PDF herunterladen
Semin Liver Dis 2006; 26(2): 171-180
DOI: 10.1055/s-2006-939759
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

In Vitro Models for Studying Hepatitis B Virus Drug Resistance

Fabien Zoulim1
  • 1INSERM Unit 271, Institut Universitaire de France, Lyon, France
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
03. Mai 2006 (online)

    Lizenzen und Reprints

ABSTRACT

Hepatitis B virus resistance to antivirals is conferred by the selection of polymerase gene mutants with reduced susceptibility to nucleoside analogues. Because of the increasing number of resistant mutants to the different available drugs, several phenotypic assays have been developed to provide cross-resistance data to guide clinicians in the management of therapy. Their possible use in the routine follow-up of antiviral treatment is also discussed. The different in vitro models for the study of HBV resistance include enzymatic and cell-based assays. Their relevance for the analysis of viral fitness, drug susceptibility, and cross-resistance is also reviewed.

KEYWORDS

Hepatitis B virus - replication - drug resistance - nucleoside analogues

REFERENCES

  • 1 Zoulim F. Mechanism of viral persistence and resistance to nucleoside and nucleotide analogs in chronic hepatitis B virus infection.  Antiviral Res. 2004;  64 1-15
    CrossrefPubMedGoogle Scholar
  • 2 Locarnini S, Hatzakis A, Heathcote J et al.. Management of antiviral resistance in patients with chronic hepatitis B.  Antivir Ther. 2004;  9 679-693
    PubMedGoogle Scholar
  • 3 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;  28 1669-1673
    CrossrefPubMedGoogle Scholar
  • 4 Xiong X, Yang H, Westland C E, Zou R, Gibbs C S. In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance.  Hepatology. 2000;  31 219-224
    CrossrefPubMedGoogle Scholar
  • 5 Seigneres B, Pichoud C, Ahmed S S, Hantz O, Trepo C, Zoulim F. Evolution of hepatitis B virus polymerase gene sequence during famciclovir therapy for chronic hepatitis B.  J Infect Dis. 2000;  181 1221-1233
    CrossrefPubMedGoogle Scholar
  • 6 Pichoud C, Seignères B, Wang Z, Trepo C, Zoulim F. Transient selection of a hepatitis B virus polymerase gene mutant associated with a decreased replication capacity and famciclovir resistance.  Hepatology. 1999;  29 230-237
    CrossrefPubMedGoogle Scholar
  • 7 Fu L, Liu S H, Cheng Y C. Sensitivity of L-(-)2,3-dideoxythiacytidine resistant hepatitis B virus to other antiviral nucleoside analogues.  Biochem Pharmacol. 1999;  57 1351-1359
    CrossrefPubMedGoogle Scholar
  • 8 Fu L, Cheng Y-C. Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(-)SddC (3TC) resistance.  Biochem Pharmacol. 1998;  55 1567-1572
    CrossrefPubMedGoogle Scholar
  • 9 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 1148-1153
    CrossrefPubMedGoogle Scholar
  • 10 Tenney D J, Levine S M, Rose R E et al.. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to Lamivudine.  Antimicrob Agents Chemother. 2004;  48 3498-3507
    CrossrefPubMedGoogle Scholar
  • 11 Wang G H, Seeger C. The reverse transcriptase of hepatitis B virus acts a protein primer for viral DNA synthesis.  Cell. 1992;  71 663-670
    CrossrefPubMedGoogle Scholar
  • 12 Zoulim F, Dannaoui E, Borel C et al.. 2′,3′-dideoxy-b-L-5-fluorocytidine inhibits duck hepatitis B virus reverse transcription and suppresses viral DNA synthesis in hepatocytes, both in vitro and in vivo.  Antimicrob Agents Chemother. 1996;  40 448-453
    PubMedGoogle Scholar
  • 13 Staschke K, Colacino J. Priming of duck hepatitis B virus reverse transcription in vitro: premature termination of primer DNA induced by the 5′-triphosphate of fialuridine.  J Virol. 1994;  68 8265-8269
    PubMedGoogle Scholar
  • 14 Le Guerhier F, Pichoud C, Guerret S et al.. Characterization of the antiviral effect of 2′,3′-dideoxy-2′, 3′- didehydro-beta-L-5-fluorocytidine in the duck hepatitis B virus infection model.  Antimicrob Agents Chemother. 2000;  44 111-122
    PubMedGoogle Scholar
