METHOD OF TREATING HEPATITIS DELTA VIRAL INFECTION

Abstract: A method for the treatment for hepatitis delta infection in a host, that includes administering an effective amount of a nucleoside or a nucleoside analog or a prodrug or pharmaceutically acceptable salt thereof that suppresses the expression of the hepatitis B surface or preS1 antigen in the host 100-fold or more relative to pretreatment values <i>in vivo</i>; or to not move than 1 microgram per milliliter <i>in vivo</i>. In a preferred embodiment, the nucleoside is L-FMAU, or a pharmaceutically acceptable salt or prodrug thereof.

Description: METHOD OF TREATING HEPATITIS DELTA VIRAL INFECTION Federal Funding Legend This invention was supported in part by the United States Department of Health and Human Services under grant numbers NTH AI-35164, Al-33655, AI- 05399, NOl-AI-45197, andNOl-AI-82698. Field of Invention This invention is in the area of methods and compositions for the treatment of a host infected with hepatitis delta virus (also referred to as "HDN") that includes administering an effective amount of a compound, in particular a nucleoside or nucleoside analog, that substantially reduces the level of hepatitis B surface antigen. In one nonlimiting embodiment, the nucleoside analog is 2'-fluoro-5-methyl-β-L- arabinofuranosyl-uridine (also referred to as "L-FMAU") or a pharmaceutically acceptable salt or prodrug thereof. BACKGROUND OF THE INVENTION Type D hepatitis, the most severe form of viral hepatitis, is caused by infection with hepatitis D (delta) virus (HDN), a sub-viral satellite of hepatitis B virus (HBN) (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75). Compared with other agents of viral hepatitis, acute HDN infection is more often associated with fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive amounts of the liver are destroyed. Chronic type D hepatitis is typically characterized by necroinflammatory lesions, similar to chronic HBN infection, but is more severe, and frequently progresses rapidly to cirrhosis and liver failure, accounting for the disproportionate association of chronic HDN infection with terminal liver disease (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75; Rizzetto, M., et al. (1983) Ann Intern Med 98, 437-41). Although HDN infection affects fewer individuals than HBN alone, the resulting acute or chronic liver failure is a common indication for liver transplantation in Europe as well as North America (Smedile, A. & Rizzetto, M. (1992) bit J Clin Lab Res 22, 211-215; Wright, T. L. & Pereira, B. (1995) Liver Transplant Surgery 1, 30-42). Chronic disease affects 15 million persons worldwide, about 70,000 of whom are in the U.S. The Centers for Disease Control estimates 1,000 deaths annually in the U.S. due to HDN infection (Alter, M. j. & Hadler, S. C. (1993) Prog Clin Biol Res 382, 243-50; Alter, M. J. & Mast, E. E. (1994) Gastroenterol Clin North Am 23, 437-55). There is currently no generally accepted effective therapy for type D hepatitis, and liver transplantation is the only option for the associated end-stage liver disease. Although interferon alpha has been moderately successful in treating some cases of type D hepatitis, the need for better treatment options is indicated by the very high doses required, variable responses, frequent relapse after cessation of treatment, and difficulties in drug administration (Thomas, H. C. et al. (1987) Prog Clin Biol Res 234, 277-90; Hoofnagle, J. et al. (1987) Prog Clin Biol Res 234, 291-8; Rosina, F.et al. (1987) Prog Clin Biol Res 234, 299-303; Rosina, F. et al. (1991) Hepatology 13, 1052-6; Farci, P. et al. (1994) NEnglJMed 330, 88-94; Hadziyannis, S. J. (1991) J Hepatol 13 Suppl LS21-6; Di Marco, N. et al. (1996) J Viral Hepat 3, 123-8; Porres, . C. et al. (1989) J Hepatol 9, 338-44). Lamivudine (β-L-2',3'-dideoxy-3'-thiacytidine, 3TC) is a synthetic nucleoside shown to be effective in treating HIN and HBN infection. See U.S. Patent No. 5,539,116 to Liotta et al. Lamivudine is known to cause sustained suppression of HBN replication during treatment (Νevens, F. et al. (1997) Gastroenterology 113:1258-1263). However, lamivudine does not improve disease activity or lower HDN-RΝA levels in patients with chronic delta hepatitis (Lau, D. T.et al. (1999) Hepatology 30, 546-9). Lamivudine was recently approved in the U.S. and several other countries for treatment of chronic HBN infection. Prolonged treatment of chronic HBN carriers with lamivudine leads to decreased levels of HBN in serum and improved liver histology (Lai, C. L. et al. (1998) N EnglJ Med 339, 61-8; Tyrrell, D. et al. (1993) Hepatology 18, 112A; Νevens, F. et al. (1997) Gastroenterology 113, 1258-63; Dienstag, j. L. et al. (1995) NEngl JMed 333, 1657-61). Despite the dramatic effects on HBN, lamivudine treatment of patients chronically infected with both HBN and HDN has little effect on circulating levels of HDN; more importantly, there is no improvement in disease activity even though HBN levels are suppressed (Honkoop, P. et al. (1997) Hepatology 24 (Suppl), 1219 (Abstract); Lau, D. T. et al. (1999) Hepatology 30, 546-9). Additional forms of treatment have been tried. For example, suramin in vitro blocks the entry of the virion into hepatocytes, but it is too toxic to be acceptable for long term use in humans (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75). Acyclovir enhances HDN replication in vitro. (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75). Ribavirin did not significantly affect virological or biochemical parameters and had severe side-effects. (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75). Synthetic analogs of thymosin have also been ineffective in the treatment of HDN infection. (Smedile, A., et al. (1994) Prog Liver Dis 12, 157-75). None of the described treatments for HDN infection are generally accepted as effective. The HDN virion is composed of a ribonucleoprotein core and an envelope. The core contains HDN-RΝA, and hepatitis delta antigen (HDAg), which is the only protein encoded by this virus. (Wang, K. S. et al. (1986) Nature 323, 508-14). The envelope is formed by the surface antigen protein (hepatitis B surface antigen, or HBsAg) of the helper virus, hepatitis B. (Bonino, F. (1984) Infect Immun 43, 1000-5; Boriino, F. et al. (1981) Hepatology 1, 127-31; Bonino, F. et al. (1986) J Virol 58, 945-50). The envelope is the sole helper function provided by HBN. HDN is able to replicate its RΝA within cells in the absence of HBN (Kuo, M. Y. et al. (1989) J Virol 63, 1945-50), but requires HBsAg for packaging and release of HDN virions (Wu, J. C. et al. (1991) J Virol 65, 1099-104; Ryu, W. S. et al. (1992) J Virol 66, 2310-2315.), as well as for infectivity. (Sureau, C, et al. (1992) J Virol 66, 1241-5). As a result of the dependence of HDN on HBN, HDN infects individuals only in association with HBN. Because the woodchuck hepatitis virus (WHN) is closely related to HBN (ca. 85% nucleic acid homology), it has been widely used as a model for HBN infection and disease in its natural host, the eastern woodchuck (M. monax). (Gerin, J. L. (1990) GastroenterolJpn 25 (Supp), 38-42; Tennant, B. C. et al. (1988) Viral Hepatitis and Liver Disease , 462-464). Experimentally infected woodchucks have also been used extensively for analysis and development of anti-HBN therapeutics. (Zahm, F. E. et al. (1998) ItalJ Gastroenterol Hepatol 30, 510-6; Tennant, B. C. et al. (1998) Hepatology 28, 179-91; Mason, W. S. et al. (1998) Virology 245, 18-32; Korba, B. E. et al. (1996) Hepatology 23, 958-63; Hurwitz, S. et al. (1998) Antimicrob Agents Chemother 42, 2804-2809; Block, T. M. et al. (1998) Nat Med 4, 610-4; Cullen, J. M. et al. (1997) Antimicrob Agents Chemother 41, 2076-82; Fourel, G. et al. (1990) Nature 347, 294-8; Gangemi, J. et al. (1997) Antivir Therap 1, 64-70; Genovesi, E. N. et al. (1998) Antimicrob Agents Chemother 42, 3209-17; Korba, B. E. et al. (2000) Antiviral Res 45, 19-32; Korba, B. E. et al. (2000) Antiviral Therapy 55, 95-105; Korba, B. E. et al. (2000) Antimicrobial Agents and Chemotherapy 44, 19-32. The efficacy of several anti-HBN agents used to experimentally treat chronic WHN infection in woodchucks (araAMP, ribavirin, AZT, ACN, 3TC, famciclovir, FTC, alpha-interferon, fialuridine ganciclovir, thymosin alpha- 1, combination therapy with 3TC and alpha-interferon or 3TC and famciclovir) has accurately paralleled the efficacy and toxicity profiles of these agents administered to HBN patients treated in the course of clinical trials. The similar efficacy observed in WHN infected woodchucks and HBN infected persons treated with anti-HBN agents demonstrates that the woodchuck animal model can be predictive for anti-HBN therapies in man (Zahm, F. E. et al. (1998) ItalJ Gastroenterol Hepatol 30, 510-6; Tennant, B. C. et al. (1998) Hepatology 28, 179-91; Mason, W. S. et al. (1998) Virology 245, 18-32; Hurwitz, S. et al. (1998) Antimicrob Agents Chemother 42, 2804-09; Fourel, G. et al. (1990) Nature 347, 294-8; Gangemi, J. et al. (1997) Antivir Therap 1, 64-70; Genovesi, E. N. et al. (1998) Antimicrob Agents Chemother 42, 3209-17; Korba, B. E. et al. (2000) Antiviral Res 44, 19-32; Korba, B. E. et al. (2000) Hepatology 31, 1165- 75; Korba, B. E. et al. (2000) Antiviral Therapy 5, 95-105; Korba, B.E. et al. (2000) Antimicrob Agents Chemother 44, 1757-60). Like HBN, WHN can support HDN particle formation and infection, and the eastern woodchuck has been a useful model for HDN infection (Negro, F. et al. (1989) J Virol 63, 1612-8; Parana, R., Gerard, F., Lesbordes, J. L., Pichoud, C, Nitvitski, L., Lyra, L. G. & Trepo, C. (1995) J Hepatol 22, 468-73; Ciccaglione, A. R. et al. (1993) Arch Virol Suppl 8, 15-21; Bergmann, K. F. et al. (1989) J Immunol 143, 3714-21; Ponzetto, A. et al. (1984) Proc Natl Acad Sci USA 81, 2208-12; Ponzetto, A. et al. (1987) Prog Clin Biol Res 234, 37-46). The dependence of HDN on its helper virus, HBN, could suggest that successful treatment of HDN infection would follow successful treatment of the supporting HBN infection. Unfortunately, this does not appear to be the case, as illustrated by recent results obtained with the drug lamivudine (Glaxo-Wellcome, Inc.). (Honkoop, P. et al. (1997) Hepatology 24 (Suppl), 1219 (Abstract); Lau, D. T. et al. (1999) Hepatology 30, 546-9). The lack of an effect of lamivudine on disease in HBN-HDN infected patients underscores the direct role of HDN in disease severity in such patients. Although lamivudine inhibits HBN and WHN replication, it does not affect the production of viral surface antigen (Lau, D. T. et al. (1999) Hepatology 30, 546-9; Doong, S. L. et al. (1991) Proc Natl Acad Sci USA 88, 8495-9; Korba et al. Hepatology, (2000) 31, 1165-75. The life cycle of HBN and other representatives of this family of viruses (for example, WHN) is unique in that the process of replicating genomic copies of the virus and the production of viral proteins (for example, HBN or WHN surface antigens) are differentially regulated (Ganem, D. 1996. Hepadnaviridae. In "Fields Virology", Fields BΝ, Knipe DM, Howley P, ed. Lippincott-Raven, Philadelphia, p. 2703-2737). Therefore, antiviral agents, such as synthetic nucleosides (for example, lamivudine) which target viral polymerases, may significantly inhibit HBN replication (for example, as measured by a reduction in viremia), but not affect the level of viral rnRΝA or viral protein production (for example, as measured by the levels of HBN surface antigen in plasma or serum). Given that the life cycle of HBN is unique in differentially regulating viral proteins and that HBsAg can be produced from a number of alternative transcripts, it has not been known to date what parameters are essential to achieving a therapeutic end point for HDN. U.S. Pat. No. 5,747,044 discloses recombinanfly produced immunogenic HDN polypeptides useful as vaccines. U.S. Pat. No. 5,932,219 to Chiron discloses the entire genome of the hepatitis D virus, a family of cDNA replicas of the entire HDN genome, and teaches that portions of these cDΝA sequences are useful as probes to diagnose the presence of virus in clinical samples. The patent also discloses proteins encoded by the cDΝA that are useful in the production of vaccines. In particular, the '219 patent discloses a vaccine for hepatitis D which incorporates the p24 and p27 viral polypeptides. U.S. Patent No. 5,750,350 to Chiron claims a kit useful in the analysis of hepatitis D virus which includes a peptide encoded by ORF 5 of the HDN genome. U.S. Patent No. 5,747,044 claims a recombinanfly produced immunogenic particle which raises antibodies against HDN, wherein the particle includes an immunogenic