Prevalence and profile of mutations associated with lamivudine therapy in Indian patients with chronic hepatitis B in the surface and polymerase genes of hepatitis B virus.
Lamivudine results in the selection of resistant hepatitis B virus (HBV) variants. Because the surface gene of HBV overlaps completely the polymerase gene, the incidence and profile of surface and polymerase gene mutations were investigated prospectively in chronic HBV patients who were on lamivudine therapy. Twenty-six patients with chronic liver disease confirmed histologically were included in this study. Extracted HBV DNA from sera samples were subjected to PCR amplification for the mutation prone regions of the surface and polymerase genes of the HBV genome. The emergence of mutant forms and biochemical derangements were studied carefully during the course of the therapy. In six of 26 (23%) patients, mutations emerged on lamivudine therapy. YM552I/VDD resistant mutants were observed in one (6%) and five (29%) patients at Month 12 and 18, respectively, out of 17 patients, who had completed more than 9 months of therapy. The mean time of emergence of resistance was 16.4 +/- 6.8 months. In three of the five patients, emergence of YM552I/VDD mutation was accompanied with a rise in HBV DNA levels. In two patients, mutations were noticed at the end of the viral breakthrough; when the DNA level went down to undetectable levels (<0.5 pg/mL). In two patients, normal ALT levels were found at the time of emergence of the YMDD mutation. YM552I/VDD mutations were observed in 43% of HBeAg positive and 20% of anti-HBe positive patients (P = ns). Although the 'a'-determinant region was found to be unaffected; in one patient, a novel pattern due to emergence of YIDD mutant was observed; the corresponding aa in the S-ORF turned to a stop codon. In summary, the frequency of emergence of YM552I/VDD mutations was 29% at Month 18 in the Indian patients. The presence of normal ALT and low levels of HBV DNA do not exclude the existence of resistant mutants. Novel mutations in the S-ORF, which lead to premature surface gene termination might affect the production of HBsAg and need further study.
Wakil
Salma M
SM
Department of Gastroenterology, G.B. Pant Hospital, New Delhi, India. sksarin@nda.vsnl.net.nl
Kazim
Syed N
SN
Khan
Luqman A
LA
Raisuddin
Sheikh
S
Parvez
Mohammad K
MK
Guptan
Rajkumar C
RC
Thakur
Varsha
V
Hasnain
Seyed E
SE
Sarin
Shiv K
SK
D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004279:DNA, Viral / Q000032:analysis / Q000097:blood; D024882:Drug Resistance, Viral / Q000235:genetics; D006514:Hepatitis B Surface Antigens / Q000097:blood / Q000235:genetics; D006515:Hepatitis B virus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology; D006801:Humans; D007194:India / Q000453:epidemiology; D019259:Lamivudine / Q000494:pharmacology / Q000627:therapeutic use*; D009154:Mutation; D016133:Polymerase Chain Reaction; D015995:Prevalence; D011446:Prospective Studies; D012194:RNA-Directed DNA Polymerase / Q000235:genetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*
D019380:Anti-HIV Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D012194:RNA-Directed DNA Polymerase