Background & Aims A combination of pegylated interferon-alpha and ribavirin (PR) is the standard therapy for patients with chronic hepatitis C. The impact of polymorphism of interleukin-28B (IL28B) on sustained virological response (SVR) to PR has been well documented in patients with CHC genotype-1 (GT1), but it is controversial in genotype-2 (GT2) CHC patients. This study investigated the predictability of six single nucleotide polymorphisms (SNP) of IL28B on the treatment responses of PR in patients with CHC GT2. Method 197 CHC GT2 consecutive patients who received PR treatment in our prospective cohort were enrolled. Hepatitis C virus (HCV) genotyping, quantification of HCV-RNA and genotyping of the ten SNPs of IL28B were performed. Six SNPs of IL28B were chosen for analysis. The propensity score matching (PSM) analysis was applied using patients with CHC GT1 in another prospective cohort as a positive comparison to avoid covariate bias. Results The distribution of the six SNPs was similar in GT1 and GT2 patients. Five of these SNPs had strong association with treatment responses in GT1 but not in GT2 patients. After PSM analysis, these five SNPs still showed strong association with rapid virological response (RVR), cEVR and SVR in GT1 and had no influence in GT2 patients. Furthermore, rs12979860 and baseline viral load were the predictors for both RVR and SVR in GT1 patients. However, only baseline viral load could predict RVR and SVR in GT2 patients. In addition, in patients without RVR, rs12979860 was the only predictor for SVR in GT1 but no predictor for SVR was found in GT2. Conclusions The genetic polymorphisms of IL28B had no impact on treatment responses in GT2 patients.
References
[1]
Davis GL, Albright JE, Cook SF, Rosenberg DM (2003) Projecting future complications of chronic hepatitis C in the United States. Liver Transpl 9: 331–338.
[2]
Ghany MG, Strader DB, Thomas DL, Seeff LB (2009) Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 49: 1335–1374.
[3]
Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, et al. (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.
[4]
Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, et al. (2002) Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 347: 975–982.
[5]
Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, et al. (2004) Peginterferon alfa-2b plus ribavirin for naive patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol 41: 474–481.
[6]
Hadziyannis SJ, Sette H Jr, Morgan TR, Balan V, Diago M, et al. (2004) Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med 140: 346–355.
[7]
Mangia A, Santoro R, Minerva N, Ricci GL, Carretta V, et al. (2005) Peginterferon alfa-2b and ribavirin for 12 vs. 24 weeks in HCV genotype 2 or 3. N Engl J Med 352: 2609–2617.
[8]
von Wagner M, Huber M, Berg T, Hinrichsen H, Rasenack J, et al. (2005) Peginterferon-alpha-2a (40KD) and ribavirin for 16 or 24 weeks in patients with genotype 2 or 3 chronic hepatitis C. Gastroenterology. 129: 522–527.
[9]
Shiffman ML, Suter F, Bacon BR, Nelson D, Harley H, et al. (2007) Peginterferon alfa-2a and ribavirin for 16 or 24 weeks in HCV genotype 2 or 3. N Engl J Med 357: 124–134.
[10]
Yu ML, Dai CY, Huang JF, Hou NJ, Lee LP, et al. (2007) A randomised study of peginterferon and ribavirin for 16 versus 24 weeks in patients with genotype 2 chronic hepatitis C. Gut. 56: 553–559.
[11]
McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, et al. (2009) Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med 361: 580–593.
[12]
Rumi MG, Aghemo A, Prati GM, D’Ambrosio R, Donato MF, et al. (2010) Randomized study of peginterferon-alpha2a plus ribavirin vs peginterferon-alpha2b plus ribavirin in chronic hepatitis C. Gastroenterology. 138: 108–115.
[13]
Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, et al. (2009) Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 461: 399–401.
[14]
Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, et al. (2009) Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 461: 798–801.
[15]
Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, et al. (2009) Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 41: 1105–1109.
[16]
Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, et al. (2009) IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet 41: 1100–1104.
[17]
Thompson AJ, Muir AJ, Sulkowski MS, Ge D, Fellay J, et al.. (2010) Interleukin-28B polymorphism improves viral kinetics and is the strongest pretreatment predictor of sustained virologic response in genotype 1 hepatitis C virus. Gastroenterology 139: 120–129 e118.
[18]
Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, et al.. (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, 827 e821.
[19]
Yu ML, Huang CF, Huang JF, Chang NC, Yang JF, et al. (2011) Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients. Hepatology 53: 7–13.
[20]
Lindh M, Lagging M, Farkkila M, Langeland N, Morch K, et al. (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.
[21]
Sarrazin C, Susser S, Doehring A, Lange CM, Muller T, et al. (2011) Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients. J Hepatol 54: 415–421.
[22]
Kawaoka T, Hayes CN, Ohishi W, Ochi H, Maekawa T, et al. (2011) Predictive value of the IL28B polymorphism on the effect of interferon therapy in chronic hepatitis C patients with genotypes 2a and 2b. J Hepatol 54: 408–414.
[23]
Chen JY, Lin CY, Wang CM, Lin YT, Kuo SN, et al. (2011) IL28B genetic variations are associated with high sustained virological response (SVR) of interferon-alpha plus ribavirin therapy in Taiwanese chronic HCV infection. Genes Immun 12: 300–309.
[24]
Hung HH, Chiou YY, Hsia CY, Su CW, Chou YH, et al. (2011) Survival rates are comparable after radiofrequency ablation or surgery in patients with small hepatocellular carcinomas. Clin Gastroenterol Hepatol 9: 79–86.
[25]
Pearl J (2009) Understanding propensity scores. Causality: models, reasoning, and inference, 2nd ed. Cambridge university press, Cambridge.
[26]
D’Agostino RB Jr (1998) Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 17: 2265–2281.
[27]
Lin CY, Chen JY, Lin TN, Jeng WJ, Huang CH, et al. (2011) IL28B SNP rs12979860 is a critical predictor for on-treatment and sustained virologic response in patients with hepatitis C virus genotype-1 infection. PLoS One 6: e18322.
[28]
Afdhal NH, McHutchison JG, Zeuzem S, Mangia A, Pawlotsky JM, et al. (2011) Hepatitis C pharmacogenetics: state of the art in 2010. Hepatology 53: 336–345.
[29]
Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, et al.. (2010) Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 138: 1338–1345, 1345 e1331–1337.
[30]
Rizzetto M HS, Ackrill AM (2004) Sustained virological response (SVR) to Peginterferon Alfa-2A (40KD) (PEGASYS) plus ribavirin (Copegus): comparison of outcomes in patients infected with HCV genotype 2 and 3. Hepatology 40: 252A.
[31]
Zeuzem S, Hultcrantz R, Bourliere M, Goeser T, Marcellin P, et al. (2004) Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 40: 993–999.
[32]
Yu ML, Dai CY, Huang JF, Chiu CF, Yang YH, et al. (2008) Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology 47: 1884–1893.
[33]
Kamal SM, Ismail A, Graham CS, He Q, Rasenack JW, et al. (2004) Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 39: 1721–1731.