polypeptide encoded within ORF 5 of the HDN nucleotide sequence or its complement. U.S. Pat. No. 6,020,167 assigned to Medeva Holdings B.V. discloses a method for treating chronic hepatitis, and in particular, hepatitis B, that includes administering a composition containing antiHBsAg. U.S. Pat. No. 5,770,584 discloses a method for treating hepatitis virus infection by administering alkyl lipids or alkyl lipid derivatives. U.S. Patent No. 4,619,896 discloses a process for unmasking delta antigen in the blood of an animal, that includes treating serum with a surfactant and optionally with an antibody-antigen dissociating agent. The blood derived delta antigen is used as a diagnostic agent in the detection and determination of different classes of antibodies to hepatitis D virus. United States statutory invention registration HI, 345 discloses a method for preventing or treating hepatitis virus by administering a protein-prenyl transferase inhibitor. Sureau, et al., Production of Infectious Hepatitis Delta Virus In Vitro and Neutralization with Antibodies Directed against Hepatitis B Virus Pre-S Antigens, Journal of Virology, Feb. 1992, p 1241-1245 discloses that HDV particles produced in vitro are infectious and that (i) infectious particles are coated with HBV envelope proteins that contain the pre-Sl and pre-S2 regions, (ii) epitopes of the pre-Sl and pre-S2 domains of HBV envelope proteins are exposed at the surface of HDV particles, and (iii) that antibodies directed against those epitopes have neutralizing activity against HDV. The nucleoside analog L-FMAU [2'-fluoro-5-methyl-β-L-arabinofuranosyl- uridine] is a known compound and has been shown to have significant antiviral activity against HBV replication in cell culture, and against the related duck hepatitis B virus in both cell culture and infected ducks (Aguesse-Germon, S. et al. (1998) Antimicrob Agents Chemother 42, 369-76; Balakrishna Pai, S. et al. (1996) Antimicrob Agents Chemother 40, 380-6; Chu, C. K. et al. (1995) Antimicrob Agents Chemother 39, 979-81; Fu, L. et al. (1999) Biochem Pharmacol 57, 1351-9; Kotra, L. P. et al. (1997) JMed Chem 40, 3635-44; Kukhanova, M. et al. (1998) Biochem Pharmacol 55, 1181-7; Ma, T. et al. (1997) JMed Chem 40, 2750-4; Ma, T. et al. (1996) JMed Chem 39, 2835-43; Xu, A. S. et al. (1998) Biochem Pharmacol 55, 1611-9; Yao, G. Q. et al. (1996) Biochem Pharmacol 51, 941-7); Peek, S. et al. (2001) Hepatology 33, 254-66; Zhu, Y. et al. (2001) J. Virol 75, 311-22. U.S. Pat. Nos. 5,587,362 and WO 95/20595 to Chu et al. disclose and claim L-FMAU and its pharmaceutical compositions for the treatment of HBV, and provides a detailed description of the synthesis of the compound. U.S. Patent No. 5,567,688 to Chu et al. claims a method for the treatment of HBV using L-nucleosides including L- FMAU. U.S. Patent No. 5,565,438 to Chu et al., claims a method to treat humans infected with Epstein-Barr virus (EBV) with L-FMAU. U.S. Patent Nos. 5,808,040 and 5,753,789 disclose the use of L-FMAU to stabilize an oligonucleotide by including the compound at the 5 '-terminus, 3 '-terminus, or the interior of the oligonucleotide. WO 98/15375 discloses a method for the manufacture of L-FMAU. L-FMAU has been shown to be a remarkably potent and fast-acting antiviral agent against WHV replication in chronically-infected woodchucks (Korba, B. et al. (1999) Antivir. Res. 41, A54; Chu, C. et al. (1998) in Therapies for viral hepatitis, eds. Schinazi, R. & Sommadossi, j. (International Medical Press, Atlanta), Vol. pp 303-12; Peek, S. F. et al. (1997) Hepatology 26, 425A(Abstract 1187); Peek, S. F. et al. (2001) Hepatology 33, 254-66; Zhu, Y. et al. (2001) J. Virol 75, 311-22. It has also been disclosed that L-FMAU induces suppression of WHN surface antigen in serum (Korba, B. et al. (1999) Antivir. Res. 41, A54; Chu, C. et al. (1998) in Therapies for viral hepatitis, eds. Schinazi, R. & Sommadossi, J. (international Medical Press, Atlanta), Vol. pp 303-12; Peek, S. B. et al. (1997) Hepatology 26, 425A and Peek, S. B. et al. (2000) Hepatology 33, 254-66. L-FMAU has been shown to have a favorable pharmacokinetic profile and sufficient oral bioavailability in rats and woodchucks that make it suitable for once daily administration (Wright, J. D. et al. (1995) Pharm Res 12, 1350-3; Wright, L D. et al. (1996) Biopharm DrugDispos 17, 197-207; Witcher, 1 W. et al. (1997) Antimicrob Agents Chemother 41, 2184-7). Because of the large number of persons infected with hepatitis delta virus, the devastating effects of hepatitis delta virus infection on the individual, and the lack of effective treatments, there is a critical need for new and effective methods and compositions for the treatment of hepatitis delta virus infection. Therefore, it is an object of the present invention to provide methods and compositions for the treatment of a host, including a human, infected with hepatitis delta virus. It is a further object of the present invention to provide a method for identifying compounds effective in the treatment of hepatitis delta virus infection. SUMMARY OF THE INVENTION It has been now been discovered that administration of a nucleoside or nucleoside analog or a prodrug or a pharmaceutically acceptable salt thereof that substantially reduces the level of hepatitis B surface antigen (referred to herein as HBsAg) in a host is useful in the treatment of hepatitis delta viral infection in that host. By substantial reduction of HBsAg in a host it is meant that the nucleoside or nucleoside analog reduces the hepatitis B surface antigen at least approximately 100- fold or more, and preferably, 200- or 500-fold relative to pretreatment values in vivo or in vitro, or to not more than 1, and preferably, 0.5 or 0.1 microgram per milliliter in vivo, as measured in serum or plasma using any appropriate standard immunoassays for example the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeNoronha, and J. Germ. 1993.) It was previously known that if a nucleoside or nucleoside analog does not significantly reduce the level of HBsAg in a hepatitis delta infected host, for example, 3TC (β-L-2',3'-dideoxy-3'-thiacytidine), then that nucleoside is not effective in the treatment of hepatitis delta virus. However, given that the life cycle of HBN is unique in differentially regulating viral proteins and that HBsAg can be produced from a number of alternative transcripts, it has not been known to date what parameters are essential to achieving a therapeutic end point for HDN, including whether reduction, as opposed to elimination, of HBsAg, by a nucleoside or nucleoside analog would translate into any therapeutic effect on HDN. Futher, there previously existed no information on the degree of HBsAg suppression needed to achieve this desired outcome, as measured by serum concentrations, or the length of treatment required for a sustained effect. Known nucleosides do not target all templates for HBsAg production and none are known to routinely suppress serum HBsAg levels. Finally, a host liver cell must be co-infected with both HBN or a hepadna virus other than hepatitis B that supports HDN infection and hepatitis delta virus in order for HBsAg suppression to be effective against hepatitis delta virus formation, and the proportion of liver cells making HBsAg but not co-infected is not known in each case. Liver cells infected with HBN alone could contribute to the serum HBsAg levels, yet suppression of HBsAg in these cells would not impact on hepatitis delta virus formation. It has now been established for the first time through the paradigm nucleoside, and a nonlimiting embodiment, L-FMAU, that if a nucleoside suppresses the production of HBsAg, so as to affect a substantial and sustained reduction in serum or plasma HBsAg levels, i.e., to approximately 100-fold or less than pretreatment values in vivo or in vitro, it will be useful in the treatment of hepatitis delta virus. Therefore, in one aspect of the invention, a method for the treatment of HDN infected host, in particular a human, is provided that includes the administration of an effective amount of a nucleoside or nucleoside analog that reduces HBsAg in the infected host at least approximately 100-fold, and preferably 200- or 500- fold, or more relative to pretreatment values in vivo or in vitro; or to not more than approximately 1 microgram, or preferably 0.5 or 0.1 microgram, per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Germ. 1993. In an alternative embodiment, it has been now been discovered that administration of a nucleoside or nucleoside analog that substantially reduces the level of preSl antigen in a host is useful in the treatment of hepatitis delta viral infection in that host. By substantial reduction of preSl antigen in a host it is meant that the nucleoside or nucleoside analog reduces the hepatitis B surface antigen at least approximately 100-fold or more, and preferably, 200- or 500-fold relative to pretreatment values in vivo or in vitro, using any appropriate assay, including that in: Deepen R, Heermann KH, Uy A, Thomssen R, Gerlich WH. "Assay of preS epitopes and preS 1 antibody in hepatitis B virus carriers and immune persons." Med Microbiol Immunol (Berl). 1990;179(l):49-60. In another aspect, a method for the treatment of an HDN infected host, in particular a human, is provided that includes the administration of an effective amount of an organic non-nucleoside small molecule (i.e., a molecule of molecular weight less than 500, which is other than a biologic material found in nature or a derivative or analog thereof retaining the desired activity, such as a peptide, protein, antibody, hormone, ribozyme, nucleic acid, or cytokine), and which is not a protein-prenyl transferase inhibitor or thymosin-alpha-1, that reduces HBsAg in the infected host to at least approximately 100-fold or more, and preferably at least 200- or 500-fold, relative to pretreatment values in vivo or in vitro; or to not more than 1 microgram, preferably 0.5 or 0.1 microgram per milliliter, as measured in serum or plasma using any appropriate assay, including standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Gerin. 1993. In one embodiment, an effective amount of L-FMAU or a pharmaceutically acceptable salt or prodrug thereof is administered to a host in need thereof to treat a hepatitis delta viral infection. In a preferred embodiment L-FMAU is administered to a host in need thereof in the absence of its corresponding β-D enantiomer (i.e., in an enantiomerically enriched or enantiomerically pure form). hi another embodiment, L-FMAU is administered in combination with at least one other HBsAg or preS 1 antigen lowering agent, which can be another nucleoside, a nucleoside analog or a non-nucleoside for the treatment of a hepatitis delta infected host. In yet another embodiment, the hepatitis delta treating agent is administered in combination with a agent that has activity against hepatitis B, whether or not the anti- hepatitis B agent lowers the hepatitis B surface antigen. In yet another embodiment, a method for treating hepatitis delta is provided that includes administering a compound, including a nucleoside, nucleoside analog or other small molecule as defined herein, that reduces the surface antigen of a hepadnavirus other than hepatitis B that supports HDN infection. In another embodiment, a method for screening a compound, including a nucleoside or a nucleoside analog, that is effective in the treatment of HDN infection is provided that includes assessing whether the compound suppresses the expression of hepatitis B surface antigen 100-fold or more (and preferably 200- or 500-fold) relative to pretreatment values in vivo or in vitro; and preferably, to not more than 1 microgram (and preferably 0.5 or 0.1 microgram) per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Gerin. 1993, using methods provided herein or otherwise available. In another embodiment, a method for screening a compound, including a nucleoside or a nucleoside analog, that is effective in the treatment of HDN infection is provided that includes assessing whether the compound suppresses the expression of hepatitis B surface antigen 100-fold or more (and preferably 200- or 500-fold) relative to pretreatment values in vivo or in vitro; or to not more than 1 microgram (and preferably 0.5 or 0.1 microgram) per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Gerin. 