New Anti-Virals Against Wild-Type and Lamivudine-Resistant Hepatitis B Virus
Background:Chronic infection with hepatitis B virus (HBV) remains among the ten most common causes of death worldwide. Lamivudine became the first approved oral therapy for the treatment of HBV. Although lamivudine treatment rapidly reduces HBV DNA levels and improves liver histology, the emergence of resistant HBV with L180M and/or M204V/I (YMDD motif mutations) in the polymerase gene following long-term treatment is becoming an important clinical problem. Thus, there is a pressing need to develop new anti-virais and new strategies to treat lamivudine-resistant HBV. Recently, we have established thein vitrofull-length HBV DNA transfection system that facilitates the testing of antivirals against HBV mutants. Using this system, we have investigated the susceptibility of wild-type and lamivudine-resistant HBV to new anti-virais.
Methods:Replication fitness and susceptibility of wild-type and lamivudineresistant HBV (M204I, M204V, and L180M/M204V) to 21 anti-virais was investigated by transient transfection of full-length HBV DNA into human hepatoma cells (HuH-7). HBV DNA replication was monitored by Southern blot hybridization, and effective concentration required to reduce HBV replication by 50% (EC50) was determined
Results:Although the replication competency of M204I and M204V was markedly decreased compared to that of wild-type HBV, L180M/M204V restored replication competence. Of 21 anti-virais, 13 anti-virais were effective against wild-type HBV, and 6 anti-virais (entecavir, MCC-478, L-D4FC, clevudine, emtricitabine, lobucavir) inhibited wild-type HBV replication more than lamivudine. However, only 4 anti-virais (entecavir, MCC-478, adefovir, lobucavir) were effective against all HBV mutants. Moreover, a higher dose of anti-viral was necessary to inhibit L180M/M204V compared to M204V.
Conclusion: Our study identified anti-virais with stronger potency than lamivudine against wild-type HBV and with potency against lamivudine-resistant HBV. They appear to be excellent candidates for the future treatment of HBV infection. L180M mutation of HBV polymerase not only restores the replication competence of M204V, but also increases drug resistance.
KeywordsAdefovir Dipivoxil YMDD Motif Mutation
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