Predominance of hepatitis B virus YMDD mutants is prognostic of viral DNA breakthrough.
OBJECTIVE
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.
Lee
Chang Hong
CH
Department of Internal Medicine, Konkuk University Medical College, Seoul, Korea.
Kim
Soo-Ok
SO
Byun
Kwan Soo
KS
Moon
Myung Soon
MS
Kim
Eun-Ok
EO
Yeon
Jong Eun
JE
Yoo
Wangdon
W
Hong
Sun Pyo
SP
D004279:DNA, Viral / Q000097:blood*; D005838:Genotype; D006515:Hepatitis B virus / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D009154:Mutation; D011379:Prognosis; D012189:Retrospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D019562:Viral Load
D004279:DNA, Viral; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine