1887

Abstract

host genetic make-up is known to play a critical role in the outcome of genotype 1 hepatitis C virus (HCV) infection in the context of both primary infection and therapy. However, the role of in subtype 3a infection remains unclear, and has not yet been assessed in the UK population where subtype 3a is dominant. In this study, we evaluated the role of the single-nucleotide polymorphism rs8099917 in 201 patients recruited from two well-defined cohorts (from Nottingham and Oxford), treated with the standard-of-care therapy of pegylated interferon and ribavirin for 24 weeks. We showed that the ‘favourable’ gene was associated with a rapid virological response to therapy at 4 weeks (<0.0001), but not with a sustained virological response to therapy. The median viral load at baseline, before therapy, was markedly increased in people with the ‘favourable’ genotype [median viral load for the TT allele, 925 961 IU ml (range 2200–21 116 965 IU ml), and for the GT or GG allele, 260 284 IU ml (range 740–7 560 000 IU ml);  = 0.0010]. Our results suggest that the host genetic response plays an important role in early viral clearance of subtype 3a virus from the blood. However, significant reservoirs of infection must persist, as viral relapse is common, even in those with the favourable host genotype.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.051052-0
2013-06-01
2019-10-16
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/6/1259.html?itemId=/content/journal/jgv/10.1099/vir.0.051052-0&mimeType=html&fmt=ahah

