Digestive Diseases and Sciences

, Volume 54, Issue 12, pp 2699–2705 | Cite as

Diabetes Mellitus Is Associated with Impaired Response to Antiviral Therapy in Chronic Hepatitis C Infection

  • Hesham M. Elgouhari
  • Claudia O. Zein
  • Ibrahim Hanouneh
  • Ariel E. Feldstein
  • Nizar N. Zein
Original Article


Insulin resistance may promote hepatic fibrosis in chronic hepatitis C (HCV) and has emerged as a cofactor in failure to achieve sustained viral response (SVR). Aims (1) To assess the association of diabetes mellitus (DM) in HCV patients to the severity of hepatic fibrosis and to the response to antiviral treatment. (2) To assess the safety of pegylated interferon and ribavirin combination therapy (Peg IFN/RBV) in diabetic HCV patients. Methods HCV diabetics (n = 61) were identified. A 2:1 matching control group was used to identify independent factors of advanced fibrosis and treatment failure. Results Compared to HCV non-diabetics, HCV diabetics were more likely to have steatosis (P < 0.0001) and advanced fibrosis (P = 0.003). Patients’ age, Caucasian ethnicity, obesity, and histologic activity index were independently associated with advanced fibrosis (P < 0.05). Only 23% of HCV diabetics achieved SVR compared to 46% of HCV non-diabetics (P = 0.003). DM, genotype 1, high baseline viral load, and African-American ethnicity were independently associated with less SVR (P < 0.05). Significant adverse events were more common in HCV diabetics compared to HCV non-diabetics (P = 0.001). Side effects did not increase in patients receiving PEG IFN/RBV and insulin sensitizers. Conclusion DM was associated with impaired virologic response to PEG IFN/RBV in HCV patients. Adverse events during therapy were more frequent in diabetic compared to non-diabetic HCV patients.


Hepatitis C infection Diabetes mellitus Insulin-sensitizing agents Sustained virologic response 


  1. 1.
    Allison ME, Wreghitt T, Palmer CR, et al. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol. 1994;21:1135–1139. doi: 10.1016/S0168-8278(05)80631-2.CrossRefPubMedGoogle Scholar
  2. 2.
    Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;30:1059–1063. doi: 10.1002/hep.510300416.CrossRefPubMedGoogle Scholar
  3. 3.
    Knobler H, Schihmanter R, Zifroni A, et al. Increased risk of type 2 diabetes in non-cirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc. 2000;75:355–359.CrossRefPubMedGoogle Scholar
  4. 4.
    Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology. 1999;29:328–333. doi: 10.1002/hep.510290235.CrossRefPubMedGoogle Scholar
  5. 5.
    Mehta SH, Brancati FL, Sulkowski MS, et al. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Hepatology. 2001;33:1554. doi: 10.1053/jhep.2001.0103306le01.CrossRefPubMedGoogle Scholar
  6. 6.
    Zein CO, Levy C, Basu A, et al. Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. Am J Gastroenterol. 2005;100:48–55. doi: 10.1111/j.1572-0241.2005.40429.x.CrossRefPubMedGoogle Scholar
  7. 7.
    Zein NN, Abdulkarim AS, Wiesner RH, et al. Prevalence of diabetes mellitus in patients with end-stage liver cirrhosis due to hepatitis C, alcohol, or cholestatic disease. J Hepatol. 2000;32:209–217. doi: 10.1016/S0168-8278(00)80065-3.CrossRefPubMedGoogle Scholar
  8. 8.
    Simo R, Lecube A, Genesca J, et al. Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care. 2006;29:2462–2466. doi: 10.2337/dc06-0456.CrossRefPubMedGoogle Scholar
  9. 9.
    Ratziu V, Munteanu M, Charlotte F, et al. Fibrogenic impact of high serum glucose in chronic hepatitis C. J Hepatol. 2003;39:1049–1055. doi: 10.1016/S0168-8278(03)00456-2.CrossRefPubMedGoogle Scholar
  10. 10.
    Davila JA, Morgan RO, Shaib Y, et al. Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut. 2005;54:533–539. doi: 10.1136/gut.2004.052167.CrossRefPubMedGoogle Scholar
  11. 11.
    Ioannou GN, Splan MF, Weiss NS, et al. Incidence and predictors of hepatocellular carcinoma in patients with cirrhosis. Clin Gastroenterol Hepatol. 2007;5:938–945.CrossRefPubMedGoogle Scholar
  12. 12.
    Conjeevaram HS, Kleiner DE, Everhart JE, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007;45:80–87. doi: 10.1002/hep.21455.CrossRefPubMedGoogle Scholar
  13. 13.
    D’Souza R, Sabin CA, Foster GR. Insulin resistance plays a significant role in liver fibrosis in chronic hepatitis C and in the response to antiviral therapy. Am J Gastroenterol. 2005;100:1509–1515. doi: 10.1111/j.1572-0241.2005.41403.x.CrossRefPubMedGoogle Scholar
  14. 14.
    Dharancy S, Malapel M, Perlemuter G, et al. Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection. Gastroenterology. 2005;128:334–342. doi: 10.1053/j.gastro.2004.11.016.CrossRefPubMedGoogle Scholar
  15. 15.
    Konishi I, Horiike N, Hiasa Y, et al. Diabetes mellitus reduces the therapeutic effectiveness of interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C. Hepatol Res. 2007;37:331–336. doi: 10.1111/j.1872-034X.2007.00052.x.CrossRefPubMedGoogle Scholar
  16. 16.
    Romero-Gomez M, Del MV, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641. doi: 10.1053/j.gastro.2004.12.049.CrossRefPubMedGoogle Scholar
  17. 17.
    Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126:840–848. doi: 10.1053/j.gastro.2003.11.056.CrossRefPubMedGoogle Scholar
  18. 18.
    Sung CK, She H, Xiong S, et al. Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004;286:G722–G729. doi: 10.1152/ajpgi.00411.2003.CrossRefPubMedGoogle Scholar
  19. 19.
    Gavin JR III. New classification and diagnostic criteria for diabetes mellitus. Clin Cornerstone. 1998;1:1–12. doi: 10.1016/S1098-3597(98)90014-X.CrossRefPubMedGoogle Scholar
  20. 20.
    Miller AB, Hoogstraten B, Staquet M, et al. Reporting results of cancer treatment. Cancer. 1981;47:207–214. doi:10.1002/1097-0142(19810101)47:1<207::AID-CNCR2820470134>3.0.CO;2-6.CrossRefPubMedGoogle Scholar
  21. 21.
    Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19:1409–1417.PubMedCrossRefGoogle Scholar
  22. 22.
    Fartoux L, Poujol-Robert A, Guechot J, et al. Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C. Gut. 2005;54:1003–1008. doi: 10.1136/gut.2004.050302.CrossRefPubMedGoogle Scholar
  23. 23.
    Romero-Gomez M. Insulin resistance and hepatitis C. World J Gastroenterol. 2006;12:7075–7080.PubMedGoogle Scholar
  24. 24.
    Ghany MG, Kleiner DE, Alter H, et al. Progression of fibrosis in chronic hepatitis C. Gastroenterology. 2003;124:97–104. doi: 10.1053/gast.2003.50018.CrossRefPubMedGoogle Scholar
  25. 25.
    Perumalswami P, Kleiner DE, Lutchman G, et al. Steatosis and progression of fibrosis in untreated patients with chronic hepatitis C infection. Hepatology. 2006;43:780–787. doi: 10.1002/hep.21078.CrossRefPubMedGoogle Scholar
  26. 26.
    Charlton MR, Pockros PJ, Harrison SA. Impact of obesity on treatment of chronic hepatitis C. Hepatology. 2006;43:1177–1186. doi: 10.1002/hep.21239.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee WM, Dienstag JL, Lindsay KL, et al. Evolution of the HALT-C Trial: pegylated interferon as maintenance therapy for chronic hepatitis C in previous interferon non-responders. Control Clin Trials. 2004;25:472–492. doi: 10.1016/j.cct.2004.08.003.CrossRefPubMedGoogle Scholar
  28. 28.
    Pearlman BL. Hepatitis C virus infection in African Americans. Clin Infect Dis. 2006;42:82–91. doi: 10.1086/498512.CrossRefPubMedGoogle Scholar
  29. 29.
    Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–982. doi: 10.1056/NEJMoa020047.CrossRefPubMedGoogle Scholar
  30. 30.
    Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965. doi: 10.1016/S0140-6736(01)06102-5.CrossRefPubMedGoogle Scholar
  31. 31.
    Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265–2271. doi: 10.1056/NEJMoa032502.CrossRefPubMedGoogle Scholar
  32. 32.
    Neuman MG, Blendis LM, Shear NH, et al. Cytokine network in non-responding chronic hepatitis C patients with genotype 1: role of triple therapy with interferon alpha, ribavirin, and ursodeoxycholate. Clin Biochem. 2001;34:183–188. doi: 10.1016/S0009-9120(01)00213-2.CrossRefPubMedGoogle Scholar
  33. 33.
    Pickup JC, Chusney GD, Thomas SM, et al. Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sci. 2000;67:291–300. doi: 10.1016/S0024-3205(00)00622-6.CrossRefPubMedGoogle Scholar
  34. 34.
    Taliani G, Badolato MC, Nigro G, et al. Serum concentration of gammaGT is a surrogate marker of hepatic TNF-alpha mRNA expression in chronic hepatitis C. Clin Immunol. 2002;105:279–285. doi: 10.1006/clim.2002.5288.CrossRefPubMedGoogle Scholar
  35. 35.
    Zein NN. Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol. 2005;42:315–322. doi: 10.1016/j.jhep.2004.11.025.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Hesham M. Elgouhari
    • 1
  • Claudia O. Zein
    • 2
  • Ibrahim Hanouneh
    • 3
  • Ariel E. Feldstein
    • 2
  • Nizar N. Zein
    • 2
  1. 1.Avera Center for Liver Disease, Transplant Institute, Sanford School of MedicineUniversity of South DakotaSioux FallsUSA
  2. 2.Department of Gastroenterology and HepatologyCleveland ClinicClevelandUSA
  3. 3.Department of Internal MedicineCleveland ClinicClevelandUSA

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