Development of resistance and perspectives for future therapies against hepatitis B infections: lessons to be learned from HIV.
Several first-generation nucleoside analogues have been tested against chronic hepatitis B virus (HBV) infection, but trials were unsuccessful or accompanied by toxicity. Recently, oral second-generation nucleoside analogues have been developed that have potent activity against HBV. The best-studied compound so far is lamivudine ((-)2'-deoxy-3'-thiacytidine; 3TC). Lamivudine is an inhibitor of reverse transcriptase (RT) activity and is in clinical use in human immunodeficiency virus (HIV)-infected individuals. As several studies on the use of lamivudine for hepatitis B show, the development of resistance in the viral polymerase under lamivudine treatment, however, causes a significant clinical problem. All other drugs in advanced clinical development for HBV are nucleosides; cross-resistance is therefore expected in most cases. The history of HIV treatment demonstrates that new classes of drugs, the protease inhibitors and non-nucleosidic inhibitors of RT, allowed for a longer-term clinical benefit when used in combination with nucleoside analogues. The development of non-nucleosidic compounds with different modes of action therefore appears very important for the treatment of chronic hepatitis B as well.
Deres
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Dept. of Virology, Geschäftsbereich Pharma, Bayer AG, Wuppertal, Germany.
Rübsamen-Waigmann
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H
D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy; D006509:Hepatitis B / Q000188:drug therapy*; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage* / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D011379:Prognosis; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D016896:Treatment Outcome
D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine