EJINME-02664; No of Pages 3 European Journal of Internal Medicine xxx (2014) xxx–xxx

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Original article

Lack of hepatitis B virus reactivation after anti-tumor necrosis factor α agents therapy in antibody to hepatitis B core antigen positive/hepatitis B surface antigen negative subjects with chronic inflammatory arthropathies M.I. Biondo a,1, V. Germano a,1, M. Pietrosanti a, M. Canzoni a, M. Marignani b, T. Stroffolini c, S. Salemi a, R. D'Amelio a,⁎ a b c

Dept. of Clinical and Molecular Medicine, Sapienza University of Rome, S. Andrea University Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy Dept. of Digestive and Liver Disease, Sapienza University of Rome, S. Andrea University Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy Dept. of Infectious and Tropical Diseases, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155, 00161 Rome, Italy

a r t i c l e

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Article history: Received 4 October 2013 Accepted 12 November 2013 Available online xxxx Keywords: Anti-TNFα HBcAb-positive HBV reactivation Rheumatic diseases

a b s t r a c t Background: Hepatitis B virus (HBV) reactivation in patients positive for antibody to HB core antigen (anti-HBc), negative for HB surface antigen (HBsAg) and HBV-DNA (potential occult HBV carriers), treated with anti-tumor necrosis factor (TNF)α, is a debated question. The aim of the study was to evaluate the safety of anti-TNFα therapy in anti-HBc positive/HBsAg negative subjects with rheumatoid arthritis (RA) and spondyloarthropathy (SpA). Methods: All consecutive HBsAg negative RA and SpA outpatients referring to the Immuno-Rheumatology Institute at the S. Andrea hospital, Sapienza, University of Rome who had to undergo anti-TNFα therapy. Results: Among the 169 enrolled subjects, 20 (12%) were potential occult HBV carriers (anti-HBc positive, HBsAg and HBV-DNA negative patients with or without anti-HBs). During the follow-up (mean ± SD 45 ± 22 months), aminotransferases and HBV-DNA, tested every two and six months respectively, did not change. Conclusion: This study confirms the substantial safety of anti-TNFα therapy in potential occult HBV carriers RA and SpA patients. © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Anti-tumor necrosis factor (TNF)-α agents are a new class of biological drugs widely used for the treatment of chronic inflammatory arthropathies, including rheumatoid arthritis (RA) and spondyloarthropathies (SpA) [psoriatic arthritis (PsA) and ankylosing spondylitis (AS)]. Despite the demonstrated efficacy in the disease activity control, these drugs seem to increase the risk of mild, severe or opportunistic infections [1]. Among viral infections, the association between hepatitis B virus (HBV) reactivation, [defined as serum HB surface antigen (HBsAg) reemergence or appearance or increase at least one logarithm of HBVDNA], and anti-TNFα therapy has been observed in patients affected by rheumatic, digestive and dermatologic autoimmune diseases [2]. This may be explained by the observation that TNFα plays a role in inhibiting HBV replication, thus its suppression could allow the HBV to avoid host defense mechanisms and encourage viral replication [3]. HBV-infected people may be divided into different categories, including HBsAg positive individuals, in turn subdivided in active and

⁎ Corresponding author. Tel.: +39 063 3775 375; fax: +39 063 3775 074. E-mail address: [email protected] (R. D'Amelio). 1 These authors contributed equally to this work.

inactive carriers, on the basis of HBV-DNA levels ≥ 2000 IU/ml and b2000 IU/ml respectively, and subjects positive for antibody to HB core antigen (anti-HBc) [2]. These HBsAg negative patients may instead be defined as occult carriers with long-lasting persistence of viral genome in the liver tissue and/or serum at very low levels [4]. The difficulty in identifying HBV-DNA in the liver biopsy (frequently not justified in subjects without clinical signs of hepatitis) and the rarity of detectable serum viremia, even with sensitive techniques, lead to consider all antiHBc positive patients (HBsAg and HBV-DNA negative, with or without anti-HBs) as potential occult HBV carriers [2]. Prevalence data on HBV reactivation in RA and SpA patients are limited. From 2003 to 2010, HBV reactivation has been reported in 52% (13/25) of HBsAg carriers (23 inactive and 2 active) with rheumatic diseases treated with TNFα inhibitors without antiviral prophylaxis/therapy [5]. Anti-viral treatment has been proven to be effective in preventing HBV reactivation in HBsAg positive subjects treated with anti-TNFα. In a recent meta-analysis, Perez-Alvarez et al., analyzing 89 HBsAg carriers affected by autoimmune diseases and treated with TNFα inhibitors, detected a lower percentage of HBV reactivation in the 39 who underwent antiviral prophylaxis (23% vs 62%, p = 0.003) [6]. In potential occult HBV carriers, HBV reactivation following antiTNFα therapy has been described [7]. However, few data on HBV reactivation risk in potential occult HBV carrier rheumatic patients treated with TNFα inhibitors are available and these are not univocal and range

0953-6205/$ – see front matter © 2014 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejim.2013.11.014

Please cite this article as: Biondo MI, et al, Lack of hepatitis B virus reactivation after anti-tumor necrosis factor α agents therapy in antibody to hepatitis B core antigen p..., Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2013.11.014

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M.I. Biondo et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

very widely according to the presence of HBV infection in the general population [8–10]. The aim of this prospective study was to evaluate the safety of antiTNFα therapy in a group of potential occult HBV carriers with RA or SpA. 2. Methods Between November 2003 and December 2011, the consecutive outpatients attending the Immuno-Rheumatology Institute at the S. Andrea Hospital, Sapienza, University of Rome, and affected by chronic inflammatory arthropathies (RA, AS and PsA), were tested for HBV markers, including HBsAg, antibody to HBsAg (anti-HBs), anti-HBc, HB envelope antigen (HBeAg), antibody to HBeAg (anti-HBe), and for aminotransferases before starting therapy with TNFα inhibitors. At the same time HBV-DNA was tested in anti-HBc positive patients. Inclusion criteria for this prospective study were: diagnosis of RA, AS and PsA according to the American College of Rheumatology (ACR) [11], the modified New York [12] and the Moll and Wright [13] criteria, respectively; indication for therapy with anti-TNFα agents; absence of active HBV replication before anti-TNFα treatment. Before starting anti-TNFα therapy (T0), disease activity was assessed using Disease Activity Score (DAS) on 44 joints [14] in RA and PsA patients (peripheral joint involvement) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) [15] in AS and PsA with axial involvement patients. Moreover, in all patients clinical and demographic characteristics including age, sex, disease duration, indicated treatment [anti-TNFα in monotherapy or combined with corticosteroids (CS) (less or more than 7.5 mg/day) and/or Disease Modifying Anti-Rheumatic Drugs (DMARDs)] were evaluated. During the follow-up patients fulfilling the criteria to be defined as potential occult carriers were checked every two months for aminotransferase levels and monitored every six months for HBV reactivation (defined as the serum appearance of either HBsAg or HBV-DNA). Serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST) were determined with standard laboratory methods. HBV markers were identified by the following techniques: HBsAg, antiHBs, anti-HBc, HBeAg, anti-HBe by CLIA [Chemiluminescence Immuno Assay (Architect)] and the HBV-DNA by real time-PCR (Roche TaqMan 96). 3. Results One hundred sixty-nine patients met the inclusion criteria of the study. Of them 20 (12%) were HBsAg negative, anti-HBc positive, and HBV-DNA negative. Twenty-four (14%) had been vaccinated against HBV. The mean follow-up was 45 ± 22 months. Clinical and demographic baseline parameters of the 20 subjects are reported in Table 1. Among the 20 anti-HBc positive patients, 10 were also anti-HBe and 14 anti-HBs positive. At baseline, the values of aminotransferases (AST and ALT) were within the normal range without any increase during the follow-up in anti-HBc positive patients. At the end of the follow-up, no case of reactivation was observed in anti-HBc positive patients independently of anti-HBs positivity. No patient, in fact, showed detectable HBsAg and/or HBV-DNA in the serum. 4. Discussion In the last decade, the increasing use of anti-TNFα therapy for chronic inflammatory arthropathies (RA, PsA, AS) has questioned the safety of these biological drugs in patients with serological signs of HBV infection and the number of studies in this area has increased. More recently, attention has been focused on anti-HBc positive/HBsAg negative subjects. The prevalence of potential occult HBV carriers in the general population ranges from 5 to 60–70% in countries with low and high HBV prevalence,

Table 1 Baseline characteristics of 20 patients with occult HBV infection. Patients

20 (100)

Female gender N (%) Age in years, mean ± SD Disease duration in years, mean ± SD RA N (%) SpA N (%) [PsA/AS] DAS, mean ± SD BASDAI score, mean ± SD Anti-TNFα N (%) Etanercept N (%) Adalimumab N (%) Infliximab N (%) Golimumab N (%) DMARDs N (%) MTX N (%) CsA N (%) SSZ N (%) CS N (%) CS ≤ 7.5 mg/die N (%)

13 (65) 63 ± 9.5 13 ± 8.1 12 (60) 8 (40) [6/2] 4.7 ± 1.13 48.9 ± 11.3 20 (100) 10 (50) 7 (35) 2 (10) 1 (5) 18 (90) 16 (80) 5 (25) 2 (10) 13 (65) 13 (65)

RA: rheumatoid arthritis; PsA: psoriatic arthritis; AS: ankylosing spondylitis; DAS: Disease Activity Score in 44 joints; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; TNF: tumor necrosis factor; DMARDs: Disease-Modifying AntiRheumatic Drugs; MTX: methotrexate; CsA: cyclosporine A; SSZ: sulfasalazine; CS: corticosteroids.

respectively. The mean reported prevalence of HBV reactivation in potential occult HBV carrier patients treated for hematological malignancies is 4.5% (range: 0.72%–50%) [16]. For this reason, HBV reactivation has also been evaluated in potential occult carriers affected by autoimmune diseases and treated with TNFα inhibitors. In the current study, no case of HBV reactivation in 20 occult carriers affected by RA, AS or PsA and treated with TNFα inhibitors has been observed. The prevalence of potential occult carriers here observed is similar to that reported by Caporali et al., who identified, at enrollment, 67 (9%) anti-HBc positive/HBsAg negative out of 732 Italian patients with inflammatory arthropathies, whereas Kim et al., in a retrospective study, identified 88/266 (34.4%) anti-HBc positive patients affected by RA, PsA, AS and juvenile rheumatoid arthritis treated with TNFα inhibitors, the discrepancy being probably due to the high HBV prevalence in Southeast Asia [9,17]. The HBV-DNA negativity at the enrolment is similar to the findings from three prospective studies conducted in Southern Europe that included 107 patients with resolved HBV infection and affected by rheumatologic diseases; none of anti-HBc positive patients resulted positive for HBV-DNA at the beginning of the study [9,10,18]. On the contrary, Lan et al. in Southeast Asia described detectable baseline viral loads in 4/12 (33.3%) anti-HBc positive/HBsAg negative RA patients [19]. Anti-HBe antibodies resulted positive in only 10/20 (50%) anti-HBc positive patients because, as well known, they tend to disappear before the anti-HBc antibodies and usually characterize recent past infection [20]. Kato et al. examined 35 anti-HBc positive/HBsAg negative patients with autoimmune diseases and showed that baseline titers of anti-HBs were significantly lower in 6 patients who experienced HBV reactivation [21]. In the current study, 14/20 (70%) potential occult carriers were anti-HBs positive, thus perhaps influencing the lack of HBV reactivation, even though HBV reactivation is generally not observed also in anti-HBs negative potential occult carriers. In a recent meta-analysis, Lee et al., in fact, reported 9 clinical studies including 468 anti-HBc positive/HBsAg negative cumulative patients treated with TNFα inhibitors and affected by rheumatologic diseases (RA, AS, PsA). In four studies, HBV reactivation has been observed in 8/231 patients (3.46%) with a percentage of HBV reactivation ranging from 1.4% (1/70) to 8.3% (5/60), not confirmed in other five studies on 237 cumulative patients. Thus HBV reactivation was globally observed in only 8 (1.7%) out of these 468 patients

Please cite this article as: Biondo MI, et al, Lack of hepatitis B virus reactivation after anti-tumor necrosis factor α agents therapy in antibody to hepatitis B core antigen p..., Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2013.11.014

M.I. Biondo et al. / European Journal of Internal Medicine xxx (2014) xxx–xxx

[22]. The lack of HBV reactivation here observed in anti-HBc positive/HBsAg negative patients during the follow-up is in line with Charpin and Caporali, who identified no HBV reactivation in 21 and 67 anti-HBc positive patients respectively [9,10]. By contrast, a study published by Urata et al. in 2011, described the reactivation in 5 (8.3%) out of 60 anti-HBc positive/HBsAg negative RA patients treated with TNFα inhibitors [8]. However, MTX, tacrolimus hydrate and CS N 5 mg/day use differed significantly in patients who did and did not develop HBV reactivation. In particular, CS N 7.5 mg/day is considered a high-risk treatment for inducing HBV reactivation [23,24]. The absence of HBV reactivation reported in this and in the Caporali's study could be related with the low CS doses taken by antiHBc positive patients [9]. Papers delineating the management of potential occult HBV carrier patients in the rheumatologic literature cite as source of evidence, among the others, the main international guidelines on chronic HBV infection management. However, these have been mostly derived from studies regarding hematological malignancies, whereas data are scarce regarding chronic rheumatic diseases [23]. Recently, Viganò et al. proposed recommendations for screening and treatment of HBV infection in anti-TNFα-treated patients and asserted the need for HBsAg, anti-HBs and anti-HBc screening and early treatment with nucleoside/nucleotide analogues and universal lamivudine prophylaxis in HBV active and inactive carriers respectively, before starting antiTNFα therapy. Furthermore, they suggested that anti-HBc positive/ HBsAg negative patients who have to undergo TNFα inhibitors do not need prophylaxis, but strict surveillance (HBsAg tests repeated every 3 months), in order to identify HBV reactivation and consequently start antiviral therapy [5]. 5. Conclusion In conclusion, the results of the current study support the relative safety of anti-TNFα therapy in anti-HBc positive/HBsAg negative patients with chronic inflammatory arthropathies, during a restricted follow-up period of almost 4 years. Studies with longer follow-up periods and including larger patient populations are needed to estimate the real risk of HBV reactivation in this type of patients under anti-TNFα therapy. In HBV negative patients who have to undergo TNFα inhibitors, HBV vaccination may be advised. Learning points • No case of reactivation after anti-TNFα therapy in 20 anti-HBc positive/ HBsAg negative rheumatic patients has been observed. • This finding supports the relative safety of anti-TNFα therapy in antiHBc positive/HBsAg negative patients with chronic inflammatory arthropathies. • However, anti-HBc positive/HBsAg negative patients who have to undergo anti-TNFα therapy need strict surveillance in order to identify HBV reactivation and consequently start antiviral therapy.

Conflict of interests The authors declare that they have no conflict of interest.

