Skip to main content
Log in

Current status of anti-HBV chemotherapy

  • Review
  • Published:
Archives of Pharmacal Research Aims and scope Submit manuscript

Abstract

In the past decade, significant progress has been achieved in the battle against hepatitis B virus. In addition to the immunomodulating agents such as interferon-α and thymosin, many novel antiviral agents have been discovered, among which nucleoside analogues are the main-stay. New-generation compounds such as 3TC and famciclovir have shown promise in the treatment of patients chronically infected by this virus, and are on the line for approval. However, viral rebound after cessation of therapy still remains a major problem. Additionally, the reports on the drug resistance to these antiviral agents suggest that combination therapy will be the eventual strategy (Bartholomewet al., 1997; Tippleset al., 1996). Therefore, developments of safe and effective antiviral agents which do not cross-resist with currently available antiviral drugs are still much needed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References Cited

  • Abbruzzese, J. L., Schmidt, S., Raber, M. N., Levy, J. K., Castellanos, A. M., Legha, S. S. and Krakoff, I. H., Phase I trial of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-methyluracil (FMAU) terminated by severe neurologic toxicity.Invest. New Drugs, 7, 195–201 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Acs, G., Sells, M. A., Purcell, R. H., Price, P., Engle, R., Shapiro, M. and Popper, H., Hepatitis B virus produced by transfected Hep G2 cells causes hepatitis in chimpanzees.Proc. Natl. Acad. Sci. USA, 84, 4641–4644 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Ashwell, G. and Harford, J., Carbohydrate-specific receptors of the liver.Ann. Rev. Biochem., 51, 531–534 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Bartholomew, M. M., Jansen, R. W., Jeffers, L. J., Reddy, K. R., Johnson, L. C., Bunzendahl, H., Condreay, L. D., Tzakis, A. G., Schiff, E. R. and Brown, N. A., Hepatitis B virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation.Lancet 349, 20–22 (1997).

    Article  PubMed  CAS  Google Scholar 

  • Beach, J. W., Jeong, L. S., Alves, A. J., Pohl, D., Kim, H. O., Chang, C.-H., Doong, S.-L., Schinazi, R. F., Cheng, Y.-C. and Chu, C. K., Synthesis of enantiomerically pure (2′R, 5′S)-(-)-1-(2-hydroxymethyl-oxathiolan-5-yl)cytosine as a potent antiviral agent against hepatitis B virus (HBV) and human immunodeficiency virus (HIV).J. Org. Chem., 57, 2217–2219 (1992).

    Article  CAS  Google Scholar 

  • Belleau, B., Dixit, D., Nguyen-Ga, N. and Kraus, J.-L.,International Conference on AIDS. Montreal, Canada, June 4–9, paper no. T.C.O.1. (1990).

  • Benhamou, Y., Dohin, E. and Lunel-Fabiani, F., Efficacy of lamivudine on replication of hepatitis B virus in HIV-infected patients.Lancet, 345, 396–397 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Berk, L., Schalm, S. W., De Man, R. A., Heijtink, R. A., Berthelot, P., Brechot, C., Boboc, B., Degos, F., Maecelling, P., Behamou, J.-P., Hess, G., Rossol, S., Meyer, B. M., Berlinger, C., Stalder, G. A., Den Ouden-Muller, J. W. and De Jong, M., Failure of acyclovir to enhance the antiviral effect of alpha lymphoblastoid interferon on HBeAg-seroconversion in chronic hepatitis B: a multi-center randomized controlled trial.J. Hepatol., 14, 305–309 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Bisacchi, G. S., Chao, S. T., Bachard, C., Daris, J. P., Innaimo, S., Jacobs, G. A., Kocy, O., Lapointe, P., Martel, A., Merchant, Z., Slusarchyk, W. A., Sundeen, J. E., Youg, M. G., Colonno, R. and Zahler, R., BMS-200475, a novel carbocyclic 2′-deoxyguanosine analogue with potent and selective anti-hepatitis B virus activityin vitro.Bioorg. Med. Chem. Lett., 7, 127–132 (1997).

    Article  CAS  Google Scholar 

  • Bruch, H. R., Korn, A., Klein, H., Markus, R., Malmus, K., Baumgarten, R., and Muller, R., Treatment of chronic hepatitis B with interferon alpha-2b and interleukin-2.J. Hepatol., 17, S52-S55 (1993).

    Article  PubMed  Google Scholar 

  • Chen, C.-H., Vazquez-Padua, M. and Cheng, Y.-C. Effect of anti-huamn immunodeficiency virus nucleoside analogues on mitochondrial DNA and its implication for delayed toxicity.Molecular Pharmacol., 39, 625–628 (1991).

    CAS  Google Scholar 

  • Cheng, Y. C., Huang, E. S., Lin, J. C., Mar, E. C., Pagano, J. S., Dutschman, G. E. and Grill, S. P., Unique spectrum of activity of 9-(1,3-dihydroxy-2-propoxymethyl) guanine against herpes virusesin vitro and its mode of action against herpes simplex virus type 1.Proc. Natl. Acad. Sci. USA, 80, 2767–2770 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Chien, R. N. and Liaw, Y. F., Drug therapy in patients with chronic type B hepatitis.J. Formos. Med. Assoc., 94, suppl. 1, S1-S9 (1995).