1993, using methods provided herein or otherwise available. In another embodiment, a method for screening a compound, including a nucleoside or a nucleoside analog, that is effective in the treatment of HDN infection is provided that includes assessing whether the compound suppresses the expression of preSl surface antigen 100-fold or more (and preferably 200- or 500-fold) relative to pretreatment values as measured in serum or plasma using standard immunoassays. The invention is based on the fundamental discovery that L-FMAU, as the model active compound, suppresses the expression of hepatitis B surface antigen by a sufficient amount that it effectively inhibits the packaging and release of HDN virions. Evidence is presented herein that L-FMAU causes a substantial decrease in levels of HDN viremia by suppressing the expression of hepatitis B surface antigen. In another embodiment, HDN infection can be treated in a host by administering at least one antisense oligonucleotide targeted to the RΝA transcript of the hepatitis B surface antigen or preSl antigen either alone or in combination with L- FMAU, or another HBsAg or preSl antigen lowering nucleoside or nucleoside analog. The term "oligonucleotide" encompasses both oligomeric nucleic acid moieties of the type found in nature, such as the deoxyribonucleotide and ribonucleoti.de structures of DΝA and RΝA, and man-made analogues which are capable of binding to nucleic acids found in nature. The oligonucleotides of the present invention can be based upon ribonucleotide or deoxyribonucleotide monomers linked by phosphodiester bonds, or by analogues linked by methyl phosphonate, phosphorothioate, phosphoroamidate, phosphorodithioate, or other oligonucleotide stabilizing bonds. They may also comprise monomer moieties which have altered base structures or other modifications, but which still retain the ability to bind to naturally occurring DΝA and RΝA structures. Such oligonucleotides may be prepared by methods well-known in the art, for instance using commercially available machines and reagents available from Perkin-Elmer/ Applied Biosystems (Foster City, Calif.). It is preferred that an antisense oligonucleotide targeting the HBN surface antigen or preS 1 gene sequence be chosen such that the oligonucleotide hybridizes within approximately 25 bases of the AUG start codon of the gene. Examples of antisense oligonucleotides directed to the HBN surface antigen and preSl gene are described in U.S. Pat. No. 5,646,262 to Korba et al. and include (SEQ ID NO.: 1) CTTAGGACTACACTACAAGAG; (SEQ ID NO.: 2) GACTACACTACAAGAG; (SEQ ID NO.: 3) AGGACTACACTACAAGAGGTA; (SEQ LD NO.: 4) TACACTACAAGAGGTA; (SEQ LD NO.: 5) TCTTCCCCAGGATCCT; (SEQ ID NO.: 6) TTTGGGGCGGACATTG; (SEQ ID NO.: 7) CCTAAGAACAGTTGTT; (SEQ ID NO.: 8) GTACAAGTCGCGTCCCAGG; (SEQ ID NO.: 9) TAGGAGCTCTTCTAAC; (SEQ LD NO.: 10) TATTCCCTAGTCTTGT; (SEQ ID NO.: 11) CAAGAGGTACAAGTC; (SEQ LD NO.: 12) CGACCACCTTTCTAAGACGGG; (SEQ LD NO.: 13) CCTTTCTAAGACGGG; (SEQ LD NO.: 14) TAAGACGGGGTA; (SEQ LD NO.: 15) GACGGGGTACGACAT; (SEQ LD NO.: 16) GTACGACATCTAGAA. Other examples of antisense oligonucleotides for the treatment of HDN infection are disclosed in U.S. Pat. No. 5,985,662 to Isis Pharmaceuticals, Inc. and include: (SEQ LD NO.: 17) CCTGATGTGATGTTCTCCAT; (SEQ LD NO.: 18) GAACTGGAGCCACCAGCAGG ; (SEQ ID NO.: 19) GAAAGATTCGTCCCCATGC; and (SEQ ID NO.: 20) CCACTGCATGGCCTGAGGATG. Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is an illustration of L-FMAU (2'-fluoro-5-methyl-β-L- arabinofuranosyl-uridine). FIG. 2 is a schematic illustration of the preparation of l-O-acetyl-2,3,5-tri-O- benzoyl-β-L-ribofuranose (compound 10). FIG. 3 is a schematic illustration of an alternative preparation of 1-O-acetyl- 2,3,5-tri-O-benzoyl-β-L-ribofuranose (compound 10). FIG. 4 is a schematic illustration of a method for the preparation of 1,3,5-tri- O-benzoyl-2-deoxy-2-fluoro-β-L-arabinofuranose (compound 13). FIG. 5 is an illustration of a method for the preparation of 5'-benzoyl protected and unprotected 2 , -deoxy-2'-fluoro-β-L-arabinofuranosyl]-5-methyl uridine (compounds 17-18). FIG. 6 A is a line graph of weeks of treatment of L-FMAU in woodchucks versus genomic equivalents per ml of HDN RΝA in serum and demonstrates the decrease in HDN RΝA in HDN-infected woodchucks treated with L-FMAU over twenty weeks. Woodchucks chronically infected with WHN were infected with a woodchuck-adapted HDN inoculum derived from a laboratory infectious clone. Chronicity was established by detectable HDN viremia for at least 74% of bleed dates for at least 11 months prior to the initiation of treatment. The results indicate that treatment with L-FMAU causes a significant decrease in serum HDN-RΝA. FIG. 6B is a line graph of weeks of treatment of L-FMAU in woodchucks versus woodchuck serum WHN-DΝA in genomic equivalents per ml. Woodchucks chronically infected with WHN were infected with a woodchuck-adapted HDN inoculum derived from a laboratory infectious clone. Chronicity was established by detectable HDN viremia for at least 74% of bleed dates for at least 11 months prior to the initiation of treatment. The results indicate that treatment with L-FMAU causes a significant decrease in serum WHN-DΝA. FIG. 6C is a line graph of weeks of treatment of L-FMAU in woodchucks versus woodchuck serum WHsAg in μg/ml. Woodchucks chronically infected with WHN were infected with a woodchuck-adapted HDN inoculum derived from a laboratory infectious clone. Chronicity was established by detectable HDN viremia for at least 74% of bleed dates for at least 11 months prior to the initiation of treatment. The results indicate that treatment with L-FMAU causes a significant decrease in serum WHsAg. FIG. 7 A is a line graph showing the presence of HDN RΝA in the serum of HDN-infected woodchucks over twenty weeks in the absence of L-FMAU. FIG. 7B is a line graph showing serum levels of WHN-DΝA in woodchucks over twenty weeks in the absence of L-FMAU. FIG. 7C is a line graph showing serum levels of WHsAg in woodchucks over twenty weeks in the absence of L-FMAU. FIG. 8 is a line graph of mean serum HDN RΝA in genomic equivalents per ml versus weeks. The graph compares the mean serum HDN level in the five untreated woodchucks (circle data points) with that of the L-FMAU treated woodchucks 4878, 4879, and 4883 (square data points), in which WHsAg levels dropped more than 100-fold during treatment (see Figure 6B). The graph shows a dramatic decline in HDN RΝA in these three treated animals by 8 weeks of the treatment compared with the level in these same animals at the start of treatment and compared with levels in the five untreated animals at any time. DETAILED DESCRIPTION OF THE INVENTION The present invention is a method for the treatment of hepatitis delta virus (HDN) infection in a host, in particular a human, by administration of an effective amount of a nucleoside or nucleoside analog or a prodrug or pharmaceutically acceptable salt thereof that provides a substantial and sustained reduction in the expression of hepatitis B surface antigen (HBsAg) or preSl antigen. The unexpected failure of lamivudine, a compound known to suppress the replication of HBN, to lower HDN-RΝA levels in patients demonstrates that the successful treatment of HBN does not necessarily correlate with a successful treatment of HDN. The present invention is based on the surprising discovery that compounds that provide a substantial and sustained reduction in the expression of hepatitis B surface antigen (HBsAg) or preSl antigen, including L-FMAU, are potent inhibitors of HDN replication. L-FMAU is a particularly strong suppressor of hepatitis B surface antigen expression. This invention thus presents the fundamental discovery that the substantial and sustained suppression of the HBsAg or preSl antigen can produce a significant reduction in HDN viremia in a host infected with these viruses. Alternatively, a host infected with hepatitis delta along with a hepadnavirus other than hepatitis B that supports HDN infection can be treated by substantially inhibiting the expression of surface antigen of that hepadnavirus. In an embodiment of present invention, there is provided a method of treating a host infected with HDN, comprising the step of administering an effective amount of a nucleoside or nucleoside analog, or a pharmaceutical acceptable prodrug or salt thereof, optionally with pharmaceutically acceptable carrier, that substantially suppresses the expression of hepatitis B surface antigen or preSl antigen. In another embodiment of present invention, there is provided a method of treating a host infected with HDN, comprising the step of administering an effective amount of L-FMAU, or a pharmaceutical acceptable prodrug or salt, optionally in a pharmaceutically acceptable carrier. In yet another embodiment, L-FMAU, or another nucleoside or nucleoside analog acting in like manner, or a pharmaceutical acceptable prodrug or salt thereof, optionally in pharmaceutically acceptable carrier, is administered to a host in need thereof, in combination with at least one other compound that reduces the level of hepatitis B surface antigen or preS 1 antigen. In still another embodiment of the present invention, there is provided a method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDN infection, comprising the steps of: a) administering a test compound to an animal model of hepatitis B virus, for example, the eastern woodchuck; b) monitoring the levels of hepatitis surface antigen or preSl antigen, as appropriate, expressed in the animal treated with the test compound; c) comparing the levels of hepatitis surface antigen or preSl antigen in animals treated with the test compound to control animals not treated with the test compound; d) selecting the compound in step (c) wherein the levels of hepatitis surface antigen or preSl antigen are significantly lower that the levels of hepatitis surface antigen in animals not treated with the test compound, and in a preferred embodiment, 100-fold or more relative to pretreatment values in vivo or in vitro; or to not more than 1 microgram per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Gerin. 1993. In still another embodiment of the present invention, there is provided a method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDN infection, comprising the steps of: a) administering a test compound to a woodchuck chronically infected with woodchuck hepatitis virus and also infected with a woodchuck-adapted HDN inoculum; b) monitoring the levels of hepatitis surface antigen or preSl antigen expressed in the animal treated with the test compound; c) comparing the levels of hepatitis surface antigen or preSl antigen in animals treated with the test compound to control animals not treated with the test compound; d) selecting the compound in step (c) wherein the levels of hepatitis surface antigen or preSl antigen are significantly lower than the levels of hepatitis surface antigen in animals not treated with the test compound, and in a preferred embodiment, 100-fold or more relative to pretreatment values in vivo or in vitro, or to not more than 1 microgram per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeΝoronha, and J. Gerin. 1993. In a preferred embodiment, a compound should be selected in which there is a concurrent reduction in the levels of hepatitis surface antigen or preS 1 antigen and hepatitis D RΝA in animals treated with the test compound. In another embodiment of the present invention, there is provided a method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDN infection comprising the steps of: a) administering a test compound to an in vitro cell that has been transfected with human hepatitis B virus, such as 2.2.15 cells (see Sells MA, et al. (1988) J. Nirol. 