Review: Current Status of Antiviral Therapy for Hepatitis B

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FULL TEXT: http://www.medscape.com/viewarticle/579589?src=mp & spon=3 & uac=31238BR

From Therapeutic Advances in Gastroenterology

Review: Current Status of Antiviral Therapy for Hepatitis B

Posted 09/10/2008

Daryl T.-Y. Lau; Wissam Bleibel

Abstract and Introduction

Abstract

Chronic hepatitis B (CHB) is a major public health problem affecting up to 400

million people globally. Complications of CHB including liver failure and

hepatocellular carcinoma result in 1.2 million deaths per year, making CHB the

10th leading cause of mortality worldwide. The natural history of CHB is

variable and complex. The past decade witnessed important developments for the

therapy of hepatitis B and marked the new era of oral therapy. The ultimate goal

of CHB therapy is to arrest the progression of liver injury and to prevent the

development of liver failure and hepatocellular carcinoma. Currently, six agents

are approved for the treatment of CHB. Each of these agents, given as

monotherapy, has been shown to produce virological, biochemical, and

histological benefits for both HBeAg positive and negative CHB. There are,

however, limitations in spite of their efficacy. The significant side-effect

profile of interferon, for example, limits its long-term use. The approved oral

agents are tolerable with prolonged use but drug resistance could limit

long-term monotherapy. To date, combination therapy with nucleoside analogue and

pegylated interferon or two nucleos(t)ide analogues given for one year does not

show superiority in durability of response compared to monotherapy. Ongoing

research effort is critical to identify the ideal hepatitis B therapy that is

safe, effective, and produces durable response with a finite course of therapy.

It is equally important to conduct a well designed, prospective natural history

study to identify predictors of disease progression. This will accurately guide

treatment strategy for this important disease.

Introduction

Hepatitis B virus (HBV) infection is a major public health problem worldwide,

responsible for significant morbidity and mortality from chronic liver disease.

It is estimated that there are 350 to 400 million HBV carriers globally [Lee,

1997]. In the United States, approximately 1.5 million people are infected and

50,000–100,000 new cases are reported annually despite the availability of

effective vaccines [McQuillan et al. 1999]. This is likely an underestimate

since prevalence of chronic hepatitis B (CHB) among immigrants from HBV endemic

areas is much higher than that in the general population [Margolis et al. 1991].

HBV is a DNA virus in the family of Hepadnaviridae [Tacke et al. 2004]. There

are eight major genotypes of HBV and their prevalence varies amongst geographic

regions ( Table 1 ) [Magnius and Norder, 1995]. The compact genome of HBV

consists of four partially overlapping open reading frames encoding for the

envelope (pre-S/S), core (precore/core), polymerase, and X proteins [Tacke et

al. 2004]. Through the process of endocytosis, HBV gains entry into the

hepatocyte. However, its surface receptor has not been identified [Doo and

Liang, 2001]. After uncoating, the relaxed circular genome is converted in the

nucleus to a covalently closed circular (ccc) DNA that is the template for viral

replication [Locarnini and Mason, 2006; Doo and Liang, 2001]. The persistence of

HBV in the liver, despite antiviral therapy, is due to the maintenance of HBV

cccDNA in the nuclei of infected cells. HBV replicates asymmetrically via

reverse transcription of an RNA intermediate. Since its polymerase/reverse

transcriptase (Pol/Rt) lacks proofreading activity, spontaneous mutations are

estimated to occur at a rate of one error per 104–105 nucleotides daily

[Locarnini and Mason, 2006]. The resulting random mutations at the

polymerase/reverse transcriptase active site may overlap with the

antiviral-induced mutations and facilitate drug resistance.

CHB is defined by the persistence of serum hepatitis B surface antigen (HBsAg)

for six months or longer [Hollinger and Lau, 2006]. The natural history of CHB

can be classified into four major clinical phases based on levels of serum

alanine aminotransferase (ALT) and HBV DNA, presence of HBeAg, and suspected

immune status [Lok et al. 2001]. These phases are: (1) immune tolerance, (2)

HBeAg-positive CHB, (3) inactive carrier, and (4) HBeAgnegative CHB. The

disease, however, can be variable and the patients may not proceed through all

phases of the disease during the course of infection ( Table 2 ) [Lok et al.

2001]. The emergence of pre-core [nucleotide 1896 mutation from guanine (G) to

adenine (A)] and basal core promoter (BCP) [adenine (A) to thymine (T)

transversion at nucleotide 1762 together with a guanine (G) to adenine (A)

transition at nucleotide 1764] mutants lead to HBeAgnegative CHB [Hunt et al.

2000; Okamoto et al. 1994; Okamoto et al. 1990]. These patients continue to have

moderate HBV replication and active liver disease. The frequency of these HBV

mutants varies worldwide as a result of the different geographic distribution of

the HBV genotypes. Patients with HBeAg-negative CHB typically have heterogeneity

of disease activities characterized by fluctuating levels of serum

aminotransferases and HBV DNA [Hadziyannis and Vassilopoulos, 2001]. These

observations underscore the importance of regular assessments of HBsAg positive

patients over time in order to confirm the diagnosis of HBeAg-negative CHB

versus inactive HBV carrier. HBeAg positive and HBeAg negative-CHB patients with

persistent or intermittent elevation of aminotransferases and HBV DNA levels,

and histological evidence of active hepatitis should be considered for antiviral

therapy.

The past decade witnessed important developments for the therapy of hepatitis B.

The availability of lamivudine in 1998 not only marked the new era of oral

therapy, it also represents a paradigm shift in the management of this important

disease (Figure 1). The focus of this review is to discuss both the advances and

the unmet needs with the current paradigm.