    PubMed  Google Scholar 

  • Chu, C. K., Ahn, S. K., Kim, H. O., Beach, J. W., Alves, A. J., Jeong, L. S., Islam, Q., Van Roey, P. and Schinazi, R. F., Asymmetric synthesis of enantiomerically pure (-)-β-D-dioxolane-thymine and its anti-HIV activity.Tetrahedron Lett., 32, 3791–3794 (1991).

    Article  CAS  Google Scholar 

  • Chu, C. K., Ma, T. W., Shanmuganathan, K., Wang, C.-G., Xiang, Y.-J., Pai, S. B., Yao, G.-Q., Sommadossi, J.-P. and Cheng, Y.-C., Use of 2′-fluoro-5-methyl-β-L-arabinofuranosyluracil as a novel antiviral agent for hepatitis B virus and Epstein-Barr virus.Antimicrob. Agents Chemother., 39, 979–981 (1995).

    PubMed  CAS  Google Scholar 

  • Civitico, G., Shaw, T. and Locarnini, S., Interaction between ganciclovir and foscarnet as inhibitors of duck hepatitis B virus replicationin vitro.Antimicrob. Agents Chemother., 40, 1180–1185 (1996).

    PubMed  CAS  Google Scholar 

  • Clark, J. M., Genovesi, E. V., Medina, I., Lamb, L., Taylor, D., Standring, D., Seifer, M., Innaimo, S. and Collono, R. J. Maintenance therapy with BMS-200475 in the woodchuck model of chronic hepatitis B infection.Abstracts of 37th ICAAC. Canada, September 28-October 1, pp 215 (1997).

  • Colonno, R. J., Innaimo, S. F., Seifer, M., Genovesi, E., Clark, J., Yamanaka, R., Hamatake, B., Terry, B., Standring, D., Bisacchi, G., Sundeen, J. and Zahler, R., Identification of BMS-200475 as a novel and potent inhibitor of hepatitis B virus replication.Abstracts of Conf. on Antiviral Res. Atlanta, 34, A51, 32 (1997).

    Google Scholar 

  • Cui, L., Schinazi, R. F., Gosselin, G., Imbach, J.-L., Chu, C. K., Rando, R. F., Revankar, G. R. and Sommadossi, J.-P., Effect of β-enantiomeric and racemic nucleoside analogues on mitochondrial functions in HepG2 cells.Biochem. Pharmacol., 52, 1577–1584 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Cui, L., Yoon, S., Schinazi, R. F. and Sommadossi, J.-P., Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-β-D-arabinofuranosyl)-5-iodouracil in human liver cells.J. Clin. Invest., 95, 555–563 (1995).

    Article  PubMed  CAS  Google Scholar 

  • De Clercq, E., Sakuma, T., Baba, M., Pauwels, R., Balzarini, J., Rosenberg, I. and Holy, A., Antiviral activity of phosphylmethoxyalkyl derivatives of purines and pyrimidines.Antiviral Res., 8, 261–272 (1987).

    Article  PubMed  Google Scholar 

  • Dienstag, J. L., Perrillo, R. P., Schiff, E. R., Bartholomew, M., Vicary, C. and Rubin, M., A preliminary trial of lamivudine for chronic hepatitis B infection.New Engl. J. Med., 333, 1657–1661 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Doong, S.-L., Tsai, C. H., Schinazi, R. F., Liotta, D. C. and Cheng, Y.-C., Inhibition of the replication of hepatitis B virusin vitro by 2′,3′-dideoxy-3′-thiacytidine and related analogues.Proc. Natl. Acad. Sci. USA., 88, 8495–8499 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Dusheiko, G. M., Treatment and prevention of chronic viral hepatitis.Pharmacol. Ther., 65, 47–73 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Fisher, K. P. and Tyrrell, D. L. J., Generation of duck hepatitis B virus polymerase mutants through sitedirected mutagenesis which demonstrate resistance to lamivudine (-)-β-L-2′,3′-dideoxy-3′-thiacytidinein vitro.Antimicrob. Agents Chemother., 40, 1957–1960 (1996).

    Google Scholar 

  • Fiume, L., Busi, C., Mattioli, A., Balboni, P. G. and Barbanti-Brodano, G., Hepatocyte targeting of adenine-9-β-D-arabinofuranoside 5′-monophosphate (ara-AMP) coupled to lactosaminated albumin.FEBS Lett., 129, 261–264 (1981).

    Article  PubMed  CAS  Google Scholar 

  • Fiume, L., Di Stefano, G., Busi, C., Mattioli, A., Rapicetta, M., Giuseppetti, R., Ciccaglione, A. and Argentini, C., Inhibition of woodchuck hepatitis virus replication by adenine arabinoside monophosphate coupled to lactosaminated poly-L-lysine and administered by intramuscular route.Hepatology, 22, 1072–1077 (1995).

    PubMed  CAS  Google Scholar 

  • Fourel, I., Cullen, J., Saputelli, J., Aldrich, C., Schaffer, P., Averett, D., Pugh, J. and Mason, W., Evidence that hepatocyte turnover is required for rapid clearance of duck hepatitis B virus during antiviral therapy of chronically infected ducks.J. Virol., 68, 8321–8330 (1994).

