Influence of human T-lymphotropic virus type 1 coinfection on the development of hepatocellular carcinoma in patients with hepatitis C virus infection

Abstract

Background

Human T-lymphotropic virus type 1 (HTLV-1) may worsen the clinical course of hepatitis C virus (HCV) infection. The aim of this study was to investigate whether HTLV-1 coinfection influences the clinical characteristics of patients with HCV infection.

Methods

This retrospective study included 523 consecutive patients from January 2001 to December 2010 with chronic liver disease due to HCV infection, in whom serum anti-HTLV-1 antibodies were examined. Among these patients, 265 were diagnosed with hepatocellular carcinoma (HCC).

Results

The seroprevalence of anti-HTLV-1 antibodies was significantly higher in patients with HCC (21.1 %) than those without HCC (10.5 %, P = 0.001). This significant difference was observed in female patients (29.5 vs. 8.5 %, P < 0.001), but not in male patients (16.5 vs. 12.9 %, P = 0.501). In multivariate analysis, anti-HTLV-1 antibody positivity was independently associated with HCC in female patients [odds ratio (OR), 5.029; 95 % confidence interval (95 % CI), 1.760–14.369; P = 0.003], in addition to age (≥65 years; OR, 10.297; 95 % CI, 4.322–24.533; P < 0.001), platelet count (<15 × 104/μL; OR, 2.715; 95 % CI, 1.050–7.017; P = 0.039), total bilirubin (≥1 mg/dL; OR, 3.155; 95 % CI, 1.365–7.292; P = 0.007), and total cholesterol (≤160 mg/dL; OR, 2.916; 95 % CI, 1.341–6.342; P = 0.007). In contrast, HTLV-1 coinfection was not associated with HCC in male patients, although age, alcohol consumption, platelet count, and albumin were independently associated with HCC.

Conclusions

HTLV-1 coinfection may contribute to the development of HCC in patients with chronic HCV infection, especially in females.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Thomas DL, Seeff LB. Natural history of hepatitis C. Clin Liver Dis. 2005;9:383–98.

    PubMed  Article  Google Scholar 

  2. 2.

    Strader DB, Seeff LB. The natural history of chronic hepatitis C infection. Eur J Gastroenterol Hepatol. 1996;8:324–8.

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Seeff LB, Hoofnagle JH. National Institutes of Health Consensus Development Conference: management of hepatitis C: 2002. Hepatology. 2002;36:S1–2.

    PubMed  Article  Google Scholar 

  4. 4.

    Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002;36:S35–46.

    PubMed  Article  Google Scholar 

  5. 5.

    Liang TJ, Rehermann B, Seeff LB, et al. Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med. 2000;132:296–305.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology. 1997;112:463–72.

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Serfaty L, Aumaitre H, Chazouilleres O, et al. Determinants of outcome of compensated hepatitis C virus-related cirrhosis. Hepatology. 1998;27:1435–40.

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Gordon SC, Bayati N, Silverman AL. Clinical outcome of hepatitis C as a function of mode of transmission. Hepatology. 1998;28:562–7.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Degos F, Christidis C, Ganne-Carrie N, et al. Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death. Gut. 2000;47:131–6.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  10. 10.

    El-Serag HB. Epidemiology of viral hepatitis and hepatocellular carcinoma. Gastroenterology. 2012;142:1264–73.

    PubMed Central  PubMed  Article  Google Scholar 

  11. 11.

    Walter SR, Thein HH, Gidding HF, et al. Risk factors for hepatocellular carcinoma in a cohort infected with hepatitis B or C. J Gastroenterol Hepatol. 2011;26:1757–64.

    PubMed  Article  Google Scholar 

  12. 12.

    Chuang SC, Lee YC, Hashibe M, et al. Interaction between cigarette smoking and hepatitis B and C virus infection on the risk of liver cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev. 2010;19:1261–8.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  13. 13.

    Suruki R, Hayashi K, Kusumoto K, et al. Alanine aminotransferase level as a predictor of hepatitis C virus-associated hepatocellular carcinoma incidence in a community-based population in Japan. Int J Cancer. 2006;119:192–5.

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Tokudome S, Tokunaga O, Shimamoto Y, et al. Incidence of adult T-cell leukemia/lymphoma among human T-lymphotropic virus type I carriers in Saga, Japan. Cancer Res. 1989;49:226–8.

