THERAPY Use of Tumor Necrosis Factor-␣ Inhibitors in Patients with Chronic Hepatitis B Infection Matthew B. Carroll, MD, FACP, and Michael I. Bond, DO Objective: Tumor necrosis factor-␣ (TNF-␣) inhibitors have emerged as a potent treatment for rheumatoid arthritis (RA), but not without significant risks. In chronic hepatitis B viral infection TNF-␣ is readily produced, and viral clearance is dependent on the amount bioavailable. Limited data suggest that TNF-␣ inhibitors may facilitate uncontrolled hepatitis B viral replication. The purpose of this article was to provide a detailed review of the role of TNF-␣ in controlling hepatitis B viral infection and the clinical impact blockade might have on viral control. Methods: We describe a patient with chronic hepatitis B viral infection and RA treated with etanercept. We then review case reports, expert opinion, and manufacturer recommendations regarding hepatitis B viral infection, TNF-␣, and TNF-␣ inhibitors. Results: To date, 13 patients with chronic hepatitis B infection treated with TNF-␣ inhibitors have been reported: 11 with infliximab and 2 with etanercept. Some patients received antiviral therapy for hepatitis B (specifically lamivudine) before, during, or after TNF-␣ inhibitors were started. Clinically apparent reactivation of hepatitis B virus typically occurred 1 month after the 3rd dose of infliximab. Etanercept was not associated with a similar reactivation. The difference between infliximab and etanercept in viral reactivation may be linked to the pharmacologic difference of each medication. Conclusions: TNF-␣ inhibitors in general should be used cautiously in chronic hepatitis B viral infection. But if necessary, when deciding which agent to use, the clinician should consider the mechanism by which the body clears TNF-␣. Published by Elsevier Inc. Semin Arthritis Rheum 38:208-217 Keywords: tumor necrosis factor alpha, hepatitis B, etanercept, infliximab, adalimumab R heumatoid arthritis (RA) is a systemic disorder characterized by the chronically inflamed synovium, which leads to gradual degradation and destruction of the joint. Underlying bone is affected, with periarticular erosive changes and diffuse cortical thinning found on radiographs. The systemic inflammation seen in RA is due in part to aberrant production of cytokines, compounds that normally help fight infection or respond to injury through modulation of the immune system. One such cytokine is tumor necrosis factor alpha (TNF␣). TNF-␣ is a pro-inflammatory cytokine that plays a San Antonio Uniformed Services Health Education Consortium (SAUSHEC), Wilford Hall Medical Center, Lackland Air Force Base, Lackland, Texas. The authors received neither financial support nor had any affiliation with organizations outside of their respective institutions. Dr. Carroll is a shareholder of Abbott Pharmaceuticals (adalimumab—Humira ®), Amgen/Wyeth (etanercept—Enbrel ®), and Gilead Sciences (adefovir dipivoxil—Hepsera ®). Address reprint requests to Matthew B. Carroll, MD, FACP, 301 Fisher Street, Keesler AFB, MS 39564. E-mail: [email protected]. 208 0049-0172/08/$-see front matter Published by Elsevier Inc. doi:10.1016/j.semarthrit.2007.10.011 key role in the host response to various types of infection (1) or other stimuli (2). In RA, continuous production of TNF-␣ in the joint space sustains inflammation, promotes osteoclast formation, and leads to the characteristic bone and cartilage destruction seen in advancing disease (3). Given such effects, TNF-␣ inhibitors (TNF-␣I) have greatly impacted how RA is currently managed. Despite their effectiveness, TNF-␣I have side effects, such as the reactivation of tuberculosis in patients given infliximab (4). At the present time it is not well known whether TNF-␣I allow reactivation of other chronic infections. Hepatitis B virus (HBV) is one such infection causing chronic disease in about 5% of individuals infected, or nearly 350 million people worldwide (5,6). A large body of evidence supports a role for TNF-␣ in the host antiviral response. Animal models demonstrate an impaired antiviral response when antibodies to TNF-␣ are administered (7). Neutralization of TNF-␣ or an imbalance with another cytokine, specifically interferon-␥ (IFN-␥), impairs viral clear- M.B. Carroll and M.I. Bond 209 ance and promotes chronic infection (8,9). A similar imbalance has been found to occur in other chronic infectious diseases, such as disseminated mycobacterial infection (10). To date, a handful of case reports suggest that TNF-␣ inhibition facilitates HBV