Perspectives for the Treatment of Hepatitis B Virus Infections

Clinical Microbiology and Antimicrobial Chemotherapy. 2000; 2(3):4-18

​ De Clercq E.
viral hepatitis B antiviral therapy
Section
Diseases and Pathogens
Type
Journal article
Publication
Clinical Microbiology and Antimicrobial Chemotherapy. 2000; 2(3):4-18

Abstract

Translated and reprinted with permission from «International Journal of Antimicrobial Agents» 1999;12⁄2:81-97.

There are an estimated 350 million people throughout the world who are chronically infected with hepatitis B virus (HBV). Although HBV infection can be prevented through vaccination, HBV has remained the most significant viral pathogen infecting man. Interferon a is currently the only treatment specifically approved by regulatory authorities throughout the world for chronic hepatitis B. However, interferon therapy is associated with several side effects and variable, and often unsatisfactory, response rates. Recent attempts at developing an effective therapy for HBV infections have capitalized on the HBV-specified DNA polymerase as target enzyme. A variety of nucleosides (and nucleotides) that had proved to be affective against other viral infections are further examined for their anti-HBV potential. Primarily resulting as a spin-off the search for effective anti-HSV and anti-HBV agents, such compounds as famciclovir (penciclovir), BMS-200475 (entecavir), lamivudine (3ТС), (-)FTC, L(-)Fd4C, L-FMAU, DAPD (DXG), bis(POM)-PMEA and bis(POC)-PMPA have been identified as effective and promising candidate anti-HBV drugs. But as it has become obvious, future HBV therapy may reside in combination drug therapy to achieve the highest possible virus reduction and minimize the likelihood of drug resistance development.

  • 1. Dusheiko G.M. Treatment and prevention of chronic viral hepatitis. Pharmacol Ther 1995;65:47-73.
  • 2. Lai C.L., Chien R.N., Leung N.W.Y., et al. A 1-year trial of lamiviuline for chronic hepatitis B. N Engl J Med 1998;339:61S.
  • 3. Lin E., Luscombe C., Colledge D., Wang Y.Y., Locarnini S. Long-term therapy with the guanine nucleoside analog penciclovir controls chronic duck hepatitis В virus infection in vivo. Antimicrob Agents Chemother 1998;42:2132-7.
  • 4. Ganem D., Varmus H.E. The molecular biology of the hepatitis В viruses. Ann Rev Biochem 1987;56:651-93.
  • 5. Yokota Т., Mochizuki S., Konno K., Mori S., Shigeta S., DeClercq E. Inhibitory effects of selected antiviral compounds on human hepatitis В virus DNA synthesis. Antimicrob Agents Chemother 1991;35:394-7.
  • 6. Korba B.E., Boyd M.R. Penciclovir is a selective inhibitor of hepatitis В virus replication in cultured human hepatoblastoma cells. Antimicrob Agents Chemother 1996;40:1282-4.
  • 7. Innaimo S.F., Seifer M., Bisacchi G.S., Standring D.N., Zahler R., Colonno R.J. Identification of BMS-200475 as a potent and selective inhibitor of hepatitis В virus. Antimicrob Agents Chemother 1997;41:1444-8.
  • 8. Ying С., Van Pelt J., Yap P., DeClercq E., Neyts J. Digoxigenin labelled probes for the detection of HBV-DNA in antiviral evaluation. Symposium on Emerging Therapies for Chronic Viral Hepatitis (Abstracts) Marriott Chateau Champlain Hotel. Montreal. Quebec, Canada. October 2–4, 1998.
  • 9. Lin T.S., Luo M.Z., Liu M.C., e.a. Design and synthesis of 2',3'-dideoxy-2',3'-dehydro-b-L-cytidine (b-L-d4C) and 2',3'-dideoxy-2',3'-didehydro-P-l-5-fluorocytidine (b-L-Fd4C), two exceptionally potent inhibitors of human hepatitis В virus (HBV) and potent inhibitors of human immunodeficiency virus (HIV) in vitro. J Med Chem 1996;39:1757-9.
  • 10. Furman P.A., Davis M., Liotta D.C., et al. The anti-hepatitis В virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-l-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Antimicrob Agents Chemother 1992;36:2682-92.