    CAS  PubMed  Google Scholar 

  15. 15.

    Arisawa K, Soda M, Endo S, et al. Evaluation of adult T-cell leukemia/lymphoma incidence and its impact on non-Hodgkin lymphoma incidence in southwestern Japan. Int J Cancer. 2000;85:319–24.

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Kondo T, Kono H, Miyamoto N, et al. Age- and sex-specific cumulative rate and risk of ATLL for HTLV-I carriers. Int J Cancer. 1989;43:1061–4.

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Gessain A, Barin F, Vernant JC, et al. Antibodies to human T-lymphotropic virus type-I in patients with tropical spastic paraparesis. Lancet. 1985;2:407–10.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Osame M, Usuku K, Izumo S, et al. HTLV-I associated myelopathy, a new clinical entity. Lancet. 1986;1:1031–2.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Yamaguchi K. Human T-lymphotropic virus type I in Japan. Lancet. 1994;343:213–6.

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Mochizuki M, Tajima K, Watanabe T, et al. Human T lymphotropic virus type 1 uveitis. Br J Ophthalmol. 1994;78:149–54.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. 21.

    Yoshida M, Seiki M, Yamaguchi K, et al. Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci USA. 1984;81:2534–7.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  22. 22.

    Takeda S, Maeda M, Morikawa S, et al. Genetic and epigenetic inactivation of tax gene in adult T-cell leukemia cells. Int J Cancer. 2004;109:559–67.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Nakashima K, Hayashi J, Hirata M, et al. Hepatitis C virus infection on Iki Island, Japan, an area endemic for human T-lymphotropic virus type-I. A preliminary study in patients at clinics or hospitals. J Epidemiol. 1994;4:17–23.

    Article  Google Scholar 

  24. 24.

    Benhamou Y, Bochet M, Di Martino V, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30:1054–8.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Graham CS, Baden LR, Yu E, et al. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001;33:562–9.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Hayashi K, Fukuda Y, Nakano I, et al. Poor response to interferon treatment for chronic hepatitis C in human immunodeficiency virus-infected haemophiliacs. Haemophilia. 2000;6:677–81.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Sauleda S, Juarez A, Esteban JI, et al. Interferon and ribavirin combination therapy for chronic hepatitis C in human immunodeficiency virus-infected patients with congenital coagulation disorders. Hepatology. 2001;34:1035–40.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Kishihara Y, Furusyo N, Kashiwagi K, et al. Human T lymphotropic virus type 1 infection influences hepatitis C virus clearance. J Infect Dis. 2001;184:1114–9.

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Ichida F, Tsuji T, Omata M, et al. New Inuyama classification; new criteria for histological assessment of chronic hepatitis. Int Hepatol Commun. 1996;6:112–9.

    Article  Google Scholar 

  30. 30.

    Okayama A, Maruyama T, Tachibana N, et al. Increased prevalence of HTLV-I infection in patients with hepatocellular carcinoma associated with hepatitis C virus. Jpn J Cancer Res. 1995;86:1–4.

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Stuver SO, Okayama A, Tachibana N, et al. HCV infection and liver cancer mortality in a Japanese population with HTLV-I. Int J Cancer. 1996;67:35–7.

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Boschi-Pinto C, Stuver S, Okayama A, et al. A follow-up study of morbidity and mortality associated with hepatitis C virus infection and its interaction with human T lymphotropic virus type I in Miyazaki. Japan. J Infect Dis. 2000;181:35–41.

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Mueller N, Okayama A, Stuver S, et al. Findings from the Miyazaki Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13:2–7.

    Article  Google Scholar 

  34. 34.

    Stuver SO, Tachibana N, Okayama A, et al. Heterosexual transmission of human T cell leukemia/lymphoma virus type I among married couples in southwestern Japan: an initial report from the Miyazaki Cohort Study. J Infect Dis. 1993;167:57–65.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Arisawa K, Soda M, Akahoshi M, et al. Human T-cell lymphotropic virus type-1 infection and risk of cancer: 15.4 year longitudinal study among atomic bomb survivors in Nagasaki, Japan. Cancer Sci. 2006;97:535–9.

