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Abstract and Introduction
Abstract
Summary: Chronic hepatitis B is a serious health problem worldwide with a substantial minority of patients experiencing premature death due to end-stage liver disease and/or hepatocellular carcinoma. Antiviral therapy may help prevent complications of chronic hepatitis B, and seven agents are currently approved in many countries. Of these agents, five are nucleos(t)ide analogs that all have a risk of antiviral drug resistance with long-term use. Efforts have been made in the recent years to prevent or to reduce the risk of viral resistance in patients treated with oral nucleos(t)ides as the majority of these patients will require therapy for 3-5 years or longer. One approach is to identify patients who would most likely develop antiviral resistance on long-term therapy using predictors obtainable early in the course of treatment, when intervention with new or additional therapy can be instituted. The most important predictors of treatment outcomes are serum HBV DNA levels at baseline and during the first 6 months of therapy. The purpose of this synopsis is to review the recent literature regarding the importance of serum HBV DNA levels in association with treatment outcomes in chronic hepatitis B, particularly the association of complete viral suppression early in the course of oral therapy with long-term treatment outcomes, particularly the incidence of antiviral drug resistance.
Introduction
Infection with hepatitis B virus (HBV) is a serious global health problem, with an estimated 350 million persons chronically infected and 500 000 to 1.2 million individuals dying per year. Chronic hepatitis B (CHB) is endemic in sub-Saharan Africa and the Asia/Pacific regions, where the vast majority of patients acquire the infection perinatally or horizontally during early childhood. In Western countries, infection with HBV spreads through high-risk sexual behavior, injection drug use and exposure to blood products.
The natural course of CHB is affected by the level of viral replication, immune response, and factors such as age, gender, alcohol consumption and concomitant infection with human immunodeficiency virus or other hepatitis viruses. The course of CHB can generally be grouped into four phases: immune tolerance, immune clearance, non-replicative inactive carrier and reactivation. Historically, clinicians have relied primarily on serum alanine aminotransferase (ALT) level as an easily accessible surrogate marker for the presence or absence of disease activity within the liver. However, important new information regarding the association of serum HBV DNA levels with cirrhosis and hepatocellular carcinoma (HCC) has emerged in recent years and posed new challenges to the management of CHB. In addition to management guidelines proposed by professional societies and an expert opinion algorithm, additional management proposals for CHB continue to be published on almost an annual basis.
The overall goal of treatment for CHB is to prevent or reduce the development of cirrhosis, end-stage liver disease, HCC and ultimately liver-related death. Since such disease endpoints generally take decades to occur, intermediate endpoints such as viral suppression, normalization of ALT, absence of viral resistance, hepatitis B e antigen (HBeAg) loss and seroconversion, hepatitis B surface antigen (HBsAg) loss and seroconversion and improvement in liver histology have been used as surrogate markers to determine if the treatment of a given patient with CHB has been successful. Current treatment guidelines for CHB are largely based on ALT levels, serum HBV DNA levels and HBeAg status. Though some of these guidelines were updated in the past 1-2 years, some patients who would eventually develop HCC or experience liver-related death could have been missed and would not have been selected for antiviral therapy by these guidelines. In addition, current treatment guidelines provide little guidance regarding the longitudinal follow-up of treated patients and the definition of optimal treatment success. Thus, in the remainder of this paper, the two most updated practice guidelines will be briefly summarized, and challenges regarding the monitoring of one of its major determinants, serum HBV DNA level, will be reviewed.
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