    PubMed  CAS  Google Scholar 

  • Fourel, I., Hantz, O., Watanabe, K. A., Jacquet, C., Chomel, B., Fox, J. and Trepo, C., Inhibitory effects of 2′-fluoro arabinosyl-pyrimidine nucleosides on woodchuck hepatitis virus replication in chronically infected woodchucks.Antimicrob. Agents Chemother., 34, 473–475 (1990).

    PubMed  CAS  Google Scholar 

  • Fourel, I., Li, J., Hantz, O., Jacquet, C., Fox, J. J. and Trepo, C., Effects of 2′-fluorinated arabinosyl-pyrimidine nucleosides on duck hepatitis B virus DNA level in serum and liver of chronically infected ducks.J. Med. Virol. 37, 122–126 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Fourel, I., Saputelli, J., Schaffer, P. and Mason, W. S., The carbocyclic analogue of 2′-deoxyguanosine induces a prolonged inhibition of duck hepatitis B virus DNA synthesis in primary hepatocyte cultures and in the liver.J. Virol., 68, 1059–1065 (1994).

    PubMed  CAS  Google Scholar 

  • Fridland, A., Robbins, B. L. and Srinivas, R. V., Antiretroviral activity and metabolism of bis(POC)PMPA, an oral bioavailable prodrug of PMPA.Antiviral Res., 34, A49 (1997).

    Google Scholar 

  • Fried, M. W., Di Bisceglie, A. M., Straus, S. E., Savarese, B., Beames, M. P. and Hoofnagle, J. H.,Hepatology, 16, 127A (1992).

    Article  Google Scholar 

  • Fried, M. W., Fong, T.-L., Swain, M. G., Park, Y., Beames, M. P., Banks, S. M., Hoofnagle, J. H. and Di Bisceglie, A. M., Therapy of chronic hepatitis B with a 6-month course of ribavirin.J. Hepatol., 21, 145–150 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Fried, M. W., Korenman, J. C., Di Bisceglie, A. M., Park, Y., Waggoner, J. G., Mitsuya, H., Hartman, N. R., Yarchoan, R., Broder, S. and Hoofnagle, J. H., A pilot study of 2′,3′-dideoxyinosine for the treatment of chronic hepatitis B.Hepatology, 16, 861–864 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Furman, P. A., Davis, M., Liotta, D. C., Paff, M., Frick, L. W., Nelson, D. J., Dornsife, R. E., Wurster, J. A., Wilson, L. J., Fyfe, J. A., Tuttle, J. V., Miller, W. H., Condreay, L., Averette, D. R., Schinazi, R. F. and Painter, G. R., The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.Antimicrob. Agents Chemother., 36, 2686–2692 (1992).

    PubMed  CAS  Google Scholar 

  • Gish, R. G., Lau, J. Y., Brooks, L., Fang, J. W., Steady, S. L., Imperial, J. C., Garcia, K. R., Esquivel, C. O. and Keeffe, E. B., Ganciclovir treatment of hepatitis B virus infection in liver transplant recipients.Hepatology, 23, 1–7 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Gosselin, G., Schinazi, R. F., Sommadossi, J.-P., Mathe, C., Bergogne, M.-C., Aubertin, A.-M., Kim, A. and Imbach, J.-L., Anti-human immunodeficiency virus activities of the β-L-enantiomer of 2′,3′-dideoxycytidine and its 5-fluoro derivativein vitro.Antimicrob. Agents Chemother., 38, 1292–1297 (1994).

    PubMed  CAS  Google Scholar 

  • Grove, K. L., Guo, X., Liu, S.-H., Gao, Z., Chu, C. K. and Cheng, Y.-C., Anticancer activity of β-L-dioxolane-cytidine, a novel nucleoside analogue with the unnatural L-configuration.Cancer Res., 55, 3008–3011 (1995).

    PubMed  CAS  Google Scholar 

  • Guidotti, L. G., Guilhot, S. and Chisari, F. V., Interleukin-2 and alpha/beta interferon down-regulate hepatitis B virus gene expression in vivo by tumor necrosis factor-dependent and independent pathways.J. Virol., 68, 1265–1270 (1994).

    PubMed  CAS  Google Scholar 

  • Hantz, O., Allaudeen, H. S., Ooka, T., De Clerq, E. and Trepo, C., Inhibition of human and woodchuck hepatitis virus DNA polymerase by the triphosphates of acyclovir, 1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)-5-iodocytosine and E-5-(2-bromovinyl)-2′-deoxyuridine.Antiviral Res., 4, 187–199 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Hantz, O., Borel, C., Trabaud, C., Zoulim, F., Dessolin, J., Camplo, M., Vlieghe, P., Bouygues, M., Trepo, Christian. and Kraus, J. L., Selective inhibition of the duck hepatitis B virus by a new class tetraazamacrocycles.Antimicrob. Agents Chemother. 41, 2579–2581 (1997).

    PubMed  CAS  Google Scholar 

  • Heijtink, R. A., De Wilde, G. A., Kruining, J., Berk, L., Balzarini J., De Clerq, E., Holy, A. and Schalm, S. W., Inhibitory effect of 9-(2-phosphanylmethoxyethyl)-adenine (PMEA) on human and duck hepatitis B virus infection.Antiviral Res., 21, 141–153 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Helgstrand, E., Eriksson, B., Johansson, N. G., Lannero, B., Larsson, A., Misiorny, A., Noren, J. O., Sjoberg, B., Stenberg, K., Stening, G., Stridh, S., Oberg, B., Alenius, S. and Philipson, L., Trisodium phosphonoformate, a new antiviral compound.Science, 201, 819–821 (1978).

