronic infection, 9 HBeAg-positive chronic hepatitis, 47 HBeAg-negative chronic infection (ENI), 29 HBeAg-negative chronic hepatitis (ENH) and 15 acute infected individuals. Samples were PCR amplified, sequenced and genetically analyzed for the overlapping POL/S genes. Most HBV carriers presented genotype A (84/113; 74.3%), subgenotype A1 (67/84; 79.7%), irrespective of group, followed by genotypes D (20/113; 17.7%), F (8/113; 7.1%) and E (1/113; 0.9%). Clinically relevant mutations in polymerase (tL180M/M204V) and in the Major Hydrophilic Region of HBsAg (sY100C, T118A/M, sM133T, sD144A and sG145R) were observed. Our findings, however, indicated that most polymorphic sites were located in the cytosolic loops (CYL1-2) and transmembrane domain 4 (TMD4) of HBsAg. Lower viral loads and higher HBV genetic diversity were observed in ENI and ENH groups ( p  < 0.001), suggesting that these groups are subjected to a higher selective pressure. Our results provide information on the molecular characteristics of HBV in a diverse clinical setting, and may guide future studies on the balance of HBV quasispecies at different stages of infection.

► Adults ≥40 years of age are commonly hypo-responsive to licensed HBV vaccines. ► HBsAg-1018 ISS elicits earlier, higher and longer lasting antibody than Engerix-B. ► 2 doses of HBsAg-1018 ISS provides superior protection over 3 doses of Engerix-B. ► HBsAg-1018 ISS was well tolerated with a similar safety profile as Engerix-B. ► HBsAg-1018 ISS may be more effective in hypo-responsive populations. Adults 40 years of age and older have been shown to be hypo-responsive immunologically to the currently available hepatitis B virus (HBV) vaccines. Three intramuscular doses of a Toll-like receptor 9 agonist, 1018 immunostimulatory sequence (1018 ISS) adjuvant, combined with recombinant hepatitis B surface antigen (HBsAg) demonstrated faster, superior, and more durable seroprotection than three doses of a licensed comparator HBV vaccine (Engerix-B®). This investigational vaccine, HBsAg-1018 ISS, was well tolerated with a safety profile similar to the comparator vaccine. These results suggest that HBsAg-1018 may be more effective in this hypo-responsive population.