Characteristics of lamivudine‐resistant hepatitis B virus (HBV) strains with and without breakthrough hepatitis in patients with chronic hepatitis B evaluated by serial HBV full‐genome sequences

Abstract

Lamivudine therapy often causes breakthrough of hepatitis B virus (HBV) DNA and breakthrough hepatitis. The aim of this study was to determine the viral factors that relate to HBV-DNA breakthrough with and without breakthrough hepatitis. Among 82 patients with chronic hepatitis B (CHB) who received lamivudine at a dose of 100 mg daily for more than 24 months, 23 patients had HBV-DNA breakthrough induced by a lamivudine-resistant mutant. Of these 23 patients, 16 had breakthrough hepatitis and 7 had only HBV-DNA breakthrough. Serial HBV-DNA full-genome sequences during therapy were examined in 10 (7 had breakthrough hepatitis and 3 did not) of these 23 patients by direct sequencing. Mutations in the S region were examined by cloning in representative patients. There were no significant differences in the baseline clinical backgrounds and virus marker between patients with and without breakthrough hepatitis. The HBV amino acid substitutions at breakthrough hepatitis were identical to those at HBV-DNA breakthrough. Cloning analysis revealed that monoclonal mutational strain appeared at breakthrough and no such mutations existed at baseline. Regarding HBV amino acid substitutions in the polymerase region, S region, X region, and precore-core region with breakthrough compared to baseline, there was no significant differences of the numbers of amino acid substitution between breakthrough hepatitis and non-breakthrough hepatitis. There were no common amino acid changes in patients with breakthrough hepatitis. Although monoclonal lamivudine-resistant strain emerged at HBV-DNA breakthrough in patients with CHB, there were no common amino acid changes, suggesting viral factor may have insignificant role in breakthrough hepatitis.

Evolution of Hepatitis B Virus in a Chronic HBV-Infected Patient over 2 Years

“…Up until now, there have been at least 15 types of spliced HBV DNA reported in the literature (Figure 3) [20, 21], which consisted of seven 5′-splice donors and six 3′-splice accepters. In our case, four types of spliced HBV DNA were found at the 3rd time point, the donor site and the receptor site of these splicers followed the GT-AT rules [22]. Among them, the 2447/489 donor/acceptor splicer existed as described in previous reports and produced a presumptive HBV spliced protein (HBSP) [23].…”

Virologic characteristics of hepatitis B virus in patients infected via maternal-fetal transmission

“…This deletion mutant has previously been reported in different clinical conditions, especially hepatocellular carcinoma (HCC) and chronic hepatitis B (CHB) infection with genotypes C and D, and fulminant hepatitis B (FHB) with genotype A in Africa. It has also been observed in isolates obtained from nonhuman primates (Table 2) [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . Interestingly, there are no reports of this deletion mutation in genotypes B, E, F and G. In a heart transplant recipient who died from fulminate hepatitis B transmitted by the donor, the 18bp deletion was detected in the recipient, but not in the donor [20] .…”

Detecting Hepatitis B Viral Amino Acid Sequence Mutations in Occult Hepatitis B Infections via Bayesian Partition Model

“…Different from other traditional methods, the Bayesian-based method is able to analyze high-order combinations of positions. This study is conducted on 358 HBV reverse transcriptase (RT) amino acid sequences from 330 chronic genotype-C HBV patients [21][22][23][24][25][26][27][28][29][30], and 28 genotype-C HBV OBI patients [31], as well as 83 chronic genotype-D and 24 genotype-D OBI nucleotide sequences [16]. We believe the findings highlighted in this paper shed light on the future understanding of genotype-C and genotype-D OBI.…”