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Treatment for HBeAg-Negative Chronic Hepatitis B

Sustained virologic responses remain difficult to induce in patients with HBeAg-negative chronic hepatitis.

Most patients with chronic hepatitis B virus (HBV) eventually lose HBe antigen (HBeAg) and develop anti-HBe antibody, which generally is associated with undetectable HBV DNA, normalization of alanine aminotransferase (ALT) levels, bland liver biopsies, and low risks for progression to cirrhosis and hepatocellular carcinoma (HCC). However, patients with HBeAg-negative chronic hepatitis (active carriers) retain HBV DNA, have persistent ALT elevations and active necroinflammation on liver biopsy, and are at higher risks for progression to end-stage liver disease and development of HCC. Presumably, HBeAg-negative hepatitis is caused by strains with mutations in the core promoter or precore regions that prevent antigen expression. Most active carriers are from southern Europe or from Asia, but the prevalence has increased worldwide. Treatment of patients with HBeAg-negative hepatitis has been discouraging; only 15% to 27% have sustained virologic responses to standard interferon, and although antiviral agents can suppress the virus and lead to undetectable HBV DNA levels, indefinite treatment is required. Two studies evaluated treatment of patients with HBeAg-negative hepatitis B.

In one study, an international group of researchers randomized 537 HBeAg-negative patients to receive 48 weeks of peginterferon alfa-2a (PEG, 180 µg weekly) plus placebo, PEG plus lamivudine (100 mg daily), or lamivudine alone. During treatment, significantly more patients in the lamivudine group had normal serum ALT levels than in either PEG group, and more patients in the each PEG group had marked ALT elevations. However, at 72 weeks, both the patients who received PEG alone and those who received PEG plus lamivudine were significantly more likely than those who received lamivudine alone to have sustained normalization of ALT and HBV DNA <20,000 copies/mL (16% and 15% vs. 6%). Similarly, a significantly greater proportion of patients who received PEG, alone or with lamivudine, achieved HBV DNA levels <400 copies/mL (19% and 20% vs. 7%). All three groups had statistically similar improvements in hepatic histology. Seven patients who received PEG monotherapy and 5 patients who received combination therapy ultimately cleared HBeAg by week 72. No lamivudine monotherapy recipients cleared the virus.

In the other study, researchers in Italy performed a retrospective analysis of 656 patients with HBeAg-negative chronic hepatitis with or without cirrhosis who had been treated with lamivudine alone for a median of 22 months; 54% had histologic diagnoses of chronic hepatitis, 46% had cirrhosis, and 40% had previously been treated unsuccessfully with standard interferon. Lamivudine induced virologic response in 94% of patients within a median of 2 months (range, 1-20 months). Virologic breakthroughs associated with ALT increases occurred in 209 patients (at a median of 18 months), most of whom had the YMDD mutation. Virologic response rates were 87% at 1 year, 63% at 2 years, 48% at 3 years, and 39% at 4 years. Liver disease worsened in only 5% of patients, and HCC developed in 4.7%. HCC incidence was highest among patients with advanced cirrhosis. Only 3.6% of patients died from liver-related causes. Eighty-two patients (12.5%) withdrew from lamivudine therapy, but none of the 58 patients with chronic hepatitis who withdrew experienced a hepatitis flare during a mean follow-up of 17 months.

Comment: As these results show, sustained virologic responses remain difficult to induce in patients with HBeAg-negative chronic hepatitis. Response rates to PEG regimens are encouraging even though the addition of lamivudine does not seem to improve response. Most patients will continue to have chronic active disease, but those patients who are persistently HBV DNA-negative might benefit from long-term viral suppression with an antiviral agent such as lamivudine in an attempt to slow disease progression and development of hepatocellular carcinoma. In addition, unlike PEG, lamivudine is not associated with hepatitis flare, and its rapid efficacy suggests that, if timed appropriately, lamivudine might serve as a rescue treatment before liver transplantation to try to prevent reemergence of disease posttransplant.

— Kenneth D. Flora, MD

Published in Journal Watch Gastroenterology October 26, 2004

Citation(s):

Marcellin P et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004 Sep 16; 351:1206-17.

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• Medline abstract (Free)

Di Marco V et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004 Oct; 40:883-91.

• Medline abstract (Free)