Concurrent infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) was not uncommon in China. To date, information on predictors of response to treatment of dually-infected HCV/HBV is limited. The aim of this study was to evaluated whether determination of the interleukin 28B (IL-28B) polymorphism statuses sufficient to predict treatment response of interferon (IFN)-based therapy in patients chronically infected with both hepatitis B and C viruses. We investigated the role of IL28B variations (rs8099917 and rs12979860) in response to IFN-based treatment and evaluated its association with the risk of the null virological response (NVR) in HCV /HBV dually-infected patients. We found that the overall distributions of the genotypes among the sustained virological response (SVR), NVR groups were significantly different (P<0.001): patients with the rs8099917 TG genotype had an increased risk of NVR (odds ratio [OR] =2.37 95% confidence interval [CI] =1.16–4.83, P =0.017), and those with the GG genotype had a further increased risk of NVR (OR=4.23, 95% CI =1.17-15.3, P=0.027). The rs12979860 allele was also highly associated with treatment failure (CT/TT vs. CC; OR =2.04, 95%CI =1.05-3.97, P =0.037). Moreover, we found that IL28B rs8099917 G variants (TG+GG) interact with HCV genotype 1(G1) to result in higher risk of NVR (P=0.009), and that they are also associated with HBV DNA reactivation (TG+GG vs. TT, P=0.005). Furthermore, multivariate regression analysis show that the rs8099917 G allele was the most important factor significantly associated with a NVR in HCV G1 patients. This study suggest that IL28B genotyping may be a valid pretreatment predictor of which patients are likely to respond to treatment in this group of difficult-to-treat HCV/HBV dually-infected patients.
References
[1]
Jamma S, Hussain G, Lau DT (2010) Current Concepts of HBV/HCV Coinfection: Coexistence, but Not Necessarily in Harmony. Curr Hepatol Rep 9: 260-269. doi:10.1007/s11901-010-0060-4.
[2]
Pontisso P, Ruvoletto MG, Fattovich G, Chemello L, Gallorini A et al. (1993) Clinical and virological profiles in patients with multiple hepatitis virus infections. Gastroenterology 105: 1529-1533. doi:10.1016/0016-5085(93)90161-5. PubMed: 8224658.
[3]
Crespo J, Lozano JL, de la Cruz F, Rodrigo L, Rodríguez M et al. (1994) Prevalence and significance of hepatitis C viremia in chronic active hepatitis B. Am J Gastroenterol 89: 1147-1151. PubMed: 8053425.
[4]
Chu CJ, Lee SD (2008) Hepatitis B virus/hepatitis C virus coinfection: epidemiology, clinical features, viral interactions and treatment. J Gastroenterol Hepatol 23: 512-520. doi:10.1111/j.1440-1746.2008.05384.x. PubMed: 18397482.
[5]
Li D, Long Y, Wang T, Xiao D, Zhang J et al. (2013) Epidemiology of hepatitis C virus infection in highly endemic HBV areas in China. PLOS ONE 8: e54815. doi:10.1371/journal.pone.0054815. PubMed: 23372775.
[6]
Bini EJ, Perumalswami PV (2010) Hepatitis B virus infection among American patients with chronic hepatitis C virus infection: prevalence, racial/ethnic differences, and viral interactions. Hepatology 51: 759-766. PubMed: 20140950.
[7]
Cacciola I, Pollicino T, Squadrito G, Cerenzia G, Orlando ME et al. (1999) Occult hepatitis B virus infection in patients with chronic hepatitis C liver disease. N Engl J Med 341: 22-26. doi:10.1056/NEJM199907013410104. PubMed: 10387938.
[8]
Chiaramonte M, Stroffolini T, Vian A, Stazi MA, Floreani A et al. (1999) Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis. Cancer 85: 2132-2137. doi:10.1002/(SICI)1097-0142(19990515)85:10. PubMed: 10326690.
[9]
Liaw YF, Chen YC, Sheen IS, Chien RN, Yeh CT et al. (2004) Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection. Gastroenterology 126: 1024-1029. doi:10.1053/j.gastro.2004.01.011. PubMed: 15057742.
[10]
Yu ML, Lee CM, Chen CL, Chuang WL, Lu SN et al. (2013) Sustained hcv clearance and increased HBsAg seroclearance in patients with dual chronic hepatitis C and B during post-treatment follow-up. Hepatology.
[11]
Liu CJ, Chuang WL, Lee CM, Yu ML, Lu SN et al. (2009) Peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses. Gastroenterology 136: 496-504 e493 doi:10.1053/j.gastro.2008.10.049. PubMed: 19084016.
