Hepatitis B: therapeutic perspectives

Therapy with interferon (IFN), an immunomodulant with anti-viral activities, is efficacious only in a minority of chronic hepatitis B (CHB); it is more efficacious in the hepatitis B e antigen (HBeAg)-positive variety sustained by the wild type hepatitis B virus (HBV) than in the HBeAg-negative variety sustained by mutant forms of the virus. Several other therapeutic approaches were attempted in recent years. The most promising is therapy with synthetic nucleosides as anti-virals capable of blocking the replicative activity of the HBV. Lamivudine (LAM) is the first of this class of compounds that has entered clinical use. It is well tolerated and highly effective in inhibiting HBV and abate HBV-related inflammation both in the HBeAg positive and negative variety of CHB. In the HBeAg positive variety it induces sero-conversion to anti-HBe at a rate that linearly increases over the years, reaching 40% at the third year. In the HBeAg-negative variety maintenance of viral repression requires continuative therapy. A major drawback of continued LAM therapy is the risk of the emergence of mutants in the tyrosine-methionine-aspartate-aspartate locus of the polymerase gene. These mutants are no longer responsive to LAM and may rekindle disease; wild type HBV and related disease often return after suspension of therapy. Other anti-viral drugs, the prototype of which is adefovir, are currently under clinical investigation in CHB as monotherapy or complementary therapy to LAM.