Folia Microbiologica

, Volume 64, Issue 2, pp 237–243 | Cite as

Evaluation of drug resistance mutations in patients with chronic hepatitis B

  • Sema AlacamEmail author
  • Nuran Karabulut
  • Ayfer Yolcu
  • Mustafa Onel
  • Alp Atasoy
  • Sabahattin Kaymakoglu
  • Ali Agacfidan
Original Article


Mutations occurring in viral polymerase gene of hepatitis B virus (HBV) due to the use of nucleos(t)id analogs reduce the activity of the drugs by causing antiviral resistance. In this study, it was aimed to evaluate mutations responsible for drug resistance and drug resistance mutation rates in patients followed up by the diagnosis of chronic hepatitis B (CHB). A total of 318 CHB patients were included in the study. HBV mutations were detected using the INNO-LiPA commercial kit based on the reverse hybridization principle. Drug resistance mutation was detected in 46.86% (149/318) of the patients. The rates of drug resistance were found 36.79% (117/318) for lamivudine resistance, 12.58% (40/318) for entecavir (ETV), and 7.86% (25/318) for adefovir. In 10 patients, the possible tenofovir (TDF) resistance (3.14%) was found. Single-drug and double-drug resistances were detected in 34.59% and in 11.01% of the patients, respectively. Triple drug resistance was detected in only 1.26% of the patients. Unlike various studies in Turkey and in other countries, remarkable resistance to ETV and TDF were found in this study. The high rate of the probable TDF resistance was striking, with 3.14%.


Compliance with ethical standards

Ethical approval for this study was obtained by Ethics Committee of Istanbul University, Istanbul Faculty of Medicine (reference number: 2017/652/11).

Conflict of interest

The authors declare that they have no competing interests.


