Antiviral Resistance Mutations and Genotype-Associated Amino Acid Substitutions in Treatment-Naïve Hepatitis B Virus-Infected Individuals from the Indian Subcontinent

Background: The reported prevalence and necessity of detection of HBV reverse transcriptase (RT) mutation prior to treatment is varied and remains controversial. This study aimed to identify the prevalence of HBV pre-existing gene resistance mutations and compare the difference between pre-existing mutations and drug-induced resistance mutations in patients with hepatitis B virus-related cirrhosis.Methods: 180 patients with hepatitis B virus-related cirrhosis which included 68 patients with virological breakthrough and 112 treatment-naive cirrhosis patients were retrospectively enrolled. The drug-resistant mutations of HBV reverse transcriptase domain were screened by direct gene sequencing. One-way ANOVA analysis was performed in the comparison among different groups. Ratios difference was compared with the chi-square test.Results: There were 48 patients (48/112, 42.86%) with drug resistance mutations in nucleoside/nucleotide analogues (NAs) treatment-naive group, 59 patients (59/68, 86.76%) showed drug-resistant mutations in the NAs treatment group. The gene resistance mutation patterns in treatment-naive group were mainly rtS213T, rtV214A, 191V/I and rtN/H238T/D, and the types of resistance mutations in the treated group were different. The adefovir (ADV) group: mainly rtA181T/V and rtS213T; lamivudine/ telbivudine (LAM/LDT) group: rtL180M+ rtM204I/V/S and rtM204I/V/S or a complex mutation pattern containing 204 site; entecavir (ETV) group: The drug resistance pattern is the simultaneous presence of multiple site mutations. LAM/LDT sequential ADV group: The variant type was multi-site and resistant to both ADV and LAM.Conclusion: There was a prevalence of pre-existing mutations in RT region of HBV polymerase in patients with hepatitis B virus-related cirrhosis, The mutation pattern is mainly related to LAM and ADV-related compensatory mutations, while the drug-induced mutation pattern is more complicated, mainly related to the antiviral drugs used and there are mainly primary mutations. Patients with cirrhosis should be tested genetic resistance mutation before using antiviral drugs.

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Localization of a unique hepatitis B virus epitope sheds new light on the structure of hepatitis B virus surface antigen

Journal of General Virology ◽

10.1099/0022-1317-80-8-2121 ◽

1999 ◽

Vol 80 (8) ◽

pp. 2121-2126 ◽

Cited By ~ 35

Author(s):

W. P. Paulij ◽

P. L. M. de Wit ◽

C. M. G. Sünnen ◽

M. H. van Roosmalen ◽

A. Petersen-van Ettekoven ◽

...

Keyword(s):

Amino Acid ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Surface Antigen ◽

Single Amino Acid ◽

Amino Acid Substitutions ◽

Virus Surface ◽

Virus Surface Antigen ◽

B Virus ◽

20 Nm

In a search for monoclonal antibodies (MAbs) that can bind hepatitis B virus surface antigen (HBsAg) with amino acid substitutions in the immune dominant ‘a’ region (escape mutants) we investigated the epitope recognition site of the human MAb 4-7B. Pepscan analysis and experiments with alanine substitution as well as substitutions known from nature pointed to residues 178–186 in the small S protein with the amino acid sequence PFVQWFVGL (key amino acids in bold) as the minimal epitope. Single amino acid substitutions at positions 122(R/K)(d/y), 134(Y/F), 145(G/R), 148(T/A) and 160(K/R)(w/r), representing ‘a’ region variants in recombinant HBsAg COS-I cells, did not influence binding of MAb 4-7B. Synthetic peptides (residues 175–189) including the 4-7B epitope sequence were able to evoke an anti-HBs response in rabbits. According to established polypeptide models, the 4-7B epitope region is located in the lipid layer of 20 nm HBsAg particles. The present results, however, suggest that residues 178–186 are exposed on the surface of the 20 nm particle. This may change our view of the structure of HBsAg.

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Dynamics of Hepatitis B Virus Resistance to Lamivudine

Journal of Virology ◽

10.1128/jvi.80.2.643-653.2006 ◽

2006 ◽

Vol 80 (2) ◽

pp. 643-653 ◽

Cited By ~ 69

Author(s):

Coralie Pallier ◽

Laurent Castéra ◽

Alexandre Soulier ◽

Christophe Hézode ◽

Patrice Nordmann ◽

...

Keyword(s):

Amino Acid ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Individual Treatment ◽

Amino Acid Substitutions ◽

Treatment Optimization ◽

Lamivudine Resistance ◽

Resistant Variant ◽

B Virus

ABSTRACT Lamivudine was the first approved inhibitor of hepatitis B virus (HBV) reverse transcriptase (RT). Lamivudine resistance develops in 53% to 76% of patients after 3 years of treatment. We extensively characterized the dynamics of HBV quasispecies variant populations in four HBV-infected patients who developed lamivudine resistance. Virological breakthrough was preceded by 2 to 4 months by the emergence of quasispecies variants bearing amino acid substitutions at RT position 204, i.e., within the YMDD catalytic motif (rtM204V/I). Three patients had a gradual switch from a YMDD variant population at baseline to a 100% lamivudine-resistant variant population, whereas the remaining patient had a fluctuating pattern of resistance variant dynamics. Careful analysis of amino acid substitutions located outside domain C of HBV RT, including those known to partially restore replication capacities in vitro, showed that the in vivo replication of HBV variants is driven by multiple forces, including intrinsic replicative advantages conferred by mutations accumulating outside domain C and the changing environment in which these variants replicate. Our findings also suggest that individual treatment optimization will require sensitive methods capable of detecting the emergence of viral resistance before the relevant variants acquire optimal replicative capacities.

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