Showing papers by "Fabien Zoulim published in 1996"

Analysis of hepatitis B virus genotypes and pre-core region variability during interferon treatment of HBe antigen negative chronic hepatitis B

Abstract: The clinical importance of hepatitis B virus (HBV) genome variability has been reported recently. One example is the occurrence of hepatitis B virus pre-core mutants, which arise during spontaneous or interferon-induced seroconversion from HBeAg to anti-HBe and are thought to be selected by immune pressure. A survey of HBV pre-core mutants and viral genotypes in 35 HBeAg negative patients during interferon therapy was carried out to understand viral pathogenesis in this form of chronic hepatitis B. Seventeen patients responded to interferon therapy as assessed by the sustained normalization of serum ALT levels and the significant decrease of viremia levels. The response rate to interferon was independent of both initial serum viral DNA level and interferon doses. During interferon therapy, a significant decrease of M0 (wild-type pre-core sequence at pos. 1887–1908), M1 (TGG to TAG at pos. 1896) or M2 (TGG to TAG at pos. 1896, and GGC to GAC at pos. 1899) positive viral genomes was found in 48%, 42%, and 33% of patients, respectively. A higher response rate to interferon therapy was observed in patients infected with HBV genotype A (70%) or M0 positive strains (75%) as compared to patients infected with genotype D/E (40%) or M1/M2 positive strains (44%). The data support the hypothesis that pre-core defective HBV represent viral mutants with an increased capacity to resist exogenous alpha interferon. These findings emphasize that characterization of HBV genome variability prior to interferon therapy may help to predict antiviral response in HBeAg negative patients. © 1996 Wiley-Liss, Inc.

2',3'-dideoxy-beta-L-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo.

Abstract: beta-L-Nucleoside analogs represent a new class of potent antiviral agents with low cytotoxicity which provide new hope in the therapy of chronic hepatitis B virus (HBV) infections. We evaluated the anti-HBV activity of 2',3'-dideoxy-beta-L-5-fluorocytidine (beta-L-F-ddC), a beta-L-nucleoside analog derived from 2',3'-dideoxycytidine (ddC), in the duck HBV (DHBV) model. This compound was previously shown to inhibit HBV DNA synthesis in a stably transfected hepatoma cell line (F2215). Using a cell-free system for the expression of an enzymatically active DHBV polymerase, we could demonstrate that the triphosphate form of beta-L-F-ddC does inhibit hepadnavirus reverse transcription. In primary duck hepatocyte culture, beta-L-F-ddC showed a potent inhibitory effect on DHBV DNA synthesis which was concentration dependent. Although beta-L-F-ddC was shown to be less active than ddC against the DHBV reverse transcriptase in vitro, beta-L-F-ddC was a stronger inhibitor in hepatocytes. The oral administration of beta-L-F-ddC in experimentally infected ducklings showed that beta-L-F-ddC is a potent inhibitor of viral replication in vivo. Short-term therapy could not prevent a rebound of viral replication after the drug was withdrawn. Preventive therapy with beta-L-F-ddC could delay the onset of viremia by only 1 day compared with the time to the onset of viremia in the control group. The in vivo inhibitory effect of beta-L-F-ddC was much stronger than that of ddC and was not associated with signs of toxicity. Our data show that beta-L-F-ddC inhibits hepadnavirus reverse transcription and is a strong inhibitor of viral replication both in vitro and in vivo.

Treatment of chronic viral hepatitis

Abstract: Recent advances have been made in the treatment of chronic viral hepatitis, mainly with recombinant interferon (IFN) alpha. However, the present treatment of chronic viral hepatitis is not entirely satisfactory because the efficacy is inconstant and/or incomplete. In chronic hepatitis B IFN-alpha induces a sustained interruption of hepatitis B virus (HBV) replication, with a HBeAg to anti-HBe seroconversion in about 30% of patients. Patients most likely to respond are those with no immunosuppression, HBV infection acquired during adulthood or active liver disease with low HBV replication. Responders usually show a significant decrease in serum HBV DNA levels during the first 2 months of therapy, followed by a significant increase in the level of aminotransferases. New nucleoside analogues might be useful in combination with IFN-alpha in the treatment of those who do not respond to IFN therapy. In chronic hepatitis B-D, the rate of sustained response to IFN-alpha therapy is low. To be effective, IFN-alpha must be used at a high dosage (9-10 mega units) with a long duration (1 year). In chronic hepatitis C, IFN-alpha at a dosage of 3 mega units over 6 months, induces a sustained response in about 20% of patients. A higher dosage of IFN (5-10 mega units) and a longer duration of treatment increases the rate of sustained response but is associated with poor tolerance. Non-responders to a first course of IFN do not respond to a second course of treatment. In patients who respond but relapse after treatment, the rate of sustained response after a second course of IFN needs to be assessed. Ribavirin, which has a significant antiviral effect on hepatitis C virus, might be useful in combination with IFN-alpha. At the dosage (3-6 mega units) usually used, IFN-alpha is relatively well tolerated. In about 10% of the patients therapy is interrupted, mainly because of severe fatigue, thyroid dysfunction or depression.