  • 11. Balzarini J., Wedgwood O., Kruining J., Pelemans H., Heijtink R., De Clercq E., McGuigan C. Anti-HIV and anti-HBV activity and resistance profile of 2',3'-dideoxy-3'-thiacytidine (3TC) and its arylphosphoramidate deri-vative CF 1109. Biochem Biophys Res Commun 1996;225:363-9.
  • 12. Staschke K.A., Colacino J.M., Mabry Т.Е., Jones C.D. The in vitro anti-hepatitis В virus activity of FIAU [l-(2'-deoxy-2'-fluoro-l-b-D-arabinofuranosyl-5-iodo)uracil] is selective, reversible, and determined, at least in part, by the host cell. Antiviral Res 1994;23:45-61.
  • 13. Pai S.B., Liu S.H., Zhu Y.L., Chu C.K., Cheng Y.C. Inhibition of hepatitis В virus by a novel L-nucleoside, 2'-fluoro-5-methyl-p-L-arabinofuranosyl uracil. Antimic.rob Agents Chemother 1996;40:380-6.
  • 14. Balzarini J., Kruining J., Wedgwood О., et al. Conversion of 2',3'-dideoxyadenosine (ddA) and 2',3'-didehydro-2',3'-dideoxyadenosine (ddA) to their corresponding aryl-oxyphosphoramidate derivatives markedly potentiates their activity against human immunodeficiency virus and hepatitis В virus. FEBS Lett 1997;410:324-8.
  • 15. Ma Т., Lin J.S., Newton M.G., Cheng Y.C., Chu C.K. Synthesis and anti-hepatitis В virus activity of 9-(2-deoxy-2-fluoro-b-L-arabino-fluranosyl)purine nucleosides. J Med Chem 1997;40:2750-4.
  • 16. Chen H., Boudinot F.D., Chu C.K., McClure H.M., Schinazi R.F. Pharmacokinetics of (-)-b-D-2-amino-purine dioxolane and (-)-b-D-2-amino-6-chloropurine dioxolane and their antiviral metabolite (-)-b-D-di-oxolane guanine in rhesus monkeys. Antimicrob Agents Chemother 1996;40:2332-6.
  • 17. Yokota Т., Konno К., Shigeta S., Holy A., Balzarini J., DeClercq E. Inhibitory effects of acyclic nucleoside phosphonate analogues on hepatitis В virus DNA synthesis in HB611 cells. Antiviral Chem Chemother 1994;5:57-63.
  • 18. Heijtink R.A., Kruining J., de Wilde G.A., Balzarini J., DeClercq E., Schalm S.W. Inhibitory effects of acyclic nucleoside phosphonates on human hepatitis В virus and duck hepatitis В virus infections in tissue culture. Antimicrob Agents Chemother 1994;38:2180-2.
  • 19. Heijtink R.A., deWilde G.A., Kruining J., et al. Inhibitory effect of 9-(2-phosphonylmethoxyethyl) adenine (PMEA) on human and duck hepatitis В virus infection. Antiviral Res 1993;21:141-53.
  • 20. Yokota T., Konno K., Chonan E., et al. Comparative activities of several nucleoside analogs against duck hepatitis В virus in vitro. Antimicrob Agents Chemother 1990;34:1326-30.
  • 21. Wang G.H., Seeger C., The reverse transcriptase of hepatitis В virus acts as a protein primer for viral DNA synthesis. Cell 1992;71:663-70.
  • 22. Shaw T., Mok S.S., Locarnini S.A. Inhibition of hepatitis В virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir. Hepatology 1996;24:996-1002.
  • 23. Liu S.H., Grove K.L., Cheng Y.C. Unique metabolism of a novel antiviral L-nucleoside analog, 2'-fluoro-5-methyl-b-L-arabino-furanosyluracil: a substrate for both thymidine kinase and deoxycytidine kinase. Antimicrob Agents Chemother 1998;42:833-9.
  • 24. Severini A., Liu X.Y., Wilson J.S., Tyrrell D.L.J. Mechanism of inhibition of duck hepatitis В virus polymerase by (-)-b-L-2',3'-dideoxy-3'-thiacytidine. Antimicrob Agents Chemother 1995;39:1430-5.
