Different variants in reverse transcriptase domain determined by ultra-deep sequencing in treatment-naïve and treated indonesian patients infected with hepatitis B virus

Widya Wasityastuti, Yoshihiko Yano, Dewiyani Indah Widasari, Laura Navika Yamani, Neneng Ratnasari, Didik Setyo Heriyanto, Rina Okada, Toshihito Tanahashi, Yoshiki Murakami, Takeshi Azuma, Yoshitake Hayashi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

A nucleos(t)ide analog (NA) is the common antiviral drug available for directly treating hepatitis B virus (HBV) infection. However, its application has led to the emergence of NA-resistant mutations mostly in a conserved region of the reverse transcriptase domain of HBV polymerase. Harboring NA-resistant mutations decreases drug effectiveness and increases the frequency of end-stage liver disease. The invention of next-generation sequencing that can generate thousands of sequences from viral complex mixtures provides opportunities to detect minor changes and early viral evolution under drug stress. The present study used ultra-deep sequencing to evaluate discrepant quasispecies in the reverse transcriptase domain of HBV including NA-resistant hotspots between seven treatment-naïve Indonesian patients infected with HBV and five at the early phase of treatment. The most common sub-genotype was HBV B3 (83.34%). The substitution rate of variants determined among amino acids with a ratio of ≥ 1% changes was higher among the population in conserved regions (23.19% vs. 4.59%, P = 0.001) and in the inter-reverse transcriptase domain (23.95% vs. 2.94%, P = 0.002) in treatment naïve, than in treated patients. Nine hotspots of antiviral resistance were identified in both groups, and the mean frequency of changes in all patients was < 1%. The known rtM204I mutation was the most frequent in both groups. The lower rate of variants in HBV quasispecies in patients undergoing treatment could be associated with virus elimination and the extinction of sensitive species by NA therapy. The present findings imply that HBV quasispecies dynamically change during treatment.

Original languageEnglish
Pages (from-to)E1-E8
JournalKobe Journal of Medical Sciences
Volume62
Issue number1
Publication statusPublished - 2016
Externally publishedYes

Keywords

  • Drug resistance
  • Hepatitis B virus
  • Indonesia
  • Reverse transcriptase domain
  • Ultra-deep sequencing

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