Virus and transaminase levels determine the emergence of drug resistance during long-term lamivudine therapy in chronic hepatitis B.
OBJECTIVE
The results of earlier studies on determinants for the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutants (rtM204 I/V) were controversial. The aim was to evaluate the impact of viral factors, host factors, host-viral interaction and drug factor on the emergence of rtM204 I/V.


METHODS
56 non-cirrhotic and 58 cirrhotic patients received lamivudine therapy for a median of 34 (12-60) months.


RESULTS
rtM204 I/V emerged in 37 noncirrhotic and 36 cirrhotic patients. Stepwise logistic regression analysis showed that baseline hepatitis B e antigen (HBeAg) status [odds ratio (OR), 7.728; 95% confidental interval (CI), 2.886-12.957; P=0.0026], HBV-DNA level (OR, 3.756; 95% CI, 1.058-5.089; P=0.0202), alanine transaminase (ALT) level (OR, 6.285; 95% CI, 1.057-11.990; P=0.00246) and treatment duration (OR, 19.88; 95% CI, 8.652-31.762; P<0.0004) were independent determinants for the emergence of rtM204 I/V. Further categorical analysis and correlation test disclosed that patients with HBeAg positivity, HBV-DNA>500 pg/ml and ALT <5x upper limit of normal had significantly higher mutation rates.


CONCLUSIONS
HBeAg status, HBV-DNA, ALT levels and treatment duration are the major determinants for the YMDD mutation during lamivudine therapy, and should be considered in designing the therapeutic strategy.
Chang
Ming-Ling
ML
Liver Research Unit, Chang Gung Memorial Hospital and University, 199, Tung Hwa North Road, Taipei, Taiwan.
Chien
Rong-Nan
RN
Yeh
Chau-Ting
CT
Liaw
Yun-Fan
YF
D000328:Adult; D000410:Alanine Transaminase / Q000097:blood*; D020816:Amino Acid Motifs / Q000235:genetics; D004259:DNA-Directed DNA Polymerase / Q000235:genetics; D004334:Drug Administration Schedule; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D006513:Hepatitis B e Antigens / Q000097:blood; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics / Q000276:immunology / Q000502:physiology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D019562:Viral Load
D006513:Hepatitis B e Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D000410:Alanine Transaminase; D004259:DNA-Directed DNA Polymerase