62:2836-2844. Korba BE and Gerin JL (1992) Antiviral Res. 19:55-70. HB611: Ueda K, et al. (1989) Virology 169:213-216); b) monitoring the levels of hepatitis surface antigen or preSl antigen expressed in the animal treated with the test compound; c) comparing the levels of hepatitis surface antigen or preSl antigen in the cells treated with the test compound to control animals not treated with the test compound; d) selecting the compound in step (c) wherein the levels of hepatitis surface antigen or preSl antigen are significantly lower that the levels of hepatitis surface antigen in animals not treated with the test compound, and in a preferred embodiment, 100-fold, and preferably 200 or 500-fold or more relative to pretreatment values in vivo or in vitro. In another embodiment of the present invention, there is provided a method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDV infection, comprising the steps of : a) administering a test compound to an in vitro cell that has been transfected to express both hepatitis B surface antigen or preSl antigen and hepatitis delta virus (e.g. Casey, J.L., A.G. Poison, B.L. Bass, J.L. Gerin; p290-294: Viral Hepatitis and Liver Disease; M. Rizzetto et al., eds. Edizione Minerva Medica, Turin, 1997); b) monitoring the levels of hepatitis B surface antigen or preSl antigen and hepatitis delta virus expressed intracellularly and secreted into the media of cells treated with the test compound; c) comparing the levels of hepatitis B surface antigen or preSl antigen and hepatitis delta virus secreted from cells treated with the test compound to control cells not treated with the test compound; d) selecting the compound in step (c) wherein the secreted levels of hepatitis surface antigen or preSl and hepatitis delta virus are significantly lower than the levels of hepatitis B surface antigen secreted from cells not treated with the compound. I. Definitions As used herein, the terms "HBsAg" and "hepatitis B surface antigen" refer to the surface antigen protein of any member of the hepadnavirus family, in particular including human hepatitis B virus (HBV) and woodchuck hepatitis virus (WHV). As used herein, the term "enantiomerically pure" refers to a nucleoside composition that includes at least approximately 95%, and preferably approximately 97%, 98%, 99% or 100% of a single enantiomer of that nucleoside. As used herein, the term "host" refers to any animal capable of infection the with hepatitis delta virus including but not limited to humans and other mammals. The term "pharmaceutical salt" refers to a salt that retains the biological activity of the parent compound and does not impart undesired toxicological effects thereto. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids well known in the pharmaceutical art. As used herein, the term "nucleoside" refers to heterocyclic nitrogenous base, preferably a purine or pyrimidine, in N-glycosidic or carbocyclic linkage with a carbohydrate or pseudo carbohydrate, preferably a pentose, or a sugar analog or a modified carbon ring system that can include one or more heteroatoms, and to which can be linked any desired substituent, and wherein the compound can be natural or synthetic, and wherein the nucleoside can exhibit any desired stereochemistry that achieves the desired result. As used herein, the term "nucleoside analog" refers to a heterocyclic nitrogenous base, preferably a purine or pyrimidine, in N-glycosidic or carbocyclic linkage with an acyclic carbon chain that can include heteroatoms, and which can include substituents on the cyclic or acyclic chain, including a hydroxyl group. The term "prodrug" is used throughout the specification to describe any derivative of the active compound, nucleoside or nucleoside analog that, upon administration to a patient, provides the parent active compound. As used herein, the term purine or pyrimidine base, includes, but is not limited to, 6-alkylpurine and N6-alkylpurines, N6-acylpurines, N6-benzylpurine, 6- halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6-thioalkyl purine, N2-alkylpurines, N4-alkylpyrimidines, N4- acylpyrimidines, 4-benzylpyrimidine, N4-halopyrimidines, N4-acetylenic pyrimidines, 4-acyl and N4-acyl pyrimidines, 4-hydroxyalkyl pyrimidines, 4-thioalkyl pyrimidines, thymine, cytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrimidine, uracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5- halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acyl pyrimidine, C5-hydroxyalkyl purine, C5-amidopyrimidine, C5-cyanopyrimidine, C5- nitropyrimidine, C5-aminopyrimidine, N2-alkylpurines, N2-alkyl-6-thiopurines, 5- azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. Examples of bases include cytosine, 5- fluorocytosine, 5-bromocytosine, 5-iodocytosine, uracil, 5-fluorouracil, 5- bromouracil, 5-iodouracil, 5-methyluracil, thymine, adenine, guanine, inosine, xanthine, 2,6-diaminopurine, 6-aminopurine, 6-chloropurine and 2,6-dichloropurine, 6-bromopurine, 2,6-dibromopurine, 6-iodopurine, 2,6-di-iodopurine, 5- bromovinylcytosine, 5-bromovinyluracil, 5-bromoethenylcytosine, 5- bromoethenyluracil, 5-trifluoromethylcytosine, 5-trifluoromethyluracil. The term "protected" as used herein and unless otherwise defined refers to a group that is added to an oxygen or nitrogen atom to prevent its further reaction during the course of derivatization of other moieties in the molecule in which the oxygen or nitrogen is located. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis. The term alkyl, as used herein, unless otherwise specified, refers to a saturated straight, branched, or cycline, primary, secondary, or tertiary hydrocarbon, typically of C t to C 18 , and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl. The alkyl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phophonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference. The term lower alkyl, as used herein, and unless otherwise specified, refers to a C, to C 4 saturated straight or branched alkyl group. The term aryl, as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl, and preferably phenyl. The aryl group can be optionally substituted with one or more moieties selected from the group consisting of hydroxyl, amino, alkylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al, "Protective Groups in Organic Synthesis," John Wiley and Sons, Second Edition, 1991. The term alkaryl or alkylaryl refers to an alkyl group with an aryl substituent. The term aralkyl or arylalkyl refers to an aryl group with an alkyl substituent. The term halo, as used herein, includes chloro, bromo, iodo, and fluoro. As used herein, the term acyl refers to a moiety of the formula -C(O)R', wherein R' is alkyl; aryl, alkaryl, aralkyl, heterocyclic, alkoxyalkyl including methoxymethyl; arylalkyl including benzyl; aryloxyalkyl such as phenoxymethyl; aryl including phenyl optionally substituted with halogen, to C 4 alkyl or C 1 to C 4 alkoxy, or the residue of an amino acid. The term amino acid includes naturally occurring and synthetic amino acids, and includes but is not limited to, alanyl, valinyl, leucinyl, isoleuccinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, and histidinyl. The term heterocyclic, as used herein, refers to a ringed moiety that includes at least one sulfur, oxygen, or nitrogen in the ring system. Nonlimiting examples are furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isooxazolyl, pyrrolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxantinyl, and pteridinyl. Functional oxygen and nitrogen groups on the heterocyclic base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenelsulfonyl. The heterocyclic group can be substituted with any appropriate substituent, including but not limited to fluoro, iodo, bromo, chloro, and lower alkyl, including cyclopropyl. The term lipophilic prodrug refers to a nucleoside that contains a covalent substituent at the 5 '-hydroxyl position that renders the nucleoside more lipophilic than the parent nucleoside with a 5 '-hydroxyl group. II. ACTIVE COMPOUNDS It has been discovered that administration of any nucleoside, nucleoside analog, or certain non-nucleosides, as specified herein or a prodrug or pharmaceutically acceptable salt thereof that reduces the level of hepatitis B surface antigen (referred to herein as HBsAg) in a host to at least approximately 100-fold or more, and preferably, 200- or 500-fold relative to pretreatment values in vivo or in vitro; and preferably, to not more than 1, and preferably, 0.5 or 0.1 microgram per milliliter in vivo, is useful in the treatment of hepatitis delta viral infection in that host. The ability of a nucleoside to reduce the level of HBsAg to the required minimum level can be easily assessed by the methods described in detail herein, or other known methods. It has been discovered that administration of any nucleoside, nucleoside analog, or certain non-nucleosides, or a prodrug or pharmaceutically acceptable salt thereof that reduces the level of preSl antigen in a host to at least approximately 100- fold or more, and preferably, 200- or 500-fold relative to pretreatment values in vivo or in vitro. The ability of a nucleoside to reduce the level of preSl antigen to the required minimum level can be easily assessed by known methods. It was previously known that if a nucleoside or nucleoside analog does not significantly reduce the level of HBsAg in a hepatitis delta infected host, for example, 3TC (2',3 '-dideoxy-3 '-thiacytidine), then that nucleoside is not effective in the treatment of hepatitis delta virus. However, the converse had to date never been established, i.e., that if a nucleoside or nucleoside analog reduces the level of 100-fold or more relative to pretreatment values in vivo or in vitro, or to not more than 1 microgram per milliliter, as measured in serum or plasma using standard immunoassays (such as the commercial assay for human HBsAg (AUSZYME ™, Abbott Laboratories) or that described for woodchuck hepatitis B surface antigen in: Viral Immunology 6:161.169; Cote, P. J., C. Roneker, K. Cass, F. Schodel, D. Peterson, B. Tennant, F. DeNoronha, and J. Gerin. 1993, it is useful in the treatment of hepatitis delta virus. This has now been established for the first time through the paradigm nucleoside analog, and a nonlimiting embodiment, L-FMAU. in. Use of L-FMAU in the Treatment of HDV Infection In one embodiment of the invention, an effective amount of a compound of Formula I, or a pharmaceutically acceptable prodrug or salt thereof, is administered of the structure: wherein R is 5 -methyl uracil (also referred to as thymine) and R' is hydrogen, acyl, alkyl, monophosphate, diphosphate, triphosphate, or a stabilized phosphate derivative, including a 5'-ether lipid or a 5'-phospholipid, or a pharmaceutically acceptable salt thereof. VI. Prodrugs of Active Compounds The active compound can be administered as any derivative that upon administration to the recipient, is capable of providing directly or indirectly, the parent compound. Nonlimiting examples are the pharmaceutically acceptable salts, and the 5' and purine or pyrimidine acylated or alkylated derivatives of the active compound (if a nucleoside or nucleoside analog). In one embodiment, the acyl group of the active compound is a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyatkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, to C 4 alkyl or C, to C 4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxytrityl, substituted benzyl, trialkylsilyl (e.g., dimethyl-t-butylsilyl) or diphenylmethylsilyl. Aryl groups in the esters optimally comprise a phenyl group. The alkyl group can be straight, branched, or cyclic, and is optimally a C, to Cι g group. The active compound can be administered as a prodrug, including a nucleotide prodrug (if a nucleoside or nucleoside analog), to increase the activity, bioavailability, stability or otherwise alter the properties of the nucleoside. A "prodrug" is a therapeutic agent that is converted to an active form within the host by the action of endogenous enzymes or other chemicals and/or conditions. A number of nucleotide prodrug ligands are known. In general, alkylation, acylation or other lipophilic modification of the mono, di or triphosphate of the nucleoside will increase the stability of the nucleotide. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides to achieve a desired effect. Examples of substituent groups that can replace one or more hydrogens on the phosphate moiety or hydroxyl are alkyl, aryl, steroids, carbohydrates, including sugars, 1,2-diacylglycerol and alcohols. Many are described in R. Jones and N. Bischofberger, Antiviral Research, 27 (1995) 1-17. Any of these can be used in combination with the disclosed nucleosides or other compounds to achieve a desire effect. The active nucleoside or other hydroxyl containing compound can also be provided as an ether lipid (and particularly a 5 '-ether lipid for a nucleoside), as disclosed in the following references, which are incorporated by reference herein: Kucera, L.S., N. Iyer, E. Leake, A. Raben, Modest E.K., D.L.W., and C. Piantadosi. 1990. "Novel membrane-interactive ether lipid analogs that inhibit infectious HIV-1 production and induce defective virus formation." DS Res. Hum. Retro Viruses. 6:491-501; Piantadosi, C, J. Marasco C.J., S.L. Morris-Natschke, K.L. Meyer, F. Gumus, J.R. Surles, K.S. Ishaq, L.S. Kucera, N. Iyer, CA. Wallen, S. Piantadosi, and E.J. Modest. 1991. "Synthesis and evaluation of novel ether lipid nucleoside conjugates for anti-HIN activity." J Med. Chem. 34:1408.1414; Hosteller, K.Y., D.D. Richman, D.A. Carson, L.M. Stuhmiller, G.M. T. van Wijk, and H. van den Bosch. 1992. "Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3,-deoxythymidine." Antimicrob. Agents Chemother. 