reactivation and replication, with fulminant hepatic failure (11,12) or fatal outcomes reported (13). Our patient with chronic HBV infection and RA tolerated etanercept without evidence of increased HBV replication. Based on this discrepancy, we undertook this review of the literature to clarify the role of TNF-␣ in HBV infection, to identify which TNF-␣I may facilitate HBV reactivation, and assist clinicians to prevent reactivation of HBV infection in their patients. METHODS A review of the published English literature was performed using Medline® and Healthstar databases through Ovid web gateway (http://gateway.ovid.com) and the New England Journal of Medicine (http://content.nejm.org). The search screened articles from 1950 (Medline®), 1966 (Healthstar), or full-text articles since 1993 (New England Journal of Medicine) to January 2007 for the keywords “tumor necrosis factor alpha,” “hepatitis B,” “etanercept,” “infliximab,” and “adalimumab.” Articles on TNF-␣ and hepatitis B were selected if a review of the title and/or abstract suggested it discussed the basic science or immunology of these areas. Articles on etanercept (Immunex, Thousand Oaks, CA), infliximab (Centocor, Horsham, PA), and adalimumab (Abbott, Abbott Park, IL) were selected if they reviewed the pharmacologic properties of these agents or if they were associated with liver toxicity or hepatitis B infection. Articles from the New England Journal of Medicine database were chosen if they were review articles or clinical practice/therapeutics. Additional articles of interest were selected from the bibliographies of the published literature. CASE REPORT A 73-year-old Hispanic man was followed in our clinic for seropositive, deforming RA previously complicated by rheumatoid vasculitis. He was infected with HBV from a blood transfusion and developed biochemical evidence of chronic infection by the mid to late 1990s. He had the following antibody profile: HBs Ag⫹, HBc IgM⫺, HBc IgG⫹, HBe Ag⫹, HBe Ab⫺, and HBs Ab⫺. His RA was refractory to d-penicillamine, hydroxychloroquine, sulfasalazine, and moderate dose prednisone. Higher doses of prednisone used during the episode of vasculitis triggered a flare of HBV infection. Methotrexate and leflonamide were not used because of possible hepatic toxicity. In March 1999, etanercept (Enbrel®) monotherapy at 25 mg subcutaneously twice a week was started for RA with marked improvement in articular symptoms. Liver biopsy done in July 1999 revealed mild to moderate histologic activity and grade 2 (of 4) fibrosis. Lamivudine (Epivir-HBV®) 100 mg daily was begun in July 1999 because of the results of his liver biopsy and markedly elevated levels of HBV DNA. Lamivudine therapy resulted in a decline in HBV DNA levels to undetectable and normalization of serum transaminases, as shown in Table 1. The trend in his HBV DNA levels is shown in Fig. 1. Lamivudine was stopped in mid 2001 due to development of the YMDD mutant but etanercept therapy was continued. In February 2003, adefovir dipivoxil (Hepsera®) 10 mg daily was initiated, but 8 months later stopped due to an increase in serum creatinine. He has not had any other antiviral treatments since then. In October Table 1 Serum Transaminase Levels and HBV DNA Levels for our Patient with Rheumatoid Arthritis and Chronic HBV Infection Date ALT* (IU/L)† Log10 HBV DNA (copies/mL) Jan 1999 Mar 1999 42 28 8.75 9.65 Nov 1999 Dec 1999 May 2000 Jun 2000 Aug 2000 Sep 2000 Dec 2000 May 2001 Aug 2002 Jun 2003 Aug 2004 May 2005 42 ND 12 14 39 ND 55 32 ND 36 36 125 6.84 5.24 Undetectable Undetectable Undetectable Undetectable Undetectable 8.19 9.06 6.71 9.40 9.40 Clinical Intervention Mar 1999: etanercept started Jul 1999: lamivudine started Jun 2002: lamivudine stopped Feb 2003 to Oct 2003: brief trial of adefovir diprovil ND, not done. Undetectable ⫽ Value less than 5 copies per milliliter on quantitative polymerase chain reaction (PCR). *Alanine aminotransferase. †Normal range for alanine aminotransferase is 0 to 40 international units per liter (IU/L). TNF-␣ inhibitors in chronic hepatitis B infection 210 12 10 Etanercept started Lamivudine started Adefovir started log HBV DNA 8 6 4 2 0 05 nJa 4 l-0 Ju 04 nJa 3 l-0 Ju 03 nJa 2 l-0 Ju 02 nJa 1 l-0 Ju 01 nJa 0 l-0 Ju 00 nJa 9 l-9 Ju 99 nJa Figure 1 Plot of the log HBV DNA versus time (month/year) for our patient with rheumatoid arthritis and chronic HBV infection. Etanercept monotherapy was started in March 1999, with our patient on this therapy as of the publication of this article. (Color version of figure is available online.) 