    Article  PubMed  CAS  Google Scholar 

  • Hitchcock, M. J. M., Jaffe, H. S., Martin, J. C. and Stagg, R. J., Cidofovir-a new agent with potent antiherpesvirus activity.Antiviral Chem. Chemother., 7, 115–127 (1996).

    CAS  Google Scholar 

  • Hoofnagle, J. H., Hanson, R. G., Minuk, G. Y., Pappas, S. C., Schafer, D. F., Dusheiko, G. M., Straus, S. E., Popper, H. and Jones, E. A., Randomized controlled trial of adenine arabinoside monophosphate for chronic type B hepatitis.Gastroenterology, 86, 150–157 (1984).

    PubMed  CAS  Google Scholar 

  • Isley, D. D., Lee, S.-H., Miller, W. H. and Kutchta, R. D., Acyclic guanosine analogs inhibit DNA polymerase α, β and ε with very different potencies and have unique mechanisms of action.Biochemistry, 34, 2504–2510 (1995).

    Article  Google Scholar 

  • Jacyna, M. R. and Thomas, H. C., Antiviral therapy: hepatitis B.Br. Med. Bull., 46, 368–382 (1990).

    PubMed  CAS  Google Scholar 

  • Jansen, R. W., Johnson, L. C. and Averett, D. R., High-capacityin vitro assessment of anti-hepatitis B virus compound selectivity by a virion-specific polymerase chain reaction assay.Antimicrob. Agents Chemother., 37, 441–447 (1993).

    PubMed  CAS  Google Scholar 

  • Kim, H. O., Schinazi, R. F., Shanmuganathan, K., Jeong, L. S., Beach, J. W., Nampalli, S., Cannon, D. L. and Chu, C. K., L-β-(2S, 4S)- and L-β-(2S, 4R)-Dioxolanyl nucleosides as potential anti-HIV agents: asymmetric synthesis and structure-activity relationships.J. Med. Chem., 36, 519–528 (1993).

    Article  PubMed  CAS  Google Scholar 

  • Kim, H. O., Shanmuganathan, K., Alves, A. J., Jeong, L. S., Beach, J. W., Schinazi, R. F., Chang, C.-N., Cheng, Y.-C. and Chu, C. K., Potent anti-HIV and anti-HBV activities of (-)-L-β-dioxolane-C and (+)-L-β-dioxolane-T and their asymmetric synthesis.Tetrahedron Lett., 33, 6899–6902 (1992).

    Article  CAS  Google Scholar 

  • Kitos, T. E., Huang, J. S., Tovell, D. and Tyrrell, D. L. J., A comparison of drug metabolism and antihepadnavirus activity in twoin vitro cell culture test systems. Abstracts, Paris, France (1991).

  • Korba, B. E. and Gerin, J. L., Antisense oligonucleotides are effective inhibitors of hepatitis B virus replicationin vitro.Antiviral Res., 28, 225–242 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Korba, B. E. and Milman, G., A cell culture assay for compounds which inhibit hepatitis B virus replication.Antiviral Res., 15, 217–228 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Korba, B. E., Baldwin, B., Cote, P., Schinazi, R., Gangemi, D., Gerin, J. L. and Tennant, B. C., Efectiveness of combination therapies with 3TC, famciclovir and alpha interferon against woodchuk hepatitis virus replication in chronically infected woodchuck: modelfor potential anti-HBV treatments. Abstracts of 37th ICAAC. Canada, September 28-October 1, pp. 219 (1997).

  • Korba, B. E. and Boyd, M. R., Penciclovir is an effective inhibitor of hepatitis B virus replicatorin vitro.Antimicrob. Agents Chemother., 40, 1282–1284 (1996).

    PubMed  CAS  Google Scholar 

  • Korenman, J., Baker, B., Waggoner, J., Everhart, J. E., Di Bisceglie, A. M. and Hoofnagle, J. H., Long-term remission of chronic hepatitis B after alpha-interferon therapy.Ann. Int. Med., 114, 629–634 (1991).

    PubMed  CAS  Google Scholar 

  • Kreis, W., Damin, L., Colacino, J., Lopez, C.,In vitro metabolism of 1-β-D-arabinofuranosylcytosine and 1-β-D-2′-fluoroarabino-5-iodocytosine in normal and herpes simplex type 1 infected cells.Biochem. Pharm., 31, 767–773 (1982).

    Article  PubMed  CAS  Google Scholar 

  • Kruining, J., Heijtink, R. A. and Schalm, S. W., Antiviral agents in hepatitis B virus transfected cell lines: inhibitory and cytotoxic effect related to time and treatment.J. Hepatol., 22, 263–267 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Lee, B., Luo, W. X., Suzuki, S., Robins, M. J. and Tyrrell, D. L.,In vitro andin vivo comparison of the abilities of purine and pyrimidine 2′,3′-dideoxynucleosides to inhibit duck hepadnavirus.Antimicrob. Agents Chemother., 33, 336–339 (1989).

