Does corticosteroid pretreatment enhance the effect of alfa interferon treatment in chronic hepatitis B

In recent years alfa interferon (IFN) treatment has become accepted therapy for chronic hepatitis B. Several studies have documented that treatment with IFN is accompanied or followed by a loss of hepatitis B virus (HBV) DNA, hepatitis B e antigen (HBeAg) to antibody to hepatitis B e antigen (anti-HBe) seroconversion and a decrease in inflammatory disease activity in approximately 35% of patients with replicative, and inflammatory active chronic hepatitis B (1,2). It is a common observation that the highest response rates occur in patients with more active inflammatory disease activity and in patients with lower levels of HBV DNA (2,3). It is also clear that the poorest response rates are achieved in immuno-compromised patients, in disease acquired in childhood and in ethnic groups where vertical transmission of hepatitis B is predominant (4-6). Whether the varying response rates observed simply reflect the difference in the underlying tendency to spontaneous HBeAg to anti-HBe seroconversion or whether there actually is a difference in the relative efficacy of IFN treatment is a matter of debate (7). Furthermore, despite treatment of several thousand patients with IFN, there are still substantial uncertainties about the optimal dose of IFN, duration of treatment, significance of development of IFN antibodies and whether there are therapeutic differences between the IFN types. Clinically the effect of IFN is unsatisfactory. The lowest response rates are obtained in patients who in the long run may have the greatest risk of developing significant liver disease, including hepatocellular carcinoma; and even in immunologically intact Caucasians with inflammatory active disease acquired as adults, a beneficial response may be expected in fewer than half of the treated patients. Moreover, it is still not known whether IFN therapy actually diminishes morbidity and mortality in chronic hepatitis B. These facts must be weighed against the inconveniences, side effects, risks and cost of IFN therapy. Increases in overall response rates and in the response in children and patients with vertically transmitted disease are therefore some of the issues that should be given priority. One of the suggested ways to improve the results of IFN therapy is combination with immune modulating therapy. In this issue of the Journal o f Hepatology, three randomised controlled trials focus on corticosteroid treatment followed by IFN in chronic hepatitis B. Dealing with treatment in children (Utili et al. (8)), Chinese adults (Liaw et al. (9)) and improvement of response in adult Caucasians (Reichen et al. (10)), these studies provide valuable information on some of the key issues in the treatment of chronic hepatitis B. Long-term treatment of chronic hepatitis B with corticosteroids was abandoned in the early eighties when it became evident that this treatment regimen was harmful (11). So what is the rationale for short-term treatment with corticosteroids? Early clinical observations showed that patients with chronic hepatitis B often cleared markers of viral replication following tapering or discontinuation of corticosteroid treatment (12-14). The corticosteroid discontinuation was generally followed by a marked flare in disease activity, which may also be observed in spontaneous seroconversion or following superinfection with other hepatotropic viruses. These findings generated the hypothesis that a state of immunological tolerance induced by corticosteroids was followed by an immunological rebound phenomenon upon discontinu-