REP 2139 is a nucleic acid polymer (NAP) currently under clinical development for chronic hepatitis B (HBV) therapy. This preclinical study investigated different REP 2139 analogs that would display reduced accumulation in the serum and tissues, while retaining an antiviral effect against HBV infection. REP 2139 analogs were evaluated in human plasma, CD-1 mice, cynomolgus monkeys, and Pekin ducks. Discrete ribose transformation to 2′OH in selected riboadenosines resulted in a slow degradation in acidified human plasma that plateaued after 48 hr. REP 2165, a REP 2139 analog containing three unmodified riboadenosines equally spaced throughout the polymer, showed similar plasma clearance and tissue distribution as REP 2139 in mice and cynomolgus monkeys after a single dose. Interestingly, after repeated administration, accumulation of REP 2165 in plasma and organs was reduced, indicating a dramatically faster rate of clearance from organs after therapy was ended in both species. Both REP 2139 and REP 2165 were well tolerated at clinically relevant doses, with no alterations in liver, kidney, or hematological function. In chronic duck HBV (DHBV) infection, REP 2165 displayed significantly reduced liver accumulation after repeated dosing but retained antiviral activity similar to REP 2139. These results indicate the therapeutic potential of REP 2165 against chronic HBV infection in patients is similar to REP 2139, but with significantly reduced drug accumulation and improved tissue clearance.
Chronic hepatitis B virus (HBV) infection remains a major public health problem worldwide, with three hundred million chronic carriers of the virus, and its serious clinical consequences include liver cirrhosis and hepatocellular carcinoma (19). Unfortunately, alpha interferon therapy induces a sustained antiviral response in only 20 to 30% of the patients (12). The development of new nucleoside analogs, such as -L(Ϫ)-2Ј,3Ј-dideoxy-3Ј-thiacytidine [L(Ϫ)SddC or 3TC or lamivudine] that exhibit a potent inhibitory effect on HBV reverse transcriptase activity and viral replication in vitro (2, 6, 31), has opened new avenues in the antiviral therapy of chronic hepatitis B. Results of phase II and phase III clinical trials have shown that administration of lamivudine results in a dramatic suppression of viral replication which is accompanied by an improvement in liver histology (16,27,44). However, because of the relatively low rate of anti-HBe seroconversion and of the special features of the viral kinetics, long-term therapy with a nucleoside analog is required to eradicate viral infection (16,28). Indeed, chronic HBV infection is characterized by a high rate of virus production, by the absence of a cytopathogenic effect (and therefore a long half-life of infected hepatocytes), and by the persistence of viral genomes as a covalently closed circular DNA (CCC DNA) in the nucleus of infected cells (9,26,28,36,40). Because of the spontaneous error rate of the viral reverse transcriptase, prolonged administration of a single nucleoside analog in chronically infected patients may select for the replication of resistant viral strains. The rate of selection of resistant mutants is 23% after 1 year of lamivudine treatment and increases to 38% at the end of the second year of therapy (16). The same observation has been made with long-term treatment with famciclovir, another inhibitor of HBV polymerase, and it was demonstrated that the resistant viruses harbor mutations in conserved domains of the viral reverse transcriptase (29,44).In order to design new strategies that combine several antiviral agents with different mechanisms of action to prevent the emergence of resistant strains, the development of new inhibitors of HBV replication is required (44). In the search for new potent antiviral agents, 2Ј,3Ј-dideoxy-2Ј,3Ј-didehydro--L-5-fluorocytidine (-L-Fd4C) was found to exhibit a potent antiviral activity against human immunodeficiency virus and HBV replication in tissue culture (7,23). -L-Fd4C was found to be at least 10 times more potent (50% inhibitory concentration [IC 50 ] at 1 nM) than lamivudine (IC 50 at 15 nM) on HBV DNA synthesis in the hepatoma cell line HepG2 2.2.15, and its triphosphate derivative specifically inhibited the virion associated HBV DNA polymerase activity (41). Detailed analysis of the intracellular metabolism of -L-Fd4C revealed that the degree of phosphorylation and retention time of the triphosphate metabolites were higher than for lamivudine which may explain, at least in part, both the m...
The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus of infected hepatocytes is an obstacle to achieving sustained viral clearance during antiviral therapy of chronic hepatitis B virus (HBV) infection. The aim of our study was to determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, the prodrug of which, adefovir dipivoxil, is in clinical evaluation, is able to suppress viral CCC DNA both in vitro and in vivo using the duck HBV (DHBV) model. First, the effect of adefovir on viral CCC DNA synthesis was examined with primary cultures of DHBV-infected fetal hepatocytes. Adefovir was administered for six consecutive days starting one day before or four days after DHBV inoculation. Dose-dependent inhibition of both virion release in culture supernatants and synthesis of intracellular viral DNA was observed. Although CCC DNA amplification was inhibited by adefovir, CCC DNA was not eliminated by antiviral treatment and the de novo formation of CCC DNA was not prevented by pretreatment of the cells. Next, preventive treatment of experimentally infected ducklings with lamivudine or adefovir revealed that both efficiently suppressed viremia and intrahepatic DNA. However, persistence of viral DNA even when detectable only by PCR was associated with a recurrence of viral replication following drug withdrawal. Taken together, our results demonstrate that adefovir is a potent inhibitor of DHBV replication that inhibits CCC DNA amplification but does not effectively prevent the formation of CCC DNA from incoming viral genomes.Despite the existence of efficient vaccines, chronic hepatitis B virus (HBV) infection continues to be a major public health problem worldwide, with more than 350 million chronic carriers. These individuals are at high risk of developing cirrhosis and hepatocellular carcinoma (28). Interferon alpha therapy is only moderately effective and often is limited by dose-dependent side effects (20). The discovery that certain nucleoside inhibitors of human immunodeficiency virus reverse transcriptase, such as lamivudine, also inhibit HBV polymerase has led to the development of these agents for the treatment of HBV infection. Lamivudine has been shown to be highly effective in inhibiting HBV replication (10, 25) and has recently been licensed in many countries for the therapy of chronic hepatitis B. However, analysis of the kinetics of viral clearance during lamivudine therapy revealed that since lamivudine does not completely inhibit viral replication and the rate of clearance of infected cells is slow, prolonged therapy is required for elimination of virus (38). The initial reactions required for the conversion of the incoming relaxed circular (RC) DNA into covalently closed circular (CCC DNA) are still not elucidated, but it can be hypothesized that HBV polymerase (23) and cellular enzymes (2) may be required for this process. CCC DNA serves as the template for viral transcription (46), and its production is regulated and amplified by an intracellular pa...
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