2004, liver biopsy was repeated, which revealed stable histologic activity and grade 1 (of 4) fibrosis. Some portal regions had a mild chronic lymphocytic inflammatory infiltrate. Although serum HBV DNA levels remain elevated and serum transaminases mildly elevated, he remains on etanercept monotherapy with no antiviral therapy and his RA continues to be remission. RESULTS All 5 keywords were entered into the Ovid web gateway databases but were limited to “English language” and “humans.” This retrieved 219 articles for hepatitis B and TNF␣, 20 articles for hepatitis B and infliximab, 6 articles for hepatitis B and etanercept, and 4 articles for hepatitis B and adalimumab. Two hundred articles were retrieved when TNF-␣ was crossed with etanercept, infliximab, and adalimumab. Our search of the New England Journal of Medicine database retrieved 173 articles for hepatitis B and 131 for TNF-␣. LITERATURE REVIEW Thirteen patients with HBV infection prescribed TNF-␣I were identified from 9 articles in our literature search (1,11-18) The first cases were published in 2003 (12,14). Table 2 summarizes the course of 11 patients who received infliximab (1,11-18), while Table 3 summarizes the course of 2 patients who received etanercept (1). Nine of the 13 patients were men and 4 were women. Eight patients had traditional rheumatic conditions with 3 of these concomitantly prescribed the disease-modifying antirheumatic drug (DMARD) methotrexate (1,14,16). Although methotrexate can cause changes in serum aminotransaminases and potentially affect HBV viral reactivation and replication, the patients reported had stable or normal serologic tests before the initiation of TNF-␣I. Three of 5 patients with Crohn’s disease were concomitantly treated with azathioprine (11,13). At present, no case reports have been published involving sole use of adalimumab. One patient died from variceal bleeding (13) and 1 patient required liver transplantation (12); both of these patients were treated with infliximab. In those patients who received infliximab, HBV reactivation seemed most likely to occur between 30 and 60 days after the 3rd infusion. Another group of authors commented in their review that HBV reactivation occurred 2 to 3 months after infliximab withdrawal (13). Of note, 1 patient with RA treated with infliximab and not given an antiviral medication experienced rapid (within 2 weeks) clearance of HBV DNA but later developed a persistent mild elevation of alanine aminotransferase (18). The majority of patients had HBV reactivation despite treatment with low (3 mg/kg) to moderate (5 mg/kg) doses. Treatment with lamuvidine 100 to 150 mg daily around the start of infliximab prevented liver function test abnormalities. Treatment with lamuvidine up to several months after starting infliximab also helped resolve liver function abnormalities and control HBV viral load, although 1 patient died from fulminant liver failure waiting for liver transplantation (12). In the 2 patients reported by Roux and coworkers who received etanercept, 1 was treated with lamivudine at the start of etanercept therapy and the other 20 months into therapy (1). Only 1 patient was on concomitant methotrexate (1). Regardless of when lamivudine was started in relationship to etanercept, HBV DNA viral load remained either the same or improved and serum aminotransferases remained stable (1). DISCUSSION What Is TNF-␣? First identified over 30 years ago by Carswell and colleagues (19), the spectrum of TNF-␣ bioactivity has yet to be completely understood. TNF-␣ is a homotrimer composed of three 17-kDa units (20,21) and is considered the main “upstream” link in the cytokine network (3,21). Rapid release of TNF-␣ can be triggered by diverse infectious (viral, bacterial, or parasitic) (22), physical, chemical, and immunological stimuli (2). Serum levels of TNF-␣ are detected about 30 minutes after a stimulus (2). Early amounts come from preformed stores cleaved from membrane bound TNF-␣ on macrophages (called soluble TNF-␣) and the release of cytoplasmic granules by mast cells and eosinophils (2). Subsequent release is due to new synthesis of TNF-␣ inserted into the cell membrane and then cleaved (23). TNF-␣ exerts numerous effects on the immune system and can amplify its own synthesis (23,24). It can also exist in either a membrane-bound or a soluble form. Soluble TNF-␣ increases the expression of adhesion molecules, stimulates the release of other cytokines like interleukin-1 (IL-1) and interleukin-6 (IL-6) (23), and can induce apoptosis (24). Membrane-bound