36:2025.2029; Hostetler, K.Y., L.M. Stuhmiller, H.B. Lenting, H. van den Bosch, and D.D. Richman, 1990. "Synthesis and antiretroviral activity of phospholipid analogs of azidothymidine and other antiviral nucleosides." J. Biol. Chem. 265:61127. Nonlimiting examples of U.S. patents that disclose suitable lipophilic substituents that can be covalently incorporated into the nucleoside or other hydroxyl or amine containing compound, preferably at the 5'-OH position of the nucleoside or lipophilic preparations, include U.S. Patent Nos. 5,149,794 (Sep. 22, 1992, Yatvin et al.); 5,194,654 (Mar. 16, 1993, Hostetler et al., 5,223,263 (June 29, 1993, Hostetler et al.); 5,256,641 (Oct. 26, 1993, Yatvin et al); 5,411,947 (May 2, 1995, Hostetler et al.); 5,463,092 (Oct. 31, 1995, Hostetler et al.); 5,543,389 (Aug. 6, 1996, Yatvin et al.); 5,543,390 (Aug. 6, 1996, Yatvin et al.); 5,543,391 (Aug. 6, 1996, Yatvin et al.); and 5,554,728 (Sep. 10, 1996; Basava et al.), all of which are incorporated herein by reference. Foreign patent applications that disclose lipophilic substituents that can be attached to the nucleosides of the present invention, or lipophilic preparations, include WO 89/02733, W0 90/00555, W0 91/16920, W0 91/18914, W0 93/00910, W0 94/26273, W0 96/15132, EP 0 350287, EP 93917054.4, and W0 91/19721. Nonlimiting examples of nucleotide prodrugs are described in the following references: Ho, D.H.W. (1973) "Distribution of Kinase and deaminase of 1 β-D-arabinofuranosylcytosine in tissues of man and mouse." Cancer Res. 33, 2816- 2820; Holy, A. (1993) Isopolar phosphorous-modified nucleotide analogues," In: De Clercq (Ed.), Advances in Antiviral Drug Design, Vol. I, JAI Press, pp. 179-231; Hong, C.I., Nechaev, A., and West, C.R. (1979a) "Synthesis and antiturnor activity of lβ-D-arabino-furanosylcytosine conjugates of cortisol and cortisone." Biochem. Biophys. Rs. Commun. 88, 1223-1229; Hong, C.I., Nechaev, A., Kirisits, A.J. Buchheit, D.J. and West, C.R. (1980) "Nucleoside conjugates as potential antiturnor agents. 3. Synthesis and antiturnor activity of l-(β-D-arabinofuranosyl) cytosine conjugates of corticosteroids and selected lipophilic alcohols." J Med. Chem. 28, 171- 177; Hosteller, K.Y., Stuhmiller, L.M., Lenting, H.B.M. van den Bosch, H. and Richman J Biol. Chem. 265, 6112-6117; Hosteller, K.Y., Carson, D.A. and Richman, D.D. (1991); "Phosphatidylazidothymidine: mechanism of antiretroviral action in CEM cells." J. Biol Chem. 266, 11714-11717; Hosteller, K.Y., Korba, B. Sridhar, C, Gardener, M. (1994a) "Antiviral activity of phosphatidyl-dideoxycytidine in hepatitis B-infected cells and enhanced hepatic uptake in mice." Antiviral Res. 24, 59-67; Hosteller, K.Y., Richman, D.D., Sridhar. CN. Feigner, P.L. Feigner, J., Ricci, J., Gardener, M.F. Selleseth, D.W. and Ellis, M.N. 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Chemother. 1, 355-360; McGuigan, C, Νicholls, S.R., O'Connor, T.J., and Kinchington, D. (1990c) "Synthesis of some novel dialkyl phosphate derivative of 3 '-modified nucleosides as potential anti-AIDS drugs." Antiviral Chem. Chemother. 1, 25-33; McGuigan, C, Devin, K.G., O'Connor, TJ., and Kinchington, D. (1991) "Synthesis and anti-HIN activity of some haloalkyl phosphoramidate derivatives of 3'-azido-3' deoxythymidine (AZT); potent activity of the trichloroethyl methoxyalaninyl compound." Antiviral Res. 15, 255-263; McGuigan, C, Pathirana, R.Ν., Balzarini, J. and DeClercq, E. (1993b) "Intracellular delivery of bioactive AZT nucleotides by aryl phosphate derivatives of AZT." J. Med. Chem. 36, 1048-1052. Alkyl hydrogen phosphate derivatives of the anti-HIN agent AZT may be less toxic than the parent nucleoside analogue. Antiviral Chem. Chemother. 5, 271- 277; Meyer, R. B., Jr., Shuman, D.A. and Robins, R.K. (1973) "Synthesis of purine nucleoside 3', 5'-cyclic phosphoramidates." Tetrahedron Lett. 269-272; Νagyvary, J. Gohil, R.Ν., Kirchner, C.R. and Stevens, J.D. (1973) "Studies on neutral esters of cyclic AMP," Biochem. Biophys. Res. Commun. 55, 1072-1077; Namane, A. Gouyette, C, Fillion, M.P., Fillion, G. and Huynh-Dinh, T. (1992) "Improved brain delivery of AZT using a glycosyl phosphotriester prodrug." J. Med. Chem. 35, 3039- 3044; Nargeot, J. Nerbonne, J.M. Engels, J. and Leser, H.A. (1983) Natl. Acad. Sci. U.S.A. 80, 2395-2399; Nelson, K.A., Bentr de, W.G. Stser, W.N. and Hutchinson, J.P. (1987) "The question of chair-twist equilibria for the phosphate rings of nucleoside cyclic 3', 5' monophosphates. 1 HNMR and x-ray crystallographic study of the diastereomers of thymidine phenyl cyclic 3', 5'-monophosphate." J Am. Chem. Soc. 109, 4058-4064; Nerbonne, J.M., Richard, S., Nargeot, J. and Lester, H.A. (1984) "New photoactivatable cyclic nucleotides produce intracellular jumps in cyclic AMP and cyclic GMP concentrations." Nature 301, 74-76; Neumann, J.M., Herv_, M., Debouzy, J.C, Guerra, F.I., Gouyette, C, Dupraz, B. and Huyny-Dinh, T. (1989) "Synthesis and transmembrane transport studies by NMR of a glucosyl phospholipid of thymidine." J. Am. Chem. Soc. Ill, 4270-4277; Ohno, R., Tatsumi, N., Hirano, M., Imai, K. Mizoguchi, H., Nakamura, T., Kosaka, M., Takatuski, K., Yamaya, T., Toyama K., Yoshida, T., Masaoka, T., Hashimoto, S., Ohshima, T., Kimura, I., Yamada, K. and Kimura, J. (1991) "Treatment of myelodysplastic syndromes with orally administered 1-β-D-arabinouranosylcytosine -5' stearylphosphate." Oncology 48, 451-455. Palomino, E., Kessle, D. and Horwitz, J.P. (1989) "A dihydropyridine carrier system for sustained delivery of 2', 3' dideoxynucleosides to the brain." J. Med. Chem. 32, 22-625; Perkins, R.M., Barney, S. Wittrock, R., Clark, P.H., Levin, R. Lambert, D.M., Petteway, S.R., Serafinowska, H.T., Bailey, S.M., Jackson, S., Harnden, M.R. Ashton, R., Sutton, D., Harvey, J.J. and Brown, A.G. (1993) "Activity of BRL47923 and its oral prodrug, SB203657A against a rauscher murine leukemia virus infection in mice." Antiviral Res. 20 (Suppl. I). 84; Piantadosi, C, Marasco, C.J., Jr., Norris-Natschke, S.L., Meyer, K.L., Gumus, F., Surles, J.R., Ishaq, K.S., Kucera, L.S. Iyer, N., Wallen, C.A., Piantadosi, S. and Modest, E.J. (1991) "Synthesis and evaluation of novel ether lipid nucleoside conjugates tor antι-HiV-1 activity." J. Med. Chem. 34, 1408-1414; Pompon, A., Lefebvre, L, Imbach, J.L., Kahn, S. and Farquhar, D. (1994). "Decomposition pathways of the mono- and bis(pivaloyloxymethyl) esters of azidothymidine-5'-monophosphate in cell extract and in tissue culture medium; an application of the 'on-line ISRP-cleaning HPLC technique." Antiviral Chem Chemother. 5, 91-98; Postemark, T. (1974) "Cyclic AMP and cyclic GMP.'Αnnu. Rev. Pharmacol. 14, 23-33; Prisbe, E.J., Martin, J.C.M., McGhee, D.P.C, Barker, M.F., Smee, D.F. Duke, A.E., Matthews, T.R. and Nerheyden, J.P.J. (1986) "Synthesis and antiherpes virus activity of phosphate an phosphonate derivatives of 9-[(l, 3-dihydroxy-2-propoxy)methyl] guanine." J. Med. Chem. 29, 671-675; Pucch, F., Gosselin, G., Lefebvre, I., Pompon, a., Aubertin, A.M. Dim, and Imbach, J.L. (1993) "Intracellular delivery of nucleoside monophosphate through a reductase-mediated activation process." Antiviral Res. 22, 155-174; Pugaeva, N.P., Klochkeva, S.L, Mashbits, F.D. and Eizengart, R.S. (1969). "Toxicological assessment and health standard ratings for ethylene sulfide in the industrial atmosphere." Gig. Trfi Prof Zabol. 14, 47-48 (Chem. Abstr. 72, 212); Robins, R.K. (1984) "The potential of nucleotide analogs as inhibitors of Retro viruses and tumors." Pharm. Res. 11-18; Rosowsky, A., Kim. S.H., Ross and J. Wick, M.M. (1982) "Lipophilic 5'-(alkylphosphate) esters of 1-β-D- arabinofuranosylcytosine and its Ν 4 -acyl and 2.2'-anhydro-3'-O-acyl derivatives as potential prodrugs." J. Med. Chem. 25, 171-178; Ross, W. (1961) "Increased sensitivity of the walker turnout towards aromatic nitrogen mustards carrying basic side chains following glucose pretreatment." Biochem. Pharm. 8, 235-240; Ryu, E.K., Ross, R.J. Matsushita, T., MacCoss, M., Hong, C.I. and West, C.R. (1982). "Phospholipid-nucleoside conjugates. 3. Synthesis and preliminary biological evaluation of 1-β-D-arabinofuranosylcytosine 5' diphosphate [-], 2-diacylglycerols." J. Med. Chem. 25, 1322-1329; Saffhill, R. and Hume, WJ. (1986) "The degradation of 5-iododeoxyuridine and 5-bromoethoxyuridine by serum from different sources and its consequences for the use of these compounds for incorporation into DNA." Chem. Biol. Interact. 57, 347-355; Saneyoshi, M., Morozumi, M., Kodama, K., Machida, J., Kuninaka, A. and Yoshino, H. (1980) "Synthetic nucleosides and nucleotides. XVI. Synthesis and biological evaluations of a series of 1-β-D- arabinofuranosylcytosine 5'-alky or arylphosphates." Chem Pharm. Butt. 28, yi5- 2923; Sastry, J.K., Nehete, P.N., Khan, S., Nowak, B.J., Plunkett, W., Axlinghaus, R.B. and Farquhar, D. (1992) "Membrane-permeable dideoxyuridine 5'- monophosphate analogue inhibits human immunodeficiency virus infection." Mol. Pharmacol. 41, 441-445; Shaw, J.P., Jones, R.J. Arimilli, M.N., Louie, M.S., Lee, W.A. and Cundy, K.C. (1994) "Oral bioavailability of PMEA from PMEA prodrugs in male Sprague-Dawley rats." 9th Annual AAPS Meeting. San Diego, CA (Abstract). Shuto, S., Ueda, S., Imamura, S., Fukukawa, K. Matsuda, A. and Ueda, T. (1987) "A facile one-step synthesis of 5' phosphatidiylnucleosides by an enzymatic two-phase reaction." Tetrahedron Lett. 28, 199-202; Shuto, S. Itoh, H., Ueda, S., Imamura, S., Kukukawa, K, Tsujino, M., Matsuda, A. and Ueda, T. (1988) Pharm. Bull. 36, 209- 217. An example of a useful phosphate prodrug group is the S-acyl-2-thioethyl group, also referred to as "SATE". V. Combination Therapy In other embodiments of the invention, treatment of HDN infection may be accomplished using L-FMAU or other nucleoside or nucleoside analog or organic small molecule meeting the requirements specified herein in combination or alternation with other agents that reduce the level of hepatitis B surface or preS 1 antigen in the host, or which are known to otherwise treat hepatitis delta infection, including but not limited to a ribozyme (see U.S. Patent No. 5,985,621), cytokine including interleukins, interferon (including α, β, or γ), an antibody to hepatitis B surface or preSl antigen or a transcriptional factor or other mediator of hepatitis B surface or preSl antigen expression (to impart passive immunity); hepatitis B surface antigen or preSl antigen or a transcriptional factor or other mediator of hepatitis B surface antigen expression (to impart active immunity), a protein-prenyl transferase inhibitor (Statutory Invention No. HI-345) or peptide hormone (for example, thymosin-alpha- 1). In general, during alternation therapy, an effective dosage of each agent is administered serially, whereas in combination therapy, an effective dosage of two or more agents are administered together. The dosages will depend on such factors as absorption, biodistribution, metabolism and excretion rates for each drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. The disclosed combination and alternation regiments are useful in the prevention and treatment of HDN infections and other related conditions. In addition, these compounds or formulations can be used prophylactically to prevent or retard the progression of clinical illness in individuals have been exposed to HDN. I. Alternative Embodiments for the Treatment of HDV Infection In an alternative embodiment of the invention, HDV infection can be treated in a host by administering at least one antisense oligonucleotide targeted to the RΝA transcript of the hepatitis B surface antigen either alone or in combination with L-FMAU. As used in this disclosure the term "oligonucleotide" encompasses both oligomeric nucleic acid moieties of the type found in nature, such as the deoxyribonucleotide and ribonucleotide structures of DΝA and RΝA, and man-made analogues which are capable of binding to nucleic acids found in nature. The oligonucleotides of the present invention can be based upon ribonucleotide or deoxyribonucleotide monomers linked by phosphodiester bonds, or by analogues linked by methyl phosphonate, phosphorothioate, or other bonds. They may also comprise monomer moieties which have altered base structures or other modifications, but which still retain the ability to bind to naturally occurring DΝA and RΝA structures. Such oligonucleotides may be prepared by methods well-known in the art, for instance using commercially available machines and reagents available from Perkin-Elmer/ Applied Biosystems (Foster City, Calif). Phosphodiester-linked oligonucleotides are particularly susceptible to the action of nucleases in serum or inside cells, and therefore in a