Overview and Introduction
The diagnosis of precore mutant chronic hepatitis B (CHB) can be made with safety only by sequencing the precore region of the hepatitis B virus (HBV) genome, a method not widely available. However, in clinical practice, hepatitis B e antigen (HBeAg)-negative CHB is frequently arbitrarily referred to as precore mutant CHB, although the 2 terms are not synonymous. Because no therapeutic trial has specifically addressed the treatment of precore mutant CHB, all patients with HBeAg-negative CHB are currently treated in the same way. The aim of therapy in this setting is to induce a sustained suppression of liver disease activity before cirrhosis or hepatocellular carcinoma (HCC) develops. This goal may be achieved by efficient suppression of HBV replication, which represents the main determinant of underlying liver necroinflammation and fibrosis. Currently available agents include interferon-alfa, lamivudine, and adefovir dipivoxil. A 12-month or longer course of interferon-alfa treatment or re-treatment achieves sustained biochemical responses in 20% to 25% of patients, with eventual hepatitis B surface antigen (HBsAg) loss and antibody to HBsAg (anti-HBs) development in a proportion of this population. Lamivudine induces initial virologic and biochemical responses in 70% to 90% of patients, but breakthroughs due to lamivudine-resistant mutants accumulate with continuation of therapy and thus, only one third of patients may remain in remission after the third year of therapy. Adefovir dipivoxil also achieves on-therapy responses in the majority of cases. It is effective against lamivudine-resistant HBV strains and is associated with little, if any, drug resistance during the first 2 years of therapy -- highlighting its applicability for long-term treatment of HBeAg-negative CHB. Many other antiviral agents and immunomodulatory approaches are currently being evaluated for HBeAg-negative CHB, but, with the exception of interferon-alfa, none have as yet been shown convincingly to induce sustained off-therapy responses.
Chronic infection with HBV is one of the most common causes of chronic liver disease worldwide and is associated with high morbidity and mortality.[2,3] Although the majority of chronic HBV infections may remain with low viral replication and in biochemical and histologic remission, a proportion of them exhibit high HBV replication and active histologic lesions.[3,4] It is estimated that about 15% to 20% of patients with CHB develop cirrhosis within 5 years[5,6] and only 55% to 85% of patients with active HBV-related cirrhosis survive 5 years later.[7,8,9] Moreover, all patients with chronic HBV infection are at higher risk for HCC when compared with the general population, but the risk is extremely high when cirrhosis is present. Thus, it is estimated that over 250,000 patients die annually from HBV-related liver disease.[1,11]
The first phase of chronic HBV infection is positive for HBeAg and is characterized by high HBV replication, low aminotransferase levels, and mild histologic activity. However, during the course of chronic HBV infection, HBeAg seroconversion and development of the corresponding antibody (anti-HBe) may occur, an event usually associated with transition from the phase of high HBV replication to an inactive phase of the infection, with little residual viral replication and essentially normal liver histology (the so-called "inactive HBsAg carrier state").[12,13] However, not all patients who lose HBeAg and seroconvert to anti-HBe antibody go into sustained remission of HBV replication and liver disease activity. A variable proportion of the HBeAg-negative and anti-HBe-positive patients, depending on HBV genotype as well as other factors, retains or redevelops high serum HBV-DNA levels and persistent or intermittent elevations in alanine aminotransferase (ALT) activity.[12,13] Such patients harbor replication-competent HBV variants that are unable to produce HBeAg due to some mutations either in the precore or the basic core promoter region of the HBV genome. This form of CHB is also referred to as HBeAg-negative, or anti-HBe-positive, CHB[12,13]; it represents a potentially severe and progressive form of liver disease, with frequent development of cirrhosis and HCC.[15,16,17,18,19]
Because mutations in the precore region of the HBV genome were detected some years before the detection of the mutations in the basic core promoter region, HBeAg-negative CHB was initially considered to be identical to precore mutant CHB. The most common precore mutation is a guanosine (G) to adenine (A) change at nucleotide 1896 (G1896A), which leads to premature termination of the translation of the precore region at codon 28, thus preventing the production of HBeAg. In many cases, a second precore G to A mutation at nucleotide 1899 is also found, but its significance remains unknown. HBV variants harboring the 1896 precore stop codon mutation are mainly responsible for "HBeAg-negative CHB" in the Mediterranean basin and Far East, and generally in geographical areas where HBV infection is transmitted vertically or even horizontally in very early life and where the B and D genotypes of HBV prevail.[13,22] In such areas, HBeAg-negative CHB is the predominant type of CHB.[13,22]
This review focuses on the practical approach to the management of patients with HBeAg-negative, precore mutant CHB.
© 2003 Medscape
Cite this: Precore Mutant Chronic Hepatitis B -- Approach to Management - Medscape - Oct 02, 2003.