TNF-␣ participates in cell-to-cell interactions, activating other effector cells such as neutrophils or M.B. Carroll and M.I. Bond macrophages involved in an immune response (25). It may also play a role with its receptor to down-regulate an immune response after a pathogen has been cleared (25). The vast majority of TNF-␣ synthesis (between 70 and 90%) is by cells of the monocyte/macrophage lineage (2,3,9,22,26). Under various circumstances, other cells contribute to TNF-␣ production, including neutrophils, mast cells, endothelial cells, hepatocytes (1), and T-lymphocytes (2,3,22). In RA, cells containing TNF-␣ are found in the synovial lining, in deeper parts of the interstitium, in blood vessels, and at the cartilage–pannus junction (3). For this reason, levels of TNF-␣ are much higher in the joint space than in the serum (20). Local production of TNF-␣ directly stimulates osteoclast formation and leads to bone resorption (3). The gene for TNF-␣ (TNFA) is found on chromosome 6 in the class III region of the major histocompatibility complex (MHC) between human leukocyte antigen (HLA)-B and HLA-DR (8,27). Expression of the TNFA gene is tightly controlled at both transcriptional and posttranscriptional levels, yet rapid expression is still possible (8,27). In response to stimulation by lipopolysaccharide, macrophage TNFA gene transcription increases 3-fold, with TNFA mRNA increasing 50- to 100-fold and TNF-␣ protein secretion increasing 10,000-fold (27). In nonmonocyte/macrophage cell lines, the constitutive activity of the TNFA gene promoter is absent; thus, it can only be induced in response to a stimulus (22). Gene promoter polymorphisms do exist, and these impact transcriptional activity (8,27,28). The best characterized TNFA gene promoter polymorphisms are those at positions ⫺308 and ⫺238 (8,28). Substitution of adenine (A) for guanine (G) at position ⫺308 is associated with higher constitutive and inducible production of TNF-␣ (8,27). Those who are guanine homozygotes (G/G genotype) at position ⫺308 of the TNFA gene produce lower levels of TNF-␣ (29). The physiologic effects of TNF-␣ are exerted through 2 receptors (TNF-R), TNF-R-p55 (CD120a) and TNFR-p75 (CD120b) (30). Both receptors are trimeric in structure (10) and are expressed on the membrane of most cells, giving TNF-␣ diverse biologic effects (24). As with TNF-␣, the 2 TNF-R exist in either a membrane-bound or cleaved (soluble) form (20,26). Binding of TNF-␣ to the membrane bound receptor activates nuclear factor-␬B (NF-␬B), triggering the release of inflammatory cytokines (31). Soluble receptor forms attenuate the bioactivity of TNF-␣ (32). The effects of TNF-␣ binding with its receptor are regulated in a variety of ways. Constitutive TNF-␣ synthesis is restricted to a small subset of immune cells (24). The relative expression of each TNF-R on a cell surface varies among tissues, implicating this as a distinct regulatory mechanism (26). The amount of TNF-␣ available to interact with its receptor also regulates biologic effects (26). Increased expression of both the membrane bound and the soluble forms of TNF-R can be found in response to various inflammatory disease states (26,30). 211 TNF-␣ and the Hepatitis B Virus Failure to secrete adequate amounts of TNF-␣ due to TNFA gene promoter polymorphisms has been shown to adversely influence the outcome of acute HBV infection (8,28). Depending on the population studied, either polymorphism (positions ⫺308 and ⫺238) may influence HBV clearance (28). In a White German population, only those with the ⫺238A allele were more likely to develop chronic HBV infection (8,33). In a Korean population, the ⫺308G/⫺238G haplotype demonstrated a higher risk of HBV persistence (28). Lower levels of TNF-␣ likely has 2 important effects. First, the cytokine cascade initiated by TNF-␣ is not as robust (30). Second, an imbalance with IFN-␥ (8,11) could impair clearance of the virus (9). Thus, not only the amount of TNF-␣ present, but its balance with IFN-␥, is important. This has been demonstrated in vitro (29), in animal studies (6), and in vivo (34). In a trial assessing the efficacy of recombinant TNF-␣, Sheron and coworkers evaluated 6 patients with untreated chronic HBV infection. Those given lower doses (10-15 ␮g/m2) demonstrated a decline in serum HBV DNA, whereas those given higher doses (over 30 ␮g/m2) had enhanced viral replication (29,34). None of these patients, however, demonstrated serologic evidence of viral eradication, and disease progression in 1 required liver transplantation (30,34). On