    PubMed  CAS  Google Scholar 

  • Lin, T. S., Luo, M. Z., Pai, S. B., Dutschuman, G. E. and Cheng, Y.-C., Synthesis and biological evaluation of 2′,3′-dideoxy-L-pyrimidine nucleosides as potential antiviral agents against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).J. Med. Chem., 37, 798–803 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Lin, T. S., Luo, M.-Z., Liu, M.-C., Zhu, Y.-L., Gullen, E., Dutschman, G. E. and Cheng, Y.-C., Design and synthesis of 2′,3′-dideoxy-2′,3′-didehydro-β-L-cytidine (β-L-d4C) and of 2′,3′-dideoxy-2′,3′-didehydro-β-L-5-fluorocytidine (β-L-Fd4C), two exceptionally potent inhibitors of human hepatitis B virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV)in vitro.J. Med. Chem., 39, 1757–1759 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Ling, R., Mutimer, D., Ahmed, M., Boxall, E. H., Elias, E., Dusheiko, G. M. and Harrison, T. J., Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine.Hepatology, 24, 711–713 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Lopez, C., Watanabe, K. A. and Fox, J. J., 2′-Fluoro-5-iodoaracytosine, a potent and selective anti-herpesvirus agent.Antimicrob. Agents Chemother., 17, 803–806 (1980).

    PubMed  CAS  Google Scholar 

  • Luscombe, C., Pedersen, J., Uren, E. and Locarnini, S., Long-term ganciclovir chemotherapy for congenital duck hepatitis B virus infection in vivo: effect on intrahepatic-viral DNA, RNA, and protein expression.Hepatology, 24, 766–773 (1996).

    PubMed  CAS  Google Scholar 

  • Macilwain, C., NIH, FDA seek lessons from the hepatitis B drug trial deaths.Nature, 364, 275–275 (1993).

    PubMed  CAS  Google Scholar 

  • Marques, A. R., Lau, D., Mckenzie, R., Strus, S. and Hoofnagle, J., Combination therapy with famciclovir and interferon for the treatment of chronic hepatitis B. Abstracts of 37th ICAAC. Canada, September 28-October 1, pp 219 (1997).

  • Martin, J. C., Dvorak, C. A., Smee, D. F., Matthews, T. R. and Verheyden, J. P. H., 9-(1,3-dihydroxy-2-propoxymethyl)guanine: a new potent and selective antiherpes agent.J. Med. Chem., 26, 759–761 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Martin, P., Kassianides, C., Hoofnagle, J. H., Mitsuya, H. and Border, S., Effects of 2′,3′-dideoxyadenosine on duck hepatitis B virus.Hepatology, 8, A1329 (1988).

    Google Scholar 

  • Matthes, E., Von Janta-lipinski, M., Will, H., Schroder, H. C., Merz, H., Steffen, R. and Muller, W. E. G., Inhibition of hepatitis B virus production by modified 2′,3′-dideoxy-thymidine and 2′,3′-dideoxy-5-methyl-cytidine derivativesin vitro andin vivo studies.Biochem. Pharmacol., 43, 1571–1577 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Miller, R. H., Kaneko, S., Chung, C. T., Girones, R. and Purcell, R. H., Compact organization of the hepatitis B virus genome.Hepatology, 9, 322–327 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Minuk, G. Y., German, G. B., Bernstein, C., Benarroch, A., Gauthier, T. and Sekla, L., A pilot study of steroid withdrawal followed by oral acyclovir in the treatment of chronic type B hepatitis.Clin. Invest. Med., 15, 506–512 (1992).

    PubMed  CAS  Google Scholar 

  • Mutchnick, M. G., Appelman, H. D., Chung, H. T., Aragona, E., Gupta, T. P., Cummings, G. D., Waggoner, J. G., Hoofnagle, J. H. and Shafritz, D. A., Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial.Hepatology, 14, 409–415 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Nicoll, A. J., Colledge, D. L., Wang, Y. Y., Toole, J. J., Dean, J. K., Angus, P. W., Smallwood, R. A. and Locarnini, S. A., PMEA, an acyclic phosphonate nucleoside analogue with activity against duck hepatitis B virusin vivo.Hepatology, 220A, 375 (1996).

    Google Scholar 

  • Norbeck, D. W., Spanton, S., Broder, S. and Mitsuya, H., (±)-Dioxolane-T {(±)-1-[(2β,4β)-2-(hydroxymethyl-4-dioxolanyl]thymine}. A new 2′,3′-dideoxy nucleoside prototype within vitro activity against HIV.Tetrahedron Lett., 30, 6263–6266 (1989).

    Article  CAS  Google Scholar 

  • Offensperger, W. B., Blum, H. E. and Gerok, W., Molecular therapeutic strategies in hepatitis B virus infection.Clin. Invest. 72, 737–741 (1994).

    Article  CAS  Google Scholar 

  • Pai, S. B., Liu, S.-H., Zhu, Y.-L., Chu, C. K. and Cheng, Y.-C., Inhibition of hepatitis B virus by a novel L-nucleoside, 2′-fluoro-5-methyl-β-L-arabinofuranosyl uridine.Antimicrob. Agents and Chemother., 40 380–386 (1996).

    CAS  Google Scholar 

  • Parker, W. B. and Cheng, Y.-C., Disruption of energy metabolism and mitochondrial function. InNeurotoxicology: Approaches and Methods. pp. 483–490. Ed. Academic Press, Inc. 1995.

