Predominance of Hepatitis B Virus YMDD Mutants Is Prognostic of Viral DNA Breakthrough

Chang Hong Lee, Soo Ok Kim, Kwan Soo Byun, Myung Soon Moon, Eun Ok Kim, Jong Eun Yeon, Wangdon Yoo, Sun Pyo Hong

Research output: Contribution to journalArticle

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Abstract

Background & Aims: Hepatitis B virus (HBV) tyrosine, methionine, aspartate, aspartate (YMDD) mutants with or without additional compensatory mutations occur in chronically infected patients during lamivudine therapy and may be associated with accompanying viral breakthrough. The aim of this study was to determine whether a predominance of YMDD mutants could be a prognostic marker for occurrence of viral DNA breakthrough. Methods: YMDD genotypes in 740 consecutive samples collected from 116 patients throughout lamivudine treatment were retrospectively analyzed using a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS)-based genotyping assay, termed restriction fragment mass polymorphism (RFMP). RFMP exploits differences in molecular masses between wild-type and variant bases of rtM204V/I following PCR amplification of HBV DNA with a lower limit of detection being 100 copies/mL. Results: The study demonstrated that YMDD mutants occur throughout the course of lamivudine therapy irrespective of occurrence of viral DNA breakthrough, indicating that a mere detection of YMDD mutants could not sufficiently predict the viral DNA breakthrough, although presence of YMDD mutants is associated with high incidence of viral DNA breakthrough (odds ratio, 7.8; P = .0012; relative risk = 8.7%), and a 5-fold predominance of YMDD mutant to wild-type virus was significantly associated with viral DNA breakthrough (odds ratio, 604.5; P < .0001; relative risk = 93.8%). Conclusions: Close and periodical testing by RFMP assay should be useful to detect the predominance of YMDD mutants for monitoring drug resistance, enabling early intervention and prevention.

Original languageEnglish
Pages (from-to)1144-1152
Number of pages9
JournalGastroenterology
Volume130
Issue number4
DOIs
Publication statusPublished - 2006 Apr 1

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Viral DNA
Hepatitis B virus
Lamivudine
Aspartic Acid
Odds Ratio
Drug Resistance
Methionine
Tyrosine
Limit of Detection
Mass Spectrometry
Lasers
Therapeutics
Genotype
Viruses
Polymerase Chain Reaction
Mutation
DNA
Incidence

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Predominance of Hepatitis B Virus YMDD Mutants Is Prognostic of Viral DNA Breakthrough. / Lee, Chang Hong; Kim, Soo Ok; Byun, Kwan Soo; Moon, Myung Soon; Kim, Eun Ok; Yeon, Jong Eun; Yoo, Wangdon; Hong, Sun Pyo.

In: Gastroenterology, Vol. 130, No. 4, 01.04.2006, p. 1144-1152.

Research output: Contribution to journalArticle

Lee, Chang Hong ; Kim, Soo Ok ; Byun, Kwan Soo ; Moon, Myung Soon ; Kim, Eun Ok ; Yeon, Jong Eun ; Yoo, Wangdon ; Hong, Sun Pyo. / Predominance of Hepatitis B Virus YMDD Mutants Is Prognostic of Viral DNA Breakthrough. In: Gastroenterology. 2006 ; Vol. 130, No. 4. pp. 1144-1152.
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N2 - Background & Aims: Hepatitis B virus (HBV) tyrosine, methionine, aspartate, aspartate (YMDD) mutants with or without additional compensatory mutations occur in chronically infected patients during lamivudine therapy and may be associated with accompanying viral breakthrough. The aim of this study was to determine whether a predominance of YMDD mutants could be a prognostic marker for occurrence of viral DNA breakthrough. Methods: YMDD genotypes in 740 consecutive samples collected from 116 patients throughout lamivudine treatment were retrospectively analyzed using a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS)-based genotyping assay, termed restriction fragment mass polymorphism (RFMP). RFMP exploits differences in molecular masses between wild-type and variant bases of rtM204V/I following PCR amplification of HBV DNA with a lower limit of detection being 100 copies/mL. Results: The study demonstrated that YMDD mutants occur throughout the course of lamivudine therapy irrespective of occurrence of viral DNA breakthrough, indicating that a mere detection of YMDD mutants could not sufficiently predict the viral DNA breakthrough, although presence of YMDD mutants is associated with high incidence of viral DNA breakthrough (odds ratio, 7.8; P = .0012; relative risk = 8.7%), and a 5-fold predominance of YMDD mutant to wild-type virus was significantly associated with viral DNA breakthrough (odds ratio, 604.5; P < .0001; relative risk = 93.8%). Conclusions: Close and periodical testing by RFMP assay should be useful to detect the predominance of YMDD mutants for monitoring drug resistance, enabling early intervention and prevention.

AB - Background & Aims: Hepatitis B virus (HBV) tyrosine, methionine, aspartate, aspartate (YMDD) mutants with or without additional compensatory mutations occur in chronically infected patients during lamivudine therapy and may be associated with accompanying viral breakthrough. The aim of this study was to determine whether a predominance of YMDD mutants could be a prognostic marker for occurrence of viral DNA breakthrough. Methods: YMDD genotypes in 740 consecutive samples collected from 116 patients throughout lamivudine treatment were retrospectively analyzed using a matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS)-based genotyping assay, termed restriction fragment mass polymorphism (RFMP). RFMP exploits differences in molecular masses between wild-type and variant bases of rtM204V/I following PCR amplification of HBV DNA with a lower limit of detection being 100 copies/mL. Results: The study demonstrated that YMDD mutants occur throughout the course of lamivudine therapy irrespective of occurrence of viral DNA breakthrough, indicating that a mere detection of YMDD mutants could not sufficiently predict the viral DNA breakthrough, although presence of YMDD mutants is associated with high incidence of viral DNA breakthrough (odds ratio, 7.8; P = .0012; relative risk = 8.7%), and a 5-fold predominance of YMDD mutant to wild-type virus was significantly associated with viral DNA breakthrough (odds ratio, 604.5; P < .0001; relative risk = 93.8%). Conclusions: Close and periodical testing by RFMP assay should be useful to detect the predominance of YMDD mutants for monitoring drug resistance, enabling early intervention and prevention.

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