initial hepatocyte infection, viral replication leads to the production of various proteins, to include surface, core, polymerase, and X proteins (35). These foreign proteins undergo intracellular processing and are presented by the HLA class I pathway. Cytotoxic (CD8⫹) T-lymphocytes bind to the HLA class I complex and with appropriate costimulation initiate a robust immune response to the virus (36). This response can inhibit HBV replication and leave the hepatocyte intact through secretion of IFN-␥ or trigger hepatocyte apoptosis through the Fas/Fas ligand pathway (36). Both responses had been observed during resolution of acute HBV infection, and the latter response may be mediated through recruitment of other nonspecific inflammatory cells or the secretion of TNF-␣ (5,6,36). If viral replication eludes this pathway, virions that are assembled and released into the circulation may be processed by antigen-presenting cells such as macrophages (5). These foreign proteins are then presented via the HLA class II pathway to CD4⫹ T-lymphocytes. Once activated, these cells recruit other T-lymphocytes, which induce cytokine secretion (to include TNF-␣) and activate B-lymphocytes for antibody production (5). As demonstrated in an animal model, the response of the CD8⫹ T-lymphocytes to HBV infection is more important in virus eradication compared with the other cells of the host immune system (37). Selective elimination of CD8⫹ T-lymphocytes responding to acute HBV infection leads to persistent viral infection with a delay in DNA clearance and prolonged hepatocyte destruction (37). When eradication of HBV is incomplete, chronic infection becomes TNF-␣ inhibitors in chronic hepatitis B infection 212 Table 2 Published Cases of Patients with Rheumatic or Gastrointestinal Disease and Chronic HBV Infection Treated with TNF-␣I Year Reference 2003 [12] Adult-onset Still’s disease 28/乆 None [14] Rheumatoid arthritis 49/么 Methotrexate 10 mg/wk, prednisone [15] Ankylosing spondylitis 32/么 None [13] Crohn’s disease 34/么 None Crohn’s disease Crohn’s disease 38/么 26/么 Azathioprine Azathioprine [16] Spondyloarthritis 35/乆 Methotrexate 15 mg/wk [17] Crohn’s disease 28/乆 None [18] Rheumatoid arthritis 36/乆 None [11] Crohn’s disease 50/么 Azathioprine [1] Spondyloarthritis 49/么 None 2004 2005 2006 Diagnosis Age/Sex Concomitant Immunosuppressive NR, not reported. *“Infliximab treatment” refers to the number of doses administered before hepatitis B reactivation occurred. †“Days after treatment” refers to the time after the last infliximab dose was given when hepatitis B reactivation occurred. established with host immunity reaching a balance between virus-specific CD8⫹ T-lymphocytes and small amounts of replicating virus (38). The same cytokines that contribute to initial viral clearance, specifically IFN-␥ and to a lesser extent TNF-␣, are important in maintaining this balance (36). The amounts secreted depend on the potency of these virus-specific CD8⫹ T- lymphocytes after recovery from acute infection as well as during the life of the host (36). Their concentration in the blood and liver may also be important (36). While secretion of TNF-␣ can be associated with hepatocyte injury or death, in chronic infection it can also serve to decrease transcriptional activity of the HBV core promoter gene and HBV gene expression, without causing hepatocyte Table 3 Published Cases of Patients with Rheumatic Disease and Chronic HBV Infection Treated with Etanercept Year Reference Diagnosis Age/Sex Other Immunosuppressive Etanercept Dose 2006 [1] Rheumatoid arthritis 54/么 Methotrexate 15 mg/wk 25 mg twice a week Rheumatoid arthritis 53/么 None 25 mg twice a week NR, not reported. Outcome Lamivudine started at same time as etanercept with no biochemical liver abnormalities; etanercept later changed to adalimumab 40 mg every 2 weeks Lamivudine started about 20 months after etanercept; no biochemical liver abnormalities but decreased HBV DNA reported M.B. Carroll and M.I. Bond 213 Table 2 Continued Infliximab Dose Infliximab Treatment* Days after Treatment† Outcome 5 mg/kg 2nd 10 6 mg/kg 12th NR NR — - 5 mg/kg 4th 60 NR NR 3rd NR 90 NR 5 mg/kg Around 3rd NR 5 mg/kg 1st 14 3 mg/kg — - 5 mg/kg 3rd 3 to 30 NR NR NR Fulminant hepatitis; lamivudine started days before liver transplant Hepatitis due to flare of HBV, treated successfully with lamivudine Pretreated with lamivudine; no biochemical liver abnormalities Spontaneous resolution of biochemical liver abnormalities Death from variceal bleeding Pretreated with lamivudine; no biochemical