  • 15 Seigneres B, Pichoud C, Martin P, Furman P, Trepo C, Zoulim F. Inhibitory activity of dioxolane purine analogs on wild-type and lamivudine-resistant mutants of hepadnaviruses.  Hepatology. 2002;  36 710-722
    CrossrefPubMedGoogle Scholar
  • 16 Seigneres B, Aguesse-Germon S, Pichoud C et al.. Duck hepatitis B virus polymerase gene mutants associated with resistance to lamivudine have a decreased replication capacity in vitro and in vivo.  J Hepatol. 2001;  34 114-122
    PubMedGoogle Scholar
  • 17 Brunelle M N, Jacquard A C, Pichoud C et al.. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.  Hepatology. 2005;  41 1391-1398
    CrossrefPubMedGoogle Scholar
  • 18 Jacquard A C, Brunelle M N, Pichoud C et al.. In vitro characterization of the anti-hepatitis B virus activity and cross-resistance profile of 2′,3′-dideoxy-3′-fluoroguanosine.  Antimicrob Agents Chemother. 2006;  50 955-961
    CrossrefPubMedGoogle Scholar
  • 19 Melegari M, Scaglioni P P, Wands J R. Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.  Hepatology. 1998;  27 628-633
    CrossrefPubMedGoogle Scholar
  • 20 Allen M I, Deslauriers M, Andrews C W et al.. Identification and characterization of mutations in hepatitis B virus resistant to Lamivudine.  Hepatology. 1998;  27 1670-1677
    CrossrefPubMedGoogle Scholar
  • 21 Gunther S, Li B C, Miska S, Kruger D H, Meisel H, Will H. A novel method for efficient amplification of whole hepatitis B virus genomes permits rapid functional analysis and reveals deletion mutants in immunosuppressed patients.  J Virol. 1995;  69 5437-5444
    PubMedGoogle Scholar
  • 22 Villeneuve J P, Durantel D, Durantel S et al.. Selection of a hepatitis B virus strain resistant to adefovir in a liver transplantation patient.  J Hepatol. 2003;  39 1085-1089
    CrossrefPubMedGoogle Scholar
  • 23 Durantel D, Carrouee-Durantel S, Werle-Lapostolle B et al.. A new strategy for studying in vitro the drug susceptibility of clinical isolates of human hepatitis B virus.  Hepatology. 2004;  40 855-864
    CrossrefPubMedGoogle Scholar
  • 24 Lada O, Benhamou Y, Cahour A, Katlama C, Poynard T, Thibault V. In vitro susceptibility of lamivudine-resistant hepatitis B virus to adefovir and tenofovir.  Antivir Ther. 2004;  9 353-363
    PubMedGoogle Scholar
  • 25 Benhamou Y, Tubiana R, Thibault V. Tenofovir disoproxil fumarate in patients with HIV and lamivudine-resistant hepatitis B virus.  N Engl J Med. 2003;  348 177-178
    CrossrefPubMedGoogle Scholar
  • 26 Dore G J, Cooper D A, Pozniak A L et al.. Efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and-experienced patients coinfected with HIV-1 and hepatitis B virus.  J Infect Dis. 2004;  189 1185-1192
    CrossrefPubMedGoogle Scholar
  • 27 van Bommel F, Wunsche T, Mauss S et al.. Comparison of adefovir and tenofovir in the treatment of lamivudine-resistant hepatitis B virus infection.  Hepatology. 2004;  40 1421-1425
    CrossrefPubMedGoogle Scholar
  • 28 Lacombe K, Gozlan J, Boelle P Y et al.. Long-term hepatitis B virus dynamics in HIV-hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate.  AIDS. 2005;  19 907-915
    PubMedGoogle Scholar
  • 29 Angus P, Vaughan R, Xiong S et al.. Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase.  Gastroenterology. 2003;  125 292-297
    CrossrefPubMedGoogle Scholar
  • 30 Sheldon J, Camino N, Rodes B et al.. Selection of hepatitis B virus polymerase mutations in HIV-coinfected patients treated with tenofovir.  Antivir Ther. 2005;  10 727-734
    PubMedGoogle Scholar
  • 31 Yang H, Westland C, Xiong S, Delaney W E. In vitro antiviral susceptibility of full-length clinical hepatitis B virus isolates cloned with a novel expression vector.  Antiviral Res. 2004;  61 27-36
    CrossrefPubMedGoogle Scholar
  • 32 Ladner S, 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 2128-2131
    PubMedGoogle Scholar
  • 33 Fu L, Cheng Y C. Characterization of novel human hepatoma cell lines with stable hepatitis B virus secretion for evaluating new compounds against lamivudine- and penciclovir-resistant virus.  Antimicrob Agents Chemother. 2000;  44 3402-3407