  • 25. Kukhanova M., Li X., Chen S.H., et al. Interaction of p-L-2',3'-dideoxy-2',3'-didehydro-5-fluoro-CTP with human immunodeficiency virus-1 reverse transcriptase and human DNA polymerases: implications for human immunodeficiency virus drug design. Mol Pharmacol 1998;53:801-7.
  • 26. Kukhanova M., Lin Z.Y., Yas'co M., Cheng Y.C. Unique inhibitory effect of l-(2'-deoxy-2'-fluoro-b-L-arabinofuranosyl)-5-methyluracil 5'-triphosphate on Epstein–Barr virus and human DNA polymerases. Biochem Pharmacol 1998;55:1181-7.
  • 27. Zhu Y.L., Dutschman G.E., Liu S.H., Bridges E.G., Cheng Y.C. Anti-hepatitis В virus activity and metabolism of 2',3'-dideoxy-2',3'-didehydro-b-L(-)-5-fluorocytidine. Antimicrob Agents Chemother 1998;2:1805-10.
  • 28. Balzarini J., Nave J.F., Becker M.A., Tatibana M., DeClercq E. Kinetic properties of adenine nucleotide analogues against purified 5-phosphoribosyl-l-pyrophosphate synthetases from E.coli, rat liver and human erythrocytes. Nucleosides Nucleotides 1995;14:1861-71.
  • 29. Merta A., Votruba I., Jindrich J., et al. Phosphorylation of 9-f2-phosphonomethoxyethyl)adenine and 9-(5')-(3-hydroxy-2-phosphonomethoxypropyl)-adenine by AMP (dAMP) kinase from L1210 cells. Biochem Pharmacol 1992;44:2067-77.
  • 30. Naesens L., Snoeck R., Andrei G., Balzarini J., Neyts J., DeClercq E. HPMPC (cidofovir), PMEA (adefovir) and related acyclic nucleoside phosphonate analogues: a review of their pharmacology and clinical potential in the treatment of viral infections. Antiviral Chem Chemother 1997;8:1-23.
  • 31. Kramata P., Votruba I., Olova B., Holy A. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs towards DNA polymerases alpha, delta and epsilon. Mol Pharmacol 1996;49:1005-11.
  • 32. Cihiar T., Chen M.S. Incorporation of selected nucleoside phosphonates and anti-human immunodeficiency virus nucleotide analogues into DNA by human DNA polymerases a, b and g. Antiviral Chem Chemother 1997; 8:187-95.
  • 33. Tsiquaye K.N., Sutton D., Maung M., Boyd M.R. Antiviral activities and pharmacokinetics of penciclovir and famciclovir in Pekin ducks chronically infected with duck hepatitis В virus. Antiviral Chem Chemother 1996;7:153-9.
  • 34. Lin E., Luscombe C., Wang Y.Y., Shaw T., Locarnini S. The guanine nucleoside analog penciclovir is active against chronic duck hepatitis В virus infection in vivo. Antimicrob Agents Chemother 1996;40:413-8.
  • 35. Zoulim F., Dannaoui E., Borel C., et al. 2',3'-Dideoxy-b-L-5-fluorocytidine inhibits duck hepatitis В virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo. Antimicrob Agents Chemother 1996;40:448-53.
  • 36. Aguesse-Germon S., Liu S.H., Chevallier M., et al. Inhibitory effect of 2'-fluoro-5-methyl-p-L-arabinofuranosyluracil on duck hepatitis В virus replication. Antimicrob Agents Chemother 1998;42:369-76.
  • 37. Cullen J.M., Smith S.L., Davis M.G., et al. In vivo antiviral activity and pharmacokinetics of (-)-cis-5-fluoro-l-[2-(hydroxymethyl)-l,3-oxathiolan-5-yl]cytosine in woodchuck hepatitis virus-infected woodchucks. Antimicrob Agents Chemother 1997;41:2076-82.
  • 38. Mason W.S., Cullen J., Moraleda G., et al. Lamivudine therapy of WHV-infected woodchucks. Virology 1998;245:18-32.
