A molecular virology analysis performed in an HIV-hepatitis B virus (HBV) co-infected patient showed the emergence of an unusual HBV polymerase gene mutation (rt A181T) under adefovir therapy, conferring resistance to adefovir but not to tenofovir, as proved by in-vitro phenotypic analysis. This observation suggests that careful monitoring of co-infected patients is required to diagnose HBV resistance to nucleos(t)ide analogues, and that tenofovir may be active at least against some of the adefovir-resistant strains.
"The major resistant mutant was rtM204I . Tenofovir has recently been found to be effective in suppressing HBV replication with a low risk of drug resistance and several reports have shown that this drug is effective against various NA resistant or cross-resistant mutants [18,19]. "
[Show abstract][Hide abstract] ABSTRACT: Development of the hepatitis B virus (HBV) rtA181T/sW172* mutant could occur during prolonged lamivudine (LAM) therapy, conferring cross resistance to adefovir. Recent studies demonstrated an increased oncogenic potential of this mutant in NIH3T3 cells. In this study, we aimed to investigate the clinical significance of this finding.
Serum samples from 123 LAM-resistant chronic hepatitis B patients were submitted for virological assays. A highly sensitive amplification created restriction enzyme site (ACRES) method was devised to detect small amounts of the rtA181T mutant in the serum. Virological factors including HBV-DNA level, genotype, precore G1896A, BCP A1762T/G1764A, rtM204I/V, rtA181T and pre-S internal deletion mutations as well as clinical variables including subsequent use of rescue drugs were submitted for outcome analysis.
By use of the highly sensitive ACRES method, the rtA181T mutant was detectable in 10 of the 123 LAM-resistant patients. During the mean follow-up period of 26.2 ± 16.4 months (range 2 to 108 months), 3 of the 10 (30.0%) rtA181T-positive patients and 2 of the 113 (1.8%) rtA181T-negative patients developed hepatocellular carcinoma (HCC). Kaplan-Meier analysis indicated that the presence of rtA181T mutation (P < 0.001), age > 50 years (P = 0.001), and liver cirrhosis (P < 0.001) were significantly associated with subsequent occurrence of HCC. All 5 HCC patients belonged to the older age and cirrhosis groups.
Emergence of the rtA181T/sW172* mutant in LAM-resistant patients increased the risk of HCC development in the subsequent courses of antiviral therapy.
BMC Cancer 09/2011; 11(1):398. DOI:10.1186/1471-2407-11-398 · 3.36 Impact Factor
"This thus suggest that HBV genotypes A and G may have an intrinsic propensity to an easier escape from the immune pressure. This is also consistent with the correlation between genotype G infection and hepatic fibrosis development, that has been observed in HBV + HIV co-infected patients . The study of genetic barrier can provide important information regarding viral ability to develop a specific drug-resistance or immune-escape mutation. "
[Show abstract][Hide abstract] ABSTRACT: Impact of hepatitis B virus genetic barrier, defined as the number and type of nucleotide substitutions required to overcome drug/immune selective pressure, on drug-resistance/immune-escape development is unknown.
Genetic barrier was calculated according to Van de Vijver (2006) in 3482 hepatitis B virus-reverse transcriptase/HBV surface antigen sequences from 555 drug-naïve patients and 2927 antiviral-treated patients infected with hepatitis B virus genotypes A-G.
Despite high natural variability, genetic barrier for drug-resistance development is identical amongst hepatitis B virus genotypes, but varies according to drug-resistance mutation type. Highest genetic barrier is found for secondary/compensatory mutations (e.g. rtL80I/V-rtL180M-rtV173L), whilst most primary mutations (including rtM204V-rtA181T/V-rtI169T-rtA194T) are associated with low genetic barrier. An exception is rtM204I, which can derive from a transition or a transversion. Genotypes A and G are more prone to develop immune/diagnostic-escape mutations sT114R and sG130N. Vaccine-escape associated sT131N-mutation is a natural polymorphism in both A and G genotypes.
Genetic barrier and reverse transcriptase/HBV surface antigen overlapping can synergistically influence hepatitis B virus drug-resistance/immune-escape development. The different immune-escape potential of specific hepatitis B virus genotypes could have important clinical consequences in terms of disease progression, vaccine strategies and correct HBV surface antigen detection.
"These early versions of the line probe assay had been shown to have a high concordance with direct sequencing and to detect antiviral drug-resistant mutations earlier    . The third version of the line probe assay (HBV DR v.3) includes 1 strip from the DR v.2 assay and a new strip that incorporates probes to detect mutations associated with resistance to entecavir (ETV) as well as mutations that had been reported to be associated with resistance to tenofovir (TDF) and primary nonresponse to adefovir      . HBV DR v.3 assay has a total of 54 probes to detect mutations at 11 amino acid positions in the reverse transcriptase region of the HBV polymerase gene. "
[Show abstract][Hide abstract] ABSTRACT: Early detection of antiviral drug-resistant mutations enables prompt initiation of rescue therapy. The aim of this study was to determine the accuracy and sensitivity of a new line probe assay in the detection of antiviral drug-resistant HBV mutations.
One-hundred samples from 54 patients with virologic breakthrough during entecavir, lamivudine or adefovir treatment and 21 samples from 21 nucleoside-naïve patients were tested by direct sequencing and an updated line probe assay (Innogenetics, HBV DR v.3) which incorporates probes that can detect mutations at 11 positions of the reverse transcriptase region of the HBV polymerase gene.
Complete concordance between line probe and sequencing results was observed for 90/121 samples (74.3%) and 1291/1331 amino acid positions (96.9%). Testing of follow-up samples and clonal analysis of discordant samples confirmed the presence of mutations where line probe assay but not direct sequencing detected mutations. HBV DR v.3 assay consistently detected mutations present in > or = 5% of the virus population when HBV DNA concentration was > or = 4 log10copies/mL.
The updated version of the line probe assay (HBV DR v.3) has high concordance with direct sequencing in detecting antiviral drug-resistant mutations but its sensitivity in detecting mutations at some positions needs to be improved.
Journal of Hepatology 12/2008; 50(1):42-8. DOI:10.1016/j.jhep.2008.08.020 · 11.34 Impact Factor
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