Role of Tumor Necrosis Factor Alpha Promoter Polymorphisms in Interferon Related Side Effects in Chronic Hepatitis B Patients Under Interferon Alpha 2b Treatment

Objective: Interferon alpha therapy is associated with series of adverse ef-fects leading premature discontinuation of treatment. Here we aimed to de-termine the effects of Tumor necrosis alpha promoter polymorphisms on in-terferon related side effects during interferon alpha 2b treatment in chron-ic hepatitis B patients.Material and Methods: This observational study enrolled 50 chronic hepati-tis B patients, who were treated with interferon alpha 2b 10 tiw plus lamivu-dine 100mg/day at Selçuk University Meram Medical Faculty Department of Infectious Diseases and Clinical Bacteriology between 2006-2007. Patients were followed-up with complete blood count, transaminases and amylase monthly at out patient clinics of our department. All patients were asked to fill a questionnaire to evaluate the interferon related side effects at every vis-it. Tumor necrosis factor alpha -238 and -308 polymorphisms were investi-gated with PCR-Restriction fragment length polymorphisms.Results: Arthralgia was present in 93.8% of patients. Exhaustion, loss of ap-petite, mount dryness and fever are the leading complaints of the patients. Median complaint scores were 9, 9.5, 11 and 5 at 4th, 12th, 24th and 48th week visits, respectively. Thrombocytopenia and leucopenia were detected in 8 (16%) and 5 (10%) patients, respectively. One-third of the patients report-ed depressive mood however, depression was diagnosed in 5 (10%) patients. TNF alpha promoter 238GG and 308GG allele was present in 42/50 and 43/50 patients, respectively. No association was found between TNF pro-moter allele and certain patient-reported side effect, complaint score, hema-tological and psychological adverse effects. Conclusion: TNF alpha promoter polymorphisms do not contribute to oc-currence of IFN alpha treatment related side effects.


Lavanchy D. Hepatitis B virus epidemiology, disease bur-den, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004; 11: 97-107.

World Health Organization. Hepatitis B Fact Sheet No. 204, Revised October 2000.

Lok AS, Heathcote EJ, Hoofnagle JH. Management of hep-atitis B: 2000–summary of a workshop. Gastroenterol 20 01; 120 : 1828 -1853.

Özkan, H. Epidemiology of Chronic Hepatitis B in Turkey. Euroasian J Hepato-Gastroenterol 2018; 8: 73-76.[5]Thomas H, Foster G, Platis D. Mechanisms of action of in-terferon and nucleoside analogues. J Hepatol 2003; 39: S93–S98 .

Sleijfer S, Bannink M, Van Gool AR, et al. Side effects of in-terferon-a therapy. Pharm World Sci 2005; 27: 423–431.

D’Alfonso S, Richiardi PM. A polymorphic variation in a putative regulation box of the TNFA promoter region. Immunogenetics 1994; 39: 150–4.

Hadziyannis SJ, and Papatheodoridis GV. Hepatitis B e Antigen–Negative Chronic Hepatitis B: Natural History and Treatment. Semin Liver Dis 2006; 26: 130–141.

Chuaypen N, Posuwan, N, Chittmittraprap S, et al. Predictive role of serum HBsAg and HBeAg kinetics in pa-tients with HBeAg-negative chronic hepatitis B receiving pegylated interferon–based therapy. Clin Microbiol Inf 2018; 24(3): 306-e7.

Bourlière M, Rabiega P, Ganne-Carrie N, et al. Effect on HBs antigen clearance of addition of pegylated interfer-on alfa-2a to nucleos (t) ide analogue therapy versus nu-cleos (t) ide analogue therapy alone in patients with HBe antigen-negative chronic hepatitis B and sustained un-detectable plasma hepatitis B virus DNA: a randomised, controlled, open-label trial. Lancet Gastroenterol Hepatol 2 017; 2(3): 17 7-18 8.

Azhari H, Swain MG, Role of Peripheral Inflammation in Hepatic Encephalopathy, Clin Exp Hepatol 2018; 8(3):281-285.

Cabal-Hierro L, Lazo PS. Signal transduction by tumor necrosis factor receptors Cellular signalling 2012; 24(6): 1297-13 05.

Santantonio T, Niro GA, Sinisi E, et al. Lamivudine/interfer-on combination therapy in anti-HBe positive chronic hep-atitis B patients: a controlled pilot study. J Hepatol 2002; 36: 799–804.

Yuki N, Nagaoka T, Nukui K, et al. Adding interferon to lamivudine enhances the early virologic response and re-version of the precore mutation in difficult-to-treat HBV infection J Gastroenterol 2008; 43(6): 457-463.

Dinarello CA, Bernheim HA, Duff GW, et al. Mechanisms of fever induced by recombinant interferon. J Clin Invest 1984; 74(3): 906–13.

Cameron DA, Cornbleet MC, Mackie RM, et al. Adjuvant interferon alpha 2b in high risk melanoma – the Scottish study. Br J Cancer 2001; 84(9): 1146–9.

Aktug-Demir N, Celik M., Kölgelier S, et al. Comparison of the level of depression and anxiety in inactive hepatitis B carriers and chronic hepatitis B patients. Turk Psikiyatri Dergisi 2013; 24(4): 248-252.

Mikova O, Yakimova R, Bosmans E. Increased serum tumor necrosis factor alpha concentrations in major depression and multiple sclerosis. Eur Neuropsychopharmacol. 2001; 11: 203–208.

Ferenci P, Staufer K. Depression in chronic hepatitis: the vi-rus, the drug, or the ethnic background? Liver International 2008; 28(4): 429-431.

Marcellin P, Lau GKK, Zeuzem S, et al. Comparison of safe-ty, tolerability and quality of life in patients with chronic hepatitis B versus chronic hepatitis C treated with pegin-terferon alfa-2a (40 KD). Liver Int 2008; 28: 474-482i

Bayley JP, Ottenhoff THM, Verweij CL Is there a future for TNF promoter polymorphisms? Genes and Immunity 2004; 5: 315-329.

Louis E, Franchimont D, Piron A, et al. Tumour necrosis fac-tor (TNF) gene polymorphism influences TNF-alpha pro-duction in lipopolysaccharide (LPS)-stimulated whole blood cell culture in healthy humans. Clin Exp Immunol 1998; 113: 401–406.

Wilson AG, Symons JA, McDowell TL, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci USA 19 97; 9 4: 3195 –319 9.

İnkaya, AÇ, Türk Arıbaş, E., Erayman, İ, et al. Association of tumor necrosis factor alpha -238G/A and -308G/A promo-tor polymorphisms with clearance of Hepatitis B virus in-fection in Turkish population. Acta Medica 2019; 50(1), 1-6.

Kaynak Göster