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Shembade N, Harhaj EW. Role of post-translational modifications of HTLV-1 Tax in NF-kappaB activation. World J Biol Chem. 2010;1:13–20.

    PubMed Central  PubMed  Article  Google Scholar 

  37. 37.

    Nagai M, Brennan MB, Sakai JA, et al. CD8(+) T cells are an in vivo reservoir for human T-cell lymphotropic virus type I. Blood. 2001;98:1858–61.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Welles SL, Tachibana N, Okayama A, et al. Decreased reactivity to PPD among HTLV-I carriers in relation to virus and hematologic status. Int J Cancer. 1994;56:337–40.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Hishizawa M, Imada K, Kitawaki T, et al. Depletion and impaired interferon-alpha-producing capacity of blood plasmacytoid dendritic cells in human T-cell leukaemia virus type I-infected individuals. Br J Haematol. 2004;125:568–75.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Soguero C, Joo M, Chianese-Bullock KA, et al. Hepatitis C virus core protein leads to immune suppression and liver damage in a transgenic murine model. J Virol. 2002;76:9345–54.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  41. 41.

    Yonkers NL, Rodriguez B, Milkovich KA, et al. TLR ligand-dependent activation of naive CD4 T cells by plasmacytoid dendritic cells is impaired in hepatitis C virus infection. J Immunol. 2007;178:4436–44.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Zhang J, Yamada O, Kawagishi K, et al. Up-regulation of hepatitis C virus replication by human T cell leukemia virus type I-encoded Tax protein. Virology. 2007;369:198–205.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Ioannou GN, Bryson CL, Weiss NS, et al. The prevalence of cirrhosis and hepatocellular carcinoma in patients with human immunodeficiency virus infection. Hepatology. 2013;57:249–57.

    PubMed  Article  Google Scholar 

  44. 44.

    Karp DR, Shimooku K, Lipsky PE. Expression of gamma-glutamyl transpeptidase protects ramos B cells from oxidation-induced cell death. J Biol Chem. 2001;276:3798–804.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Ikeda K, Saitoh S, Suzuki Y, et al. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. J Hepatol. 1998;28:930–8.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Takahashi M, Higuchi M, Makokha GN, et al. HTLV-1 Tax oncoprotein stimulates ROS production and apoptosis in T cells by interacting with USP10. Blood. 2013;122:715–25.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Akuta N, Suzuki F, Seko Y, et al. Complicated relationships of amino acid substitution in hepatitis C virus core region and IL28B genotype influencing hepatocarcinogenesis. Hepatology. 2012;56:2134–41.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Kobayashi M, Suzuki F, Akuta N, et al. Association of two polymorphisms of the IL28B gene with viral factors and treatment response in 1,518 patients infected with hepatitis C virus. J Gastroenterol. 2012;47:596–605.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Uto H, Stuver SO, Hayashi K, et al. Increased rate of death related to presence of viremia among hepatitis C virus antibody-positive subjects in a community-based cohort study. Hepatology. 2009;50:393–9.

    PubMed  Article  Google Scholar 

  50. 50.

    Hanaoka M, Kubo T, Saitoh A. Discrepancy between human T-cell lymphotropic virus type I screening test and confirmatory tests in non-endemic areas. J Obstet Gynaecol Res. 2012;38:793–6.

    PubMed  Article  Google Scholar 

  51. 51.

    Meytes D, Schochat B, Lee H, et al. Serological and molecular survey for HTLV-I infection in a high-risk Middle Eastern group. Lancet. 1990;336:1533–5.

    CAS  PubMed  Article  Google Scholar 

Download references

Conflict of interest

H. Tsubouchi holds endowed faculty positions in research for HGF tissue repair and regenerative medicine, and has received funds from Eisai Co., Ltd. The other authors declare that they have no conflict of interest.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hirofumi Uto.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tokunaga, M., Uto, H., Oda, K. et al. Influence of human T-lymphotropic virus type 1 coinfection on the development of hepatocellular carcinoma in patients with hepatitis C virus infection. J Gastroenterol 49, 1567–1577 (2014). https://doi.org/10.1007/s00535-013-0928-5

Download citation

Keywords

  • HTLV-1
  • Risk factor
  • Hepatitis C virus
  • Hepatocellular carcinoma
  • Coinfection