  1. Ahn HJ, Song MJ, Jang JW, Bae SH, Choi JY, Yoon SK (2017) Treatment efficacy and safety of tenofovir-based therapy in chronic hepatitis B: a real life cohort study in Korea. PLoS One 12:e0170362. CrossRefGoogle Scholar
  2. Aydogan S et al (2013) Detection of resistance mutations in chronic hepatitis B patients receiving antiviral therapy for over one year. Mikrobiyol Bul 47:472–481CrossRefGoogle Scholar
  3. Chantratita W, Song KS, Pongthanapisith V, Thongbaiphet N, Angkanavin K, Nimse SB, Sonawane MD, Kim T (2016) HBV/4DR 9G test and its comparison with INNO-LiPA HBV multi-DR test for the detection of drug-resistant. Hepatitis B virus. J Virol Methods 237:58–63. CrossRefGoogle Scholar
  4. De Francesco MA et al (2015) Clinical course of chronic hepatitis B patients receiving nucleos(t)ide analogues after virological breakthrough during monotherapy with lamivudine. New Microbiol 38:29–37Google Scholar
  5. Dupouey J, Gerolami R, Solas C, Colson P (2012) Hepatitis B virus variant with the a194t substitution within reverse transcriptase before and under adefovir and tenofovir therapy. Clin Res Hepatol Gastroenterol 36:e26–e28. CrossRefGoogle Scholar
  6. Ergunay K et al (2013) Investigation of baseline antiviral resistance in treatment-naive chronic hepatitis B cases. Mikrobiyol Bul 47:628–635CrossRefGoogle Scholar
  7. Ezzikouri S, Ozawa M, Kohara M, Elmdaghri N, Benjelloun S, Tsukiyama-Kohara K (2014) Recent insights into hepatitis B virus-host interactions. J Med Virol 86:925–932. CrossRefGoogle Scholar
  8. Hermans LE, Svicher V, Pas SD, Salpini R, Alvarez M, Ben Ari Z, Boland G, Bruzzone B, Coppola N, Seguin-Devaux C, Dyda T, Garcia F, Kaiser R, Köse S, Krarup H, Lazarevic I, Lunar MM, Maylin S, Micheli V, Mor O, Paraschiv S, Paraskevis D, Poljak M, Puchhammer-Stöckl E, Simon F, Stanojevic M, Stene-Johansen K, Tihic N, Trimoulet P, Verheyen J, Vince A, Weis N, Yalcinkaya T, Lepej SZ, Perno C, Boucher CA, Wensing AM, HEPVIR Working Group of the European Society for Translational Antiviral Research (2016) Combined analysis of the prevalence of drug-resistant hepatitis B virus in antiviral therapy-experienced patients in Europe (CAPRE). J Infect Dis 213:39–48. CrossRefGoogle Scholar
  9. Jiang B, Dai CY, Li XM, Su R, Xu J, Cao Y, Hou W, Lu W (2016) Drug-resistant mutations in hepatitis B virus found in chronic HBV carriers using PCR sequencing technology. Zhonghua Gan Zang Bing Za Zhi 24:36–39. Google Scholar
  10. Kalaycı R, Altındiş M, Gülamber C, Demirtürk N, Akcan Y, Demirdal T (2010) Kronik hepatit B ve hepatit C’li hastalarda genotip dağılımı ve hepatit B olgularında direnç paterninin araştırılması. Mikrobiyol Bul 44:237–243Google Scholar
  11. Kırdar S, Yaşa MH, Aydın N, Gültekin Korkmazgil B (2016) Detection of resistance mutations in chronic hepatitis B patients receiving lamivudine therapy using molecular method. Türk Mikrobiyol Cem Derg
  12. Kose S, Turken M, Gul S (2015) Evaluation of lamivudine resistance assay using a molecular method in patients with chronic hepatitis B. Viral Hepat J 21:17–19CrossRefGoogle Scholar
  13. Lok AS, Ganova-Raeva L, Cloonan Y, Punkova L, Lin HHS, Lee WM, Ghany MG, the Hepatitis B Research Network (HBRN) (2017) Prevalence of hepatitis B antiviral drug resistance variants in North American patients with chronic hepatitis B not receiving antiviral treatment. J Viral Hepat 24:1032–1042. CrossRefGoogle Scholar
  14. Meng T, Shi X, Gong X, Deng H, Huang Y, Shan X, Shan Y, Huang A, Long Q (2017) Analysis of the prevalence of drug-resistant hepatitis B virus in patients with antiviral therapy failure in a Chinese tertiary referral liver centre (2010-2014). J Glob Antimicrob Resist 8:74–81. CrossRefGoogle Scholar
  15. Motahar M, Arabzadeh SA, Mollaei H, Iranmanesh Z, Nikpour N, Soleimani F (2016) Evaluation of HBV resistance to tenofovir in patients with chronic hepatitis B using ZNA probe assay in Kerman, southeast of Iran. Asian Pac J Trop Dis 6:513–516. CrossRefGoogle Scholar
  16. Ohno M, Otsuka M, Kishikawa T, Yoshikawa T, Takata A, Koike K (2015) Novel therapeutic approaches for hepatitis B virus covalently closed circular DNA. World J Gastroenterol 21:7084–7088. CrossRefGoogle Scholar
  17. Pastor R, Habersetzer F, Fafi-Kremer S, Doffoël M, Baumert TF, Gut JP, Stoll-Keller F, Schvoerer E (2009) Hepatitis B virus mutations potentially conferring adefovir/tenofovir resistance in treatment-naive patients. World J Gastroenterol 15:753–755. CrossRefGoogle Scholar
  18. Sayan M, Akhan SC, Senturk O (2011) Frequency and mutation patterns of resistance in patients with chronic hepatitis B infection treated with nucleos(t)ide analogs in add-on and switch strategies. Hepat Mon 11:835–842. Google Scholar
  19. Sayan M, Senturk O, Akhan SC, Hulagu S, Cekmen MB (2010) Monitoring of hepatitis B virus surface antigen escape mutations and concomitantly nucleos(t)ide analog resistance mutations in Turkish patients with chronic hepatitis B. Int J Infect Dis 14(Suppl 3):e136–e141. CrossRefGoogle Scholar
  20. Schreiner S, Nassal M (2017) A role for the host DNA damage response in hepatitis B virus cccDNA formation-and beyond? Viruses 9:125. CrossRefGoogle Scholar
  21. Sharma V (2016) First report of primary tenofovir resistance in a hepatitis B viral hepatitis patient from India without human immunodeficiency virus co-infection. J Liver Res Disord Ther 2:5. Google Scholar
  22. Shirvani-Dastgerdi E, Winer BY, Celià-Terrassa T, Kang Y, Tabernero D, Yagmur E, Rodríguez-Frías F, Gregori J, Luedde T, Trautwein C, Ploss A, Tacke F (2017) Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy. J Hepatol 67:246–254. CrossRefGoogle Scholar
  23. Tacke F, Kroy DC (2016) Treatment for hepatitis B in patients with drug resistance. Ann Transl Med 4:334. CrossRefGoogle Scholar
  24. Tozun N, Ozdogan O, Cakaloglu Y, Idilman R, Karasu Z, Akarca U, Kaymakoglu S, Ergonul O (2015) Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study. Clin Microbiol Infect 21:1020–1026. CrossRefGoogle Scholar
  25. WHO (2017) Hepatitis B fact sheet. Accessed 21.11.2017
  26. Yamada N, Sugiyama R, Nitta S, Murayama A, Kobayashi M, Okuse C, Suzuki M, Yasuda K, Yotsuyanagi H, Moriya K, Koike K, Wakita T, Kato T (2017) Resistance mutations of hepatitis B virus in entecavir-refractory patients. Hepatol Commun 1:110–121. CrossRefGoogle Scholar

Copyright information

© Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i. 2018

Authors and Affiliations

  • Sema Alacam
    • 1
    Email author
  • Nuran Karabulut
    • 1
  • Ayfer Yolcu
    • 1
  • Mustafa Onel
    • 1
  • Alp Atasoy
    • 2
  • Sabahattin Kaymakoglu
    • 2
  • Ali Agacfidan
    • 1
  1. 1.Istanbul Faculty of Medicine, Department of Medical Microbiology, Division of Virology and Fundamental ImmunologyIstanbul UniversityIstanbulTurkey
  2. 2.Istanbul Faculty of Medicine, Department of GastroenterohepatologyIstanbul UniversityIstanbulTurkey

Personalised recommendations