Marc G Ghany MDa Edward C Doo MDb

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aLiver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 9B-06, 10 Center Drive, MSC 1800, Bethesda, MD 29892-1800, USA bLiver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 6707 Democracy Boulevard, MSC 5450, Bethesda, MD 20892-5450, USA

Infection with the hepatitis B virus (HBV) is a significant global public health problem. Over one third of the world population has been exposed to the virus, and an estimated 400 million people are chronically infected [1,2]. Up to 40% of chronically infected individuals will be at risk for cirrhosis, decompensated liver disease, and hepatocellular carcinoma (HCC), and each year, an estimated 500,000 deaths occur from these complications. Advances in molecular biology techniques have led to a better understanding of the natural history and pathogenesis of HBV-related liver disease, resulting in the development of potent antiviral agents. Some of these agents can be used safely as maintenance therapy for patients who fail to clear the virus following standard durations of treatment. Overall, the advent of newer therapies has provided a wider range of therapeutic options for chronic hepatitis B (CHB) infection. This article focuses on the natural history of CHB-related liver disease, assessment and selection of patients for therapy, and new therapeutic options. It is meant to provide a succinct update on the management of CHB based on recent advancements in knowledge of the disease.

A version of this article originally appeared in the 33:3 issue of Gastroenterology Clinics of North America.

* Corresponding author.

E-mail address: [email protected] (M.G. Ghany).

0891-5520/06/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.idc.2006.01.009 id.theclinics.com

Natural history

The natural history of HBV infection is variable and influenced by a complex interplay between the host immune response and the replication fitness of the virus. Other factors impacting on the course of HBV infection include age at time of exposure, integrity of the immune system, alcohol consumption, obesity, and concurrent viral infections such as hepatitis C virus (HCV), hepatitis D virus (HDV), and HIV. In addition, viral load, viral variants, and perhaps HBV genotype may affect the clinical course. Ultimately, the outcome of HBV infection is determined by the robustness of the immune response as highlighted by the different clinical courses of perinatally and adult-acquired infection. Exposure at birth or at a young age when the immune system is thought to be immature represents the highest risk for developing CHB, where 90-95% of exposed infants develop chronic infection. In stark contrast, 90-95% of adult cases of HBV infection resolve spontaneously.

The natural history of HBV can be divided into 3 phases, an immune tolerant phase, an immune active phase, and an inactive phase. The immune tolerant phase is generally absent in adult acquired infection. The immune tolerant phase is characterized by a lack of symptoms, no or minimal elevation in serum aminotransferase levels and mild inflammation on liver biopsy. However, HBV DNA levels can be quite high and hepatitis B e antigen (HBeAg), a surrogate marker of viral replication is found in serum [3]. Immune tolerance is believed to be due to the inability of the host immune system to fully recognize viral antigens and may persist for 10 to 30 years [3] (Fig. 1A). During this period there is a low rate of spontaneous viral clearance.

The immune active phase is characterized by fluctuating HBV DNA levels, high serum aminotransferase levels, and hepatic necroinflammation. This phase is thought to be the result of incomplete attempts by the host immune response to eradicate virally infected hepatocytes [4] (Fig. 1B). Clinical manifestations of chronic liver disease may appear during repeated bouts of immune-mediated aminotransferase flares and may accelerate the progression of hepatic fibrosis to cirrhosis [5-7]. During these flares, a small number of patients (10-15%) may lose HBeAg spontaneously, followed by the development of antibody to HBeAg (anti-HBe), a so called HBeAg seroconver-sion heralding a period of quiescence in liver disease and the inactive phase [5-7]. This phase is associated with normal aminotransferase levels and less hepatic inflammation [6].

Attainment of the inactive phase has also been referred to as the transition from a high to low viral replicative status due to the marked drop in HBV DNA levels. Hepatitis B surface antigen (HBsAg), however, remains detectable in serum. The inactive phase may last for many years, and in the absence of cirrhosis, there is diminished risk for disease progression or hepatocellular carcinoma [8,9]. Thus the loss of HBeAg is an important clinical event associated with a period of disease inactivity and improved prognosis, and it

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