Characterization of naturally occurring and Lamivudine-induced surface gene mutants of hepatitis B virus in patients with chronic hepatitis B in India.
BACKGROUND
Besides vaccine escape or immune escape hepatitis B virus (HBV) mutants, naturally occurring and drug-induced mutations have been reported in the surface gene (S-gene) of HBV.


OBJECTIVE
To investigate the frequency and profile of naturally occurring S-gene mutants and the influence of long-term lamivudine therapy in patients with chronic hepatitis B (CHB).


METHODS
57 patients with histologically proven CHB, on lamivudine 100 mg/day for more than 24 months, were included. Viral DNA was extracted at baseline and from on-therapy serum samples. The region encoding the complete major hydrophilic region (MHR) and flanking regions (nucleotides 425-840) of major S-gene that overlapped with the viral polymerase was PCR amplified and sequenced. End-of-therapy response (ETR) was assessed.


RESULTS
Two (3.5%) patients had naturally occurring HBV mutants, sP127S and sS143L seen in the 'a' determinant of the S-gene. Following lamivudine therapy, 14 of 57 (24.5%) patients developed 16 types of S-gene mutations (sP120S, sA128V, sS143L, sW182St., sT189I, sV190A, sS193L, sI195M, sW196L, sW196St., sS207R, sI208T, sS210E, sF219S, sF220L and sC221G). Thirteen (81.2%) of these mutations emerged downstream to the MHR. Nine of 16 types of S-gene mutations observed with lamivudine therapy were also associated with the corresponding changes in the polymerase gene. Baseline viral DNA was significantly higher (2,093 vs. 336 pg/ml; p < 0.05) among patients developing S-gene mutants and the ETR in them was significantly lower [3 of 16 (18.8%) vs. 17 of 41 (41.5%); p < 0.05].


CONCLUSIONS
Naturally occurring S-gene mutations are uncommon and are restricted to the 'a' determinant region. Mutations develop in about a quarter of the patients on lamivudine therapy, mostly downstream to the MHR. They may contribute to non-response to the antiviral therapy.
Kazim
Syed Naqui
SN
Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India.
Sarin
Shiv Kumar
SK
Sharma
Barjesh Chander
BC
Khan
Luqman Ahmad
LA
Hasnain
Seyed Ehtesham
SE
D000328:Adult; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000627:therapeutic use*; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D005814:Genes, Viral / Q000187:drug effects; D006514:Hepatitis B Surface Antigens / Q000235:genetics*; D006515:Hepatitis B virus / Q000187:drug effects / Q000235:genetics; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D007194:India; D019259:Lamivudine / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein; D016896:Treatment Outcome; D019562:Viral Load
D000998:Antiviral Agents; D006514:Hepatitis B Surface Antigens; D019259:Lamivudine