Impact of tumor necrosis factor alpha antagonist treatment on antibody titer of hepatitis B surface antigen



Tumor necrosis factor antagonist, Hepatitis B surface antigen antibody, Autoimmune diseases


Aim: Tumor necrosis factor alpha antagonists (anti-TNF-α) have recently been used successfully in various diseases. On the other hand, due to their potential immunogenic effects, they cause hepatitis B virus (HBV) reactivation. The objective of this study is to examine the change in the levels of hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) in patients with negative HBsAg who were administered different anti-TNF-α drugs as well as the factors that influence this change. Methods: This research was designed as a retrospective cohort study. Patients with autoimmune diseases who were followed up at General Internal Medicine outpatient clinics between 2012 and 2019, screened for hepatitis B virus (HBV) infection prior to treatment, checked for serological markers (HBsAg, anti-HBs, hepatitis B core antigen antibody (anti-HBc)), and treated with anti-TNF for at least a year were included. The inclusion criteria were as follows: Patients with negative HBsAg and whose liver function tests were within normal limits, and the exclusion criteria included patients with positive HBsAg and whose liver function tests were above the normal upper limit. Results: A total of 221 adult patients who were treated with anti-TNF-α were included in the study. The pretreatment anti-HBs levels of the patients were significantly higher than the posttreatment levels (P<0.001). Of the 211 patients with positive pretreatment anti-HBs levels, 17 patients had posttreatment anti-HBs levels below 10 IU/L. The anti-HBs levels of five patients with positive anti-HBc dropped below 10 IU/L. Conclusions: The anti-HBs levels of the patients who were administered anti-TNF-α agent decreased significantly, whereas there was no reactivation of HBV or de novo HBV infection in HBsAg-negative patients. It was observed in a small group of patients (8.0%) that the levels of anti-HBs decreased to a risky level.


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Donahue KE, Gartlehner G, Schulman ER, Jonas B, Coker-Schwimmer E, Patel SV, et al. Drug therapy for early rheumatoid arthritis: a systematic review update. Agency for Healthcare Research and Quality (US); 2018 Jul. Report No: 18-EHC015-EFReport No: 2018-SR-02

Adegbola SO, Sahnan K, Warusavitarne J, Hart A, Tozer P. Anti-TNF therapy in Crohn’s disease. Int J Mol Sci. 2018;19:2244.

Rahier JF, Magro F, Abreu C, Armuzzi A, Ben-Horin S, Chowers Y, et al. Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease. J Crohns Colitis. 2014;8:443-68.

Vaughn BP, Doherty GA, Gautam S, Moss AC, Cheifetz AS. Screening for tuberculosis and hepatitis B prior to the initiation of anti-tumor necrosis therapy. Inflamm Bowel Dis. 2011;18:1057-63.

Zingarelli S, Frassi M, Bazzani C, Scarsi M, Puoti M, Airò P. Use of tumor necrosis factor-α-blocking agents in hepatitis B virus-positive patients: reports of 3 cases and review of the literature. J Rheumatol. 2009;36:1188-94.

Chung SJ, Kim JK, Park MC, Park YB, Lee SK. Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-α therapy. Journal Rheumatol. 2009;36:2416-20.

Murdaca G, Spanò F, Contatore M, Guastalla A, Penza E, Magnani O, et al. Infection risk associated with anti-TNF-α agents: a review. Expert Opin Drug Saf. 2015;14:571-82.

Nathan DM, Angus PW, Gibson PR. Hepatitis B and C virus infections and anti‐tumor necrosis factor‐α therapy: Guidelines for clinical approach. J Gastroenterol Hepatol. 2006;21:1366-71.

Herbein G, O'brien WA. Tumor Necrosis Factor (TNF)–α and TNF Receptors in Viral Pathogenesis. Proc Soc Exp Biol Med. 2000;223:241-57.

Kasahara S, Ando K, Saito K, Sekikawa K, Ito H, Ishikawa T, et al. Lack of tumor necrosis factor alpha induces impaired proliferation of hepatitis B virus-specific cytotoxic T lymphocytes. J Virol. 2003;77:2469-76.

Carroll MB, Bond MI, editors. Use of tumor necrosis factor-α inhibitors in patients with chronic hepatitis B infection. Semin Arthritis Rheum. 2008;38:208-17.

