Precore stop codon mutation of hepatitis B virus is associated with low breakthrough rate following long-term lamivudine therapy.
BACKGROUND
Frequent viral breakthroughs limit the usefulness of lamivudine in the treatment of chronic hepatitis B (CHB). The purpose of the present study was to evaluate the effects of precore stop codon mutation (G to A mutation at nucleotide 1896; A(1896)) of hepatitis B virus (HBV) on the occurrence of viral breakthrough following lamivudine therapy.


METHODS
Among 260 consecutive CHB patients treated with lamivudine for >12 months, 231 patients whose pretreatment sera were available were tested for A(1896) variant of HBV using direct sequencing.


RESULTS
Between patients with A(1896) variant (n = 74) and those without it (n = 157), there was no difference in age, gender, serum alanine aminotransferase (ALT) level, the duration of therapy and prevalence of core promoter mutants. Serum hepatitis B e antigen (HBeAg) positivity and HBV-DNA level were lower (P = 0.00 and P = 0.01) and liver cirrhosis was more commonly associated in patients with A(1896) variant mutant compared with those without it. In univariate analysis, viral breakthrough was more frequent in HBeAg-positive patients (P = 0.03) and in those with high serum HBV-DNA level (P = 0.01) as well as in those without A(1896) variant (P = 0.01). However, in multivariate analysis, the absence of A(1896) variant (P = 0.02) and high serum HBV-DNA level (P = 0.03) were independent factors for viral breakthrough following lamivudine therapy. The cumulative viral breakthrough rates at 1 and 2 years were much lower in patients with A(1896) variant compared with those without it (P = 0.01).


CONCLUSIONS
The stop codon mutation at the precore region of HBV in addition to low serum HBV-DNA level may be associated with low breakthrough rate following lamivudine therapy.
Shin
Jung Woo
JW
Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 388-1 Poongnap-dong Songpa-ku, 138-040 Seoul, Korea.
Chung
Young-Hwa
YH
Choi
Min Hee
MH
Kim
Jeong A
JA
Ryu
Soo Hyung
SH
Jang
Myoung Kuk
MK
Kim
In Sook
IS
Park
Neung Hwa
NH
Lee
Han Chu
HC
Lee
Yung Sang
YS
Suh
Dong Jin
DJ
D000328:Adult; D018388:Codon, Terminator / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006513:Hepatitis B e Antigens / Q000276:immunology; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load
D018388:Codon, Terminator; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine