Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy.
Lamivudine has been shown to be effective in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B, but its long-term efficacy and the rate of resistant mutations in patients with HBeAg-negative chronic hepatitis B is less clear. Twenty-nine patients with HBeAg-negative chronic hepatitis B, who have received lamivudine for at least 1 year were studied to determine the antiviral response, the rate and pattern of lamivudine-resistant mutations, and the effect of lamivudine-resistant mutations on HBeAg status. The mean duration of treatment was 21 +/- 7 months. Before treatment, core promoter variant was detected in 16 (55%) patients and precore stop codon variant in 18 (62%) patients. Serum hepatitis B virus (HBV) DNA was detected by solution hybridization assay in 62%, 4%, and 24% and by polymerase chain reaction (PCR) assay in 100%, 31%, and 40% at months 0, 6, and 24, respectively. The cumulative rates of detection of lamivudine-resistant mutations after 1 and 2 years of treatment were 10% and 56%, respectively. In addition to the duration of treatment, core promoter mutation was associated with the selection of lamivudine-resistant mutants. Three patients with lamivudine-resistant mutations had reversion of the precore stop codon mutation; in 2 patients this was accompanied by the reappearance of HBeAg. We found that lamivudine-resistant mutants were detected at similar rates in patients with HBeAg-negative as in patients with HBeAg-positive chronic hepatitis B. Additional changes in other parts of the HBV genome may restore the replication fitness of lamivudine-resistant mutants.
Lok
A S
AS
Division of Gastroenterology, University of Michigan and VA Medical Center, Ann Arbor, MI, USA. aslok@umich.edu
Hussain
M
M
Cursano
C
C
Margotti
M
M
Gramenzi
A
A
Grazi
G L
GL
Jovine
E
E
Benardi
M
M
Andreone
P
P
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D015684:Gene Products, pol / Q000235:genetics*; D005838:Genotype; D006513:Hepatitis B e Antigens / Q000032:analysis*; D006515:Hepatitis B virus / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*; D014758:Viral Core Proteins / Q000235:genetics
D015684:Gene Products, pol; D006513:Hepatitis B e Antigens; C066027:P protein, Hepatitis B virus; D018894:Reverse Transcriptase Inhibitors; D014758:Viral Core Proteins; D019259:Lamivudine