Vassilopoulos D, Apostolopoulou A, Hadziyannis E, Papatheodoridis GV, Manolakopoulos S, Koskinas J, et al. Long-term safety of anti-TNF treatment in patients with rheumatic diseases and chronic or resolved hepatitis B virus infection. Ann Rheum Dis. 2010;69:1352-5.

Loomba R, Liang TJ. Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions. Gastroenterology. 2017;152:1297-309.

Esteve M, Saro C, Gonzalez-Huix F, Suarez F, Forne M, Viver J. Chronic hepatitis B reactivation following infliximab therapy in Crohn’s disease patients: need for primary prophylaxis. Gut. 2004;53:1363-5.

Kato M, Atsumi T, Kurita T, Odani T, Fujieda Y, Otomo K, et al. Hepatitis B virus reactivation by immunosuppressive therapy in patients with autoimmune diseases: risk analysis in Hepatitis B surface antigen-negative cases. J Rheumatol. 2011;38:2209-14.

Tamori A, Koike T, Goto H, Wakitani S, Tada M, Morikawa H, et al. Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol. 2011;46:556-64.

Stoop JN, Woltman AM, Biesta PJ, Kusters JG, Kuipers EJ, Janssen HL, et al. Tumor necrosis factor alpha inhibits the suppressive effect of regulatory T cells on the hepatitis B virus–specific immune response. Hepatology. 2007;46:699-705.

Velu V, Saravanan S, Nandakumar S, Shankar EM, Vengatesan A, Jadhav SS, et al. Relationship between T-lymphocyte cytokine levels and sero-response to hepatitis B vaccines. World j Gastroenterol: WJG. 2008;14:3534.

Kerdel FA. UpdateonTNF Inhibitors. Semin Cutan Med Surg. 2016;35(4 Suppl 4):S67-70

Khanna I, Kozicky O, Fischer H. Use of FDA‐Approved Medications: Biologics for Psoriatic Arthritis in Patients at an Urban Outpatient Rheumatology Clinic. ACR Open Rheumatology. 2019;1:580-4.

Taylor PC, Feldmann M. Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 2009;5:578-82.

Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Takasaki H, et al. Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B-cell lymphoma: a prospective observational study. Clin Infect Dis. 2015;61:719-29.

Pauly MP, Tucker LY, Szpakowski JL, Ready JB, Baer D, Hwang J, et al. Incidence of hepatitis B virus reactivation and hepatotoxicity in patients receiving long-term treatment with tumor necrosis factor antagonists. Clin Gastroenterol Hepatol. 2018;16:1964-73.

Ozaras R, Ozaras N, Demirel A. The Risk of Hepatitis B Virus Reactivation in HBsAg-Negative and Anti-HBc-Positive Patients Receiving Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol. 2019;17:210.

Tozun N, Ozdogan O, Cakaloglu Y, Idilman R, Karasu Z, Akarca U, et al. Seroprevalence of hepatitis B and C virus infections and risk factors in Turkey: a fieldwork TURHEP study. Clin Microbiol Infect. 2015;21:1020-6.

Charpin C, Guis S, Colson P, Borentain P, Mattéi J-P, Alcaraz P, et al. Safety of TNF-blocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients. Arthritis Res Ther. 2009;11:R179.

Ballanti E, Conigliaro P, Chimenti MS, Kroegler B, Di Muzio G, Guarino MD, et al. Use of Anti‐Tumor Necrosis Factor Alpha Therapy in Patients with Concurrent Rheumatoid Arthritis and Hepatitis B or Hepatitis C: A Retrospective Analysis of 32 Patients. Drug Dev Res. 2014;75:42-5.

Caporali R, Bobbio‐Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, et al. Safety of tumor necrosis factor α blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti–hepatitis B core antigen positive) with rheumatic diseases. Arthritis Care Res (Hoboken). 2010;62:749-54.

Yeo W, Zee B, Zhong S, Chan P, Wong W, Ho W, et al. Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy. Br J Cancer. 2004;90:1306-11.

Mori S. Past hepatitis B virus infection in rheumatoid arthritis patients receiving biological and/or nonbiological disease-modifying antirheumatic drugs. Mod Rheumatol. 2011;21:621-7.






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Yalçın Kehribar D, Okuyucu M, Özgen M, Ketenci YB, Ayyıldız T, Yıldırım B. Impact of tumor necrosis factor alpha antagonist treatment on antibody titer of hepatitis B surface antigen. J Surg Med [Internet]. 2020 Aug. 1 [cited 2024 Jun. 23];4(8):678-81. Available from: