Natural occurrence of NS5B inhibitor resistance-associated variants in Brazilian patients infected with HCV or HCV and HIV

Abstract

Resistance-associated variants (RAVs) represent a challenge to the success of new HCV therapies. The aim of this study was to describe the prevalence of naturally occurring NS5B RAVs in Brazilian direct acting antivirals (DAA)-naïve patients infected with HCV genotype 1, or co-infected with HIV. Patient enrollment and sample collection were performed between 2011 and 2013. Using Sanger-based sequencing, 244 sequences were obtained. RAVs detected in HCV-1a sequences were V321A (1.6 %), M414V (1.3 %), A421V (21.4-23.7 %), A421G (1.3 %) and Y448H (1.3 %); and in HCV-1b sequences were L159F (16.1 %), C316N (7.1-16.3 %) and A421V (3.2-6.3 %). Understanding the real RAVs scenario in patients is fundamental to establishing the most effective therapeutic strategy and in minimizing the risks for their selection.

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References

  1. 1.

    Hajarizadeh B, Grebely J, Dore GJ (2013) Epidemiology and natural history of HCV infection. Nat Rev Gastroenterol Hepatol 10:553–562

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Morsica G, Bagaglio S, Cicconi P, Capobianchi MR, Pellizzer G, Caramello P, Orani A, Moioli C, Rizzardini G, Uberti-Foppa C, Puoti M, Monforte AD (2009) Viral interference between hepatitis B, C, and D viruses in dual and triple infections in HIV-positive patients. J Acquir Immune Defic Syndr 51:574–581

    Article  PubMed  Google Scholar 

  3. 3.

    Sulkowski MS, Thomas DL (2003) Hepatitis C in the HIV-infected patient. Clin Liver Dis 7:179–194

    Article  PubMed  Google Scholar 

  4. 4.

    Weber R, Sabin CA, Friis-Moller N, Reiss P, El-Sadr WM, Kirk O, Dabis F, Law MG, Pradier C, De Wit S, Akerlund B, Calvo G, Monforte A, Rickenbach M, Ledergerber B, Phillips AN, Lundgren JD (2006) Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A: D study. Arch Intern Med 166:1632–1641

    Article  PubMed  Google Scholar 

  5. 5.

    Gower E, Estes C, Blach S, Razavi-Shearer K, Razavi H (2014) Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 61:S45–S57

    Article  PubMed  Google Scholar 

  6. 6.

    Pereira LM, Martelli CM, Moreira RC, Merchan-Hamman E, Stein AT, Cardoso MR, Figueiredo GM, Montarroyos UR, Braga C, Turchi MD, Coral G, Crespo D, Lima ML, Alencar LC, Costa M, dos Santos AA, Ximenes RA (2013) Prevalence and risk factors of hepatitis C virus infection in Brazil, 2005 through 2009: a cross-sectional study. BMC Infect Dis 13:60

    Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Campiotto S, Pinho JR, Carrilho FJ, Da Silva LC, Souto FJ, Spinelli V, Pereira LM, Coelho HS, Silva AO, Fonseca JC, Rosa H, Lacet CM, Bernardini AP (2005) Geographic distribution of hepatitis C virus genotypes in Brazil. Braz J Med Biol Res 38:41–49

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Rockstroh JK (2015) Optimal therapy of HIV/HCV co-infected patients with direct acting antivirals. Liver Int 35(Suppl 1):51–55

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Sarrazin C (2016) The importance of resistance to direct antiviral drugs in HCV infection in clinical practice. J Hepatol 64:486–504

    Article  PubMed  Google Scholar 

  10. 10.

    Feld JJ (2014) Interferon-free strategies with a nucleoside/nucleotide analogue. Semin Liver Dis 34:37–46

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Franco S, Casadella M, Noguera-Julian M, Clotet B, Tural C, Paredes R, Martinez MA (2013) No detection of the NS5B S282T mutation in treatment-naive genotype 1 HCV/HIV-1 coinfected patients using deep sequencing. J Clin Virol 58:726–729

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, Hindes RG, Berrey MM (2013) Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. N Engl J Med 368:34–44

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Nguyen LT, Hall N, Sheerin D, Carr M, De Gascun CF (2016) Naturally occurring HCV NS5A/B inhibitor resistance-associated mutations to direct-acting antivirals. Antivir Ther 21:447–453

    Article  PubMed  Google Scholar 

  14. 14.

