The HBeAg Negative, HBV-DNA Positive Patient Causes and Therapy

To review:
* A diagnostic algorithm in HBeAg negative chronic hepatitis B
* Pathogenesis and natural course of this patient population
* Treatment strategies for these patients

Abstract:

HBsAg positive patients with chronic hepatitis may be either positive or negative for serum HBeAg. The former cases represent the [email protected] forms of chronic hepatitis B while the HBeAg negative group is more heterogeneous and includes different etiologies. These patients should be tested for HCV and HDV markers, to assess coinfection with these agents, for non-organ specific autoantibodies, to exclude an autoimmune hepatitis in an HBsAg carrier, and should be evaluated for alcohol abuse and other hepatotoxic agents. In the absence of these cofactors, HBeAg negative (anti-HBe positive) chronic hepatitis B should be suspected. This form is characterized by persistent or intermittent serum HBV-DNA positivity. Therefore diagnosis requires serial HBV-DNA testing or detection of HBcAg in the liver biopsy. Presence of serum IgM anti-HBc is a specific but less sensitive marker of the disease. Anti-HBe positive chronic hepatitis B may follow HBeAg positive disease after anti-HBe seroconversion not accompanied by permanent remission of liver damage and of virus replication, however, most patients are HBeAg negative since clinical presentation is without a recognized HBeAg positive phase. Most patients appear to be infected with precore mutants of HBV with stop codons which explain the lack of HBeAg production. The most frequent HBV precore variant has a point mutation at position 1896 but other mutants, deletions or genomic rearrangements may also be present. Multiple mutations are observed also in the core region and their frequency increases with the severity of liver disease, suggesting a pathogenetic implication. Anti-HBe positive chronic hepatitis B is frequent in the Mediterranean area where its prevalence has progressively increased over that of the classical HBeAg positive forms. Although a wide spectrum of histologic lesions can be found in these patients, they are more likely to have severe necroinflamatory changes and fibrosis at the time of clinical presentation and during follow-up compared to the HBeAg positive cases. Two main patterns of liver enzyme activity can be observed, with about one third of the cases having persistently increased ALT levels with continuing serum HBV-DNA positivity while the remaining patients show waxing and waning of enzyme activity with prolonged periods of ALT normality and serum HBV-DNA negativity. The risk of disease progression is higher in the former group.

Therapy of anti-HBe and HBV-DNA positive chronic hepatitis B is far from satisfactory. Most patients, and particularly those without cirrhosis, respond promptly when treated with interferon, but most of them relapse when treatment is withdrawal. Late relapses may occur up to three to five years after therapy. Most published studies indicate that the rate of sustained response after six month treatment with 3 to 10 MU tiw of alpha-interferon is between 10% to 25% at three to four years after therapy. More recent data would suggest that prolonged treatment for at least 12 months may result in a significant reduction of post-treatment relapses. On the basis of these studies patients with anti-HBe positive chronic hepatitis B should be treated with 3 to 6 tiw for 12 months. Therapy should be stopped in the absence of biochemical response during the first six months. The predictive value of pretreatment variables is controversial. Serum HBV-DNA levels may be less useful than in HBeAg positive forms and not all authors agree that presence and prevalence of pre-core mutants have a major influence on the response. Some reports have suggested that pretreatment IgM anti-HBc may predict a favourable response to interferon. Most studies agree that patients with cirrhosis have an extremely low chance of developing a sustained response. They may possibly benefit from long-term suppressive therapy. Ongoing studies are evaluating the response of anti HBe and HBV-DNA positive chronic hepatitis B to nucleoside analogues.

Alfredo Alberti, MD
Professor of Medicine
Department of Clinical and Experimental Medicine
University of Padova
Padova, Italy

References:

1. Fattovich G , Farci P, Rugge M, et al. A randomized controlled trial of lymphoblastoid interferon alpha in patients with chronic hepatitis B lacking HBeAg. Hepatology 1992;15:584-9.

2. Hadziyannis SJ. Hepatitis Be antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment. Viral Hepatitis Reviews 1995;1(1):7-36.

3. Fattovich G, McIntyre G, Thrusz M, et al. Hepatitis B virus precore/core variation and interferon therapy. Hepatology 1995;22:1355-62.

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