  • Parker, W. B. and Cheng, Y.-C., Mitochondrial toxicity of antiviral nucleoside analogues.J. NIH Res., 6, 57–61 (1994).

    Google Scholar 

  • Peek, S. F., Jacob, J. R., Tochkov, I. A., Kobra, B. E., Gerin, J. L., Chu, C. K. and Tennant, B. C., Sustained antiviral activity of 1-(2-fluoro-methyl-β-L-arabinofuranosyl)uracil (L-FMAU) in the woodchuck model of hepatitis B virus (HBV) infection. Abstract of 37th ICAAC. Canada, September 28-October 1, pp. 215 (1997).

  • Perry, C. M. and Wagstaff, A. J., Famciclovir: a review of its pharmacological properties and therapeutic efficacy in herpesvirus infections.Drugs, 50, 396–415 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Ponzetto, A., Fiume, L., Forzani, B., Song, S. Y., Busi, C., Mattioli, A., Spinelli, M., Smedile, A., Chiaberge, E., Bonino, F., Gervasi, G. B., Rapicetta, M. and Verme, G., Adenine arabinoside monophosphate and acyclovir monophosphate coupled to lactosaminated albumin reduce woodchuck hepatitis virus viremia at doses lower than do the unconjugated drugs.Hepatology, 14, 16–24 (1991).

    Article  PubMed  CAS  Google Scholar 

  • Price, P. M., Banerjee, R. and Acs, G., Inhibition of the replication of hepatitis B virus by the carbocyclic analogue of 2′-deoxyguanosine.Proc. Natl. Acad. Sci. USA, 86, 8541–8544 (1989).

    Article  PubMed  CAS  Google Scholar 

  • Price, P. M., Banerjee, R., Jeffrey, A. M. and Acs, G., The mechanism of inhibition of hepatitis B virus replication by the carbocyclic analogue of 2′-deoxyguanosine.Hepatology, 16, 8–12 (1992).

    Article  PubMed  CAS  Google Scholar 

  • Purcell, R. H. and Gerin, J. L., Hepatitis B vaccines on the threshold.Am. J. Clin. Pathol., 70, 159–169 (1978).

    PubMed  CAS  Google Scholar 

  • Rajagopalan, P. F., Boudinot, F. D., Chu, C. K., McClure, H. M. and Schinazi, R. F., Pharmacokinetics of (-)-β-D-2,6-diaminopurine dioxolane and its metabolite dioxolane guanosine in rhesus monkeys.Pharm. Res., 11, suppl. 381 (1994).

    Google Scholar 

  • Rajagopalan, P., Boudinot, F. D., Chu, C. K., Tennant, B. C., Baldwin, B. H. and Schinazi, R. F., Pharmacokinetics of (-)-β-D-2,6-diaminopurine dioxolane and its metabolite, dioxolane guanosine, in woodchucks (Marmota monax).Antiviral Chem. Chemother., 7, 65–70 (1996).

    CAS  Google Scholar 

  • Ryff, J. C., To treat or not to treat? The judicious use of interferon-α-2a for the treatment of chronic hepatitis B virus.J. Hepatology., 17, suppl. 3, S42-S46 (1993).

    Article  Google Scholar 

  • Schalm, S. W., Heijitink, R. A., Van Buuren, H. R. and De Man, R. A., Acyclovir, oral, intravenous and combined with interferon for chronic HBeAg-positive hepatitis.J. Hepatol., 3, suppl. 2, S137-S141 (1986).

    Article  PubMed  Google Scholar 

  • Schalm, S. W., Heijitink, R. A., Van Buuren, H. R. and De Man, R. A., Lymphoblastoid alpha-interferon, weekly, daily and combined with acyclovir for chronic HBeAg-positive hepatitis.J. Hepatol., 3, suppl. 2, S189-S192 (1986).

    Article  PubMed  Google Scholar 

  • Schinazi, R. F., McClure, H. M., Boudinout, F. D., Xiang, Y.-J. and Chu, C. K., Development of (-)-β-D-2, 6-diaminopurine dioxolane as a potential antiviral agent.Antiviral Res., 23, suppl. 81 (1994).

    Google Scholar 

  • Schinazi, R. F., McMillan, A., Cannon, D., Mathis, R., Lloyd, R. M., Peck, A., Sommadossi, J.-P., St Clair, M., Wilson, J., Furman, P. A., Painter, G., Choi, W. B. and Liotta, D. C., Selective inhibition of human immunodeficiency viruses by racemates and enatiomers ofcis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.Antimicrob. Agents Chemother., 36, 2423–2431 (1992).

    PubMed  CAS  Google Scholar 

  • Sells, M. A., Chen, M.-L. and Acs, G., Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA.Proc. Natl. Acad. Sci. USA, 84, 1005–1009 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Sells, M. A., Zelent, A. Z., Shvartsman, M. and Acs, G., Replicative intermediate of hepatitis B virus in HepG2 cells that produce infectious virions.J. Virol., 62, 2836–2844 (1988).

    PubMed  CAS  Google Scholar 

  • Severini, A., Liu, X.-Y., Wilson, J. S. and Tyrrell, D. L. J., Mechanism of inhibition of duck hepatitis B virus polymerase by (-)-β-L-2′,3′-dideoxy-3′-thiacytidine.Antimicrob. Agents Chemother., 39, 1430–1435 (1995).