References

  1. Bochud P. Y. , Bibert S. , Kutalik Z. , Patin E. , Guergnon J. , Nalpas B. , Goossens N. , Kuske L. , Müllhaupt B. . & other authors ( 2012; ). IL28B alleles associated with poor hepatitis C virus (HCV) clearance protect against inflammation and fibrosis in patients infected with non-1 HCV genotypes. . Hepatology 55:, 384–394. [CrossRef] [PubMed]
    [Google Scholar]
  2. De Nicola S. , Aghemo A. , Rumi M. G. , Galmozzi E. , Valenti L. , Soffredini R. , De Francesco R. , Prati G. M. , D’Ambrosio R. . & other authors ( 2012; ). Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4. . Hepatology 55:, 336–342. [CrossRef] [PubMed]
    [Google Scholar]
  3. Fried M. W. , Shiffman M. L. , Reddy K. R. , Smith C. , Marinos G. , Gonçales F. L. Jr , Häussinger D. , Diago M. , Carosi G. . & other authors ( 2002; ). Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. . N Engl J Med 347:, 975–982. [CrossRef] [PubMed]
    [Google Scholar]
  4. Ge D. , Fellay J. , Thompson A. J. , Simon J. S. , Shianna K. V. , Urban T. J. , Heinzen E. L. , Qiu P. , Bertelsen A. H. . & other authors ( 2009; ). Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. . Nature 461:, 399–401. [CrossRef] [PubMed]
    [Google Scholar]
  5. Hayes C. N. , Kobayashi M. , Akuta N. , Suzuki F. , Kumada H. , Abe H. , Miki D. , Imamura M. , Ochi H. . & other authors ( 2011; ). HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy. . Gut 60:, 261–267. [CrossRef] [PubMed]
    [Google Scholar]
  6. Health Protection Agency ( 2009; ). Hepatitis C in the UK: Annual Report 2009. . London:: Health Protection Agency Centre for Infections;.
  7. Hézode C. , Forestier N. , Dusheiko G. , Ferenci P. , Pol S. , Goeser T. , Bronowicki J. P. , Bourlière M. , Gharakhanian S. . & other authors ( 2009; ). Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. . N Engl J Med 360:, 1839–1850. [CrossRef] [PubMed]
    [Google Scholar]
  8. Ishak K. , Baptista A. , Bianchi L. , Callea F. , De Groote J. , Gudat F. , Denk H. , Desmet V. , Korb G. . & other authors ( 1995; ). Histological grading and staging of chronic hepatitis. . J Hepatol 22:, 696–699.[CrossRef]
    [Google Scholar]
  9. Jacobson I. M. , McHutchison J. G. , Dusheiko G. , Di Bisceglie A. M. , Reddy K. R. , Bzowej N. H. , Marcellin P. , Muir A. J. , Ferenci P. . & other authors ( 2011; ). Telaprevir for previously untreated chronic hepatitis C virus infection. . N Engl J Med 364:, 2405–2416. [CrossRef] [PubMed]
    [Google Scholar]
  10. Kwo P. Y. , Lawitz E. J. , McCone J. , Schiff E. R. , Vierling J. M. , Pound D. , Davis M. N. , Galati J. S. , Gordon S. C. . & other authors ( 2010; ). Efficacy of boceprevir, an NS3 protease inhibitor, in combination with peginterferon alfa-2b and ribavirin in treatment-naive patients with genotype 1 hepatitis C infection (SPRINT-1): an open-label, randomised, multicentre phase 2 trial. . Lancet 376:, 705–716. [CrossRef] [PubMed]
    [Google Scholar]
  11. Labie D. , Gilgenkrantz H. . ( 2010; ). [IL28 (interferon λ3) gene polymorphisms and response to IFN-α treatment in patients infected with hepatitis virus C]. . Med Sci (Paris) 26:, 225–226 (in French). [CrossRef] [PubMed]
    [Google Scholar]
  12. Lindh M. , Lagging M. , Färkkilä M. , Langeland N. , Mørch K. , Nilsson S. , Norkrans G. , Pedersen C. , Buhl M. R. . & other authors ( 2011; ). Interleukin 28B gene variation at rs12979860 determines early viral kinetics during treatment in patients carrying genotypes 2 or 3 of hepatitis C virus. . J Infect Dis 203:, 1748–1752. [CrossRef] [PubMed]
    [Google Scholar]
  13. Mangia A. , Santoro R. , Minerva N. , Ricci G. L. , Carretta V. , Persico M. , Vinelli F. , Scotto G. , Bacca D. . & other authors ( 2005; ). Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. . N Engl J Med 352:, 2609–2617. [CrossRef] [PubMed]
    [Google Scholar]
  14. Mangia A. , Thompson A. J. , Santoro R. , Piazzolla V. , Tillmann H. L. , Patel K. , Shianna K. V. , Mottola L. , Petruzzellis D. . & other authors ( 2010; ). An IL28B polymorphism determines treatment response of hepatitis C virus genotype 2 or 3 patients who do not achieve a rapid virologic response. . Gastroenterology 139:, 821–827.[CrossRef]
    [Google Scholar]
  15. Manns M. P. , McHutchison J. G. , Gordon S. C. , Rustgi V. K. , Shiffman M. , Reindollar R. , Goodman Z. D. , Koury K. , Ling M. , Albrecht J. K. . ( 2001; ). Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. . Lancet 358:, 958–965. [CrossRef] [PubMed]