  • 39. Korba B.E., Peek S.F., Toshkov I.A., et al. Treatment with lamivudine (3TC, 3'-thiacytidine) delays development of hepato-cellular carcinoma (HCC) in woodchucks chronically infected with woodchuck hepatitis В virus (WHV). Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, September 24–27, 1998, Abstract no. H-54.
  • 40. Boker K.H., Ringe K., Kruger M., Pichlmayr R., Manns M.P. Prostaglandin E plus famciclovir–a new concept for the treatment of severe hepatitis В after liver transplantation. Transplantation 1994;57:1706-8.
  • 41. Kruger M., Tillmann H.L., Trautwein C., et al. Famciclovir treatment of hepatitis В virus recurrence after liver transplantation: a pilot study. Liver Transpl Surg 1996;2:253-62.
  • 42. Main J., Brown J.L., Howells C., et al. A double blind, placebo-controlled study to assess the effect of famciclovir on virus replication in patients with chronic hepatitis В virus infection. J Viral Hepatitis 1996;3:211-5.
  • 43. Singh N., Gayowski T., Wannstedt C.F., Wagener M.M., Marino I.R. Pretransplant famciclovir as prophylaxis for hepatitis В virus recurrence after liver transplantation. Transplantation 1997;63:1415-9.
  • 44. Kruger M., Boker K.H.W., Zeidler H., Manns M.P. Treatment of hepatitis B-related polyarteritis nodosa with famciclovir and interferon a-2b. J Hepatol 1997;26:935-9.
  • 45. Milich D.R., Jones J.E., Huehes J.L., Price J., Raney A.K., McLachlan A. Is a function of the secreted hepatitis В е antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA 1990;87:6599-603.
  • 46. Deeks S.G., Collier A., Lalezari J., et al. The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV-infected adults: a randomized, double-blind, placebo-controlled trial. J Infect Dis 1997;176:1517-23.
  • 47. Barditch-Crovo P., Toole J., Hendrix C.W., et al. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxyl 9-[2-bis-pivaloyloxymethyl)phosphonylmethoxyethyl]adenine) in HIV-infected patients. J Infect Dis 1997;176:406-13.
  • 48. Gilson R.J., Cliopra K., Murray-Lyon I., et al. Adefovir dipivoxil (Bis-POM PMEA) treatment for chronic hepatitis B infection: a placebo-controlled phase I/II study. 36th Annual Meeting ol' the American Society lor Microbiology, New Orleans. LO. September 15–18, 1999A. Late Breakers, p.7, no.LBI.
  • 49. Jeffers L., Heathcote E., Wright T., et al. A phase II dose-ranging. placebo-controlled trial of adefovir dipivoxil for the treatment of chronic hepatitis B virus infection. Abstracts of the Eleventh International Conference on Antiviral Research. San Diego. California. April 5–10. 1998. Late Breakers, p.9, no.197.
  • 50. Ling R., Mutimer D., Ahmed M., et al. Selection of mutations in the hepatitis B virus polymerase during therapy of transplantation recipients with lamivudine. Hepatology 1996;24:711-3.
  • 51. Tipples G.A.., Ma M.M., Fischer K.P., Bain V.G., Kneteman N.M., Tyrrell D.L. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. Hepatology 1996;24:714-7.
  • 52. Bartholomew M.M., Jansen R.W., Jeffers L.J., et al. Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet 1997;349:20-2.
  • 53. Honkoop P., Niesters H.G., deMan R.A., Osterhaus A.D., Sclialm S.W. Lamivudine resistance in immunocompetent chronic hepatitis B. Incidence and patterns. J Hepatol 1997;26:1393-5.
  • 54. Fischer K.P., Tyrrell D.L.J. Generation of duck hepatitis B virus polymerase mutants through site-directed mutagenesis which demonstrate resistance to lamivudine [(-)-p-L-2',3'-dideoxy-3'-thiacytidine] in vitro. Antimicrob Agents Chemother 1996;40:1957-60.
  • 55. Fu L., Cheng Y.C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TO resistance. Biochem Pharmacol 1998;55:1567-72.
  • 56. Niesters H.G.M., Honkoop P., Haagsma E.B., et al. Identification of more than one mutation in the hepatitis B virus polymerase gene arising during prolonged lamivudine treatment. J Infect Dis 1998;177:1382-5.
