Genetic heterogeneity of the precore and the core promoter region of genotype C hepatitis B virus during lamivudine therapy

Abstract

It has been reported that spontaneous or interferon (IFN)-induced hepatitis B e (HBe) seroconversion has usually been associated with the development of a stop codon in the precore region. However, the difference between lamivudine-induced seroconversion and spontaneous or IFN-induced seroconversion is not known. The aim of this study was to investigate the correlation between the evolution of the precore and core promoter mutations and lamivudine-induced seroconversion. Forty-five patients with chronic hepatitis B virus (HBV) infection who were treated with lamivudine for more than 1 year were enrolled. The nucleotide sequence of the precore and core promoter region was determined before and after treatment with lamivudine for 1 year. Among 29 patients who were hepatitis B e antigen (HBeAg)-positive before treatment, 12 (41.3%) lost HBeAg during the course of treatment for 1 year. Of these, eight patients (66.7%) still had precore wild type HBV after 1 year. After 1 year, reversion to precore wild type HBV was detected in 11 (64.7%) of 17 patients who had precore mutant HBV before treatment. Twelve (70.6%) of 17 patients who were persistently HBeAg-positive had precore wild type HBV before and after treatment for 1 year. Despite the loss of HBeAg, two thirds of the patients still had precore wild type HBV after the 1-year treatment. It is suggested that lamivudine-induced seroconversion differs from spontaneous or IFN-induced seroconversion in the change of nucleotides in the precore region. The reversion in the precore region may be caused by the difference of drug-susceptibility to lamivudine. The antiviral effect of lamivudine may be more effective in the precore mutant HBV than in the precore wild type HBV.

Evolution of precore/core promoter mutations in hepatitis B carriers with hepatitis B e antigen seroreversion

“…Particularly, at the end of follow-up, only one patient (Case II-3) had both precore and BCP mutations. Consistently, three recent studies demonstrated that in patients receiving lamivudine for chronic hepatitis B, the presence of precore and/or BCP mutation was associated with the loss of HBeAg and the lack of such mutations was frequently associated with the reversion of HBeAg [Asahina et al, 2003;Kuwahara et al, 2004;Lin et al, 2004]. Collectively, these facts support the hypothesis that the development of transient HBeAg seroconversion and seroreversion might be due to the lack of sustained precore nucleotide 1896 and BCP dinucleotide 1762/ 1764 mutations after HBeAg seroconversion.…”

Ultra-deep pyrosequencing analysis of the hepatitis B virus preCore region and main catalytic motif of the viral polymerase in the same viral genome

“…Likewise, in HBeAg-negative patients, wild-type codon 28 preCore genomes were detected in lower percentages (0.02–0.14%), explaining cases of natural or LMV-related seroreversion (38,39). An interesting observation in the longitudinally studied patient was the significant decrease in the main preCore mutation at VBK, which coincides with reports suggesting that HBV strains carrying preCore stop codon 28 and no Pol resistant variants are more sensitive to LMV treatment than preCore wild-type sequences (35,38,39). However, additional longitudinal UDPS analyses, as reported in the present study, must be performed to further substantiate this possibility.…”

Novel Type of Hepatitis B Virus Mutation: Replacement Mutation Involving a Hepatocyte Nuclear Factor 1 Binding Site Tandem Repeat in Chronic Hepatitis B Virus Genotype E

“…Insertions at the HNF1 site were observed in sequences from patients with immunosuppressive therapy (10,19,30); no therapy except IFN was included in this case. Although sequences for many patients undergoing IFN therapy have been reported (7,12,18,42), the HNF1 replacement has not been reported, as mentioned in the database research results. However, most of the database-deposited HBV genome sequences for patients with IFN therapy are genotypes HBV/A, -B, -C, and -D. There have been no reports of HBV/E-related chronic hepatitis patients who were treated with IFN therapy.…”