    Svarovskaia ES, Dvory-Sobol H, Parkin N, Hebner C, Gontcharova V, Martin R, Ouyang W, Han B, Xu S, Ku K, Chiu S, Gane E, Jacobson IM, Nelson DR, Lawitz E, Wyles DL, Bekele N, Brainard D, Symonds WT, McHutchison JG, Miller MD, Mo H (2014) Infrequent development of resistance in genotype 1–6 hepatitis C virus-infected subjects treated with sofosbuvir in phase 2 and 3 clinical trials. Clin Infect Dis 59:1666–1674

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Gaudieri S, Rauch A, Pfafferott K, Barnes E, Cheng W, McCaughan G, Shackel N, Jeffrey GP, Mollison L, Baker R, Furrer H, Gunthard HF, Freitas E, Humphreys I, Klenerman P, Mallal S, James I, Roberts S, Nolan D, Lucas M (2009) Hepatitis C virus drug resistance and immune-driven adaptations: relevance to new antiviral therapy. Hepatology 49:1069–1082

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Lawitz E, Poordad F, Kowdley KV, Cohen DE, Podsadecki T, Siggelkow S, Larsen L, Menon R, Koev G, Tripathi R, Pilot-Matias T, Bernstein B (2013) A phase 2a trial of 12-week interferon-free therapy with two direct-acting antivirals (ABT-450/r, ABT-072) and ribavirin in IL28B C/C patients with chronic hepatitis C genotype 1. J Hepatol 59:18–23

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Donaldson EF, Harrington PR, O’Rear JJ, Naeger LK (2015) Clinical evidence and bioinformatics characterization of potential hepatitis C virus resistance pathways for sofosbuvir. Hepatology 61:56–65

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Castilho MC, Martins AN, Horbach IS, Perez Rde M, Figueiredo FA, Pinto Pde T, Nabuco LC, Lima DB, Tanuri A, Porto LC, Ferreira Junior Oda C (2011) Association of hepatitis C virus NS5B variants with resistance to new antiviral drugs among untreated patients. Mem Inst Oswaldo Cruz 106:968–975

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Hall T (1999) BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucl Acids Symp Ser 41:95–98

    CAS  Google Scholar 

  20. 20.

    Tamura K, Stecher G, Peterson D, Filipski A, Kumar S (2013) MEGA6: molecular evolutionary genetics analysis version 6.0. Mol Biol Evol 30:2725–2729

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Lontok E, Harrington P, Howe A, Kieffer T, Lennerstrand J, Lenz O, McPhee F, Mo H, Parkin N, Pilot-Matias T, Miller V (2015) Hepatitis C virus drug resistance-associated substitutions: state of the art summary. Hepatology 62:1623–1632

    Article  PubMed  Google Scholar 

  22. 22.

    Gamal N, Andreone P (2015) Working together to tackle HCV infection: ombitasvir/paritaprevir/ritonavir and dasabuvir combination. Drugs Today (Barc) 51:303–314

    CAS  Article  Google Scholar 

  23. 23.

    McQuaid T, Savini C, Seyedkazemi S (2015) Sofosbuvir, a significant paradigm change in HCV treatment. J Clin Transl Hepatol 3:27–35

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Lawitz E, Jacobson IM, Nelson DR, Zeuzem S, Sulkowski MS, Esteban R, Brainard D, McNally J, Symonds WT, McHutchison JG, Dieterich D, Gane E (2015) Development of sofosbuvir for the treatment of hepatitis C virus infection. Ann N Y Acad Sci 1358:56–67

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Pawlotsky JM (2015) Hepatitis C treatment: the data flood goes on-an update from the liver meeting 2014. Gastroenterology 148:468–479

    Article  PubMed  Google Scholar 

  26. 26.

    Ludmerer SW, Graham DJ, Boots E, Murray EM, Simcoe A, Markel EJ, Grobler JA, Flores OA, Olsen DB, Hazuda DJ, LaFemina RL (2005) Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob Agents Chemother 49:2059–2069

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Andre-Garnier E, Ribeyrol O, Gournay J, Besse B, Coste-Burel M, Mabille-Archambeaud I, Billaud E, Biron C, Pineau S, Raffi F, Imbert-Marcille BM (2016) Emergence of HCV resistance-associated variants in patients failing sofosbuvir-based regimens: an observational cohort. Antivir Ther. doi:10.3851/IMP3053

    PubMed  Google Scholar 

  28. 28.