  • 57. Ladner S.K., Miller T.J., King R.W. The M539V polymerase variant of human hepatitis B virus demonstrates resistance to 2'-deoxy-3'-thiacytidine and a reduced ability to synthesize viral DNA. Antimicrob Agents Chemother 1998;42:2128-31.
  • 58. Ladner S.K., Miller T.J., Otto M.J., King R.W. The hepatitis B virus M539V polymerase variation respon-sible for 3TC resistance also confers cross-resistance to other nucleoside analogues. Antiviral Chem Chemother 1998;9:65-72.
  • 59. Aye T.T., Bartholomeusz A., Shaw T., et al. Hepatitis B virus polymerase mutations during antiviral therapy in a patient following liver transplantation. J Hepatol 1997;26:1148-53.
  • 60. Mulato A.S., Lamy P.D., Miller M.D., et al. Genotypic and phenotypic characterization of human immunodeficiency virus type I variants isolated from AIDS patients after prolonged adefovir dipivoxil therapy. Antimicrob Agents Chemother 1998;42:1620-8.
  • 61. Naesens L., Bischofberger N., Auaustijns P., et al. Antiretrovinil efficacy and pharmacokineties of oral bisfisopropyloxycarbonyloxymethyl')-9-(2-phosphonylmethoxypropyl)adenine in mice. Antimicrob Agents Chemoter 1998;42:1568-73.
  • 62. Robbins B.L., Srinivas R.V., Kim C., Bischofberger N., Fridland A. Anti-human imunodeficiency virus activity and cellular metabolism of a potential prodrug of the acyclic nucleoside phosphonate 9-R-(2-phosphonomethoxypropyl)adenine (PMPA) histisopropyloxymethylcarbonyl)PMPA. Antimicrob Agents Chemother 1998;42:612-7.
  • 63. Tsai C.C., Follis K.E., Sabo A., et al. Prevention of SIV infection in macaques by (R)-9-2-phosphonylmethoxypropyl)adenine. Science 1995;270:1197-9.
  • 64. Van Rompay K.K.A., Martha M.L., Lifson I.D., et al. Administration of 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) for prevention of perinatal simian immunodeficiency virus infection in rhesus macaques. AIDS Res Hum Retrovir 1998;14:761-72.
  • 65. Van Rompay K.K.A., Berardi C.J., Aguirre N.L., et al. Two doses of PMPA protect newborn macaques against oral simian immunodeficiency virus infection. AIDS 1998;12: F79-F83.
  • 66. Havlir D.V., Richman D.D. Viral dynamics of HIV: implications for drug development and therapeutic strategies. Ann Intern Med 1996;124:984-94.
  • 67. Shaw T., Colledge D., Locarnini S.A. Synergistic inhibition of in vitro hepadnaviral replication by PMEA and penciclovir or lamivudine. Abstracts of the Tenth International Conference on Antiviral Research. Atlanta. Georgia. April 6–11. 1997, Abstract no.33, p.A51.
  • 68. Zembower D.E., Lin Y.M., Flavin M.T., Chen F.C., Korba B.E. Robustaflavone, a potential non-nucleoside anti-hepatitis B agent. Antiviral Res 1998;39:81-8.
  • 69. Dutschman G.E., Bridges E.G., Liu S.H., et al. Metabolism of 2',3'-dideoxy-2',3'-didehydro-p-L-(-)-5-fluorocytidine' and its activity in combination with clinically approved anti-human immunodeficiency virus P-D(+) nucleoside analogs in vitro. Antimicrob Agents Chemother 1998;42:1799-804.
  • 70. Colledge D., Locarnini S., Shaw T. Synergistic inhibition of hepadnaviral replication by lamivudine in combination with penciclovir in vitro. Hepatology 1997;26:216-25.
  • 71. Xiong X., Flores C., Yang H., Toole J.J., Gibbs C.S. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro. Hepatology 1998;27 (in press).
  • 72. Block T.M., Lu X., Mehta A.S., et al. Treatment of chro-nic hepadnavirus infection in a woodchuck animal model with an inhibitor of protein folding and trafficking. Nat Med 1998;4:610-4
Views
0 Abstract
0 PDF
0 Crossref citations
Shared