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Hepatitis B virus reverse transcriptase polymorphisms between treated and treatment-naïve chronically infected patients

  • Masoumeh Rezanezhadi
  • Alireza Mohebbi
  • Fatemeh Sana Askari
  • Seyyede Delafruz Hosseini
  • Alijan TabarraeiEmail author
Original Article
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Abstract

The aim of this study was investigation of variation(s) in the Hepatitis B virus (HBV) reverse transcriptase domain. 120 patients with chronic HBV infection recruited. 104 patients were received nucleos(t)ide analogs treatments. DNA extractions were done from plasma samples. Direct sequencing and alignment of Polymerase Chain Reaction products were applied for further analysis. HBV genotypes determined by NCBI’s Genotyping Tool. Polymorphism(s) were detected by using DnaSP software. Of 120 samples, 98 were sequenced. All of products were HBV genotype D. 13/98 (13.27%) of patients had M539I/V substitutions corresponding to YMDD motif. FLLAQ to FLMAQ was observed among 22/98 (22.98) patients. Two substitutions N459Y and L515M were significantly correlated (R2 = 0.486 and R2 = 0.941 respectively) with FLLAQ motif variation. Mutation ratio among treatment-received patients to treatment-naïve patients was 0.2–0.6. Drug resistance conferring substitutions (DRCSs) were rtL180M (22/98), rtA194V (11/98), rtM204V (1/98), and rtM204I (11/98). Furthermore, six variants were observed among all patients. Appearance of DRCSs in HBV polymerase is a major obstacle to the virus treatments. In the present study, it was shown that DRCSs are more prevalent among treated patients. Therefore, replacement of current anti-viral regimen with novel anti-HBV drugs is warranted in the future.

Keywords

Chronic hepatitis B virus Hepatitis B virus polymerase HBV reverse transcriptase Nucleotide analogues resistance mutation Drug resistance conferring substitution 

Notes

Acknowledgements

This article was derived from a grant in the field of Virology and fully supported by Golestan University of Medical Sciences, Gorgan, Iran.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest to declare.

Supplementary material

13337_2018_510_MOESM1_ESM.xlsx (3.8 mb)
Supplementary material 1 (XLSX 3897 kb)