    PubMed  CAS  Google Scholar 

  • Shaw, T., Amor, P., Civitico, G., Boyd, M. and Locarnini, S.,In vitro antiviral activity of penciclovir, a novel purine nucleoside, against duck hepatitis B virus.Antimicrob. Agents Chemother., 38, 719–723 (1994).

    PubMed  CAS  Google Scholar 

  • Sheron, N., Lau, J. Y., Daniels, H. M., Webster, J., Eddleston, A. L., Alexander, G. J. and Williams, R., Tumor necrosis factor to treat chronic hepatitis B virus infection.Lancet, 336, 321–322 (1990).

    Article  PubMed  CAS  Google Scholar 

  • Sidewell, R. W., Huffman, J. H., Khare, G. P., Allen, L. B., Witkowski, J. T. and Robins, R. K., Broadspectrum antiviral activity of virazole: 1-β-D-ribofuranosyl-1,2,4-tiazole-3-carboxamide.Science, 177, 705–706 (1972).

    Article  Google Scholar 

  • Sidewell, R. W., Revankar, G. R. and Robin, R. K., Ribavirin: review of a broad-spectrum antiviral agent. InViral Chemotherapy Vol. 2. Ed. by D. Shugar., pp. 49–108. Oxford: Pergamon Press (1985).

    Google Scholar 

  • Smith, K. O., Galloway, K. S., Kennell, W. L., Ogilvie, K. K. and Radatus, B. K., A new nucleoside analogue, 9-(1,3-dihydroxy-2-propoxymethyl)guanine, highly active in vitro against herpes simplex virus types 1 and 2.Antimicrob. Agents Chemother., 22, 55–61 (1982).

    PubMed  CAS  Google Scholar 

  • Soudeyns, H., Yao, Q., Belleau, B., Kraus, J.-L., Nguyen-Ga, N., Spira, B. and Wainberg, M. A., Antihuman immunodeficiency virus type 1 activity andin vitro toxicity of 2′-deoxy-3′-thiacytidine (BCH-189), a novel heterocyclic nucleoside analogue.Antimicrob.Agents Chemother., 35, 1386–1390 (1991).

    CAS  Google Scholar 

  • Spector, S. A., McKinley, G. S., Lalezari, J. P., Samo, T., Andruczk, R., Follansbee, S., Sparti, P. D., Havlir, D. V., Simpson, G., Buhles, W., Wong, R. and Stempien, M. J., Oral ganciclovir for the prevention of cytomegalovirus disease in persons with AIDS.New. Engl. J. Med., 334, 1491–1497 (1996).

    Article  PubMed  CAS  Google Scholar 

  • Starnes, M. C. and Cheng, Y.-C., Cellular metabolism of 2′,3′-dideoxycytidine, a compound active against human immunodeficiency virusin vitro.J. Biol. Chem., 262, 988 (1987).

    PubMed  CAS  Google Scholar 

  • Sureau, C., Romet-Lemonne, J. L., Mullins, J. I. and Essex, M., Production of hepatitis B virus by a differentiated human hepatoma cell line after transfection with cloned circular HBV DNA.Cell, 47, 37–47 (1986).

    Article  PubMed  CAS  Google Scholar 

  • Tennant, B., Jacob, J., Graham L. A., Peek, S., Du, J. and Chu, C. K., Pharmacokinetic and pharmacodynamic studies of 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)uracil (L-FMAU) in the woodchuck model of hepatitis B virus (HBV) infection.Antiviral Res., 34, A52, 36 (1997).

    Google Scholar 

  • Tenney, D. J., Yamanaka, G., Voss, S. M., Cianci, C. W., Tuomari, A. V., Sheaffer, A. K., Alam, M. and Colonno, R. J., Lobucavir is phosphorlated in human cytomegalovirus-infected and uninfected cell and inhibitis the viral DNA polymerase.Antimicrob. Agents Chemother., 41, 2680–2685 (1997).

    PubMed  CAS  Google Scholar 

  • Thymosin alpha 1 shows efficacy for hepatitis B.Antiviral Agents Bull., 9, 194–195 (1996).

    Google Scholar 

  • Tiollais, P., Pourcel, C. and Dejean, A., The hepatitis B virus.Nature, 317, 489–495 (1985).

    Article  PubMed  CAS  Google Scholar 

  • Tipples, G. A., Ma, M. M., Fisher, K. P., Bain, V. G., Kneteman, N. M. and Tyrrell, D. J. L., Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudinein vivo.Hepatology, 24, 714–717 (1996).

    PubMed  CAS  Google Scholar 

  • Touchette, N., HBV-drug deaths prompt restudy of similar antivirals.J. NIH Res., 5, 33–36 (1993).

    Google Scholar 

  • Tsiquaye, K., Slomka, M. J. and Maung, M., Oral famciclovir against duck hepatitis B virus replication in hepatic and nonhepatic tissues of ducklings infectedin vivo.J. Med. Virol., 42, 306–310 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Tsurimoto, T., Fujiyama, A. and Matsubara, K., Stable expression and replication of hepatitis B virus genome in an integrated state in a human hepatoblastoma cell line transfected with the cloned viral DNA.Proc. Natl. Acad. Sci. USA, 84, 444–448 (1987).

