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      Safety and efficacy of telbivudine for the treatment of chronic hepatitis B

      Therapeutics and Clinical Risk Management

      Dove Medical Press

      telbivudine, hepatitis B, antivirals, resistance

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          Abstract

          Telbivudine was recently approved for the treatment of chronic hepatitis B. Phase III studies indicated its antiviral potency with 6- to 6.5-log copies/mL reductions in hepatitis B DNA levels at year 1, comparable to other potent agents such as entecavir or tenofovir. Genotypic resistance rates, however, reached 25% at year 2 in hepatitis B e-antigen positive subjects and 11% in hepatitis B e-antigen negative subjects, preventing it from becoming a preferred first-line drug for hepatitis B. Furthermore, its signature resistance mutation (a change from methionine to isoleucine at position 204 in the reverse transcriptase domain of the hepatitis B polymerase) also confers cross-resistance to entecavir, lamivudine, and emtricitabine. Telbivudine is well tolerated, with elevations in creatine phosphokinase being the most common abnormality observed in clinical trials. Most often, elevations were asymptomatic. Future research in hepatitis B will focus on the best ways to use existing therapies, including telbivudine, sequentially or in combination in order to maximize viral suppression and minimize the development of antiviral resistance.

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          Most cited references 10

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          Telbivudine, a nucleoside analog inhibitor of HBV polymerase, has a different in vitro cross-resistance profile than the nucleotide analog inhibitors adefovir and tenofovir.

          Telbivudine, a nucleoside analog inhibitor of the viral polymerase of hepatitis B virus (HBV), has been approved for the treatment of chronic HBV infection, along with the nucleoside inhibitors lamivudine and entecavir, and the nucleotide inhibitors adefovir and tenofovir. The resistance profiles of these agents were investigated via drug treatment of HepG2 cells stably transfected with wild-type or mutant HBV genomes bearing known resistance mutations. Telbivudine was not active against HBV strains bearing lamivudine mutations L180M/M204V/I but remained active against the M204V single mutant in vitro, potentially explaining the difference in resistance profiles between telbivudine and lamivudine. Against HBV genomes with known telbivudine-resistance mutations, M204I and L80I/M204I, telbivudine, lamivudine and entecavir lost 353- to >1000-fold activity whereas adefovir and tenofovir exhibited no more than 3-5-fold change. Conversely, against HBV cell lines expressing adefovir resistance mutations N236T and A181V, or the A194T mutant associated with resistance to tenofovir, telbivudine remained active as shown by respective fold-changes of 0.5 (N236T) and 1.0 (A181V and A194T). These in vitro results indicate that nucleoside and nucleotide drugs have different cross-resistance profiles. The addition of telbivudine to ongoing adefovir therapy could provide effective antiviral therapy to patients who develop adefovir resistance.
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            Combinations of adefovir with nucleoside analogs produce additive antiviral effects against hepatitis B virus in vitro.

            Combination therapies may be required for long-term management of some patients chronically infected with hepatitis B virus (HBV). Adefovir is a nucleotide analog that has similar activity against wild-type and lamivudine-resistant HBV. In contrast to lamivudine, clinical resistance to the prodrug adefovir dipivoxil emerges infrequently. Based on its clinical efficacy and low frequency of resistance, adefovir dipivoxil may form an important component of combination regimens. We therefore investigated the in vitro antiviral efficacy of combinations of adefovir with other nucleoside analogs (lamivudine, entecavir, emtricitabine [FTC],and telbivudine [L-dT]) and the nucleotide analog tenofovir. Using a novel stable cell line that expresses high levels of wild-type HBV, we assayed the antiviral activity of each drug alone and in combination with adefovir. All two-drug combinations resulted in greater antiviral effects than treatments with single agents and could be characterized as additive by the Bliss independence model. Analysis using the Loewe additivity model indicated that adefovir exerted additive antiviral effects when combined with lamivudine, FTC, or L-dT and moderately synergistic effects when combined with entecavir or tenofovir. There was no evidence of cytotoxicity with any of the drugs when used alone or in combination at the tested doses.
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              Prolonged use of tenofovir in HIV/hepatitis B virus (HBV)-coinfected individuals does not lead to HBV polymerase mutations and is associated with persistence of lamivudine HBV polymerase mutations.

              The aim of the study was to identify and characterize hepatitis B virus (HBV) polymerase gene mutations associated with ongoing HBV replication in HIV/HBV-coinfected individuals receiving tenofovir (TDF). This retrospective cross-sectional study identified 28 HIV/HBV-coinfected individuals who had received TDF for at least 3 months. All patients had samples available while receiving TDF (on-TDF), and 24 also had samples available prior to treatment (pre-TDF). Case records were reviewed to obtain clinical and virological data at the times of sampling (+/-3 months). The HBV DNA of all samples was amplified using polymerase chain reaction (PCR), and the polymerase region of PCR-positive samples was sequenced and compared with reference HBV data. Of the pre-TDF samples, 15 of 24 (63%) were HBV PCR positive. Of the on-TDF samples, four of 28 (14%) were HBV PCR positive (mean time on TDF 13.5 months; range 3-23 months). Lamivudine (3TC)-resistance mutations were detected in three of four (75%) of these viraemic samples. The previously identified putative TDF-resistance mutations, rtA194T+rtL180M+rtM204V, were not detected in any individual. Unique mutations in the HBV polymerase gene associated with TDF resistance are rare in HIV/HBV coinfection. 3TC-resistance mutations persist and a significant proportion of patients are HBV PCR positive despite the addition of TDF.
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                Author and article information

                Journal
                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                1176-6336
                1178-203X
                2009
                2009
                12 October 2009
                : 5
                : 789-798
                Affiliations
                Department of Medicine, Emory, University School of Medicine, Atlanta, GA, USA
                Author notes
                Correspondence: Melissa Osborn, Emory University School of Medicine, 550 Peachtree St. NE, 7th Floor Medical Office Tower, Atlanta, GA 30308, USA, Tel +1 404 686 8114, Fax +1 404 686 4841, Email mkosbor@ 123456emory.edu
                Article
                tcrm-5-789
                2762437
                19851526
                © 2009 Osborn, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Categories
                Review

                Medicine

                antivirals, hepatitis b, resistance, telbivudine

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