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Perspectives for the treatment of hepatitis B virus infections.




 

Int J Antimicrob Agents. 1999 Jul;12(2):81-95. Unique Identifier :

Primarily resulting as a spin-off of the search for effective anti-HSV or anti-HIV agents, several compounds have been identified as effective and promising candidate anti-HBV drugs, i.e. famciclovir (penciclovir), BMS-200475, lamivudine (3TC), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA. They all inhibit HBV replication in Hep G2 2.2.15 at concentrations that are well below the cytotoxicity threshold. All these nucleoside analogues require three phosphorylation steps to be active, in their triphosphate form, as inhibitors of the HBV DNA polymerase, except for PMEA (adefovir) and PMPA (tenofovir), which need only two phosphorylation steps, to PMEApp and PMPApp, respectively, to interact as chain terminators with the HBV DNA polymerase reaction. Several of these compounds (for example, famciclovir, lamivudine and adefovir) have proven to be efficacious in the duck and/or woodchuck hepatitis models, and, accordingly, famciclovir, lamivudine and adefovir have also proven to be effective (i.e. in reducing HBV DNA levels) in patients with chronic HBV infection. Yet, famciclovir and lamivudine may lead to the emergence of resistance mutations (i.e. L528M and M552V/I) in the HBV DNA polymerase upon long-term treatment. These penciclovir- and lamivudine-resistant HBV mutants still retain susceptibility to adefovir, which, in turn, has so far not been found to engender resistance mutations in HBV. As has become obvious from the experience with the treatment of HIV infections, future HBV chemotherapy may reside in combination drug therapy so as to achieve the highest possible virus reduction, thereby minimizing the likelihood of drug resistance development.

JOURNAL ARTICLE REVIEW REVIEW, TUTORIAL Acute Disease Animal Anti-HIV Agents/CHEMISTRY/PHARMACOLOGY Antiviral Agents/CHEMISTRY/*PHARMACOLOGY Cell Line/VIROLOGY Clinical Trials/METHODS Comparative Study Disease Models, Animal Drug Resistance, Microbial Ducks DNA, Viral/DRUG EFFECTS Hepadnaviridae Infections/DRUG THERAPY Hepatitis B Virus/DRUG EFFECTS/GENETICS Hepatitis B Virus, Duck Hepatitis B Virus, Woodchuck Hepatitis B, Chronic/*DRUG THERAPY/VIROLOGY Hepatitis, Viral, Animal/DRUG THERAPY/VIROLOGY Human Marmota Structure-Activity Relationship Virus Replication/DRUG EFFECTS



 




Information in this article was accurate in November 30, 1999. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.