HBeAg(+), Nomral ALT: To Treat or Not to Treat?

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[B]HBe-Ag Positive Hepatitis B Patients with Normal Aminotransferase Levels: To Treat or Not to Treat? [/B]

In a Letter to the Editor published in the March 2003 issue of Hepatology, Drs. A. Geier, C.G. Dieterich and C. Cartung of Aachen University in Aachen, Germany argue for offering therapy to HBe-Ag positive HBV patients irrespective of their chances of virologic response. This recommendation is counter to current AASLD Guidelines, according to the German investigators. Following is the text of their letter:

”Practice Guidelines of the AASLD do not recommend any antiviral treatment of patients with hepatitis B e antigen (HBe-Ag)–positive chronic hepatitis B and normal aminotransferase levels despite a substantial risk for developing hepatocellular carcinoma (HCC).

Worldwide, chronic hepatitis B virus (HBV) infection affects more than 350 million people and is the primary cause of cirrhosis and HCC as well as one of the 10 leading causes of death. Clearance of HBe-Ag, whether spontaneous or after antiviral therapy, reduces the risk for hepatic decompensation and improves survival in individuals with chronic HBV infection.

As reported recently in a large, prospective, population-based, Taiwanese study, the risk for hepatocellular carcinoma is increased by a factor of 60.2 among HBe-Ag–positive individuals, but only 9.6-fold among HBe-Ag–negative HBs-Ag carriers.

Although the pathogenesis of HBV-associated HCC is multifactorial and the mechanism of HBe-Ag–associated carcinogenesis is unknown, there is evidence that this antigen may have an immunomodulatory role.

In general, the objective of treating chronic HBV infection is to prevent progression of liver injury to cirrhosis and liver-related death by suppressing viral replication or eliminating viremia.

Pretreatment alanine aminotransferase (ALT) levels have been found to be the most important predictor of response to both interferon alfa and lamivudine. Virologic response to interferon alfa is observed in less than 10% of these patients compared with an overall HBe-Ag clearance of 33%.

In parallel, HBe-Ag seroconversion rate after 1 year of lamivudine treatment is only 5% in patients with pretreatment levels less than 2 times normal. Thus, current guidelines do not consider HBe-Ag–positive patients with normal ALT levels for treatment and recommend further monitoring unless ALT levels are elevated over a 3- to 6-month period.

However, aminotransferase levels do not correlate prospectively with hepatocellular carcinogenesis in HBV-infected patients. Chen et al [1] reported in a re-analysis of their data a 61-fold increased relative risk for HCC in HBe-Ag–positive patients with normal ALT levels (defined as  45 IU/mL).

Although these patients have a lower virologic response to either therapy, one has to raise the question whether or not these patients should be treated to reduce their substantial risk for HCC based solely on the detection of HBe-Ag [2]. This question is of particular importance for the therapy of millions of patients worldwide, especially in Asia, where patients with perinatally acquired infection usually show normal aminotransferase levels.

Because of the findings of Chen et al [1] in their re-analysis, the treatment recommendations of the American Association for the Study of Liver Diseases Practice Guidelines might require an update regarding the indication for treatment in this large group of HBe-Ag–positive patients.

Facing an over 60-fold increased risk for HCC despite normal aminotransferase levels, therapy should not be withheld from these patients for ethical reasons irrespective of their chance of virologic response. However, the effects of either interferon alfa or lamivudine treatment in HBe-Ag–positive patients with normal ALT levels on the incidence of HCC as an endpoint are so far unknown and need to be studied in the future. “

04/18/03

Selected Citations

(1) CJ Chen, H Yang and SL You. HBe antigen and the risk of hepatocellular carcinoma. The New England journal of Medicine 2002; 347:1721-1722.

(2)  A Geier, C Gartung and CG Dietrich. Hepatitis B e antigen and the risk of hepatocellular carcinoma. The  New England journal of Medicine 2002; 347:1721-1722.

Reference
A Geier, CG Dieterich and C Cartung. Antiviral therapy in HBe-Ag–positive hepatitis B with normal aminotransferase levels. Letter to the Editor. Hepatology 37(3); 712; March 2003.

medline

一份Drs. A. Geier, C.G. Dieterich and C. Cartung of Aachen University in Aachen, Germany给hepatology得信大意。
对alt正常，hbeag+是否需要治疗有争议。
Practice Guidelines of the AASLD不建议对alt正常，hbeag+治疗。
然而，hbeag+不论alt正常与否，hcc的几率均比hbeag-的高6倍(60.2:9.6)