[12]
Liu CJ, Chen PJ, Lai MY, Kao JH, Jeng YM et al. (2003) Ribavirin and interferon is effective for hepatitis C virus clearance in hepatitis B and C dually infected patients. Hepatology 37: 568-576. doi:10.1053/jhep.2003.50096. PubMed: 12601355.
[13]
Hung CH, Lee CM, Lu SN, Wang JH, Tung HD et al. (2005) Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection. J Gastroenterol Hepatol 20: 727-732. doi:10.1111/j.1440-1746.2005.03791.x. PubMed: 15853986.
[14]
Hung CH, Lee CM, Lu SN, Wang JH, Chen CH et al. (2010) Hepatic steatosis with hepatitis B virus/hepatitis C virus dual infection. Hepatology 52: 1521-1522. doi:10.1002/hep.23740. PubMed: 20672387.
[15]
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. doi:10.1038/nature08309. PubMed: 19684573.
[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. doi:10.1038/ng.447. PubMed: 19749758.
[17]
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. doi:10.1038/ng.449. PubMed: 19749757.
[18]
Lampertico P, Viganò M, Cheroni C, Facchetti F, Invernizzi F et al. (2013) IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen-negative patients with chronic hepatitis B. Hepatology 57: 890-896. doi:10.1002/hep.25749. PubMed: 22473858.
[19]
Sonneveld MJ, Wong VW, Woltman AM, Wong GL, Cakaloglu Y et al. (2012) Polymorphisms near IL28B and serologic response to peginterferon in HBeAg-positive patients with chronic hepatitis B. Gastroenterology 142: 513-520 e511 doi:10.1053/j.gastro.2011.11.025. PubMed: 22108195.
[20]
Aparicio E, Parera M, Franco S, Pérez-Alvarez N, Tural C et al. (2010) IL28B SNP rs8099917 is strongly associated with pegylated interferon-alpha and ribavirin therapy treatment failure in HCV/HIV-1 coinfected patients. PLOS ONE 5: e13771. doi:10.1371/journal.pone.0013771. PubMed: 21048934.
[21]
Ank N, West H, Bartholdy C, Eriksson K, Thomsen AR et al. (2006) Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol 80: 4501-4509. doi:10.1128/JVI.80.9.4501-4509.2006. PubMed: 16611910.
[22]
Ank N, West H, Paludan SR (2006) IFN-lambda: novel antiviral cytokines. J Interferon Cytokine Res 26: 373-379. doi:10.1089/jir.2006.26.373. PubMed: 16734557.
[23]
Strader DB, Wright T, Thomas DL, Seeff LB (2004) Diagnosis, management, and treatment of hepatitis C. Hepatology 39: 1147-1171. doi:10.1002/hep.20119. PubMed: 15057920.
[24]
Lok AS, McMahon BJ (2007) Chronic hepatitis B. Hepatology 45: 507-539. doi:10.1002/hep.21513. PubMed: 17256718.
[25]
Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ (1994) Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 19: 1513-1520. doi:10.1002/hep.1840190629. PubMed: 8188183.
[26]
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 doi:10.1053/j.gastro.2010.04.013. PubMed: 20399780.
[27]
Guo X, Zhao Z, Xie J, Cai Q, Zhang X et al. (2012) Prediction of response to pegylated-interferon-alpha and ribavirin therapy in Chinese patients infected with different hepatitis C virus genotype. Virol J 9: 123. doi:10.1186/1743-422X-9-123. PubMed: 22713131.
[28]
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. doi:10.1038/nature08463. PubMed: 19759533.
[29]
Yu ML, Chuang WL (2009) Treatment of chronic hepatitis C in Asia: when East meets West. J Gastroenterol Hepatol 24: 336-345. doi:10.1111/j.1440-1746.2009.05789.x. PubMed: 19335784.
[30]
Georgel P, Schuster C, Zeisel MB, Stoll-Keller F, Berg T et al. (2010) Virus-host interactions in hepatitis C virus infection: implications for molecular pathogenesis and antiviral strategies. Trends Mol Med 16: 277-286. doi:10.1016/j.molmed.2010.04.003. PubMed: 20537953.
[31]
Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM et al. (1996) Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med 334: 1422-1427. doi:10.1056/NEJM199605303342202. PubMed: 8618580.
[32]
ter Borg MJ, van Zonneveld M, Zeuzem S, Senturk H, Akarca US et al. (2006) Patterns of viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B: relation to treatment response. Hepatology 44: 721-727. doi:10.1002/hep.21302. PubMed: 16941701.
[33]
Hung CH, Lu SN, Wang JH, Lee CM, Chen TM et al. (2003) Correlation between ultrasonographic and pathologic diagnoses of hepatitis B and C virus-related cirrhosis. J Gastroenterol 38: 153-157. doi:10.1007/s005350300025. PubMed: 12640529.
