Archives of Virology

, Volume 160, Issue 11, pp 2881–2885 | Cite as

Predominance of hepatitis C virus Q80K among NS3 baseline-resistance-associated amino acid variants in direct-antiviral-agent-naïve patients with chronic hepatitis: single-centre experience

  • Tina RuggieroEmail author
  • Alex Proietti
  • Lucio Boglione
  • Maria Grazia Milia
  • Tiziano Allice
  • Elisa Burdino
  • Giancarlo Orofino
  • Stefano Bonora
  • Giovanni Di Perri
  • Valeria Ghisetti
Rapid Communication


In the era of direct-acting antiviral agents (DAAs), hepatitis C virus (HCV) genotyping tests at baseline are controversial. The HCV NS3-Q80K polymorphism is associated with resistance to the recently approved NS3 inhibitor simeprevir (SMV) when combined with PEG-interferon and ribavirin (PEG-IFN/RBV) and alternative therapy should be considered for patients with baseline Q80K. The aim of this study was to provide an estimate of Q80K prevalence at baseline in a study group of 205 DAA-naïve patients (21 % of them with HIV coinfection) using NS3 full-population direct sequencing to detect resistance-associated amino acid variants (RAVs). NS3 RAVs were identified in 56 patients (27.3 %). Q80K was the most frequently reported one (41 %), in both HIV/HCV-coinfected and HCV-monoinfected patients, but it was only detectable in cases of HCV-subtype 1a infection. Therefore, in clinical practice, an NS3-Q80K genotyping test prior to simeprevir plus PEG-IFN/RBV treatment is highly recommended.


Sustained Virological Response Sofosbuvir Potent Antiviral Agent Baseline RAVs Baseline Q80K 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Liang TJ, Ghany MG (2013) Current and future therapies for hepatitis C virus infection. N Engl J Med 368:1907–1917. doi: 10.1056/NEJMra1213651 PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Schneider MD, Sarrazin C (2014) Antiviral therapy of hepatitis C in 2014: do we need resistance testing? Antiviral Res 105:64–71. doi: 10.1016/j.antiviral.2014.02.011 CrossRefPubMedGoogle Scholar
  3. 3.
    De Luca A, Bianco C, Rossetti B (2014) Treatment of HCV infection with the novel NS3/4A protease inhibitors. Curr Opin Pharmacol 18C:9–17. doi: 10.1016/j.coph.2014.07.016 CrossRefGoogle Scholar
  4. 4.
    Schweitzer CJ, Liang TJ (2013) Impact of host and virus genome variability on HCV replication and response to interferon. Curr Opin Virol 3:501–507. doi: 10.1016/j.coviro.2013.06.005 PubMedCentralCrossRefPubMedGoogle Scholar
  5. 5.
    Bartels DJ, Zhou Y, Zhang EZ et al (2008) Natural prevalence of hepatitis C virus variants with decreased sensitivity to NS3.4A protease inhibitors in treatment-naive subjects. J Infect Dis 198:800–807. doi: 10.1086/591141 CrossRefPubMedGoogle Scholar
  6. 6.
    Vicenti I, Rosi A, Saladini F et al (2012) Naturally occurring hepatitis C virus (HCV) NS3/4A protease inhibitor resistance-related mutations in HCV genotype 1-infected subjects in Italy. J Antimicrob Chemother 67:984–987. doi: 10.1093/jac/dkr581 CrossRefPubMedGoogle Scholar
  7. 7.
    Sarrazin C, Kieffer TL, Bartels D et al (2007) Dynamic hepatitis C virus genotypic and phenotypic changes in patients treated with the protease inhibitor telaprevir. Gastroenterology 132:1767–1777. doi: 10.1053/j.gastro.2007.02.037 CrossRefPubMedGoogle Scholar
  8. 8.
    Susser S, Welsch C, Wang Y et al (2009) Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. Hepatology 50:1709–1718. doi: 10.1002/hep.23192 CrossRefPubMedGoogle Scholar
  9. 9.
    Boglione L, De Nicolò A, Cardellino CS et al (2015) Relationship between the early Boceprevir-S isomer plasma concentrations and the onset of breakthrough during HCV genotype 1 triple therapy. Clin Microbiol Infect 21(205):e1–e3. doi: 10.1016/j.cmi.2014.07.009 PubMedGoogle Scholar
  10. 10.
    Palanisamy N, Danielsson A, Kokkula C et al (2013) Implications of baseline polymorphisms for potential resistance to NS3 protease inhibitors in Hepatitis C virus genotypes 1a, 2b and 3a. Antiviral Res 99:12–17. doi: 10.1016/j.antiviral.2013.04.018 CrossRefPubMedGoogle Scholar
  11. 11.
    Jacobson IM, Dore GJ, Foster GR et al (2014) Simeprevir with pegylated interferon alfa 2a plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-1): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet 384:403–413. doi: 10.1016/S0140-6736(14)60494-3 CrossRefPubMedGoogle Scholar
  12. 12.
    Manns M, Marcellin P, Poordad F et al (2014) Simeprevir with pegylated interferon alfa 2a or 2b plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 infection (QUEST-2): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 384:414–426. doi: 10.1016/S0140-6736(14)60538-9 CrossRefPubMedGoogle Scholar
  13. 13.
    Lenz O, Verbinnen T, Lin TI et al (2010) In vitro resistance profile of the hepatitis C virus NS3/4A protease inhibitor TMC435. Antimicrob Agents Chemother 54:1878–1887. doi: 10.1128/AAC.01452-09 PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Vallet S, Viron F, Henquell C et al (2011) NS3 protease polymorphism and natural resistance to protease inhibitors in French patients infected with HCV genotypes 1-5. Antiviral Ther 16:1093–1102. doi: 10.3851/IMP1900 CrossRefGoogle Scholar
  15. 15.
    Shepherd SJ, Abdelrahman T, MacLean AR et al (2015) Prevalence of HCV NS3 pre-treatment resistance associated amino acid variants within a Scottish cohort. J Clin Virol 65:50–53. doi: 10.1016/j.jcv.2015.02.005 CrossRefPubMedGoogle Scholar
  16. 16.
    Nguyen LT, Gray E, Dean J, Carr M, Connell J, De Gascun C, Nguyen LA, O’Leary A, Bergin C, Hall WNS (2015) Baseline prevalence and emergence of protease inhibitor resistance mutations following treatment in chronic HCV genotype 1-infected individuals. Antiviral Ther 107:3851. doi: 10.3851/IMP2964 Google Scholar
  17. 17.
    Manns MP, Fried MW, Zeuzem S et al (2014) Simeprevir with peginterferon/ribavirin for treatment of chronic hepatitis C virus genotype 1 infection: pooled safety analysis from Phase IIb and III studies. J Viral Hepat 22:366–375. doi: 10.1111/jvh.12346 CrossRefPubMedGoogle Scholar
  18. 18.