liver abnormalities Resolution of biochemical liver abnormalities when treated with lamivudine Spontaneous resolution of biochemical liver abnormalities but persistence of HBV DNA in serum Abnormal alanine transaminase values noted 16 weeks after starting infliximab but clearance of HBV DNA in serum Spontaneous resolution of biochemical liver abnormalities after 1 month Concomitant start of lamivudine with infliximab with no biochemical liver abnormalities death (7,8,23,28,29,36,39). Thus, the cytokine profile of CD8⫹ T-lymphocytes impacts viral clearance in acute infection and contains viral replication in chronic infection (36-38). Not all TNF-␣I Are Created Equal As a class, TNF-␣I exhibit a high affinity for TNF-␣ and are effective in the treatment of a variety of inflammatory disorders. Each medication, however, is biochemically distinct and thus exerts different effects on TNF-␣. Infliximab (Remicade®), the first of 3 TNF-␣I marketed in the United States, is a chimeric monoclonal antibody to TNF-␣ that consists of a mix of human constant and murine variable regions (3). It is about 66% human to minimize immunogenicity and is administered intravenously (20,40). Infliximab can neutralize either soluble or membrane-bound TNF-␣, and as a result, cells bearing TNF-␣ can be destroyed through complement fixation or cytotoxic killing (2,3,21,32,40). This destruction of TNF-␣-bearing cells by infliximab has been demonstrated in vivo (41). Adalimumab (Humira®), a newer monoclonal antibody, is similar to infliximab in that it also serves as an antibody to TNF-␣ but is a fully human IgG1 molecule administered subcutaneously (3). Like infliximab, it can neutralize either soluble or membranebound TNF-␣, resulting in cell death through similar mechanisms (3,32). Etanercept, although administered subcutaneously like adalimumab, is distinct from the other TNF-␣I. It is a recombinant, covalently bound dimer of soluble p75 TNF-R fused to the Fc portion of IgG1 (2,40). It binds to soluble TNF-␣ longer than the naturally occurring soluble p75 TNF-R, yet has no effect on membranebound TNF-␣ (3,20). In vitro etanercept has been shown to be less avid for TNF-␣ than infliximab, with etanercept dissociating from both soluble and membrane-bound TNF-␣ much more quickly than infliximab (42). In addition to the unique ways in which the TNF-␣I interact with TNF-␣, other differences in the mechanism of action have been noted. Infliximab, given on an every other month basis, may cause a “cytokine washout,” whereas etanercept, administered more frequently and in smaller doses, may lack such an effect (2). It has been noted that infliximab blood levels reach well over 100 ␮g/mL, whereas etanercept reaches a steady state of 3 ␮g/mL (2). Greater immunogenicity with infliximab leads to higher autoantibody production (2). In patients with ankylosing spondylitis, in vitro data suggest that infliximab down-regulates Th1 cytokine expression on both CD4⫹ and CD8⫹ T-lymphocytes (which includes IFN␥), while etanercept up-regulates such expression (43-45). Statistically significant changes in Th1 cytokine expression with both agents were noted as early as 6 weeks into TNF-␣I therapy and affected antigen-specific and nonspecific responses (44,45). From a hepatic standpoint, other differences in the effects of TNF-␣I are noted. In postmarketing surveillance, infliximab is associated with 214 acute hepatic reactions such as elevated liver enzymes with jaundice, autoimmune hepatitis, and liver failure, which in some cases these reactions have been fatal (46,47). A patient with severe psoriasis who developed an elevated alanine aminotransferase after 2 doses of infliximab switched to etanercept and methotrexate and did not experience a similar reaction (48). In patients infected with hepatitis C virus (HCV), etanercept has been shown not to affect liver function or HCV viral loads (49). Etanercept has been tested as an adjunct to interferon and ribavirin therapy in HCV with improvement in virologic response noted after 24 weeks (50). Finally, it has been noted that etanercept increases peripheral T-lymphocyte reactivity to several microbial antigens and results in a significant increase in IFN-␥ production (1,10). TNF-␣I in Patients with Chronic Hepatitis B Infection It is intriguing to consider why infliximab has been more likely to allow HBV reactivation compared with etanercept (and to date adalimumab). The trend of infliximab causing more reactivation and dissemination of chronic infections is not unique to HBV. Based on postmarketing