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References [1] Furst DE. The risk of infections with biologic therapies for rheumatoid arthritis. Semin Arthritis Rheum 2010;39:327–46. [2] Marzano A, Angelucci E, Andreone P, Brunetto M, Bruno R, Burra P, et al. Prophylaxis and treatment of hepatitis B in immunocompromised patients. Dig Liver Dis 2007;39:397–408. [3] Nathan DM, Angus PW, Gibson PR. Hepatitis B and C virus infections and anti-tumor necrosis factor-alpha therapy: guidelines for clinical approach. J Gastroenterol Hepatol 2006;21:1366–71. [4] Raimondo G, Pollicino T, Cacciola I, Squadrito G. Occult hepatitis B virus infection. J Hepatol 2007;46:160–70. [5] Viganò M, Degasperi E, Aghemo A, Lampertico P, Colombo M. Anti-TNF drugs in patients with hepatitis B or C virus infection: safety and clinical management. Expert Opin Biol Ther 2012;12:193–207. [6] Pérez-Alvarez R, Díaz-Lagares C, García-Hernández F, Lopez-Roses L, Brito-Zerón P, Pérez-de-Lis M, et al. Hepatitis B virus (HBV) reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy: analysis of 257 cases. Medicine (Baltimore) 2011;90:359–71. [7] 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. [8] Urata Y, Uesato R, Tanaka D, Kowatari K, Nitobe T, Nakamura Y, et al. Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients. Mod Rheumatol 2011;21:16–23. [9] Caporali R, Bobbio-Pallavicini F, Atzeni F, Sakellariou G, Caprioli M, Montecucco C, et al. Safety 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 2010;62:749–54. [10] Charpin C, Guis S, Colson P, Borentain P, Mattéi JP, Alcaraz P, et al. Safety of TNFblocking agents in rheumatic patients with serology suggesting past hepatitis B state: results from a cohort of 21 patients. Arthritis Res Ther 2009;11:R179. [11] Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. [12] Van der Linden S, Valkenburg HA, Cats A. Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 1984;27:361–8. [13] Moll JM, Wright V. Psoriatic arthritis. Semin Arthritis Rheum 1973;3:55–78. [14] Van der Heijde DM, Van't Hof MA, Van Riel PL, Theunisse LA, Lubberts EW, Van Leeuwen MA, et al. Judging disease activity in clinical practice in rheumatoid arthritis: first step in the development of a disease activity score. Ann Rheum Dis 1990;49:916–20. [15] Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 1994;21:2286–91. [16] Marignani M, Gigante E, Begini P, Marzano A, di Fonzo M, Deli I, et al. Patients with hematological malignancies and serological signs of prior resolved hepatitis B. World J Gastrointest Oncol 2012;4:37–45. [17] Kim YJ, Bae SC, Sung YK, Kim TH, Jun JB, Yoo DH, et al. Possible reactivation of potential hepatitis B virus occult infection by tumor necrosis factor-alpha blocker in the treatment of rheumatic diseases. J Rheumatol 2010;37:346–50. [18] 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. [19] Lan JL, Chen YM, Hsieh TY, Chen YH, Hsieh CW, Chen DY, et al. Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy. Ann Rheum Dis 2011;70:1719–25. [20] Pondé RA. Atypical serological profiles in hepatitis B virus infection. Eur J Clin Microbiol Infect Dis 2012;32:461–76. [21] 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. [22] Lee YH, Bae SC, Song GG. Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy. Clin Exp Rheumatol 2013;31:118–21. [23] Marignani M, Canzoni M, D'Amelio R, De Santis E, Pecchioli A, Delle Fave G. Should we routinely treat patients with autoimmune/rheumatic diseases and chronic hepatitis B virus infection starting biologic therapies with antiviral agents? NO. Eur J Intern Med 2011;22:576–81. [24] Cheng AL, Hsiung CA, Su IJ, Chen PJ, Chang MC, Tsao CJ, et al. Steroid-free chemotherapy decreases risk of hepatitis B virus (HBV) reactivation in HBV-carriers with lymphoma. Hepatology 2003;37:1320–8.

Please cite this article as: Biondo MI, et al, Lack of hepatitis B virus reactivation after anti-tumor necrosis factor α agents therapy in antibody to hepatitis B core antigen p..., Eur J Intern Med (2014), http://dx.doi.org/10.1016/j.ejim.2013.11.014