    Bae A, Sun SC, Qi X et al (2010) Susceptibility of treatment-naive hepatitis C virus (HCV) clinical isolates to HCV protease inhibitors. Antimicrob Agents Chemother 54:5288–5297. doi: 10.1128/AAC.00777-10 PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Pickett BE, Striker R, Lefkowitz EJ (2011) Evidence for separation of HCV subtype 1a into two distinct clades. J Viral Hepat 18:608–618. doi: 10.1111/j.1365-2893.2010.01342.x PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Sarrazin C, Lathouwers E, Peeters M et al (2015) Prevalence of the hepatitis C virus NS3 polymorphism Q80K in genotype 1 patients in the European region. Antiviral Res 116:10–16. doi: 10.1016/j.antiviral.2015.01.003 CrossRefPubMedGoogle Scholar
  21. 21.
    Lawitz E, Sulkowski MS, Ghalib R et al (2014) Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study. Lancet 384:1756–1765. doi: 10.1016/S0140-6736(14)61036-9 CrossRefPubMedGoogle Scholar
  22. 22.
    EASL (European Association for Study of Liver) (2014) EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 60:392–420. doi: 10.1016/j.jhep.2013.11.003 CrossRefGoogle Scholar
  23. 23.
    Janssen (2013) Olysio (Simeprevir). Highlights of prescribing information. Janssen Product, LP, TitusvilleGoogle Scholar
  24. 24.
    Berger KL, Triki I, Cartier M et al (2014) Baseline hepatitis C virus (HCV) NS3 polymorphisms and their impact on treatment response in clinical studies of the HCV NS3 protease inhibitor faldaprevir. Antimicrob Agents Chemother 58:698–705. doi: 10.1128/AAC.01976-13 PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    HCV, DRM (HCV Phenotype Working Group). HCV Drug Development Advisory Group (2012) Clinically relevant HCV Drug resistance mutations figure and tables. Public Health 14:1–8Google Scholar
  26. 26.
    Morsica G, Bagaglio S, Uberti-Foppa C, LA Galli L (2009) Detection of hepatitis C mutants with natural resistance to NS3/4A protease inhibitors in HIV-HCV coinfected individuals treated with antiretroviral therapy. J Acquir Immune Defic Syndr 51(106–10):104–110Google Scholar
  27. 27.
    Ogishi M, Yotsuyanagi H, Tsutsumi T et al (2015) Deconvoluting the composition of low-frequency hepatitis C viral quasispecies: comparison of genotypes and NS3 resistance-associated variants between HCV/HIV coinfected hemophiliacs and HCV monoinfected patients in Japan. PLoS ONE 10:e0119145. doi: 10.1371/journal.pone.0119145 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Silva T, Cortes Martins H, Coutinho R, Leitao E, Silva RPE (2015) Molecular characterization of hepatitis C virus for determination of subtypes and detection of resistance mutations to protease inhibitors in a group of intravenous drug users co-infected with HIV. J Med Virol. doi: 10.1002/jmv.24213 Google Scholar
  29. 29.
    Ehret R, Neifer S, Walter H et al (2014) Appearance of NS3 Q80K mutation in HCV genotype 1a mono- or HIV/HCV co-infected patients in a Berlin laboratory. J Int AIDS Soc 17:19741PubMedCentralPubMedGoogle Scholar
  30. 30.
    Halfon P, Bourliere MKH et al (2008) Mutation rate in hepatitis C virus NS3 protease is not influenced by HIV-1 protease inhibitor therapy. AIDS 22(1683–1):1683–1698Google Scholar
  31. 31.
    Trimoulet P, Belzunce C, Faure M et al (2011) Hepatitis C virus (HCV) protease variability and anti-HCV protease inhibitor resistance in HIV/HCV-coinfected patients. HIV Med 12:506–509. doi: 10.1111/j.1468-1293.2011.00913.x CrossRefPubMedGoogle Scholar
  32. 32.
    Kieffer TL, George S (2014) Resistance to hepatitis C virus protease inhibitors. Curr Opin Virol 8:16–21CrossRefPubMedGoogle Scholar
  33. 33.
    Lenz O, Fevery K, Thys K et al (2013) Simeprevir in HCV genotype-1-infected patients: deep sequencing analyses of the PILLAR and ASPIRE Phase IIb trials. Antiviral Ther 18 suppl 1A:14Google Scholar

Copyright information

© Springer-Verlag Wien 2015

Authors and Affiliations

  • Tina Ruggiero
    • 1
    Email author
  • Alex Proietti
    • 1
  • Lucio Boglione
    • 3
  • Maria Grazia Milia
    • 1
  • Tiziano Allice
    • 1
  • Elisa Burdino
    • 1
  • Giancarlo Orofino
    • 2
  • Stefano Bonora
    • 3
  • Giovanni Di Perri
    • 3
  • Valeria Ghisetti
    • 1
  1. 1.Laboratory of Microbiology and Virology, Department of Infectious DiseasesAmedeo di Savoia HospitalTurinItaly
  2. 2.Unit A of Infectious Diseases, Department of Infectious DiseasesAmedeo di Savoia HospitalTurinItaly
  3. 3.Unit of Infectious Diseases, Department of Medical Sciences, Amedeo di Savoia HospitalUniversity of TurinTurinItaly

Personalised recommendations