    CrossrefPubMedGoogle Scholar
  • 34 Delaney W E, Miller T G, Isom H C. Use of the hepatitis B virus recombinant baculovirus-HepG2 system to study the effects of (-)-beta-2′,3′-dideoxy-3′-thiacytidine on replication of hepatitis B virus and accumulation of covalently closed circular DNA.  Antimicrob Agents Chemother. 1999;  43 2017-2026
    PubMedGoogle Scholar
  • 35 Delaney W E, Edwards R, Colledge D et al.. Cross-resistance testing of antihepadnaviral compounds using novel recombinant baculoviruses which encode drug-resistant strains of hepatitis B virus.  Antimicrob Agents Chemother. 2001;  45 1705-1713
    CrossrefPubMedGoogle Scholar
  • 36 Harrison T J. Hepatitis B virus: molecular virology and common mutants.  Semin Liver Dis. 2006;  26 87-96
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 37 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 20-22
    CrossrefPubMedGoogle Scholar
  • 38 Gripon P, Rumin S, Urban S et al.. Infection of a human hepatoma cell line by hepatitis B virus.  Proc Natl Acad Sci USA. 2002;  99 15655-15660
    CrossrefPubMedGoogle Scholar
  • 39 Urban S, Gripon P. Inhibition of duck hepatitis B virus infection by a myristoylated pre-S peptide of the large viral surface protein.  J Virol. 2002;  76 1986-1990
    CrossrefPubMedGoogle Scholar
  • 40 Glebe D, Urban S, Knoop E V et al.. Mapping of the hepatitis B virus attachment site by use of infection-inhibiting preS1 lipopeptides and Tupaia hepatocytes.  Gastroenterology. 2005;  129 234-245
    CrossrefPubMedGoogle Scholar
  • 41 Delaney W E, Edwards R, Colledge D et al.. Phenylpropylamine derivatives AT-61 and AT-130 inhibit replication of wild-type and lamivudine-resistant strains of hepatitis B virus in vitro.  Antimicrob Agents Chemother. 2002;  46 3057-3060
    CrossrefPubMedGoogle Scholar
  • 42 Ying C, De Clercq E, Nicholson W, Furman P, Neyts J. Inhibition of the replication of the DNA polymerase M550V mutation variant of human hepatitis B virus by adefovir, tenofovir, L-FMAU, DAPD, penciclovir and lobucavir.  J Viral Hepat. 2000;  7 161-165
    CrossrefPubMedGoogle Scholar
  • 43 Ying C, Holy A, Hockova D, Havlas Z, De Clercq E, Neyts J. Novel acyclic nucleoside phosphonate analogues with potent anti-hepatitis B virus activities.  Antimicrob Agents Chemother. 2005;  49 1177-1180
    CrossrefPubMedGoogle Scholar
  • 44 Yang H, Qi X, Sabogal A, Miller M, Xiong S, Delaney W E. Cross-resistance testing of next-generation nucleoside and nucleotide analogues against lamivudine-resistant HBV.  Antivir Ther. 2005;  10 625-633
    PubMedGoogle Scholar
  • 45 Stuyver L, Van Geyt C, De Gendt S et al.. Line probe assay for monitoring drug resistance in hepatitis B virus-infected patients during antiviral therapy.  J Clin Microbiol. 2000;  38 702-707
    PubMedGoogle Scholar
  • 46 Nafa S, Ahmed S, Tavan D et al.. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B.  Hepatology. 2000;  32 1078-1088
    CrossrefPubMedGoogle Scholar
  • 47 Aberle S W, Kletzmayr J, Watschinger B, Schmied B, Vetter N, Puchhammer-Stockl E. Comparison of sequence analysis and the INNO-LiPA HBV DR line probe assay for detection of lamivudine-resistant hepatitis B virus strains in patients under various clinical conditions.  J Clin Microbiol. 2001;  39 1972-1974
    CrossrefPubMedGoogle Scholar
  • 48 Clavel F, Hance A J. HIV drug resistance.  N Engl J Med. 2004;  350 1023-1035
    CrossrefPubMedGoogle Scholar
  • 49 Hanna G J, D'Aquila R T. Clinical use of genotypic and phenotypic drug resistance testing to monitor antiretroviral chemotherapy.  Clin Infect Dis. 2001;  32 774-782
    CrossrefPubMedGoogle Scholar
  • 50 Garcia-Lerma J G, Heneine W. Resistance of human immunodeficiency virus type 1 to reverse transcriptase and protease inhibitors: genotypic and phenotypic testing.  J Clin Virol. 2001;  21 197-212
    CrossrefPubMedGoogle Scholar

Fabien ZoulimM.D. Ph.D. 

INSERM Unit 271, Institut Universitaire de France

151 Cours Albert Thomas, 69003 Lyon, France

      >