    [Google Scholar]
  16. McCarthy J. J. , Li J. H. , Thompson A. , Suchindran S. , Lao X. Q. , Patel K. , Tillmann H. L. , Muir A. J. , McHutchison J. G. . ( 2010; ). Replicated association between an IL28B gene variant and a sustained response to pegylated interferon and ribavirin. . Gastroenterology 138:, 2307–2314. [CrossRef] [PubMed]
    [Google Scholar]
  17. McHutchison J. G. , Everson G. T. , Gordon S. C. , Jacobson I. M. , Sulkowski M. , Kauffman R. , McNair L. , Alam J. , Muir A. J. . PROVE1 Study Team ( 2009; ). Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. . N Engl J Med 360:, 1827–1838. [CrossRef] [PubMed]
    [Google Scholar]
  18. Moghaddam A. , Melum E. , Reinton N. , Ring-Larsen H. , Verbaan H. , Bjøro K. , Dalgard O. . ( 2011; ). IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection. . Hepatology 53:, 746–754. [CrossRef] [PubMed]
    [Google Scholar]
  19. Montes-Cano M. A. , García-Lozano J. R. , Abad-Molina C. , Romero-Gómez M. , Barroso N. , Aguilar-Reina J. , Núñez-Roldán A. , González-Escribano M. F. . ( 2010; ). Interleukin-28B genetic variants and hepatitis virus infection by different viral genotypes. . Hepatology 52:, 33–37. [CrossRef] [PubMed]
    [Google Scholar]
  20. Mosbruger T. L. , Duggal P. , Goedert J. J. , Kirk G. D. , Hoots W. K. , Tobler L. H. , Busch M. , Peters M. G. , Rosen H. R. . & other authors ( 2010; ). Large-scale candidate gene analysis of spontaneous clearance of hepatitis C virus. . J Infect Dis 201:, 1371–1380. [CrossRef] [PubMed]
    [Google Scholar]
  21. Poordad F. , McCone J. Jr , Bacon B. R. , Bruno S. , Manns M. P. , Sulkowski M. S. , Jacobson I. M. , Reddy K. R. , Goodman Z. D. . & other authors ( 2011; ). Boceprevir for untreated chronic HCV genotype 1 infection. . N Engl J Med 364:, 1195–1206. [CrossRef] [PubMed]
    [Google Scholar]
  22. Rallón N. I. , Naggie S. , Benito J. M. , Medrano J. , Restrepo C. , Goldstein D. , Shianna K. V. , Vispo E. , Thompson A. . & other authors ( 2010; ). Association of a single nucleotide polymorphism near the interleukin-28B gene with response to hepatitis C therapy in HIV/hepatitis C virus-coinfected patients. . AIDS 24:, F23–F29. [CrossRef] [PubMed]
    [Google Scholar]
  23. Rauch A. , Kutalik Z. , Descombes P. , Cai T. , Di Iulio J. , Mueller T. , Bochud M. , Battegay M. , Bernasconi E. . & other authors ( 2010; ). Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. . Gastroenterology 138:, 1338–1345.[CrossRef]
    [Google Scholar]
  24. Scherzer T. M. , Stättermayer A. F. , Strasser M. , Laferl H. , Maieron A. , Stauber R. , Datz C. , Dulic-Lakovic E. , Steindl-Munda P. . & other authors ( 2011; ). Impact of IL28B on treatment outcome in hepatitis C virus G1/4 patients receiving response-guided therapy with peginterferon alpha-2a (40KD)/ribavirin. . Hepatology 54:, 1518–1526. [CrossRef] [PubMed]
    [Google Scholar]
  25. Sherman K. E. , Flamm S. L. , Afdhal N. H. , Nelson D. R. , Sulkowski M. S. , Everson G. T. , Fried M. W. , Adler M. , Reesink H. W. . & other authors ( 2011; ). Response-guided telaprevir combination treatment for hepatitis C virus infection. . N Engl J Med 365:, 1014–1024. [CrossRef] [PubMed]
    [Google Scholar]
  26. Smith K. R. , Suppiah V. , O’Connor K. , Berg T. , Weltman M. , Abate M. L. , Spengler U. , Bassendine M. , Matthews G. . & other authors ( 2011; ). Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. . Genome Med 3:, 57.[CrossRef]
    [Google Scholar]
  27. Suppiah V. , Moldovan M. , Ahlenstiel G. , Berg T. , Weltman M. , Abate M. L. , Bassendine M. , Spengler U. , Dore G. J. . & other authors ( 2009; ). IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. . Nat Genet 41:, 1100–1104. [CrossRef] [PubMed]
    [Google Scholar]
  28. Tanaka Y. , Nishida N. , Sugiyama M. , Kurosaki M. , Matsuura K. , Sakamoto N. , Nakagawa M. , Korenaga M. , Hino K. . & other authors ( 2009; ). Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. . Nat Genet 41:, 1105–1109. [CrossRef] [PubMed]
    [Google Scholar]
  29. Thomas D. L. , Thio C. L. , Martin M. P. , Qi Y. , Ge D. , O’Huigin C. , Kidd J. , Kidd K. , Khakoo S. I. . & other authors ( 2009; ). Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. . Nature 461:, 798–801. [CrossRef] [PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.051052-0
Loading
/content/journal/jgv/10.1099/vir.0.051052-0
Loading

Data & Media loading...

Most Cited This Month

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error