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Background: Hepatitis B virus (HBV) is a gradually evolving virus. The aim of this study was to characterize the distribution pattern of HBV genotypes and subgenotypes and HBsAg subtypes in chronic hepatitis B subjects from the Indian subcontinent. We also sought to investigate the genetic diversity of HBV genotypes and its influence on the therapeutic response., Methods: A total of 295 chronic hepatitis B subjects were studied. HBV genotypes and subgenotypes were determined using the generated HBV reverse transcriptase (rt) sequences. HBsAg subtypes were predicted using a newly developed automated program in Microsoft Visual Basic (VB6). Genetic diversity was characterized by calculating the mean genetic distance (d), the number of synonymous substitutions per synonymous site (dS), and the number of non-synonymous substitutions per non-synonymous site (dN). The virological response was measured by HBV DNA levels., Results: In southern India, the predominant HBV subgenotype/subtype was D2/ayw3 (79.1%). In eastern India, C1/adr (28.2%) was found to be the predominant subgenotype/subtype, followed by A1/adw2 (25.4%). In the north-eastern region, C2/adr, D2/ayw3, and D5/ayw3 were predominant and were each identified in 20.8% of subjects. In treatment-naïve subjects, the d, dS, and dN of genotype D sequences were higher compared to genotypes C and A. Additionally, the d, dS, and dN of HBV rt sequence were higher in subjects who subsequently showed a virological response to nucleos(t)ide analogues as compared to non-responders, irrespective of the genotypes tested (p=0.014 to p<0.0001)., Conclusions: We have described the distribution of HBV genotypes and subgenotypes and HBsAg subtypes in three major regions of the Indian subcontinent. HBV genetic diversity may play a pivotal role in the clinical outcome of chronic hepatitis B., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Objective: Management of chronic hepatitis B is a global public health challenge. There are several updated guidelines proposed based on treatment outcome data from the respective study populations. In this study, we aim to characterize the antiviral resistance mutations to lamivudine monotherapy in patients diagnosed with chronic hepatitis B from the Indian subcontinent., Methods: A total of 147 lamivudine-treated patients with a median treatment duration of 13 (interquartile range 8-24) months were studied. Virological response was measured by hepatitis B virus (HBV) DNA levels. Antiviral resistance mutations were identified by sequencing HBV reverse transcriptase domains. Factors associated with virological response and antiviral resistance mutations were analyzed., Results: Virological response was observed in 50 (35 %) patients while 84 (57 %) were non-responders. The virological response for the remaining 13 (9 %) patients was undetermined. Forty patients (27 %) developed lamivudine-resistant mutations. HBV genotypes, subgenotypes and hepatitis B surface antigen subtypes did not show significant association with virological response or lamivudine-resistant mutations. High HBV DNA levels and increased treatment duration were strongly associated with the development of lamivudine-resistant mutations (p = 0.002 and p < 0.001). Patients who continued to be positive for hepatitis B e antigen have an increased risk for treatment failure (p = 0.010). High baseline aspartate transaminase levels were significantly associated with subsequent lamivudine response (p = 0.037)., Conclusion: Considering the limited potency and high resistance rates to lamivudine therapy, our study emphasizes the use of more potent drugs in the management of chronic hepatitis B in the Indian subcontinent.

Hepatitis B virus (HBV) genotypes have known to show a geographical pattern in their distribution and have been used to trace the migration of populations from geographically distant regions. Novel recombinants between HBV genotypes A, G and C referred as genotype I has been recently reported from Eastern India. In our investigation to characterise antiviral resistance mutations, we identified a rare case of HBV genotype I infection in chronic hepatitis B subject. We encountered confounding results of this emerging genotype 'designated as genotype G' in three widely used HBV sequence database for genotype determination. The recombinant fragment of genotype G largely occupies the surface gene sequence of the newly identified genotype I and could hence lead to misclassification of genotype I. Additionally, recombination analysis of the generated sequences in Simplot and jpHMM model showed two different patterns of recombination events. In conclusion, the increasing recognition of genotype I in this population suggests that further studies may reveal uncommon genotypes from other geographically distant regions. Our observation of potential genotype I misclassification despite the use of public HBV sequence database and other recombination analysis tools highlights the need for updating and validating public sequence domains of diagnostic importance., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Entecavir is one of the therapeutic options currently available for the management of chronic hepatitis B. In this study, we aimed to analyse the virological response and antiviral resistance mutations in chronic hepatitis B subjects experiencing entecavir therapy from the Indian subcontinent. A total of 45 chronic hepatitis B subjects were studied at baseline and were followed up on entecavir treatment. Among these subjects, 25 (56%) were HBeAg-positive at baseline. Virological response was measured by hepatitis B virus (HBV) DNA levels. HBV reverse transcriptase (rt) domains were sequenced for the identification of resistance mutations. Three-Dimensional (3D) model of HBV polymerase/rt protein, docking and molecular dynamics simulation (MDS) studies were performed for characterization of antiviral resistance mutations. At the median treatment duration of 6 (IQR 6-11) months, 38 (84%) showed virological response. Subjects who showed anti-HBe response demonstrated significant association with virological response (p=0.034). On sequence analysis, none of the subjects were identified with signature entecavir resistance mutations. However, one subject was exclusively detected with rtV173L mutation. Molecular modeling, docking and MDS studies revealed that the rtV173L mutation cannot confer resistance to entecavir independently. Our findings also showed that the prevailing HBV genotypes, subgenotypes and HBsAg subtypes in this population does not influence treatment outcome to entecavir therapy. In conclusion, entecavir is a potent drug in terms of viral DNA suppression. In addition, none of the subjects developed antiviral resistance mutations to entecavir. Therefore entecavir is a suitable drug of choice in the management of chronic HBV., (Copyright © 2013 Elsevier B.V. All rights reserved.)