reports, it has been reported that infliximab was associated with more cases of Mycobacterium tuberculosis infection compared with etanercept (4) and adalimumab (24). The risk of reactivation of tuberculosis is almost 10-fold higher in patients treated with infliximab when compared with etanercept (10). A similar trend is noted with other opportunistic infections such as histoplasmosis, listeriosis, cryptococcal infection, systemic candidiasis, and Pneumocystis carinii (24). Although postmarketing surveillance data do have inherent limitations, the rates of these infections in infliximab patients were higher when compared with background rates (4). Also of interest, reactivation of such infections typically occurs around the third dose of infliximab (4,24). Histoplasmosis infection was seen with infliximab doses between 3 and 5 mg/kg (24), similar to that in patients listed in Table 2. Pharmacologic and biochemical differences between infliximab and etanercept may explain why this agent is more likely to facilitate HBV reactivation. Etanercept has a shorter half-life than infliximab, and this may ensure rapid clearance once the agent is stopped (51). As previously noted, infliximab binds both membrane-bound and soluble TNF-␣ and is much more avid for TNF-␣. Infliximab cannot be dissociated from membrane-bound TNF-␣ in the presence of soluble monomeric TNF-Rp55, whereas etanercept nearly completely dissociates in vitro (42). The avidity of infliximab for either form of TNF-␣ likely causes widespread depletion of macrophages. This has been noted in an animal model of infection with parainfluenza type 1 (Sendai) virus (52). Bronchoalveolar lavage specimens from rats treated with soluble TNF-R-p55 IgG demonstrated significant reduc- TNF-␣ inhibitors in chronic hepatitis B infection tions in the number of macrophages and lymphocytes but higher pulmonary viral titers (52). The authors concluded that inhibition of TNF-␣ decreased the cellular inflammatory response to viral infection, allowed prolonged viral replication, and prevented destruction of infected epithelial cells (52). This could be what occurs in chronic HBV infection with infliximab treatment. On cessation of infliximab therapy, macrophages and T-lymphocytes may reconstitute in greater numbers, generating a brisk response to replicating virus and potentially causing fulminant hepatic injury. In their hepatitis B animal study, Thimme and coworkers noted that depletion of CD8⫹ T-lymphocytes led to an unexpected rebound of these cells to baseline levels several months later (37). This was associated with a surge in liver enzymes and increased clearance of viral DNA without the production of anti-hepatitis B surface neutralizing antibodies (37). Their results suggested that viral clearance was due to the reconstitution of previously eradicated CD8⫹ T-lymphocytes (37). In an animal model of latent tuberculosis, infliximab caused a marked increase in the number of immune cells, out of proportion to the bacillary load (4). Also of interest, concomitant use of methotrexate with infliximab may reduce clearance of intrahepatic HBV specific CD8⫹ T-lymphocytes (53). This increases the risk of exacerbating HBV infection as infliximab is gradually cleared and these surviving CD8⫹ Tlymphocytes respond to viral replication that was previously kept in check by the inhibitory effects of TNF-␣ (53). Finally, the degree of depletion of TNF-␣ may play a role. As discussed earlier, it has been postulated that the balance of IFN-␥ with TNF-␣ presented to infected hepatocytes helps drive viral clearance with or without hepatocyte destruction (9). Since TNF-␣ clearance is more pronounced with infliximab compared with etanercept, it could more dramatically shift such a balance toward hepatocyte destruction. In our patient, the use of etanercept did not cause an immediate rise of his HBV viral load or serum transaminases. When started on lamivudine several months later, the HBV viral load became undetectable and the alanine aminotransferase normalized. It was not until the HBV viral load rose again that the YMDD mutant was detected and lamuvidine was stopped. Adefovir dipivoxil was given for several months in 2003 but stopped due to a mild increase in serum creatinine. To this day, the patient remains on etanercept with an elevated HBV viral load and persistent mild serum transaminitis, but without histologic progression on biopsy and without clinical or biochemical evidence of hepatic decompensation. Current Recommendations No consensus currently exists about whether or not TNF-␣I can be safely used in patients with chronic HBV infection. In 2004 Centocor, Inc. and the Food and Drug Administration updated the infliximab label to include a M.B. Carroll and M.I. Bond comment that use had been associated with reactivation of HBV and chronic carriers should be evaluated and monitored before and during treatment (46). The current package insert for infliximab states that prescribers “should exercise caution in prescribing TNF blockers, including Remicade®, for patients identified as carriers of HBV” (47). The package inserts for etanercept and adalimumab do not provide any specific comments about the reactivation of HBV infection (54,55). Given the immunosuppressive nature of this class of medications and postmarketing problems encountered with reactivation of other latent infections, a conservative approach would be to consider not using TNF-␣I in this population (40,56). From the case reports reviewed in this article, this may be most applicable when considering whether or not to use infliximab. One fatal outcome due to a variceal bleed (13) and 1 patient who developed fulminant hepatic failure which required liver transplantation (12) have been reported with infliximab in chronic HBV infection. Use of etanercept may be relatively safer since HBV viral loads and serum transaminases did not worsen in either our patient or the 1 reported by Roux and coworkers before institution of antiviral therapy (1). For patients who need a TNF-␣I due to severe rheumatologic or autoimmune disease, no guidelines currently exist on which antiviral medication to use or how long to use it to prevent reactivation of HBV (35). Although the current literature exclusively reflects experiences with lamivudine, no antiviral agent can be assumed to be better than another. Chronic use of lamivudine may lead to development of the YMDD mutant. Guidelines from the European Association for the Study of the Liver International Consensus Conference on hepatitis B state that “antiviral therapy should be given 2 to 4 weeks before the initiation of immunosuppressive therapy or if hepatitis develops in this group of patients” (57). Antiviral therapy should be continued for 3 to 6 months after completion of TNF-␣I therapy and close monitoring of serum transaminases and HBV viral loads are extremely important (57). The New Zealand MEDSAFE guidelines issued in 2006 do not recommend a particular antiviral agent but do state that “patients who are carriers of HBV and require treatment with anti-TNF agents should be closely monitored for signs and symptoms” of reactivation during therapy and several months afterward (58). Finally, no guidelines have been established regarding who to screen for chronic HBV infection before starting TNF-␣I (35). It is our routine practice to screen all patients for chronic HBV infection before initiating therapy. The New Zealand MEDSAFE bulletin in November 2006 recommended that patients at risk for HBV infection “should be evaluated for evidence of prior HBV infection before anti-TNF therapy is initiated” (58). In their discussion on this issue, Calabrese and coworkers have recommended a potential way to risk-stratify patients with chronic HBV infection before starting TNF-␣I (35). 215 Although TNF-␣I are effective agents in the treatment of various rheumatologic and autoimmune conditions, they have been associated with the reactivation of latent infections. Reactivation of HBV infection in patients started on TNF-␣I is currently limited to a handful of case reports, but the TNF-␣I used could make a difference. Infliximab, because of its effect on membrane-bound and soluble TNF-␣, may more potently suppress the cellular immune response compared with etanercept and adalimumab. This suppression may lead to a disproportionate immune response on reconstitution. No guidelines currently exist that help formulate a treatment plan for a patient with chronic HBV infection who may need a TNF-␣I to ease the symptoms of a rheumatic illness. Studies exploring the optimal way to screen and treat patients with chronic HBV infection requiring TNF-␣I are greatly needed. ACKNOWLEDGMENTS We are indebted to Michelle Bond and Jennifer Carroll for insightful review and grammatical revision of this manuscript. REFERENCES 1. Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Safety of anti-TNF-␣ therapy in rheumatoid arthritis and spondyloarthropathies with concurrent B or C chronic hepatitis. Rheumatology 2006;45:1294-7. 2. Feldmann M, Ravinder NM. 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