    Hedskog C, Dvory-Sobol H, Gontcharova V, Martin R, Ouyang W, Han B, Gane EJ, Brainard D, Hyland RH, Miller MD, Mo H, Svarovskaia E (2015) Evolution of the HCV viral population from a patient with S282T detected at relapse after sofosbuvir monotherapy. J Viral Hepat 22:871–881

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Svarovskaia ES, Gane E, Dvory-Sobol H, Martin R, Doehle B, Hedskog C, Jacobson IM, Nelson DR, Lawitz E, Brainard DM, McHutchison JG, Miller MD, Mo H (2015) L159F and V321A sofosbuvir-associated hepatitis C virus NS5B substitutions. J Infect Dis 213:1240–1247

    Article  PubMed  Google Scholar 

  30. 30.

    Ito J, Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kumagai K, Kikuchi H, Miyagishima T, Kobayashi T, Kimura M, Yamasaki K, Umemura M, Izumi T, Tsunematsu S, Sato F, Tsukuda Y, Terashita K, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N (2016) Prevalence and characteristics of naturally occurring sofosbuvir resistance-associated variants in patients with hepatitis C virus genotype 1b infection. Hepatol Res

  31. 31.

    Eltahla AA, Luciani F, White PA, Lloyd AR, Bull RA (2015) Inhibitors of the hepatitis C virus polymerase; mode of action and resistance. Viruses 7:5206–5224

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Bartels DJ, Sullivan JC, Zhang EZ, Tigges AM, Dorrian JL, De Meyer S, Takemoto D, Dondero E, Kwong AD, Picchio G, Kieffer TL (2013) Hepatitis C virus variants with decreased sensitivity to direct-acting antivirals (DAAs) were rarely observed in DAA-naive patients prior to treatment. J Virol 87:1544–1553

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Halfon P, Sarrazin C (2012) Future treatment of chronic hepatitis C with direct acting antivirals: is resistance important? Liver Int 32(Suppl 1):79–87

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Legrand-Abravanel F, Henquell C, Le Guillou-Guillemette H, Balan V, Mirand A, Dubois M, Lunel-Fabiani F, Payan C, Izopet J (2009) Naturally occurring substitutions conferring resistance to hepatitis C virus polymerase inhibitors in treatment-naive patients infected with genotypes 1-5. Antivir Ther 14:723–730

    CAS  PubMed  Google Scholar 

  35. 35.

    Aissa Larousse J, Trimoulet P, Recordon-Pinson P, Papuchon J, Azzouz MM, Ben Mami N, Cheikh I, Triki H, Fleury H (2014) Natural prevalence of hepatitis C virus (HCV) variants resistant to protease and polymerase inhibitors in patients infected with HCV genotype 1 in Tunisia. J Med Virol 86:1350–1359

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Everson GT, Sims KD, Thuluvath PJ, Lawitz E, Hassanein T, Rodriguez-Torres M, Desta T, Hawkins T, Levin JM, Hinestrosa F, Rustgi V, Schwartz H, Younossi Z, Webster L, Gitlin N, Eley T, Huang SP, McPhee F, Grasela DM, Gardiner DF (2016) Daclatasvir + asunaprevir + beclabuvir +/− ribavirin for chronic HCV genotype 1-infected treatment-naive patients. Liver Int 36:189–197

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Patino-Galindo JA, Salvatierra K, Gonzalez-Candelas F, Lopez-Labrador FX (2016) Comprehensive screening for naturally occurring hepatitis C virus resistance to direct-acting antivirals in the NS3, NS5A, and NS5B genes in worldwide isolates of viral genotypes 1 to 6. Antimicrob Agents Chemother 60:2402–2416

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Correspondence to Fernanda Malta.

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The authors declare that they have no conflict of interest.

Financial support

This project was supported by grant 2011/50633-4 São Paulo Research Foundation (FAPESP) and Alves de Queiroz Family Fund for Research. João Renato Rebello Pinho and Maria Cassia Mendes Correa receive fellowships from CNPq (Bolsista de Produtividade). Caroline Furtado Noble is a graduate student from the Department of Gastroenterology at the University of São Paulo who received a fellowship from CAPEs.

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Noble, C.F., Malta, F., Lisboa-Neto, G. et al. Natural occurrence of NS5B inhibitor resistance-associated variants in Brazilian patients infected with HCV or HCV and HIV. Arch Virol 162, 165–169 (2017). https://doi.org/10.1007/s00705-016-3094-2

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Keywords

  • Human Immunodeficiency Virus
  • Sofosbuvir
  • NS5B Region
  • NS5A RAVs
  • NS5B Gene