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• Hepatitis B Virus and tumour necrosis factor alpha blocking agents
  Graham M Raftery
  Published on: 15 February 2005

• Published on: 15 February 2005

  Hepatitis B Virus and tumour necrosis factor alpha blocking agents

  • Graham M Raftery, Specialist Registrar
  • Other Contributors:
    • Bridget Griffiths, Lesley Kay, and David Kane.

  Dear Editor,

  With the increasing number of patients now being treated with tumour necrosis factor alpha (TNF-alpha) blocking agents, the publication of an updated consensus statement in the Advances in Targeted Therapies VI supplement of Annals of the Rheumatic Diseases was both timely and relevant. However we notice that conflicting advice on the management of patients with Hepatitis B Virus (HBV) infection is...

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  Dear Editor,

  With the increasing number of patients now being treated with tumour necrosis factor alpha (TNF-alpha) blocking agents, the publication of an updated consensus statement in the Advances in Targeted Therapies VI supplement of Annals of the Rheumatic Diseases was both timely and relevant. However we notice that conflicting advice on the management of patients with Hepatitis B Virus (HBV) infection is given in this supplement in 2 separate articles. Furst et al[1] comment on the paucity of data on this situation which leads them to conclude that "TNF blockers should not be used in patients with HBV infection (category C evidence)". In a subsequent article, Calabrese et al[2] review the evidence obtained from 4 cases and conclude that when there is no alternative to TNF blockade the potential exists for safe administration of TNF blocking agents through careful monitoring of viral status, prior or concurrent prescription of lamuvidine and/or temporary discontinuation of anti-TNF therapy should HBV re-activation occur. Given that HBV infection and inflammatory arthritis are common conditions, this is a not uncommon situation that most rheumatology centres will encounter at some point and we wish to clarify the correct position on the management of patients with HBV infection and TNF-alpha blocking agents.

  Since Calabrese et al’s[2] article, Esteve et al[3] have reported 3 cases of Crohn’s disease patients with chronic HBV who received infliximab. From 80 patients tested prospectively for HBV prior to infliximab therapy for Crohn’s disease, 3 were identified with chronic HBV infection and 2 of the 3 patients developed severe reactivation of HBV at 2 and 3 months after the last infliximab infusion. One patient made a complete recovery after 3 months while the second died from advanced hepatic failure. A third patient was treated with lamivudine therapy prior to treatment with infliximab therapy and has had no clinical or biochemical worsening of liver disease either during or after therapy.

  We also have experience of safely and successfully using TNF blockade in 2 patients with RA and chronic HBV infection who had failed standard DMARD therapy and continued to have severely active RA. A 50 year old woman with RA and chronic HBV infection who had failed treatment with 5 DMARDs – including cyclophosphamide – was commenced on etanercept 25mg twice weekly s.c. At present she has completed 12 months of treatment with a reduction in DAS28 from 7.22 to 5.56. She did not receive any antiviral therapy prior to or during etanercept treatment and has had no evidence of HBV reactivation - HBV surface antigen is negative and HBV DNA undetectable. Etanercept was recently stopped due to persistent diarrhoea and she continues on treatment with adalimumab which has been temporarily discontinued during surgery for atlanto-axial subluxation. In a second case, a 62 year old woman with RA and chronic HBV infection (HBsAg negative) who had failed treatment with 3 DMARDs received etanercept 25mg twice weekly in combination with 15mg methotrexate s.c. After 3 months DAS28 reduced from 8.16 to 2.63. No antiviral therapy was given prior to treatment with etanercept, and we have seen no evidence of HBV reactivation to date – HBV DNA undetectable. She has now had 6 months of treatment with etanercept with no complications.

  Clearly the limited number of reports of anti-TNF therapy in HBV infected patients raise a number of important issues. We believe that the currently available data suggests that TNF blockade is a therapeutic option in patients with RA and chronic HBV infection, though the risk/benefit ratio must be carefully assessed in each patient. Furthermore, the European Association for the Study of the Liver International Consensus on Hepatitis B has produced guidelines on the safe treatment of patients with HBV who require immunosuppressive treatment. These guidelines led Calabrese et al[2] to advise that TNF blockade may be prescribed in patients with HBV infection. This should include assessment by a hepatologist and close monitoring of liver enzymes and HBV viral load during TNF blockade. Anti-viral therapy is effective for HBV re-activation but it is not yet clear whether anti-viral therapy should be administered prior to or during anti-TNF therapy or solely when HBV re-activation is detected. We believe that since HBV screening has not been mandatory in the pre-treatment assessment of patients receiving TNF blockade there are likely to already be a small but considerable number of patients with HBV infection who are already receiving TNF blockade. Further reporting of these cases would help clarify the risks of HBV re-activation, whether it is more frequent with infliximab, etanercept, or adalimumab and provide information on the outcome of anti-viral treatment.

  Graham Raftery 1, Bridget Griffiths 2, Lesley Kay 3, David Kane 4.

  Freeman Hospital, High Heaton, Newcastle upon Tyne, NE7 7DN, UK.

  Correspondence to: Dr. Graham Raftery, Department of Rheumatology, Freeman Hospital, High Heaton, Newcastle-upon-Tyne, NE7 7DN, UK.

  Tel: 44-191-233-6161, Fax: 44-191-223-1159, e-mail: grahamraftery@doctors.org.uk

  References

  1 Furst D E, Breedveld F C, Kalden J R, Smolen JS, Burmester G R, Bijlsma, J W, et al. Updated consensus statement on biologic agents, specifically tumour necrosis factor alpha; (TNFalpha) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2004. Ann Rheum Dis 2004;64(Suppl 2):ii2-ii12.

  2 Calabrese L H, Zein N, Vassilopoulos. Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B and HIV infection. Ann Rheum Dis 2004;63(Suppl 2)ii18-ii24.

  3 Esteve M, Saro C, Gonzalea-Huix, Suarez F, Forne M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy for Crohn’s disease patients: need for primary prophylaxis. Gut 2004 Sep;53(9):1363-5.

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  Conflict of Interest:
  None declared.

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