preferred embodiment the oligonucleotides of the present invention are phosphorothioate or methyl phosphonate-linked analogues, which have been shown to be nuclease-resistant. Persons knowledgeable of this field will be able to select other linkages for use in the present invention. The relative activity of antisense oligonucleotides directed against a specific gene is generally inversely proportional to its location relative to the AUG start codon of the target gene. In the prior art it is known that antisense oligonucleotides targeting sequences more than 60 bases downstream from the AUG start codon of chromosomally integrated HBN surface antigen (HBsAg) gene (S gene) sequences in HBsAg-producing PLC/PRF/5 cells are ineffective in inhibiting HBsAg production, while oligonucleotides placed within 20 bases of the AUG inhibit HBsAg production by 50% to 90%. Therefore, it is preferred that an antisense oligonucleotide targeted the HBN surface antigen gene sequence be chosen such that the oligonucleotide hybridizes within approximately 25 bases of the AUG start codon of the gene. Preferred oligonucleotides directed to the HBN surface antigen gene are described in U.S. Pat. No. 5,646,262 to Korba et al. and include (SEQ ID NO.: 1) CTTAGGACTACACTACAAGAG; (SEQ ID NO.: 2) GACTACACTACAAGAG; (SEQ ID NO.: 3) AGGACTACACTACAAGAGGTA; (SEQ ID NO.: 4) TACACTACAAGAGGTA; (SEQ ID NO.: 5) TCTTCCCCAGGATCCT; (SEQ ID NO.: 6) TTTGGGGCGGACATTG; (SEQ ID NO.: 7) CCTAAGAACAGTTGTT; (SEQ LD NO.: 8) GTACAAGTCGCGTCCCAGG; (SEQ ID NO.: 9) TAGGAGCTCTTCTAAC; (SEQ ID NO. : 10) TATTCCCTAGTCTTGT; (SEQ ID NO.: 11) CAAGAGGTACAAGTC; (SEQ ID NO.: 12) CGACCACCTTTCTAAGACGGG; (SEQ ID NO.: 13) CCTTTCTAAGACGGG; (SEQ LD NO.: 14) TAAGACGGGGTA; (SEQ ID NO.: 15) GACGGGGTACGACAT; (SEQ ID NO.: 16) GTACGACATCTAGAA. Other examples of antisense oligonucleotides for the treatment of HDN infection are disclosed in U.S. Pat. No. 5,985,662 to Isis Pharmaceuticals, Inc. and include: (SEQ ID NO.: 17) CCTGATGTGATGTTCTCCAT; (SEQ ID NO.: 18) GAACTGGAGCCACCAGCAGG ; (SEQ ID NO.: 19) GAAAGATTCGTCCCCATGC; and (SEQ LD NO.: 20) CCACTGCATGGCCTGAGGATG To select the preferred length for an antisense oligonucleotide, a balance must be struck to gain the most favorable characteristics. Shorter oligonucleotides 10- 15 bases in length readily enter cells, but have lower gene specificity. In contrast, longer oligonucleotides of 20-30 bases offer superior gene specificity, but show decreased kinetics of uptake into cells. See Stein et al., PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE ANALOGUES in "Oligodeoxynucleotides- Antisense Inhibitors of Gene Expression" Cohen, Ed. McMillan Press, London (1988). In a preferred embodiment this invention contemplates using oligonucleotides approximately 14 to 25 nucleotides long. VII. Synthesis of L- FMAU The L-nucleosides disclosed herein can be prepared as described in detail below, or by other assays known to those skilled in the art. Referring to FIG. 3, starting from L-xylose (la), the key intermediate l-O- acetyl-2,3,5-tri-O-benzoyl-α-L-ribofuranose (10) was synthesized in a total yield of 20% (L. Vargha, Chem. Ber., 1954, 87, 1351; Holy, A., et al, Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). As shown in FIG. 4, compound 10 can also be synthesized from the more expensive starting material L-ribose (Holy, A., et al, Synthetic Procedures in Nucleic Acid Chemistry, VI, 163-67). FIG. 3 illustrates an alternative synthesis of compound 10 (yield of 53%), which was subsequently fluorinated at C 2 (J. Org. Chem. 1985, 50, 3644-47) to obtain l,3,5-tri-O-benzoyl-2- deoxy-2-fluoro-L-arabinofuranose (13), which was condensed with silylated thymine through the bromosugar to provide the protected L-FMAU. 1,2-Di-O-isopropylidene-α-L-xylofuranose (3) To 650 ml of anhydrous acetone was added 4 ml of cone, sulfuric acid, 5 g of molecular sieve (4A), 80 g of anhydrous cupric sulfate and 50 g of L-xylose and the mixture was stirred at room temperature for 36 hours. The reaction mixture was filtered and washed thoroughly with acetone, the combined filtrate was neutralized with ammonium hydroxide then evaporated to dryness. Ethyl acetate (200 ml) was added, then filtered and evaporated, yielded an oil which was dissolved in 250 ml of 0.2% HCl solution and stirred at room temperature for 2.5 hours. The pH was adjusted to 8 with sat. NaHCO 3 , then evaporated to dryness, the residue was extracted with ethyl acetate. Removal of the solvent provided a yellow oil of compound 3 (41.7 g, 82.3%). 1 H-NMR(CDC1 3 ): δ5.979 (d, J=3.78 Hz,lH, H-l); 4.519 (d, J=3.6 Hz, 1H, H-2); 4.308 (bd, 1H, H-3); 4.080 (m, 3H, H-4 and H-5); 1. 321 (s, 3H, CH 3 ); 1.253 (s, 3H, CH 3 ). 1,2-Di -O-isopropylidene-3,5-di -O-o-tolylsulfonyl-α-L-xylofiiranose (4) Compound 3 (40 g, 210 mmol) was stirred in 500 ml of anhydrous pyridine at 0° C, while TsCl (75 g, 393 mmol) was dissolved in 100 ml of CHC1 3 was added dropwise. After 3 hours, another portion of TsCl (50 g, 262 mmol) in 50 ml of CHC1 3 was added the same as above. The mixture was stirred at r.t. for 24 hrs, then chilled at 0° C, water (10 ml) was added, then stirred at r.t. for 30 minutes. The reaction mixture was poured into 500 ml of ice- water, extracted with CHC1 3 (150 mlX4), washed with 1.5M H 2 SO 4 (150 mlX4), sat.NaHCO 3 (200 mlX2), dried (MgSO 4 ). Removing solvent gave a brown syrup, which upon crystallization from EtOH, gave 4 as a white solid (103.8 g, 99%). 1 H-NMR(CDC1 3 ): 87.282, 7.836 (m, 8H, OTs); 5.849 (d, J=3.51 Hz, 1H, H-l); 4.661, 4.779 (m, 2H, H-3 and H-4); 4.193 (dd, 1H, H-2); 4.011 (d, 2H, H-5); 2.448, 2.478 (2s, 6H, -OTs); 1.261, 1.320 (2s, 6H, CH 3 ). 1 ,2-Di-O-acetyl-3,5-di-O-p-tolylsulfonyl-α-β-xylofuranose (5) Compound 4 (70 g, 140.5 mmol) was dissolved in 700 ml of glacial AcOH and 100 ml of Ac 2 O while 50 ml of cone, sulfuric acid was added dropwise at 0° C The resulting solution was stirred at r.t overnight and then poured into 1 L of ice- water, extracted with CHC1 3 (200 mlX4), washed with sat. NaHCO 3 , dried (MgSO 4 ). After removing solvent in vacuo, gave 5 as a syrup (84.2 g, crude yield 110%). Methyl-3,5-di-O-p-tolylsulfonyl-α,β-xylofuranose (6) The crude 5 (80 g) was stirred in 500 ml of 1% HC1/CH 3 OH at r.t. for 30 hrs. The solvent was removed under reduced pressure, the residue dissolved in 300 ml of CHC1 3 , washed with sat. NaHCO 3 , dried (MgSO 4 ). Removing solvent gave 6 as a syrup (60 g, 90% from 4). Methyl-2-O-beιιzoyl-3,5-di-O-p-tolylsulfonyl-α,β-xylofuranoside (7) The syrup 6 (60 g, 127 mmol) was dissolved in 200 ml of pyridine and stirred at 0° C, while benzoyl chloride (40 ml, 345 mmol) was added dropwise, the resulting solution was stirred at r.t. for 17 hrs. It was concentrated to about 50 ml, then poured into 300 ml of ice-water, extracted with CHC1 3 , washed with 3N H 2 SO 4 and sat. NaHCO 3 , dried (MgSO 4 ). After evaporation of the solvent, gave 7 as a syrup (71 g, 97%). Methyl-2,3,5-tri-O-benzoyl-α-β-L-ribofuranoside (9) The syrup 7 (70 g) and sodium benzoate (100 g, 694 mmol) were suspended in 1200 ml of DMF and mechanically stirred under reflux for 16 hrs. It was cooled to r.t. and then poured into 1 L of ice-water, extracted with ether, dried (MgSO 4 ). Evaporation of solvent gave a syrup (50 g, 8a and 8b), which was dissolved in 180 ml of pyridine and benzoylated (BzCl, 20 ml, 172 mmol) for 17 hrs at r.t. After work up, gave 9 as a brown syrup (48 g, 83% from 7). l-O-acetyl-2,3,5-fri-O-berizoyl-β-L-ribofuranose (10) Compound 9 (26 g, 54.6 mmol) was treated with 275 ml of glacial acetic acid, 55 ml of acetic anhydride and 16 ml of cone, sulfuric acid at 0° C to r.t. for 17 hrs. Then poured into 1 L of ice- water, extracted with chloroform (200 mlX4). The combined extract was washed with sat. NaHCO 3 and dried (MgSO 4 ). Removing solvent gave a brown syrup which was treated with ethanol to give 10 as a white solid. (8.8 g, 32%). m.p.l24.7° C, lit.l29°-130° C; D from: 130°-131° C [α] D =-45.613 (C 1.0, CHCI 3 ), D form: [α] D =+44.2. ' H-NMR(CDC1 3 ): 67.317, 8.134 (m, 15H, OBz); 6.437 (s, 1H, H-l); 5.835 (m, 2H, H-2 and H-3); 4.649 (m, 3H, H-4 and H-5); 2.003 (s, 3H, CH 3 COO--). l-O-acetyl-2,3,5-tri-O-benzoyl-β-L-ribofuranose (from L-ribose) L-Ribose (5 g, 33.3 mmol) was suspended in 120 ml of 1% HCl/MeOH and stirred at r.t. for 3 hrs, when a clear solution was obtained. The reaction was quenched by adding 30 ml of anhydrous pyridine, then evaporated under reduced pressure. The resulting syrup was coevaporated with pyridine (30 mlX2), then dissolved in 80 ml of anhydrous pyridine, and stirred at 0° C while benzoyl chloride (20 ml, 172 mmol) was added dropwise. After stirring at r.t. for 17 hrs, the reaction was complete. Water (10 ml) was added and the mixture was stirred at r.t. for 0.5 hr, then concentrated to about 50 ml, poured into 150 ml of ice- water, extracted with chloroform (50 mlX4), washed successively with 3N H 2 SO 4 (30 mlX2), sat. NaHCO 3 (30 mlX3), dried (MgSO 4 ). Removing solvent gave 9 as a syrup of 13 g. The crude 9 was dissolved in 80 ml of HBr/AcOH (45%, w/v) and stirred at r.t. for 1.5 hrs. To this mixture, was added glacial acetic acid (50 ml) and the resulting solution stirred at 0° C, while 34 ml of water was added slowly to keep the temperature below 7° C, then it was stirred at r.t. for 1 hr, poured into 200 ml of ice- water, extracted with chloroform (50 mlX5), the combined extracts were washed with sat. NaHCO 3 , dried (MgSO 4 ). Removing solvent gave a syrup (13 g), which was dissolved in 40 ml of anhydrous pyridine, stirred at 0° C, when acetic anhydride (14 ml, 148.4 mmol) was added dropwise. After the reaction completed, it was poured into 150 ml of ice-water, extracted with chloroform (50 mlX4), washed successively with 3N H 2 SO 4 (30 mlX2), sat. NaHCO 3 (50 mlX2), dried (MgSO 4 ). Removing solvent and treating with methanol, gave 10 as a white solid (9.2 g, 53.7% from L- ribose). 1,3,5-Tri-O-benzoyl-α-L-ribofuranose (11) Compound 10 (9 g, 17.84 mmol) was stirred in 100 ml of CH 2 C1 2 at 0° C while 70 ml of CH 2 C1 2 containing HBr (3.2 g, 30.5 mmol) was added in one portion. The mixture was stirred at 0° C for 3.5 hrs, water (55 ml) was added and the mixture stirred at r.t. for 18 hrs. The organic layer was separated, washed with sat. NaHCO 3 , dried (MgSO 4 ). After evaporation of the solvent, a foam was obtained, which upon recrystallization from CH 2 C1 2 and n-hexane, gave 11 as a white solid. (6.2 g, 75.5%). m.p. 137°-138° C, lit. 140°-141° C, [α] D =-81.960 (C 0.55, CHC1 3 ; D form: [α] D =+83.71. 1 H-NMR(CDC1 3 ): 67.312, 8.187 (m, 15H, OBz); 6.691 (d, J=4.59 Hz, H-l); 5.593 (dd, J 4 . 3 =6.66 Hz; J 2 . 3 =1.8 Hz, 1H, H-30; 4.637, 4.796 (m, 4H, H-2, H-4 and H-5); 2.3 (b, OH). l,3,5-Tri-O-benzoyl-2-O-imidazosulfuryl-α-L-ribofuranose (12) Compound 11 15.94 g, 12.84 mmol) was stirred in 50 ml of anhydrous CH 2 C1 2 at -15° C (dry ice-CCl 4 ). Anhydrous DMF (15 ml) and sulfuryl chloride (3.2 ml, 3.98 mmol) was added sequentially. The solution was stirred at -15° C for 30 minutes then left at r.t. for 4 hrs. Imidazole (8.7 g, 12.78 mmol) was added in three portions while the reaction mixture was cooled in an ice bath, then it was stirred at r.t. for 17 hrs. The mixture was poured into 150 ml of ice- water and the water phase extracted with CH 2 C1 2 (50 mlX3). The combined organic layer was washed with water, dried (MgSO 4 ). After purification on column (Hexane: EtO Ac/5: 1-1:1) gave 12 as a white solid (3.7 g, 49%). m.p. 124.5°-125.5° C, lit: 129° C; [α] D =-68.976; D form: +66.154. 1 H-NMR (CDC1 3 ): 66.9, 8.2 (m, 18H, Ar-H); 6.67 (d, J=4.4 Hz, 1H, H-l); 5.59 (dd, 1H, H-3), 5.21 (dd, 1H, H-2); 4.5, 4.8 (m, 3H, H-4 and H-5). l,3,5-Tri-O-benzoyl-2-deoxy-2-fluoro-α-L-arabinofuranose (13). A suspension of 12 (3.33 g, 5.62 mmol), KHF 2 (1.76 g, 22.56 mmol) in 30 ml of 2,3-butanediol was stirred under argon. It was heated to 150° C while 1 ml of HF/H 2 O (48%, 27.6 mmol) was added and the mixture was stirred at 160° C for 1.5 hrs. Brine-ice was added to quench the reaction, then extracted with methylene chloride (50 mlX4), the combined extract was washed with brine, water, sat. NaHCO 3 , dried over anhydrous magnesium sulfate and activated carbon (Darco-60). It was poured on a silica gel pad (5 cm X 5 cm), washed with methylene chloride and then EtOAc, to give a syrup which from 95% EtOH, 13 (1.3 g, 49.8%) was crystallized. m.p. 77°-78° C; lit.: 82° C. l H-NMR(CDC1 3 ): 67.314, 8.146 (m, 15H, OBz); 6.757 (d, J=9.1 Hz, 1H, H-l); 5.38 (d, J=48.5 Hz, 1H, H-2); 5.630 (dd, J=22.5Hz, 1H, H-3); 4.768 (m, 3H, H-4 and H-5). Compound 13 (464 mg, 1 mmol) was dissolved in 10 ml of methylene chloride while 1.4 ml of HBr/AcOH (45% w/v) was added. The solution was stirred at r.t. for 24 hrs, then evaporated to dryness, the residue was dissolved in 20 ml of methylene chloride, washed with water, sat. NaHCO 3 , dried (MgSO 4 ). Filtration and evaporation gave the bromosugar 14 (1 0%, based on TLC). x -(2 , -Deoxy-2'-fluoro-3',5 , -di-O-benzyl-β-L-arabinofuranosyl)-thymine (17) To a solution of 13 (400 mg, 0.86 mmol) in anhydrous CH 2 C1 2 (10 ml) was added hydrogen bromide in acetic acid (45% w/v, 1.5 ml), and the resulting solution was stirred at r.t. for 17 hrs. After evaporation of the solvent and coevaporation with toluene, 14 was obtained. At the same time, thymine (215 mg, 1.72 mmol) was refiuxed in HMDS (25 ml) under nitrogen for 17 hrs, to get a homogeneous solution. After evaporation of the solvent, gave a silylated thymine. A solution of 14 in dichloroethane (50 ml) was added to the silylated thymine and the resulting solution was refiuxed under nitrogen for 3 days. Water was added and then extracted with CHC1 3 . The organic layer was washed with water, brine and dried (MgSO 4 ). Evaporation of the solvent gave the crude product, which was purified on preparative TLC using 2% MeOH/CHCl 3 to give 17 (235 mg, 58%). m.p. 99°-101° C. UV(Methanol): 230, 264 nm [α] D =+22.397. x H-NMR (CDC1 3 ): 67.343-8.389 (m, 12H, Ar-H, NH); 6.34 (dd, J H.H =2.97 Hz, J F . H =28.32 Hz, IH, H-l'); 5.383 (dd, J H . H =2.7 Hz, J F . H =63.27 Hz, IH, H-2'); 5.565 (dd, IH, H-3'); 4.812 (d, 2H, H-5'); 4.466 (m, IH, H-4'); 1.775 (s, 3H, CH 3 ) Anal. (C 24 H 2 lN 2 O 7 F), C: 61.01; H, 4.57; N: 5.73; F: 3.92. Ni -(2'-Deoxy-2'-fluoro-β-L-arabinofuranosyl)-thymine (18) Compound 17 (145 mg, 0.309 mmol) was treated with NH 3 /CH 3 OH at r.t. for 18 hrs. After evaporation of the solvent and purified on preparative TLC (15% MeOH/CHCl 3 , 18 (70 mg, 87.5%) was obtained, m.p. 174°-175° C. UV: 264 nm, [α] D =-104.36. H-NMR (DMSO-d 6 ): 611.401 (s, IH, NH); 7.575 (s, IH, H-6); 6.093 (dd, J M =4.41 Hz, J F . H =15.6 Hz, H-l'); 5.844 (d, IH, 3'-OH); 5.019 (dt, J F . H =53.3 Hz, IH, H-2'); 5.087 (t, IH, 5'-OH); 4.194 (dq, IH, H-3*); 3.647 (m, 3H, H-4' and H-5'); 1.781 (s, 3H, CH 3 ). Anal. (C 10 H 13 N 2 FO 5 ), C: 44.80; H: 4.97; N: 10.04; F: 7.03. 5 '-alkyl and mono- di- and tri-phosphate derivatives of L-FMAU The derivative of L-FMAU wherein there is an alkyl group in the 5 '-position can be prepared via protection of the thymine base using sodium hydride and t-butyl- di-phenyl silo protecting group. Benzoylation of the 5'-hydroxyl group can be achieved with benzoyl hydride. The resulting compound can be desilylated using tetrabutylammonium fluoride. Introduction of alkyl groups to the 5'-position is accomplished using sodium hydride and alkyl bromide, the benzoyl group can be removed with a base. The mono, di, and triphosphate derivative of L-FMAU can be prepared as described below. The monophosphate can be prepared according to the procedure of Imai et al., J. Org. Chem., 34(6), 1547-1550 (June 1969). For example, about 100 mg of L-FMAU and about 280 μl of phosphoryl chloride are reacted with stirring in about 8 ml of dry ethyl acetate at about 0 °C for about four hours. The reaction is quenched with ice. The aqueous phase is purified on an activated charcoal column, eluting with 5% ammonium hydroxide in a 1 :1 mixture of ethanol and water. Evaporation of the eluant gives ammonium L-FMAU-5'-monophosphate. The diphosphate can be prepared according to the procedure of Davisson et al., J. Org. Chem., 52(9), 1794-1801 (1987). L-FMAU diphosphate can be prepared from the corresponding tosylate, that can be prepared, for example, by reacting the nucleoside with tosyl chloride in pyridine at room temperature for about 24 hours, working up the product in the usual manner (e.g., by washing, drying, and crystallizing it). The triphosphate can be prepared according to the procedure of Hoard et al., J Am. Chem. Soc, 87(8), 1785-1788 (1965). For L-FMAU is activated (by making a imidazolide, according to methods known to those skilled in the art) and treating with tributyl ammonium pyrophosphate in DMF. The reaction gives primarily the triphosphate of the nucleoside, with some unreacted monophosphate and some diphosphate. Purification by anion exchange chromatography of a DEAE column is followed by isolation of the triphosphate, e.g., as the tetrasodium salt. VIII. Illustrative Example The woodchuck was used as an experimental model of chronic HDV infection to assess the effect of L-FMAU treatment on HDV replication. Woodchucks chronically infected with WHV were infected with a woodchuck-adapted HDV inoculum derived from a laboratory infectious clone. Nine of eleven infected animals were determined to have chronic HDV infection, as defined by RT/PCR-detectable HDV viremia (Niro et al. (1997) Hepatology 25, 728-734) for at least 74% of bleed dates for at least 11 months prior to the initiation of treatment. The range of duration of viremia prior to the start of the study was 11.4 - 20 months; the range of positive bleed dates was 74% to 100%. Animals in the treatment group (4) were given lOmg/kg L-FMAU daily; animals in the control group (5) were given placebo. Serum samples were obtained before the initiation of treatment, and at weeks 2, 4, 8, 12, 16 and 20. Serum samples were analyzed for WHV DNA, WHN surface antigen, and HDV RΝA. All treated animals exhibited marked decreases in serum WHV DΝA by 4 weeks of treatment (>10 7 -fold reduction), as has been previously observed with this compound. (Peek, S. et al. (2001) Hepatology 33, 254-66). (Fig. 6B). A nearly 1,000- fold decrease in surface antigen levels was observed by 12 weeks in all but one (animal 4543) of the treated animals. (Fig. 6C). HDV RΝA became undetectable in 3/4 treated animals by 16 weeks of treatment. (Fig. 6A). No substantial changes were observed for any of these viral markers in the control group. (Fig. 7A, Fig. 7B, Fig. 7C, Fig. 8). Notably, decreased HDV viremia correlated with decreased serum levels of surface antigen. HDV virema became undetectable following reduction of hepatitis B surface antigen concentrations by 100-fold or more and notably, after reduction to less than lmicrogram/ml. This effect was sustained for the remainder of the treatment period. HDV RNA became undetectable in all animals exhibiting decreased levels of surface antigen. One animal in the treated group, animal 4543, did not exhibit decreased levels of surface antigen (although WHV DNA levels did decrease), and HDV viremia remained high in this animal. When the three L-FMAU- treated animals in which WHsAg declined are grouped together (WHsAg-responders), it is clear that HDV RNA levels decline dramatically compared to pre-treatment levels and compared with levels in the control group at any time (Fig. 8). Statistical analysis by Student's t-test indicates this dramatic decline is highly statistically significant (P=0.02 for paired, 1 -tail comparison of week 0 vs. week 20 in the WHsAg-responders, and P=0.02 for unpaired 1 -tail comparison of week 20 levels in untreated vs WHsAg-responders). It was discovered that L-FMAU is a potent inhibitor of HDV in chronically infected animals, in part due to its strong suppression of surface antigen expression. Previous studies have shown a close correlation between levels of chronic HDV viremia and disease severity (Smedile, A. et al. (1986) Hepatology 6, 1297-302; Smedile, A. et al. (1987) Prog Clin Biol Res 234, 235-41; Niro, G. A. et al. (1997) Hepatology 25, 728-734; Shakil, A. O. et al. (1997) Virology 234, 160-7). Because there is no long-standing cellular repository for HDV as there is for HBV (i.e., no covalently closed circular DNA), and the half-life of HDV-infected cells may be as short as two weeks (Netter, H. J. et al. (1993) J Virol 61, 3357-62.), based on these results, L-FMAU and other nucleosides, nonnucleosides, and nucleoside analogs could be used to eliminate HDV infection altogether in treated patients by prolonged reduction of viremia to low levels. IX. Preparation of Pharmaceutical Compositions Humans suffering from diseases caused by HDV infection can be treated by administering to the patient an effective amount of a nucleoside or nucleoside analog or a pharmaceutically acceptable salt or prodrug thereof, in the presence of a pharmaceutically acceptable carrier or diluent, that reduces the level of hepatitis B surface or preS 1 antigen in the host to not more than approximately 100-fold or more, and preferably, 200- or 500-fold relative to pretreatment values in vivo or in vitro, or with respect to HBsAg, to not more than 1, and preferably, 0.5 or 0.1 microgram per milliliter in vivo, as measured in serum or plasma using standard immunoassays. hi a preferred embodiment, the nucleoside is 2'-fluoro-5-methyl-β-L- arabmofuranosyluridme or a pharmaceutically acceptable prodrug or salt thereof. The active compound (or prodrug form thereof) can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically, in liquid or solid form. The active compound (or prodrug thereof) is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount of compound to reduce HDV viremia or the symptoms thereof in vivo without causing serious toxic effects in the patient treated. A "reducing amount" is meant as an amount of active ingredient sufficient to decrease levels of HDV viremia as measured by, for example, an assay such as the ones described herein or other known methods. A preferred dose of the compound for all of the above-mentioned conditions will be in the range from about 1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day, more generally 0.1 to about 100 mg per kilogram body weight of the recipient per day. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent nucleoside to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using weight of the derivative, or by other means known to those skilled in the art. The compound is conveniently administered in units of any suitable dosage form, including but not limited to one containing 7 to 3000 mg, preferably 70 to 1400 mg of active ingredient per unit dosage form. An oral dosage of 50-1000 mg is usually convenient. Ideally the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.2 to 70 μM, preferably about 1.0 to 10 μM. This may be achieved, for example, by the intravenous injection of a 0.1 to 5% solution of the active ingredient, optionally in saline, or administered as a bolus of the active ingredient. The concentration of active compound in the drug composition will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition. The active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. A preferred mode of administration of the active compound is oral. Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil. In addition, dosage unit forms can contain various other materials which modify the physical form of the dosage unit, for example, coatings of sugar, shellac, or other enteric agents. The compound can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum or the like. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. The compound or a pharmaceutically acceptable derivative or salts thereof can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, such as antibiotics, antifungals, anti-inflammatories, or other anti-virals, including nucleoside anti-HIN compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS). In a preferred embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene v yl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) are also preferred as pharmaceutically acceptable carriers. These may be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (which is incorporated herein by reference in its entirety). For example, liposome formulations may be prepared by dissolving appropriate lipid(s) (such as stearoyl phosphatidyl ethanolamine, stearoyl phosphatidyl choline, arachadoyl phosphatidyl choline, and cholesterol) in an inorganic solvent that is then evaporated, leaving behind a thin film of dried lipid on the surface of the container. An aqueous solution of the active compound or its monophosphate, diphosphate, and/or triphosphate derivatives is then introduced into the container. The container is then swirled by hand to free lipid material from the sides of the container and to disperse lipid aggregates, thereby forming the liposomal suspension. This invention has been described with reference to its preferred embodiments. Variations and modifications of the invention, will be obvious to those skilled in the art from the foregoing detailed description of the invention. It is intended that all of these variations and modifications be included within the scope of the appended claims.

Claims: What is claimed is: 1. A method for the treatment of hepatitis delta infection comprising: administering to a host infected with hepatitis delta virus an effective amount of a nucleoside or nucleoside analog compound, or a pharmaceutically acceptable salt or prodrug thereof, that reduces the level of hepatitis B surface antigen in the host 100- fold or more relative to pretreatment value. 2. The method of treatment of claim 1 , wherein the compound is of the formula wherein R is 5-methyl uracil (also referred to as thymine) and R' is hydrogen, acyl, alkyl, monophosphate, diphosphate, triphosphate, or a stabilized phosphate derivative, including a 5 '-ether lipid or a 5'-phospholipid, or a pharmaceutically acceptable salt or prodrug thereof. 3. The method of claim 2, wherein the compound is 2'-fluoro-5-methyl-β- L-arabinofuranosyl-uridine, or its pharmaceutically acceptable salt or prodrug. 4. The method of claim 3, wherein the compound is administered in an enantiomerically enriched form. 5. A method for the treatment of hepatitis delta infection comprising: administering to a host infected with hepatitis delta virus an effective amount of a nucleoside or nucleoside analog compound, or a pharmaceutically acceptable salt or prodrug thereof, that reduces the level of preSl antigen in the host 100-fold or more relative to pretreatment value. 6. A method for the treatment of HDV infected host comprising administering of an effective amount of a nucleoside or nucleoside analog that reduces HBsAg in the infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 7. A method for the treatment of an HDV infected host comprising administering an effective amount of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, honnone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein- prenyl transferase inhibitor or thymosin-alpha-1; that that reduces HBsAg in the infected host to at least approximately 100-fold or more or that reduces HBsAg in an infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 8. A method for the treatment of an HDV infected host comprising administering an effective amount of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, hormone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein- prenyl transferase inhibitor or thymosin-alpha-1; that that reduces preSl antigen in the infected host to at least approximately 100-fold or more. 9. A method for screening a compound that is effective in the treatment of HDV infection comprising assessing whether the compound suppresses the expression of hepatitis B surface antigen 100-fold or more relative to pretreatment values in vivo or in vitro, or to not more than 1 microgram per milliliter, as measured in serum or plasma. 10. A method for screening a compound that is effective in the treatment of HDV infection comprising assessing whether the compound suppresses the expression of preSl antigen 100-fold or more relative to pretreatment values in vivo or in vitro 11. A method for treating HDV infection comprising administering at least one antisense oligonucleotide targeted to the hepatitis B surface preSl antigen. 12. The method of claim 11, wherein the antisense oligonucleotide is selected from the group consisting of (SEQ LD NO.: 1) CTTAGGACTACACTACAAGAG; (SEQ ID NO.: 2) GACTACACTACAAGAG; (SEQ ID NO.: 3) AGGACTACACTACAAGAGGTA; (SEQ ID NO.: 4) TACACTACAAGAGGTA; (SEQ ID NO.: 5) TCTTCCCCAGGATCCT; (SEQ LD NO.: 6) TTTGGGGCGGACATTG; (SEQ LD NO.: 7) CCTAAGAACAGTTGTT; (SEQ LD NO.: 8) GTACAAGTCGCGTCCCAGG; (SEQ LD NO.: 9) TAGGAGCTCTTCTAAC; (SEQ LD NO.: 10) TATTCCCTAGTCTTGT; (SEQ LD NO.: 11) CAAGAGGTACAAGTC; (SEQ LD NO.: 12) CGACCACCTTTCTAAGACGGG; (SEQ LD NO.: 13) CCTTTCTAAGACGGG; (SEQ ID NO.: 14) TAAGACGGGGTA; (SEQ LD NO.: 15) GACGGGGTACGACAT; and (SEQ ID NO.: 16) GTACGACATCTAGAA 13. The method of claim 11 , wherein the antisense sequence is selected from the group consisting of (SEQ LD NO. : 17) CCTGATGTGATGTTCTCCAT; (SEQ ID NO.: 18) GAACTGGAGCCACCAGCAGG ; (SEQ ID NO.: 19) GAAAGATTCGTCCCCATGC; and (SEQ ID NO.: 20) CCACTGCATGGCCTGAGGATG. 14. A method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDV infection, comprising the steps of: a) administering a test compound to a woodchuck chronically infected with woodchuck hepatitis virus and also infected with a woodchuck-adapted HDV inoculum; b) monitoring the levels of hepatitis surface antigen expressed in the animal treated with the test compound; c) comparing the levels of hepatitis surface antigen in animals treated with the test compound to control animals not treated with the test compound; d) selecting the compound in step (c) wherein the levels of hepatitis surface antigen are significantly lower that the levels of hepatitis surface antigen in animals not treated with the test compound, and in a preferred embodiment, not higher than 1 microgram/milliliter in serum. 15. The method of claim 14, wherein there is a concurrent reduction in the levels of hepatitis surface antigen and hepatitis D RNA in animals treated with the test compound. 16. A method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDV infection, comprising the steps of: a) admmistering a test compound to an in vitro cell that has been transfected with human hepatitis B virus, such as 2.2.15 cells; b) momtoring the levels of hepatitis surface antigen expressed in the cell treated with the test compound; c) comparing the levels of hepatitis surface antigen in animals treated with the test compound to control animals not treated with the test compound; d) selecting the compound in step (c) wherein the levels of hepatitis surface antigen are significantly lower that the levels of hepatitis surface antigen not treated with the test compound, and in a preferred embodiment, 100-fold or more relative to a control. 17. The method of claim 1, further comprising administering the compound in combination or alternation with other agents that reduce the level of hepatitis B surface or preSl antigen in the host, or which are known to otherwise treat hepatitis delta infection. 18. The method of claim 17, wherein the agent is selected from the group consisting of a ribozyme, a cytokine including interleukin, interferon, an antibody to hepatitis B surface antigen or a transcriptional factor or other mediator of hepatitis B surface antigen expression; hepatitis B surface antigen or a transcriptional factor or other mediator of hepatitis B surface antigen expression; a protein-prenyl transferase inhibitor or thymosin-alpha- 1. 19. The method of claim 18, wherein the agent is an antisense oligonucleotide that inhibits the expression of hepatitis B surface antigen or preSl antigen. 20. The method of claim 19, wherein the antisense oligonucleotide has a sequence selected from the group consisting of SEQ LD NO.: 1, SEQ LD NO.: 2, SEQ LD NO.: 3, SEQ LD NO.: 4, SEQ ID NO.: 5, SEQ LD NO.: 6, SEQ LD NO.: 7, SEQ ID NO.: 8, SEQ ID NO.: 9, SEQ LD NO.: 10, SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ LD NO.: 14, SEQ ID NO.: 15, SEQ ID NO.: 16, SEQ ID NO.: 17, SEQ ID NO.: 18, SEQ LD NO.: 19, and SEQ ID NO.: 20. 21. A method of identifying a compound, including a nucleoside or nucleoside analog, that is effective in the treatment of HDV infection, comprising the steps of : a) administering a test compound to an in vitro cell that has been transfected in order to express both hepatitis B surface or preSl antigen and hepatitis delta; b) monitoring the levels of hepatitis B surface antigen or preSl antigen and hepatitis delta virus expressed intracellularly and secreted into the media of cells treated with the test compound; c) comparing the levels of hepatitis B surface or preSl antigen and hepatitis delta virus secreted from cells treated with the test compound to control cells not treated with the test compound; d) selecting the compound in step (c) wherein the secreted levels of hepatitis surface antigen or preSl antigen and hepatitis delta virus are significantly lower than the levels of hepatitis B surface antigen secreted from cells not treated with the compound. 22. The use of a nucleoside or nucleoside analog, or a pharmaceutically acceptable salt or prodrug thereof in the treatment of a host infected with hepatitis delta infection wherein the compound reduces the level of hepatitis B surface antigen in the host 100-fold or more relative to pretreatment value. 23. The use of claim 22, wherein the compound is of the formula wherein R is 5 -methyl uracil (also referred to as thymine) and R' is hydrogen, acyl, alkyl, monophosphate, diphosphate, triphosphate, or a stabilized phosphate derivative, including a 5 '-ether lipid or a 5'-phospholipid, or a pharmaceutically acceptable salt or prodrug thereof. 24. The use of claim 23, wherein the compound is 2'-fluoro-5-methyl-β-L- arabinofuranosyl-uridine, or its pharmaceutically acceptable salt or prodrug. 25. The use of claim 22, wherein the compound is administered in an enantiomerically enriched form. 26. The use of a nucleoside or nucleoside analog compound, or a pharmaceutically acceptable salt or prodrug thereof in the treatment of a host infected with hepatitis delta virus wherein compound reduces the level of preSl antigen in the host 100-fold or more relative to pretreatment value. 27. The use of a nucleoside or nucleoside analog compound or a prodrug or pharmaceutically acceptable salt thereof in the treatment of a host infected with hepatitis B wherein the compound reduces the level of hepatitis B surface antigen in the infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 28. The use of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, hormone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein-prenyl transferase inhibitor or thymosin-alpha-1; to treat a host infected with hepatitis delta, wherein the molecule reduces HBsAg in the infected host to at least approximately 100-fold or more or that reduces HBsAg in an infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 29. The use of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, hormone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein-prenyl transferase inhibitor or thymosin-alpha-1 ; to treat a host infected with hepatitis delta virus that reduces preSl antigen in the infected host to at least approximately 100- fold or more. 30. The use of an antisense oligonucleotide targeted to the hepatitis B surface antigen to treat a host infected with hepatitis delta virus . 31. The use of claim 30, wherein the antisense oligonucleotide is selected from the group consisting of (SEQ ID NO.: 1) CTTAGGACTACACTACAAGAG; (SEQ ID NO.: 2) GACTACACTACAAGAG; (SEQ ID NO.: 3) AGGACTACACTACAAGAGGTA; (SEQ ID NO.: 4) TACACTACAAGAGGTA; (SEQ LD NO.: 5) TCTTCCCCAGGATCCT; (SEQ ID NO.: 6) TTTGGGGCGGACATTG; (SEQ LD NO. : 7) CCTAAGAACAGTTGTT; (SEQ ID NO.: 8) GTACAAGTCGCGTCCCAGG; (SEQ ID NO.: 9) TAGGAGCTCTTCTAAC; (SEQ LD NO.: 10) TATTCCCTAGTCTTGT; (SEQ ID NO.: 11) CAAGAGGTACAAGTC; (SEQ ID NO.: 12) CGACCACCTTTCTAAGACGGG; (SEQ ID NO.: 13) CCTTTCTAAGACGGG; (SEQ LD NO. : 14) TAAGACGGGGTA; (SEQ LD NO. : 15) GACGGGGTACGACAT; and (SEQ LD NO.: 16) GTACGACATCTAGAA 32. The use of claim 30, wherein the antisense sequence is selected from the group consisting of (SEQ LD NO.: 17) CCTGATGTGATGTTCTCCAT; (SEQ LD NO.: 18) GAACTGGAGCCACCAGCAGG ; (SEQ ID NO.: 19) ) GAAAGATTCGTCCCCATGC; and (SEQ LD NO. : 20) CCACTGCATGGCCTGAGGATG. 33. The use of a nucleoside or nucleoside analog, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment of a host infected with hepatitis delta infection wherein the compound reduces the level of hepatitis B surface antigen in the host 100-fold or more relative to pretreatment value. 34. The use of a nucleoside or nucleoside analog compound, or a pharmaceutically acceptable salt or prodrug thereof in the manufacture of a medicament for the treatment of a host infected with hepatitis delta virus, wherein the compound reduces the level of preSl antigen in the host 100-fold or more relative to pretreatment value. 35. The use of a nucleoside or nucleoside analog compound or a prodrug or pharmaceutically acceptable salt thereof in the manufacture of a medicament wherein the compound reduces the level of heptatitis B surface antigen in the infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 36. The use of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, hormone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein-prenyl transferase inhibitor or thymosin-alpha-1 ; in the manufacture of a medicament to treat a host infected with hepatitis delta, wherein the molecule reduces HBsAg in the infected host to at least approximately 100-fold or more or that reduces HBsAg in an infected host to not more than approximately 1 microgram per milliliter, as measured in serum or plasma. 37. The use of an organic non-nucleoside small molecule of molecular weight less than 500, and which is not (i) a biologic material found in nature or a derivative thereof retaining the desired activity comprising a protein, antibody, hormone, ribozyme, nucleic acid, protein, or cytokine; or (ii) not a protein-prenyl transferase inhibitor or thymosin-alpha-1; in the manufacture of a medicament to treat a host infected with hepatitis delta virus that reduces preSl antigen in the infected host to at least approximately 100-fold or more. 38. The use of an antisense oligonucleotide targeted to the hepatitis B surface antigen in the manufacture of a medicament to treat a host mfected with hepatitis delta virus.

Inventors: CASEY JOHN L, CHU CHUNG K, COTE PAUL J, GERIN JOHN L, KORBA BRENT E, TENNANT BUD C, CASEY, JOHN, L., CHU, CHUNG, K., COTE, PAUL, J., GERIN, JOHN, L., KORBA, BRENT, E., TENNANT, BUD, C.
Applicants: CASEY JOHN L, CHU CHUNG K, CORNELL RES FOUNDATION INC, COTE PAUL J, GERIN JOHN L, KORBA BRENT E, TENNANT BUD C, UNIV GEORGETOWN, UNIV GEORGIA, CASEY, JOHN, L., CHU, CHUNG, K., CORNELL RESEARCH FOUNDATION, INC., COTE, PAUL, J., GEORGETOWN UNIVERSITY, GERIN, JOHN, L., KORBA, BRENT, E., TENNANT, BUD, C., UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.
Application year: 2001
Main classification: A61K31
IPC codes: A61K31, A61K38, A61K39, A61K45, A61K48, A61P1, A61P31, A61P43, C07H19, C12N9, C12N15, G01N33