    Article  PubMed  CAS  Google Scholar 

  • Tuttleman, J. S., Pugh, J. C. and Summers, J. W.,In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus.J. Virol., 58, 17–25 (1986).

    PubMed  CAS  Google Scholar 

  • Tyrrell, D. L. J., Fisher, K., Savani, K., Ian, W. and Jewell L., Treatment of chimpanzees and ducks with lamivudine, 2′,3′-dideoxy-3′-thiacytidine results in a rapid suppression of hepadnaviral DNA in sera.Clin. Invest. Med., 16, Suppl. 4, B77. Abstract (1993).

    Google Scholar 

  • Vere Hodge, R. A. and Cheng, Y. C., The mode of action of penciclovir.Antiviral Chem. Chemother., 4, 13–24 (1993).

    Google Scholar 

  • Wagstaff, A. J. and Bryson, H. M., Foscarnet, a reappraisal of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with viral infections.Drugs, 48, 199–226 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, K. A., Reichman, U., Hirota, K., Lopez, C. and Fox J. J., Nucleosides. 110. Synthesis and antiherpes virus activity of some 2′-fluoro-2′-deoxy-arabinofuranosylpyrimidine nucleosides.J. Med. Chem., 22, 21–24 (1979).

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, K. A., Su, T.-L., Klein, R. S., Chu, C. K., Matsuda, A., Chun, M. W., Lopez, C. and Fox, J. J., Nucleosides. 123. Synthesis of antiviral nucleosides, 5-substituted 1-(2-deoxy-2-halogeno-β-D-arabinofuranosyl) cytosines and uracils, some structure-activity relationships.J. Med. Chem., 26, 152–156 (1983).

    Article  PubMed  CAS  Google Scholar 

  • Watanabe, K. A., Su, T.-L., Reichman, U., Greenberg, N., Lopez, C. and Fox, J. J., Nucleosides. 129. Synthesis of antiviral nucleosides, 5-alkenyl-1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracils.J. Med. Chem., 27, 91–94 (1984).

    Article  PubMed  CAS  Google Scholar 

  • Witcher, J. W., Boudinot, F. D., Baldwin, B. H., Ascenzi, M. A., Tennant, B. C., Du, J. F. and Chu, C. K., Pharmacokinetics of 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl) uracil (L-FMAU) in woodchucks.Antimicrob. Agents Chemother., 41, 2184–2187 (1997).

    PubMed  CAS  Google Scholar 

  • Wright, J. D., Ma, T.-W., Chu, C. K. and Boundinot, F. D., Pharmacokinetics of 1-(2-deoxy-2-fluoro-β-L-arabinofuranosyl)-5-methyluracil in rats.Pharm. Res., 12, 1350–1353 (1995).

    Article  PubMed  CAS  Google Scholar 

  • Wright, J. D., Ma, T.-W., Chu, C. K. and Boudinot, F. D., Discontinuous oral absorption pharmacokinetic model and bioavailability of 1-(2-fluoro-5-methyl-β-L-arabinofuranosyl)-uracil (L-FMAU) in rats.Biopharm. and Drug Disposition, 17, 948, 1–11 (1996).

    Google Scholar 

  • Wu, G. Y. and Wu, C. H., Specific inhibition of hepatitis B viral gene expressionin vitro by targeted antisense oligonucleotides.J. Biol. Chem. 267, 12436–12439 (1992).

    PubMed  CAS  Google Scholar 

  • Wu, J., Sullivan, D. E. and Gerber, M. A., Quantitative polymerase chain reaction for the hepatitis B virus DNA.J. Virol. Methods, 49, 331–341 (1994).

    Article  PubMed  CAS  Google Scholar 

  • Yokota, T., Konno, K., Chonan, E., Mochizuki, S., Kojima, K., Shigeta, S. and De Clerq E., Comparative activities of several nucleoside analogues against duck hepatitis B virusin vitro.Antimicrob. Agents Chemother., 34, 1326–1330 (1990).

    PubMed  CAS  Google Scholar 

  • Yokota, T., Mochizuki, S., Konno, K., Mori, S., Shigeta, S. and De Clerq, E., Inhibitory effects of selected antiviral compounds on human hepatitis B virus DNA synthesis.Antimicrob. Agents Chemother., 35, 394–397 (1991).

    PubMed  CAS  Google Scholar 

  • Zoulim, F., Aguesse, S., Borel, C., Trepo, C. and Cheng, Y.-C., 2′-Fluoro-5-methyl-β-L-arabinofuranosyluracil, a novel L-nucleoside analogue, inhibits hepatitis B virus replication in primary hepatocytes andin vivo.Antiviral Res. 30, A24 (1996).

    Google Scholar 

  • Zoulim, F., Dannaoui, E., Borel, C., Hantz, O., Lin, T.-S., Liu, S.-H., Trepo, C. and Cheng, Y.-C., 2′,3′-Dideoxy-β-L-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppress viral DNA synthesis in hepatocytes, bothin vitro andin vivo.Antimicrob. Agents Chemother., 40, 448–453 (1996).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hong, J.H., Choi, Y., Chun, B.K. et al. Current status of anti-HBV chemotherapy. Arch. Pharm. Res. 21, 89–105 (1998). https://doi.org/10.1007/BF02974012

Download citation

  • Received:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02974012

Key words

Navigation