Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation

Maria M. Bartholomew, Robert W. Jansen, Lennox J Jeffers, K. Rajender Reddy, Lance C. Johnson, Hartwig Bunzendahl, Lynn D. Condreay, Andreas G. Tzakis, Eugene R Schiff, Nathaniel A. Brown

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Abstract

Background. Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV. Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B. Methods. Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain - the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine. Findings. DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all patients during lamivudine treatment. In hepatocyte cultures infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrations as low as 0.03 μmol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20% of control values, even with lamivudine at 30 μmol/L. Interpretation. Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.

Original languageEnglish
Pages (from-to)20-22
Number of pages3
JournalLancet
Volume349
Issue number9044
DOIs
StatePublished - Jan 4 1997

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Lamivudine
Hepatitis B virus
Liver Transplantation
Infection
Recurrence
Virus Diseases
Transplantation
Serum
Aspartic Acid
Hepatocytes
DNA
HIV
Therapeutics
Mutation
End Stage Liver Disease
Cytosine
Hepatitis B
DNA Sequence Analysis
Nucleosides
Point Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bartholomew, M. M., Jansen, R. W., Jeffers, L. J., Reddy, K. R., Johnson, L. C., Bunzendahl, H., ... Brown, N. A. (1997). Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet, 349(9044), 20-22. https://doi.org/10.1016/S0140-6736(96)02266-0

Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. / Bartholomew, Maria M.; Jansen, Robert W.; Jeffers, Lennox J; Reddy, K. Rajender; Johnson, Lance C.; Bunzendahl, Hartwig; Condreay, Lynn D.; Tzakis, Andreas G.; Schiff, Eugene R; Brown, Nathaniel A.

In: Lancet, Vol. 349, No. 9044, 04.01.1997, p. 20-22.

Research output: Contribution to journalArticle

Bartholomew, MM, Jansen, RW, Jeffers, LJ, Reddy, KR, Johnson, LC, Bunzendahl, H, Condreay, LD, Tzakis, AG, Schiff, ER & Brown, NA 1997, 'Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation', Lancet, vol. 349, no. 9044, pp. 20-22. https://doi.org/10.1016/S0140-6736(96)02266-0
Bartholomew MM, Jansen RW, Jeffers LJ, Reddy KR, Johnson LC, Bunzendahl H et al. Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. Lancet. 1997 Jan 4;349(9044):20-22. https://doi.org/10.1016/S0140-6736(96)02266-0
Bartholomew, Maria M. ; Jansen, Robert W. ; Jeffers, Lennox J ; Reddy, K. Rajender ; Johnson, Lance C. ; Bunzendahl, Hartwig ; Condreay, Lynn D. ; Tzakis, Andreas G. ; Schiff, Eugene R ; Brown, Nathaniel A. / Hepatitis-B-virus resistance to lamivudine given for recurrent infection after orthotopic liver transplantation. In: Lancet. 1997 ; Vol. 349, No. 9044. pp. 20-22.
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abstract = "Background. Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV. Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B. Methods. Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain - the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine. Findings. DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all patients during lamivudine treatment. In hepatocyte cultures infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6{\%} of those in control cultures by addition of lamivudine in concentrations as low as 0.03 μmol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20{\%} of control values, even with lamivudine at 30 μmol/L. Interpretation. Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.",
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AU - Bartholomew, Maria M.

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AU - Jeffers, Lennox J

AU - Reddy, K. Rajender

AU - Johnson, Lance C.

AU - Bunzendahl, Hartwig

AU - Condreay, Lynn D.

AU - Tzakis, Andreas G.

AU - Schiff, Eugene R

AU - Brown, Nathaniel A.

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N2 - Background. Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV. Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B. Methods. Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain - the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine. Findings. DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all patients during lamivudine treatment. In hepatocyte cultures infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrations as low as 0.03 μmol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20% of control values, even with lamivudine at 30 μmol/L. Interpretation. Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.

AB - Background. Orthotopic liver transplantation for end-stage hepatitis-B-virus (HBV) infection is commonly complicated by recurrence of HBV. Lamivudine, a cytosine nucleoside analogue, has been shown to suppress HBV infection. We report the development of resistance to lamivudine in three patients who underwent transplantation for end-stage liver disease secondary to hepatitis B. Methods. Two of the patients received lamivudine for recurrent HBV infection after transplantation, whereas the third patient began treatment 1 month before transplantation in an attempt to prevent HBV recurrence after transplantation. The three patients initially responded well to treatment, but viral recurrence occurred after 9-10 months of treatment in all patients. HBV DNA was amplified from serum and sequenced through a conserved polymerase domain - the tyrosine, methionine, aspartate, aspartate (YMDD) locus. We assessed the susceptibility of HBV to lamivudine by infecting primary human hepatocytes with serum taken before the start of treatment and after recurrence in varying concentrations of lamivudine. Findings. DNA sequencing showed a common mutation within the YMDD locus of the HBV polymerase gene in all patients during lamivudine treatment. In hepatocyte cultures infected with pretreatment serum, HBV DNA concentrations were reduced to less than 6% of those in control cultures by addition of lamivudine in concentrations as low as 0.03 μmol/L. By contrast, in cultures treated with serum taken after recurrence, HBV DNA concentrations did not fall below 20% of control values, even with lamivudine at 30 μmol/L. Interpretation. Resistance to lamivudine has been reported in HIV patients with mutations in the YMDD locus of the polymerase gene. Our findings indicate a common mechanism of lamivudine resistance for HIV and HBV that involves similar point mutations in homologous domains of the viral polymerases.

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