Characterization of Naturally Occurring and Lamivudine-Induced Surface Gene Mutants of Hepatitis B Virus in Patients with Chronic Hepatitis B in India

• Published in: Intervirology Vol. 49; no. 3; pp. 152 - 160
• Main Authors: Kazim, Syed Naqui, Sarin, Shiv Kumar, Sharma, Barjesh Chander, Khan, Luqman Ahmad, Hasnain, Seyed Ehtesham
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland S. Karger AG 01.01.2006
• Subjects: Adult; Amino Acid Sequence; Antiviral Agents - therapeutic use; Drug Resistance, Viral - genetics; Female; Genes, Viral - drug effects; Hepatitis B; Hepatitis B Surface Antigens - genetics; Hepatitis B virus; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Hepatitis B, Chronic - drug therapy; Hepatitis B, Chronic - virology; Humans; India; Lamivudine - therapeutic use; Male; Middle Aged; Molecular Sequence Data; Mutation; Original Paper; Sequence Alignment; Sequence Analysis, Protein; Treatment Outcome; Viral Load; India; Mutations; Lamivudine; Antiviral therapy; Resistance, lamivudine; Hepatitis B virus
• ISSN: 0300-5526; 1423-0100
• DOI: 10.1159/000089376

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. Aim: 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). Materials and 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.