Recent Research on Treatment of Chronic Hepatitis B 6

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Genotype Influences Response Rates to Interferon in Hepatitis B



The response rate to interferon varies significantly depending on the genotype of hepatitis C infection.  Therefore, it should not be surprising that different genotypes of hepatitis B might also have different response rates to interferon.  Hou and colleagues studied differences in response rate in two populations, one Caucasian and the other predominantly Asian, all of whom were HBeAg + at the beginning of study.  Response was measured by seroconversion to HBeAb.  They reported that genotype A was more responsive than genotype D in Caucasians and genotype B was more responsive than genotype C in Asians.  However, the higher rate of response was also associated with a higher rate of core promoter mutations at the end of treatment, particularly in the responders.  The rate of pre-core mutations was similar in all groups and did not change with treatment.  The significance of these mutations is not yet clear based on the study, but does suggest that genotype may be a prognostic factor worth measuring in future studies. (Abstract 1100)



Combination therapy has become the standard of care in treatment of both chronic hepatitis C infection and HIV infection.  In some ways, the success of monotherapy with either lamivudine or interferon is surprising and probably relates to the importance of an active immune response in recovery from hepatitis B.  Although the rates of histological improvement with lamivudine monotherapy noted in the study mentioned above were lower than those previously reported, the seroconversion rates were similar.  This important study lends support to the idea of combining interferon with lamivudine to achieve better efficacy.  Furthermore, the improved pharmacokinetics of pegylated interferon will likely make it a better choice for HBV infection as well as for HCV. Studies of pegylated interferon in combination with lamivudine are currently ongoing and may provide even more exciting results than those already reported



Other New Drugs for HBV Infection



Several phase 1-2 dose ranging studies were reported at this year’s meeting.  L-deoxythymidine (LdT) showed promising dose-related reductions in HBV DNA levels between 2.5-4.0 log fold with 4 weeks administration of 25-400 mg daily.  No serious adverse events were noted in this study.  One important observation was that the second phase of viral clearance (due to clearance of virus from infected liver cells, not from plasma is dose dependent).  The first phase of clearance from plasma was similar at all doses tested.  (Abstracts 597 & 697)



A dose-ranging study with clevudine (L-FMAU) was reported to show 2.0-3.8 log reductions in HBV DNA with 100 mg daily for 4 weeks.  There was a transient, but reversible increase in ALT in 3/19 patients treated with 100 mg daily.  Suppression of viral replication continued for up to 6 months following 28 days of therapy.  (Abstract 593)



One of the most promising, innovative approaches to treatment of chronic viral hepatitis is ribozyme therapy.  Ribozymes are small nucleic acid sequences that contain a catalytic subunit to bind to specific regions of a viral genome and destroy the virus by cutting the viral nucleic acid chain.  Ribozymes are currently in clinical trial in combination with interferon for treatment of chronic hepatitis C.  The investigators reported at this meeting that combining a hepatitis B ribozyme with interferon or lamivudine inhibited HBV DNA replication in a model cell line in vitro.  The effects of the ribozyme were additive with those of interferon or lamivudine.  The company plans further clinical trials with ribozymes for hepatitis B within the next year.  (Abstract 1101)