Preface

Hepatitis is inflammation of the liver that can result from a variety of causes such as heavy alcohol use, autoimmune disease, drugs, or toxins. However, the most frequent cause of hepatitis is a viral infection, known as viral hepatitis.

Acute hepatitis is self-resolving in most cases but can cause fulminant liver failure depending on the etiology. In contrast, chronic hepatitis can cause liver damage that includes liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC), and features of portal hypertension leading to significant morbidity and mortality.

Worldwide, hepatitis B and hepatitis C viruses (HBV and HCV) are the most relevant causative viral agents of chronic hepatitis (inflammation of the liver). At present, more than 250 million people suffer from a chronic HBV infection globally, resulting in 0.8 million deaths per year.

Chronic HCV infection accounts for about 70 million cases worldwide, leading to a death toll of about 1 million per year. An approved vaccine is only available against an HBV infection.

Both HBV and HCV infections result in a highly increased risk of developing liver fibrosis, cirrhosis, and HCC. This book describes the mechanisms of HBV and associated pathogenesis.

The book's focus is on the interplay between chronic infection with intracellular signaling transduction, metabolic pathways with an emphasis on lipid metabolism, the establishment of liver fibrosis and cirrhosis during chronic infection, and the mechanisms of the onset of virally induced HCC.

Despite there being great advances in the characterization of viral life cycles and the development of robust antiviral strategies, significant hurdles persist in gaining a better understanding of the mechanisms that drive virus-associated pathogenesis as well as increasing insights regarding different viral genotypes having impacts on alternate pathogeneses.

The first experimental vaccinations against HBV were performed in 1970, even before the nature of the administered "Australia antigen" was known. Soon, it was realized that this antigen was the envelope protein (HBV surface antigen, HBsAg), and it was purified from HBV-containing human plasma. Later, it was produced in genetically engineered yeast cells.

The excellent efficacy of the HBsAg vaccine was confirmed in numerous studies, particularly in newborns from HBV-infected mothers who almost always become chronic HBV carriers without vaccination. The vaccine is also highly effective in older children and adults and has been applied worldwide since 1984, leading to about a tenfold decrease in HBV infections in the vaccinated.

Chronic HBV infection is one of the most common factors associated with HCC, which is the sixth most prevalent cancer among all cancers worldwide. However, the pathogenesis of HBV-mediated hepatocarcinogenesis is unclear. Evidence currently available suggests that the HBV core protein (HBc) plays a potential role in the development of HCC, such as the HBV X protein.

The core protein, which is the structural component of the viral nucleocapsid, contributes to almost every stage of the HBV life cycle and occupies diverse roles in HBV replication and pathogenesis.

Recent studies have shown that HBc was able to disrupt various pathways involved in liver carcinogenesis, including the signaling pathways implicated in migration and proliferation of hepatoma cells, apoptosis pathways, and cell metabolic pathways inducing the development of HCC, and the immune system, through the expression and production of proinflammatory cytokines.

The future of a cure for HBV lies in triple combination therapies with concerted action on replication inhibition, antigen reduction, and immune stimulation. Many obstacles remain, such as overcoming translational failures, choosing the right endpoint using the right biomarkers, and leveraging current treatments in combination regimens to enhance response rates.

In this book, the authors present current therapies for CHB, HBV biomarkers used to evaluate treatment response, and the development of direct-acting antivirals (DAAs) and immune-targeting drugs and discuss the limitations and unanswered questions on the journey to an HBV cure.

> **Luis Rodrigo MD** Professor, Emeritus Professor of Medicine, University of Oviedo, Oviedo, Spain

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