References

  1. 1.
    Ahn SH, Kim DH, Lee AR, Kim BK, Park YK, Park ES, et al. Substitution at rt269 in hepatitis B virus polymerase is a compensatory mutation associated with multi-drug resistance. PLoS ONE. 2015;10:1–17.Google Scholar
  2. 2.
    Dandri M, Locarnini S. New insight in the pathobiology of hepatitis B virus infection. Gut. 2012;61:i6–17.CrossRefGoogle Scholar
  3. 3.
    Gomes-Gouvêa MS, Ferreira AC, Teixeira R, Andrade JR, Ferreira ASP, Barros LMF, et al. HBV carrying drug-resistance mutations in chronically infected treatment-naive patients. Antivir Ther. 2015;20:387–95.CrossRefGoogle Scholar
  4. 4.
    Han Y, Huang LH, Liu CM, Yang S, Li J, Lin ZM, et al. Characterization of hepatitis B virus reverse transcriptase sequences in Chinese treatment naive patients. J Gastroenterol Hepatol. 2009;24:1417–23.CrossRefGoogle Scholar
  5. 5.
    Jardi R, Rodriguez-Frias F, Schaper M, Ruiz G, Elefsiniotis I, Esteban R, et al. Hepatitis B virus polymerase variants associated with entecavir drug resistance in treatment-naive patients. J Viral Hepat. 2007;14:835–40.Google Scholar
  6. 6.
    Karami C, Adli AH, Zhand S, Tabarraei A, Talei R, Saeidi M, et al. Study of genotype, subtype and mutation in the S gene in hepatitis B patients co-infected with HIV in Iran. Jundishapur J Microbiol. 2016;9:1–5.CrossRefGoogle Scholar
  7. 7.
    Katoh K, Standley DM. MAFFT multiple sequence alignment software version 7: improvements in performance and usability. Mol Biol Evol. 2013;30:772–80.CrossRefGoogle Scholar
  8. 8.
    Keeffe EB, Dieterich DT, Pawlotsky JM, Benhamou Y. Chronic hepatitis B: preventing, detecting, and managing viral resistance. Clin Gastroenterol Hepatol. 2008;6:268–74.CrossRefGoogle Scholar
  9. 9.
    Lee CZ, Lee HS, Huang GT, Yang PM, Sheu JC. Detection of YMDD mutation using mutant-specific primers in chronic hepatitis B patients before and after lamivudine treatment. World J Gastroenterol. 2006;12:5301–5.CrossRefGoogle Scholar
  10. 10.
    Liaw YF, Gane E, Leung N, Zeuzem S, Wang Y, Lai CL, et al. 2-year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology. 2009;136:486–95.CrossRefGoogle Scholar
  11. 11.
    Librado P, Rozas J. DnaSP v5: a software for comprehensive analysis of DNA polymorphism data. Bioinformatics. 2009;25:1451–2.CrossRefGoogle Scholar
  12. 12.
    Lim Y-S. Management of antiviral drug resistance in chronic hepatitis B. World J Gastroenterol. 2017;11:189–95.Google Scholar
  13. 13.
    Liu BM, Li T, Xu J, Li XG, Dong JP, Yan P, et al. Characterization of potential antiviral resistance mutations in hepatitis B virus reverse transcriptase sequences in treatment-naïve Chinese patients. Antiviral Res. 2010;85:512–9.CrossRefGoogle Scholar
  14. 14.
    Lok AS, Zoulim F, Locarnini S, Bartholomeusz A, Ghany MG, Pawlotsky JM, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254–65.CrossRefGoogle Scholar
  15. 15.
    Mirandola S, Campagnolo D, Bortoletto G, Franceschini L, Marcolongo M, Alberti A. Large-scale survey of naturally occurring HBV polymerase mutations associated with anti-HBV drug resistance in untreated patients with chronic hepatitis B. J Viral Hepat. 2011;18:212–6.CrossRefGoogle Scholar
  16. 16.
    Mirarab A, Mohebbi A, Javid N, Moradi A, Vakili MA, Tabarraei A. Human cytomegalovirus pUL97 drug-resistance mutations in congenitally neonates and HIV-infected, no-drug-treated patients. Future Virol. 2017;12:13–8.CrossRefGoogle Scholar
  17. 17.
    Mohebbi A, Mohammadi S, Memarian A. Prediction of HBF-0259 interactions with hepatitis B virus receptors and surface antigen secretory factors. VirusDisease. 2016;27:234–41.CrossRefGoogle Scholar
  18. 18.
    Mohebbi A, Lorestani N, Tahamtan A, Kargar NL, Tabarraei A. An overview of hepatitis B virus surface antigen secretion inhibitors. Front Microbiol. 2018;9:1–9.CrossRefGoogle Scholar
  19. 19.
    Moradi A, Zhand S, Ghaemi A, Javid N, Tabarraei A. Mutations in the S gene region of hepatitis B virus genotype D in Golestan Province-Iran. Virus Genes. 2012;44:382–7.CrossRefGoogle Scholar
  20. 20.
    Moradi A, Zhand S, Ghaemi A, Javid N, Bazouri M, Tabarraei A. Mutations in pre-core and basal-core promoter regions of hepatitis B virus in chronic HBV patients from Golestan, Iran. Iran J Basic Med Sci. 2014;17:370–7.Google Scholar
  21. 21.
    Murakami E, Tsuge M, Hiraga N, Kan H, Uchida T, Masaki K, et al. Effect of tenofovir disoproxil fumarate on drug-resistant HBV clones. J Infect. 2016;72:91–102.CrossRefGoogle Scholar
  22. 22.
    Nguyen MH, Garcia RT, Trinh HN, Nguyen HA, Nguyen KK, Nguyen LH, et al. Prevalence of hepatitis B virus DNA polymerase mutations in treatment-naïve patients with chronic hepatitis B. Aliment Pharmacol Ther. 2009;30:1150–8.CrossRefGoogle Scholar
  23. 23.
    Reva B, Antipin Y, Sander C. Predicting the functional impact of protein mutations: application to cancer genomics. Nucleic Acids Res. 2011;39:e118.CrossRefGoogle Scholar
  24. 24.
    Rozanov M, Plikat U, Chappey C, Kochergin A, Tatusova T. A web-based genotyping resource for viral sequences. Nucleic Acids Res. 2004;32:W654–9.CrossRefGoogle Scholar
  25. 25.
    Tamura K, Stecher G, Peterson D, Filipski A, Kumar S. MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol. 2013;30:2725–9.CrossRefGoogle Scholar
  26. 26.
    Vigano M, Lampertico P, Iavarone M, Tontini GE, Facchetti F, Colombo M. High risk of renal impairment during long-term adefovir and lamivudine combination therapy in patients with lamivudine-resistant chronic hepatitis B. J Hepatol. 2009;50(Suppl):S338–9.CrossRefGoogle Scholar
  27. 27.
    Vutien P, Trinh HN, Garcia RT, Nguyen HA, Levitt BS, Nguyen K, et al. Mutations in HBV DNA polymerase associated with nucleos(t)ide resistance are rare in treatment-naive patients. Clin Gastroenterol Hepatol. 2014;12:1363–70.CrossRefGoogle Scholar
  28. 28.
    Warner N, Locarnini S. Mechanisms of hepatitis B virus resistance development. Intervirology. 2014;57:218–24.CrossRefGoogle Scholar
  29. 29.
    Zhang Q, Liao Y, Cai B, Li Y, Li L, Zhang J, et al. Incidence of natural resistance mutations in naïve chronic hepatitis B patients: a systematic review and meta-analysis. J Gastroenterol Hepatol. 2015;30:252–61.CrossRefGoogle Scholar
  30. 30.
    Zhao Y, Wu J, Sun L, Liu G, Li B, Zheng Y, et al. Prevalence of mutations in HBV DNA polymerase gene associated with nucleos(t)ide resistance in treatment-naive patients with Chronic Hepatitis B in Central China. Braz J Infect Dis. 2016;20:173–8.CrossRefGoogle Scholar
  31. 31.
    Zoulim F, Locarnini S. Hepatitis B virus resistance to nucleos(t)ide analogues. Gastroenterology. 2009;137:1593–608.CrossRefGoogle Scholar

Copyright information

© Indian Virological Society 2019

Authors and Affiliations

  • Masoumeh Rezanezhadi
    • 1
  • Alireza Mohebbi
    • 1
    • 2
  • Fatemeh Sana Askari
    • 1
  • Seyyede Delafruz Hosseini
    • 1
  • Alijan Tabarraei
    • 2
    Email author
  1. 1.Student Research CommitteeGolestan University of Medical SciencesGorganIran
  2. 2.Infectious Diseases Research CentreGolestan University of Medical SciencesGorganIran

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