Hepatitis B “e” antigen (HBeAg) negative chronic hepatitis B (CHB), 40 years since discovery in the Mediterranean area, has become the most prevalent form of HBV-induced liver disease worldwide and a ...major health care burden caused by HBV infection. A great deal of knowledge accumulated over the last decades provides consistent evidence on the bimodal dynamics of the expression of structural and non-structural forms of the viral core proteins which associate with different virologic and clinic–pathologic outcomes of HBV infection. In absence of serum HBeAg, the presence and persistence of HBV replication causes and maintains virus-related liver injury. Thus, in clinical practice it is mandatory to screen HBV carriers with HBeAg-negative infection for the early diagnosis of HBeAg-negative CHB since antiviral therapy can cure HBV-induced liver disease when started at early stages.
Hepatitis B virus (HBV) produces high quantities of subviral surface antigen particles (HBsAg) which circulate in the blood outnumbering virions of about 1\10(3-6) times. In individuals coinfected ...with the defective hepatitis Delta virus (HDV) the small HDV-RNA-genome and Delta antigen circulate as ribonucleoprotein complexes within HBsAg subviral particles. We addressed the question whether subviral HBsAg particles may carry in the same way cellular microRNAs (miRNAs) which are released into the bloodstream within different subcellular forms such as exosomes and microvescicles. Circulating HBsAg particles were isolated from sera of 11 HBsAg carriers by selective immunoprecipitation with monoclonal anti-HBs-IgG, total RNA was extracted and human miRNAs were screened by TaqMan real-time quantitative PCR Arrays. Thirty-nine human miRNAs were found to be significantly associated with the immunoprecipitated HBsAg, as determined by both comparative DDCT analysis and non-parametric tests (Mann-Whitney, p<0.05) with respect to controls. Moreover immunoprecipitated HBsAg particles contained Ago2 protein that could be revealed in ELISA only after 0.5% NP40. HBsAg associated miRNAs were liver-specific (most frequent = miR-27a, miR-30b, miR-122, miR-126 and miR-145) as well as immune regulatory (most frequent = miR-106b and miR-223). Computationally predicted target genes of HBsAg-associated miRNAs highlighted molecular pathways dealing with host-pathogen. The finding that HBsAg particles carry selective pools of hepatocellular miRNAs opens new avenues of research to disentangle the complex interactions between host and HBV and provides a non invasive tool to study the physiopathology of liver epigenetics.
Representatives from academia, industry, regulatory agencies, and patient groups convened in March 2019 with the primary goal of developing agreement on chronic HBV treatment endpoints to guide ...clinical trials aiming to ‘cure’ HBV. Agreement among the conference participants was reached on some key points. ‘Functional’ but not sterilising cure is achievable and should be defined as sustained HBsAg loss in addition to undetectable HBV DNA 6 months post-treatment. The primary endpoint of phase III trials should be functional cure; HBsAg loss in ≥30% of patients was suggested as an acceptable rate of response in these trials. Sustained virologic suppression (undetectable serum HBV DNA) without HBsAg loss 6 months after discontinuation of treatment would be an intermediate goal. Demonstrated validity for the prediction of sustained HBsAg loss was considered the most appropriate criterion for the approval of new HBV assays to determine efficacy endpoints. Clinical trials aimed at HBV functional cure should initially focus on patients with HBeAg-positive or negative chronic hepatitis, who are treatment-naïve or virally suppressed on nucleos(t)ide analogues. A hepatitis flare associated with an increase in bilirubin or international normalised ratio should prompt temporary or permanent cessation of an investigational treatment. New treatments must be as safe as existing nucleos(t)ide analogues. The primary endpoint for phase III trials for HDV coinfection should be undetectable serum HDV RNA 6 months after stopping treatment. On treatment HDV RNA suppression associated with normalisation of alanine aminotransferase is considered an intermediate goal. In conclusion, regarding HBV ‘functional cure’, the primary goal is sustained HBsAg loss with undetectable HBV DNA after completion of treatment and the intermediate goal is sustained undetectable HBV DNA without HBsAg loss after stopping treatment.
Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. ...Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.
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•Vesatolimod was safe and well-tolerated in patients with chronic HBV infection.•Dose-dependent pharmacodynamic induction of ISGs was demonstrated with vesatolimod.•No significant ...HBsAg declines were observed with vesatolimod treatment.
Vesatolimod (GS-9620) is an oral agonist of toll-like receptor 7, an activator of innate and adaptive immune responses. Herein the safety and efficacy of vesatolimod is assessed after once-weekly treatment in patients with chronic hepatitis B (CHB) infection suppressed on oral antiviral treatment.
In a phase II, double-blind, randomized, placebo (PBO)-controlled study, 162 patients stratified by hepatitis B surface antigen (HBsAg) levels and serum hepatitis B e antigen (HBeAg) status were randomized 1:3:3:3 to once-weekly oral PBO or vesatolimod (1-, 2-, or 4-mg doses) for 4, 8 or 12 weeks per cohort. Efficacy was assessed by change in baseline HBsAg (log10 IU/ml) at the primary endpoint (Week 24). Safety assessments included adverse events (AE) and laboratory abnormality monitoring. Pharmacodynamic assessments included peripheral cytokine level quantification and interferon-stimulated gene (ISG) mRNA expression evaluation.
The majority of patients were male (76%) and HBeAg-negative (79%) at baseline. Most (41–80%) experienced ≥1 AE during the study with the majority of AEs mild or moderate in severity. No significant declines in HBsAg were observed at the primary (Week 24) or secondary endpoints (Weeks 4, 8, 12, and 48). ISG15 induction was dose-dependent and consistent after repeat dosing, returning closer to baseline by one week after treatment at all dose levels; no patient demonstrated significant serum interferon alpha (IFNα) expression at any timepoint evaluated. Multivariate analyses showed that ≥2-fold ISG15 induction is associated with 2- or 4-mg vesatolimod dose and female sex.
Vesatolimod was safe and well-tolerated in patients with CHB, demonstrating consistent dose-dependent pharmacodynamic induction of ISG15 without significant systemic induction of IFNα expression or related symptoms. However, no significant HBsAg declines were observed.
In a phase II study, vesatolimod, an oral, once-weekly, experimental immune-activating drug for the treatment of hepatitis B virus (HBV), is safe and well-tolerated in chronic HBV patients who are virally suppressed on oral antiviral treatment. Despite demonstrating on-target biomarker responses in patients, no significant declines in hepatitis B surface antigen were observed.
Clinical Trial Number: GS-US-283-1059; NCT 02166047.
The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV ...infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.
Lifestyle modification is the primary intervention to control NAFLD progression, but despite evidence-based effectiveness it is difficult to distinguish the benefits of nutrition from physical ...activity and the optimal diet composition is not established. Macronutrients as saturated fatty acids, sugars and animal proteins are harmful in NAFLD and the Mediterranean Diet reducing sugar, red meat and refined carbohydrates and increasing unsaturated-fatty-acids was reported to be beneficial. However one size cannot fit all since NAFLD is a multifaceted syndrome encompassing many diseases of unknown etiologies, different clinical severity and outcomes. Studies of the intestinal metagenome, provided new insights into the physio-pathological interplay between intestinal microbiota and NAFLD. How much the microbiota heterogeneity can influence response to diet remains unknown. New knowledge indicates that AI guided personalized nutrition based on clinic-pathologic and genetic data combined with pre/post nutritional intervention gut metagenomics/metabolomics will be part of the future management of NAFLD.
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