Lamivudine resistance in patients with chronic hepatitis B: role of clinical and virological factors.
BACKGROUND
Lamivudine resistance is associated with long-term monotherapy for chronic hepatitis B and can lead to potentially serious clinical consequences. Scant information exists regarding the influence of hepatitis B virus variants in the development of resistance. The present study was designed to identify factors predictive of lamivudine resistance, with a particular focus on the role of precore and basal core promoter variants in the setting of hepatitis B e antigen-negative disease.


METHODS
Eighty-five patients, representing four major genotypes, were followed prospectively on lamivudine therapy. Resistance was defined as an increase in viral load, with polymerase gene sequencing confirming a lamivudine resistance mutation. Median follow up was 19 months (6-54 months). The Cox proportional hazards model was used to determine variables independently predicting for the early onset of lamivudine resistance.


RESULTS
The rate of lamivudine resistance was 6%, 31% and 51% at 12, 24 and 48 months, respectively. Multivariate analysis identified the precore variant, high baseline alanine aminotransferase (ALT), and persistent viremia (at 6 months) as independent predictors of the early development of lamivudine resistance, with rate ratios of 4.93 (95% confidence interval [CI]: 1.32-18.5), 1.22 (95%CI: 1.08-1.49), and 4.73 (95%CI: 1.49-15.0), respectively (P < 0.05). Female sex predicted early resistance (rate ratio 5.27 [95%CI: 1.23-22.5, P < 0.05]) although numbers were small (n = 12). Genotype did not influence treatment response nor time to onset of resistance.


CONCLUSIONS
Patients with precore variant hepatitis B virus are likely to develop lamivudine resistance early and should be considered for alternate first-line monotherapy. In the future, combination antiviral therapy may limit the development of resistance.
Thompson
Alexander J V
AJ
St Vincent's Hospital, Melbourne, Victoria, Australia.
Ayres
Anna
A
Yuen
Lilly
L
Bartholomeusz
Angeline
A
Bowden
D Scott
DS
Iser
David M
DM
Chen
Robert Y M
RY
Demediuk
Barbara
B
Shaw
Gideon
G
Bell
Sally J
SJ
Watson
Katrina J R
KJ
Locarnini
Stephen A
SA
Desmond
Paul V
PV
D000328:Adult; D024882:Drug Resistance, Viral; D005260:Female; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine