Drug-related mutational patterns in hepatitis B virus (HBV) reverse transcriptase proteins from Iranian treatment-naïve chronic HBV patients

Abstract

Background: Immunomodulators and Nucleotide analogues have been used globally for the dealing of chronic hepatitis B virus (HBV) infection. However, the development of drug resistance is a major limitation to their long-term effectiveness.

Objectives: The aim of this study was to characterize the hepatitis B virus reverse transcriptase (RT) protein variations among Iranian chronic HBV carriers who did not receive any antiviral treatments.

Materials and methods: Hepatitis B virus partial RT genes from 325 chronic in active carrier patients were amplified and directly sequenced. Nucleotide/amino acid substitutions were identified compared to the sequences obtained from the database.

Results: All strains belonging to genotype D.365 amino-acid substitutions were found. Mutations related to lamivudine, adefovir, telbivudine, and entecavir occurred in (YMDD) 4% (n = 13), (SVQ) 17.23% (n = 56), (M204I/V + L180M) 2.45% (n = 8) and (M204I) 2.76% (n = 9) of patients, respectively.

Conclusions: RT mutants do occur naturally and could be found in HBV carriers who have never received antiviral therapy. However, mutations related to drug resistance in Iranian treatment-naïve chronic HBV patients were found to be higher than other studies published formerly. Chronic HBV patients should be monitored closely prior the commencement of therapy to achieve the best regimen option.

Keywords: Drug-Resistance; Hepatitis B Virus; Iran; Therapy.

Figure 1. Schematic Figure Showing Polymerase Protein

A) Four main domains include the RT region, B) RT region including domains and inter domains, C) Mutation frequency in the F domain to the C-D inter-domain, D) Individual drug-resistance mutation to LAM (Lamivudine), ADF (Adefovir), ETV (Entacavir), and LdT (Telbivudine).

Figure 2. Neighbor joining phylogenetic analysis based on the alignment of the RT gene region (approximately 750-bp) of 325 HBV isolates from Iran as well as other HBV genotypes from Gen Bank as reference. Bootstrap values indicate 1000-foldreplicates. Due to clarity, the 325 isolates from Iran and 6 reference genes of HBV genotype D was collapsed. Woolly monkey HBV was used as the out-group sequence.