Variability of reverse transcriptase and overlapping S gene in hepatitis B virus isolates from untreated and lamivudine-resistant chronic hepatitis B patients.
BACKGROUND
The high degree of diversity of the hepatitis B virus (HBV) quasispecies in chronically infected individuals raises the possibility that HBV genetic variants favouring resistance to nucleoside/nucleotide analogues (NAs) might pre-exist to treatment. The aim of this study was to investigate the genetic variability of the entire HBV reverse transcriptase (RT) domain and of the overlapping S gene in a large series of untreated hepatitis B surface antigen carriers and in lamivudine (3TC)-resistant patients.


METHODS
Sequencing analysis of the entire HBV RT domain of isolates from 100 untreated (treatment-naive group) and 59 3TC-resistant (3TC-resistant group) consecutive patients with chronic hepatitis B was performed.


RESULTS
In the treatment-naive group, primary mutations known to cause resistance to NAs were not detected, but variably combined secondary/compensatory mutations were found in 46 (46%) patients. Moreover, four patients carried mutations that modified the S protein antigenicity. In the 3TC-resistant group, besides the primary 3TC-resistant mutations, various combinations of primary and secondary mutations conferring resistance to other NAs were detected in 41/59 (69.5%) patients. Importantly, the RT mutations induced by 3TC provoked stop codons in the overlapping S gene in two patients and modified the S protein antigenicity in another nine.


CONCLUSIONS
This study shows that HBV mutants associated with resistance to NAs might already be present as the major infecting population in untreated patients, and that variants emerging under 3TC might also carry mutations favouring resistance to other NAs and/or potentially altering the S protein immunoreactivity.
Pollicino
Teresa
T
Unit of Clinical and Molecular Hepatology, Department of Internal Medicine, University of Messina, Messina, Italy. tpollicino@unime.it
Isgrò
Graziella
G
Di Stefano
Rosa
R
Ferraro
Donatella
D
Maimone
Sergio
S
Brancatelli
Santa
S
Squadrito
Giovanni
G
Di Marco
Vito
V
Craxì
Antonio
A
Raimondo
Giovanni
G
D000328:Adult; D000368:Aged; D024882:Drug Resistance, Viral; D005260:Female; D014644:Genetic Variation; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000302:isolation & purification; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012194:RNA-Directed DNA Polymerase / Q000235:genetics*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome
D006514:Hepatitis B Surface Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase