Hepatitis B Annual
Home

Current Issue  

Back Issues   

Instructions   

Search Login    Users online: 210 Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
>>> Ahead of Print <<<


 
 Table of Contents    
REVIEW ARTICLE  
Year : 2009  |  Volume : 6  |  Issue : 1  |  Page : 89-109
Safety of Anti-tumor necrosis factor ( Anti-TNF) therapy in patients with chronic Hepatitis B


United States Air Force, 301 Fisher Street, Keesler AFB, MS, USA

Click here for correspondence address and email

Date of Web Publication19-Feb-2011
 

   Abstract 

The anti-tumor necrosis factor (TNF) agents are a class of medications which have given clinicians a new level of control over inflammatory illnesses that was previously unattainable with older disease modifying agents. Though each medication has unique molecular differences, they all have as their specific target the proinflammatory cytokine TNF-α. With the great improvements provided by the anti-TNF agents though has come a new spectrum of side effects. On the basis of the importance of TNF-α in granuloma formation, neutralization of TNF-α has led to reactivation of latent infections, the most notable being Mycobacterium tuberculosis. Another infectious agent that can elude eradication and enter a latent state, reactivating when the immune system is depressed, is the hepatitis B virus (HBV). Inhibition of TNF-α could also lead to immune suppression and reactivation of the virus much like that experienced with the reactivation of TB. The purpose of this article is to review the current medical literature for cases where anti-TNF agents were used to treat an inflammatory illness such as rheumatoid arthritis or Crohn's disease in patients chronically infected with HBV. Additionally, the role of TNF-α in HBV infection is explored, the differences in the anti-TNF agents are examined, and guidelines regarding the screening for and prophylaxis of HBV are discussed.

Keywords: Crohn′s disease, hepatitis B virus, rheumatoid arthritis, tumor necrosis factor-α

How to cite this article:
Carroll MB, Holmes R. Safety of Anti-tumor necrosis factor ( Anti-TNF) therapy in patients with chronic Hepatitis B. Hep B Annual 2009;6:89-109

How to cite this URL:
Carroll MB, Holmes R. Safety of Anti-tumor necrosis factor ( Anti-TNF) therapy in patients with chronic Hepatitis B. Hep B Annual [serial online] 2009 [cited 2019 Jul 19];6:89-109. Available from: http://www.hepatitisbannual.org/text.asp?2009/6/1/89/76907



   Introduction Top


The anti-tumor necrosis factor (TNF) agents infliximab, etanercept, adalimumab, certolizumab, and golimumab represent the avant-garde of medications which have afforded clinicians a level of control over inflammatory rheumatologic, dermatologic, and gastrointestinal illnesses that was previously unattainable with disease modifying agents available a little over a decade ago. Though each medication has unique molecular differences, they all have as their specific target the critical proinflammatory cytokine TNF-α. In inflammatory illnesses such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis and psoriasis, the aberrant production of TNF-α is often the initiator as well as the perpetuator of these diseases. Neutralization of TNF-α thus represented a logical therapeutic target and has provided significant control over these diseases, especially when combined with other disease modifying agents such as methotrexate and azathioprine. With the great improvements provided by the anti-TNF agents though has come a new spectrum of side effects. Given the importance of TNF-α in granuloma formation, neutralization of TNF-α has led to reactivation of latent infections, the most notable being Mycobacterium tuberculosis (TB). [1] Although the U.S. Food and Drug Administration (FDA) label for infliximab published at the time of its approval in 1998 did not include a warning about the reactivation of TB infection, [2] by 2001, a cohort of 70 patients had been reported documenting the need to screen all patients prior to therapy with this agent. [1] Another infectious agent that can elude complete eradication and enter a latent state, reactivating when the immune system is depressed, is the hepatitis B virus (HBV). Affecting up to 400 million people worldwide, [3] the acute eradication and the chronic containment of the virus is dependent on the production of TNF-α by various cells of the immune system. Inhibition of this cytokine could in theory lead to immune suppression and reactivation of the virus much like that experienced with the reactivation of TB. The purpose of this article is to review the current medical literature for cases where anti-TNF agents were used to treat an inflammatory illness such as rheumatoid arthritis or Crohn's disease in patients chronically infected with HBV. Additionally, the differences in the anti-TNF agents are examined, the role of TNF-α in HBV infection is explored, and thoughts about screening for and prophylaxis of HBV are reviewed.


   Methods Top


A review of the published English literature was performed using PubMed® (http://www.ncbi.nlm.nih.gov/PubMed) and the Medline database through Ovid® ( http://gateway.ovid.com ). The search screened articles for the keywords "tumor necrosis factor" and "hepatitis B" as well as the current anti-TNF agents "infliximab," "etanercept," "adalimumab," certolizumab," and "golimumab." Articles were selected if a review of the title and/or abstract suggested it discussed the interaction of anti-TNF agents in patients with hepatitis B infection. Additional articles of interest were selected from the bibliographies of articles reviewed during our search.

Review of the literature

The literature describing the effects of anti-TNF agents on hepatitis B infected patients is currently limited to case reports and case series. Reports included in our review were those that described patients with inflammatory illnesses typically treated with any of the five currently available anti-TNF agents who had documented HBsAg positivity. Two patients reported by Raftery et al, were not included in the data analysis as both were HBsAg negative, [4] and one patient reported by Cansu et al, was not included as the patient was coinfected with HCV and HBV. [5] The total number of patients identified was 30. [5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23] Illnesses treated were rheumatoid arthritis (13 cases), Crohn's disease (seven cases), spondyloarthropathies (nine cases), and adult onset Still's disease (one case). Eighteen cases were male and 12 were female patients. The age range of the patients in this review was from 26 to 73 years, with a mean age of 45 years.

In addition to the bias introduced by retrospective reviews of small numbers of patients without appropriate control cases, a confounding bias could have been introduced by the absence of information regarding the seropositivity or the destructive nature of a patient's rheumatoid arthritis. As an example, some patients who had a diagnosis of rheumatoid arthritis and were documented as having satisfied the 1987 American College of Rheumatology revised criteria, [21] had serologic features such as anti-CCP IgG positivity which is fairly specific for rheumatoid arthritis, [21] or were labeled as having a "destructive" or "severe" course. [6] However, other case reports did not include sufficiently descriptive information, and it is possible that some cases of RF positive rheumatoid arthritis were actually cases of polyarthritis due to the immune response mounted to active HBV infection. [10],[14],[17],[18],[19] While such a response is typically seen during acute infection with HBV and is self-limiting, a chronic arthritis can occur in the setting of HBV-associated polyarteritis nodosa. [24] One reason for the limitation in descriptive information could have been the lack of access to anti-CCP IgG testing in the earlier part of the 2000s for the early detection and diagnosis of rheumatoid arthritis. For the other inflammatory illnesses included in this review, the majority of authors provided either enough information to support the presence of the underlying inflammatory illness in their HBV infected patient or stated that their patients satisfied established criteria for it.

To date, the most commonly reported anti-TNF agent used in patients with chronic hepatitis B infection has been inflimixab (17 cases) followed by etanercept (nine cases) and then adalimumab (four cases). These counts are based on the first agent used, as several patients changed anti-TNF agent during their therapy. [6],[12],[20],[21],[22],[23] Currently, no cases have been reported with the use of certolizumab or golimumab. While a similar trend in the reactivation of other latent organisms, such as TB, has been reported, [1],[25],[26] this trend could also be related to the length of time that they have been approved for use, as infliximab was first approved over 10 years ago followed by etanercept and adalimumab several years later. Certolizumab and golimumab have been most recently approved, thus these anti-TNF agents have not had as broad an exposure to patients with a spectrum of comorbidities. Additionally, as adverse outcomes continue to come into better focus with long-term use of infliximab, etanercept, and adalimumab, it is possible that certolizumab and golimumab will not be used in selected patient populations based on new screening measures implemented. A little over half of the 30 cases reported the concomitant use of a non-biologic disease modifying agent. For rheumatologic illnesses, the most common disease modifying agents were methotrexate and glucocorticoids. For Crohn's disease, the most common disease modifying agent was azathioprine with some patients taking glucocorticoids as well.

Infliximab was the anti-TNF agent most likely to be associated with HBV reactivation when patients were not pretreated with an antiviral agent at or prior to the start of therapy. Usually HBV reactivation occurred about 30 days following the third dose, after attainment of maximal efficacy of the medication. [7],[16],[17],[27] A similar pattern has again been observed in the reactivation of other latent infections, such as tuberculosis [1] and histoplasmosis. [28] Esteve et al, however, stated that HBV reactivation occurred 2-3 months after infliximab cessation. [9] Reactivation occurred at low (3 mg/kg) to moderate (5 mg/kg) doses, [17],[23] similar to doses which have been associated with histoplasmosis infection. [28] One patient treated with infliximab who experienced HBV reactivation developed subacute fulminant hepatitis, [7] another patient developed fulminant hepatitis, [8] and a third patient died from variceal bleeding which complicated viral reactivation. [9] Those pretreated with lamivudine before starting infliximab had no biochemical liver abnormalities or elevations in HBV DNA levels. [6],[9],[11],[19],[29] When biochemical evidence of hepatitis did occur in patients with HBV infection treated with infliximab, lamivudine given even after the onset of such changes was effective in reducing viral load. [7],[23],[29]

For patients treated with etanercept, no evidence of HBV reactivation occurred when pretreatment with an antiviral agent such as lamivudine was instituted. [6],[19],[22] Variable increases in HBV DNA have been reported in patients started on etanercept without antiviral prophylaxis. One patient started on etanercept (later transitioned to adalimumab) without antiviral prophylaxis demonstrated no significant increase in HBV DNA levels or changes in AST or ALT during therapy, [20] whereas several other patients did have noteworthy changes in HBV DNA levels, one of which occurred when the YMDD mutant developed during therapy with lamivudine. [17],[21],[22] Concomitant marked elevations in AST or ALT have not been reported with such elevations in HBV DNA levels. [17],[21],[22] No cases of fulminant hepatitis or deaths have been reported in patients with chronic HBV infection treated with etanercept. Adalimumab has had a HBV reactivation profile similar to that of etanercept, with no reactivation reported when antiviral therapy pretreatment was given. [19] When antiviral pretreatment was not instituted, in separate cases elevations in AST and ALT were reported [21] and a prominent rise in HBV DNA levels was reported within the first few months of adalimumab treatment. [18] HBV DNA levels improved with the institution of lamivudine after adalimumab was started. [18] No cases of fulminant hepatitis or deaths have been reported in patients with chronic HBV infection treated with adalimumab.

Two cases of the 30 cases reviewed in this article described the results of liver biopsies performed in patients with chronic HBV infection treated with anti-TNF agents. The first case described a patient treated with etanercept who had two liver biopsies, one several months after starting etanercept therapy and the second several years into therapy while on treatment with lamivudine and then adefovir. [17] Mild to moderate histologic activity was reported in both biopsies with no significant change in fibrosis noted after 5 years of therapy. [17] The second case described a patient treated with adalimumab who had one biopsy done 4 months into therapy not on antiviral prophylaxis. [18] Minimal active chronic hepatitis was reported with 0/4 portal and lobular changes and 0/4 fibrosis. [18]


   Not all TNF-α Inhibitors are the Same Top


While as a class all the anti-TNF agents have a high affinity for TNF-α, they are all distinctly different molecules which exploit different facets of the cytokine and how it interacts with its cognate receptor to modulate its pleotropic effects. These molecular differences translate into in vitro differences which explain some of the efficacy and adverse effects they have on the immune system, specifically the reactivation of latent infections. The first anti-TNF agent approved by the U.S. FDA for the treatment of an inflammatory illness was infliximab. It was approved for the treatment of Crohn's disease in 1998, and later for the treatment of rheumatoid arthritis in 1999. [30] In addition to these illnesses, infliximab has also been approved for the treatment of adults with psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and ulcerative colitis. Infliximab is a chimeric IgG1κ monoclonal antibody about 149 kilodaltons (kD) in weight. [30] About 75% of the protein is human which comprises the constant region and Fc portions of the molecule; the remaining 25% is of murine origin and comprises the variable regions. [31] It is currently the only anti-TNF agent that is administered intravenously. Three months after infliximab was approved for the treatment of Crohn's disease, the U.S. FDA approved etanercept for the treatment of rheumatoid arthritis. [3]2 Since its initial approval, etanercept has also been approved for the treatment of adults with psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis. Etanercept is a dimeric fusion protein consisting of the extracellular ligand of the higher affinity p75 subtype of the human TNF-α receptor covalently linked to a human Fc portion of IgG1. [32] It has a molecular weight of 150 kD and is administered subcutaneously weekly or twice a week. [32] In 2002, the U.S. FDA approved adalimumab for the treatment rheumatoid arthritis. It has since been approved for the treatment of adults with psoriatic arthritis, plaque psoriasis, ankylosing spondylitis, and Crohn's disease too. [33] Adalimumab is a fully human IgG1 monoclonal antibody with a molecular weight of 148 kD. [31],[33] It is administered subcutaneously typically once every other week. In 2008, the U.S. FDA approved certolizumab pegol for the treatment of Crohn's disease. [34] Certolizumab is a humanized Fab' fragment 91 kD in weight conjugated to a 40 kD polyethylene glycol (PEG) molecule. [34] To avoid interference by the PEG molecule with the biologic properties of the Fab' fragment, the Fab' fragment has been constructed to have a free cysteine residue in the hinge region, [35] enabling the antigen binding site to bind unrestricted to TNF-α. [36] It is also administered subcutaneously once every other week but only during the first month of therapy. If patients have an adequate response to the every other week regimen, after the first month of therapy the subcutaneous injections can be spaced out to every 28 days. [34] The last anti-TNF agent approved by the U.S. FDA was golimumab. It was approved in 2009 for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. It is a fully human IgG1monoclonal antibody about 150 kD in weight that is administered subcutaneously once every 28 days. [31],[37]

Knowledge of the molecular structures of each of the five currently available anti-TNF agents draws attention to several distinctions from which in vitro differences have been noted. These differences have clinical ramifications regarding the efficacy and side effects of each agent. As a p75 TNF receptor fusion protein, etanercept is the only anti-TNF agent which does not target TNF-α as an antibody but instead interacts with it as the TNF receptor does. This restricts the binding of etanercept to trimeric TNF-α, the biologically active form of the cytokine, whereas monoclonal anti-TNF antibody agents such as infliximab and adalimumab can bind both monomeric and trimeric TNF-α. As would be expected of a receptor binding to its ligand, etanercept binds TNF-α in a 1:1 ratio and recent data has demonstrated that it is the most potent agent in vitro to bind soluble TNF-α, [38] whereas the monoclonal antibody anti-TNF agents such as infliximab and adalimumab bind TNF-α in 2:1 ratios but with a potency less than etanercept. [38],[39] Binding two soluble TNF-α molecules enables the monoclonal antibody anti-TNF agents to form multimeric complexes, [31] facilitating greater clearance. Certolizumab binds TNF-α in a 1:1 ratio like etanercept and in vitro is a more potent binder of soluble TNF-α compared to infliximab and adalimumab but remains weaker than etanercept. [31],[38] Etanercept is also the only anti-TNF agent to bind both TNF-α and lymphotoxin-α (TNF-β), whereas the other anti-TNF agents do not interact with other ligands of the TNF superfamily. [30],[33],[34],[37] Although this interaction with lymphotoxin-α may prevent granuloma formation, the clinical importance of this in the reactivation of latent infections is not well understood. [39] The unique property of binding to lymphotoxin-α also does not appear to offer any clinical advantages in the treatment of rheumatoid arthritis. [31] As a Fab' fragment conjugated to PEG, certolizumab lacks the Fc portion typical of antibodies. [31] While certolizumab will in vitro neutralize soluble and transmembrane TNF-α, it will not trigger complement-dependent or antibody-dependent cell-mediated cytotoxicity through transmembrane TNF-α. [31],[35],[40],[41] For the anti-TNF agents with a Fc portion incorporated into their structure, infliximab and adalimumab were more potent activators of complement-dependent cytotoxicity compared to etanercept but all three of these agents were equipotent activators of antibody-dependent cell-mediated cytotoxicity. [31],[35],[42],[43],[44] Another transmembrane TNF-α dependent phenomenon is apoptosis. [42] While certolizumab is unable to induce apoptosis, infliximab and adalimumab are more potent inducers compared to etanercept. [25],[35],[42] As transmembrane TNF-α is important in granuloma formation, it plays a role not only in the host defense against Mycobacterium tuberculosis but also in the histopathologic changes noted in Crohn's disease. The potent destruction of cells bearing transmembrane TNF-α by infliximab and adalimumab may in part explain the higher rates of TB reactivation associated with these anti-TNF agents as compared with etanercept. [1],[26],[31],[42] Apoptosis of cells bearing transmembrane TNF-α may also explain the efficacy of infliximab and adalimumab in the treatment of granulomatous diseases such as Crohn's disease, as specimens from patients with Crohn's disease treated with infliximab lack significant granuloma formation. [42] Despite this association, data from recent randomized trials suggest that certolizumab is still associated with the risk of reactivating TB and thus it carries the same warnings for this complication as the other anti-TNF agents. [36],[40] As the only anti-TNF agent currently administered intravenously, and the only one administered up to once every 8 weeks, infliximab can reach a higher serum peak concentration when compared to the other anti-TNF agents which are administered in lower doses and more frequent intervals. [31],[39] Some of the efficacy of infliximab has been linked to its intravenous administration, as the infusion of a large amount of anti-TNF agent may result in a "cytokine washout." [45] While a "cytokine washout" may be helpful in suppressing inflammation, as repeated doses of the medication are cleared, a rebound phenomenon may occur in which the dose needs to be gradually increased to address breakthrough symptoms, an effect known as "dose creep." [44] As the only chimeric protein, infliximab has consistently been shown to be the most immunogenic, with the most reported autoantibody and human anti-drug antibodies formation after exposure to the medication. [31],[43],[46] While the production of antinuclear antibodies has resulted in some patients developing a lupus-like syndrome, the production of human anti-chimeric antibodies seen with infliximab has been linked more consistently with decreased efficacy of the medication, increased clearance, and increased risk of infusion site reactions. [31]


   Current Recommendations Top


The American College of Rheumatology (ACR) and British Society of Rheumatology (BSR) have published guidelines regarding the use of anti-TNF agents in patients chronically infected with HBV. [47],[48] In July 2004, the BSR released an update of their 2001 guidelines for the use of anti-TNF agents in patients with rheumatoid arthritis. [48] For rheumatoid arthritis patients infected with HBV, Ledingham et al, have stated that "the effects of anti-TNF therapy on patients with hepatitis B are contradictory" and "until more data are available, anti-TNF therapy should be avoided in patients with hepatitis B infection." [48] BSR guidelines for the treatment of other rheumatologic conditions such as ankylosing spondylitis and psoriatic arthritis do not offer a position regarding the use of anti-TNF agents in patients infected with HBV, but presumably the same position as for RA would apply. [49] The ACR guidelines for the use of anti-TNF agents in rheumatologic conditions were published in 2008 and to date remains as the most comprehensive guidance. [47] For patients acutely infected with HBV, "biologic agents" were contraindicated per the task force panel. [47] For patients chronically infected with HBV, regardless of whether they were receiving antiviral therapy or not, "biologic agents" were contraindicated in those who were Child-Pugh class B or C. [47] While no affirmative recommendation was made, use of anti-TNF agents in patients with chronic HBV infection and Childs-Pugh class A was not listed as a contraindication. [47] For an inflammatory gastrointestinal disease such as Crohn's disease which might require the use of an anti-TNF agent, a review of published treatment guidelines from both the American Gastroenterological Association and the British Society of Gastroenterology do not provide a position on how to approach such patients who are also infected with HBV. [50],51]

Incorporating data gathered both during post-marketing surveillance and the evolving medical literature, the labels for the 5 U.S. FDA approved anti-TNF agents have statements about the use of each agent in patients infected with HBV. As noted earlier, although certolizumab and golimumab have not had any case reports of their use in patients with HBV infection, their FDA labels still include a statement about use in such patients. [34],[37] They also have had these statements since their approvals in 2008 and 2009, respectively. [34],[37] Infliximab, the anti-TNF agent that was FDA approved in 1998, has had a statement about reactivation of HBV infection with use of the medication since 2004. [46] Adalimumab incorporated a similar statement in 2006 [52] and etanercept in 2007. [52] In the European Public Assessment Report (EPAR) made available by the European Medicines Agency (EMEA), infliximab, etanercept, and adalimumab all have statements about the issue of reactivation of HBV, with wording similar to that found in the previously described FDA labels. [53],[55],[56] At the time when this paper was written, the Committee for Medicinal Products for Human Use of the EMEA was reviewing certolizumab and golimumab and no EPAR were available for review. [57]

Apart from the current professional society guidelines and regulatory agency product labels discussed above, a host of authors have provided their recommendations on the use of anti-TNF agents in patients infected with HBV who have an inflammatory rheumatologic or gastrointestinal illness. As a consensus, most authors proposed the cautious administration of anti-TNF agents to patients with HBV infection with close monitoring of HBV DNA and AST/ALT levels and the caveat that clinical trials are needed to effectively assess the safety of this practice. [6],[8],[10],[11],[13],[21],[29] With the current arsenal of effective medications for prophylaxis against HBV reactivation, and based on the literature from patients undergoing chemotherapy, [58] screening for HBV infection has also been recommended by a host of authors prior to the start of an anti-TNF agent. [7],[10],[16],[22],[27],[29],[58],[59],[60],[61] Calabrese et al, recommended antiviral prophylaxis for all patients who are HBsAg positive and need a disease modifying drug (to include anti-TNF agents) for their rheumatologic illness. [61] Nathan et al. made similar recommendations for the antiviral prophylaxis of all HBsAg positive patients but proposed that antiviral agents could be started 1-2 weeks prior to anti-TNF agent use or once the ALT rose above the upper limit of normal and HBV DNA load increased. [27] Nathan et al, further recommended monitoring of ALT monthly in those patients who received antiviral prophylaxis (to be continued upto 3 months after cessation of therapy) with more frequent ALT testing and HBV DNA measurements in those who did not receive prophylaxis. [27]

For antiviral therapy, most cases reported use of lamivudine as either prophylaxis for or treatment of HBV reactivation. [6],[7],[8],[9],[12],[13],[17],[18],[19],[23],[27] This trend probably reflects the widespread availability of the medication, but based on the currently limited information, no specific antiviral agent can be assumed to be better than the others. One drawback of continuous lamivudine use is the development of the YMDD mutant, with 15-30% of immunocompetent adults developing virologic breakthrough after 1 year of therapy. [62],[63] The YMDD mutant has developed as rapidly as within the first 6-9 months of therapy [9] and rare cases of hepatic decompensation have been reported when this occurred. [64] The typical dose of lamivudine used has been 100 mg daily. While the optimal time and duration of lamivudine therapy is unknown, insight gathered from the use of immunosuppressive medications in chemotherapy trials and organ transplantation suggest that when given prophylatically lamivudine should be started 2-4 weeks before the institution of anti-TNF agents. [8],[16],[19],[65] It should be continued for around 3 - 6 months after the cessation of anti-TNF agent therapy, as HBV reactivation in chemotherapy trials occurred weeks after immunosuppressive agents were stopped, suggesting that immune reconstitution occurs. [19],[22],[59],[66],[67] When used for antiviral treatment, lamivudine could be started whenever HBV reactivation became clinically or serologically evident. For those patients who develop the YMDD mutant or who are intolerant to lamivudine, adefovir would be one of the several newer antiviral agents to be considered for treatment, [17],[19] although little has been reported about the efficacy of these medications in patients concomitantly using immunosuppressive therapies in rheumatologic conditions. [68]

Finally, a long-term consideration that remains to be addressed is the impact that prolonged use (more than 5-10 years) of continuous anti-TNF therapy, with or without antiviral therapy, has the complications of chronic liver disease such as hepatic fibrosis, cirrhosis, or hepatocellular carcinoma. [20] For inflammatory rheumatologic or gastrointestinal illnesses that require anti-TNF agents for control, once patients start such therapy they generally remain on it for years, depending on the sustainability of the response that they experience. In chronic HBV infection, TNF-α has a dual role that protects the hepatocyte by decreasing transcriptional activity of the HBV core promoter gene but yet can through different mechanisms lead to hepatocyte injury and apoptosis. [69],[70],[71],72],[73] Liver biopsy data from two of the cases in this review suggest that 2-5 years of continuous etanercept or adalimumab use partially treated with lamivudine does not lead to accelerated hepatic fibrosis. [17],[18] One case underwent repeat liver biopsy about 5 years into etanercept therapy with stable fibrotic changes noted. [17] Ultimately long-term prospective trials with such endpoints in mind will need to be designed to address these important concerns.


   Conclusions Top


Anti-TNF agents are a potent new class of medications available for the treatment of rheumatologic, dermatologic, and gastrointestinal inflammatory illnesses. With this new potency comes several side effects, the most prominent of which is the reactivation of latent infections. This side effect has been well described for the reactivation of latent tuberculosis, and multiple guidelines recommend screening for TB prior to starting therapy with anti-TNF agents. For other chronic infections, specifically HBV, the role for screening and the actual effects anti-TNF agents have on the reactivation of the virus remains limited to case reports and reviews. In the absence of large clinical trials, a growing consensus of professional societies, drug regulatory agencies, and published reports recommend screening prior to starting anti-TNF agents in patients who are at risk for chronic infection with HBV. Additionally, in patients who are HBsAg positive and need an anti-TNF agent for the treatment of an inflammatory illness, the recommendation of multiple authors and information gathered from trials using other immunosuppressive agents suggest that an antiviral agent should be started prior to and continued for up to 6 months after therapy. Long-term trials with larger cohorts of patients and information gathered from liver biopsies are needed to elucidate the potential impact of long-term anti-TNF therapy that will have on the progression of HBV infection to cirrhosis and hepatocellular carcinoma.

 
   References Top

1.Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab: A tumor necrosis factor α-neutralizing agent. N Engl J Med 2001;345:1098-103.   Back to cited text no. 1
    
2.U.S. food and drug administration: Center for drug evaluation and research Drugs@FDA: Infliximab label information. 24 August 1998. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/1998/inflcen082498lb.pdf. [cited on 2009 Aug 21].   Back to cited text no. 2
    
3.Dienstag JL. Hepatitis B virus infection. N Engl J Med 2008;359:1486-500.   Back to cited text no. 3
    
4.Raftery G, Griffiths B, Kay L, Kane D. Chronic viral hepatitis and TNF-α blockade. Rheumatology 2007;46:1381-2.   Back to cited text no. 4
    
5.Cansu DU, Kalifoglu T, Korkmaz C. Short-term course of chronic hepatitis B and C under treatment with etanercept associated with different disease modifying antirheumatic drugs without antiviral prophylaxis. J Rheumatol 2008;35:421-4.   Back to cited text no. 5
    
6.Roux CH, Brocq O, Breuil V, Albert C, Euller-Ziegler L. Safety of anti-TNF-α therapy in rheumatoid arthritis and spondyloarthropathies with concurrent B or C chronic hepatitis. Rheumatology 2006;45:1294-7.   Back to cited text no. 6
    
7.Millonig G, Kern M, Ludwiczek O, Nachbaur K, Vogel W. Subfulminant hepatitis B after infliximab in Crohn′s disease: Need for HBV-screening? World J Gastroenterol 2006;12:974-6.   Back to cited text no. 7
    
8.Michel M, Duvoux C, Hezode C, Cherqui D. Fulminant hepatitis after infliximab in a patient with hepatitis B virus treated for an adult onset still′s disease. J Rheumatol 2003;30:1624-5.  Back to cited text no. 8
    
9.Esteve M, Saro C, Gonzαlez-Huix F, Suarez F, Forné M, Viver JM. Chronic hepatitis B reactivation following infliximab therapy in Crohn′s disease patients: Need for primary prophylaxis. Gut 2004;53:1363-5.   Back to cited text no. 9
    
10.Ostuni P, Botsios C, Punzi L, Sfriso P, Todesco S. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62:686-7.   Back to cited text no. 10
    
11.Oniankitan O, Duvous C, Challine D, Mallat A, Chevalier X, Pawlotsky JM, et al. Infliximab therapy for rheumatic diseases in patients with chronic hepatitis B or C. J Rheumatol 2004;31:107-9.   Back to cited text no. 11
    
12.Wendling D, Auge B, Bettinger D, Lohse A, Le Huede G, Bresson-Hadni S, et al. Reactivation of a latent precore mutant hepatitis B virus related chronic hepatitis during infliximab treatment for severe spondyloarthropathy. Ann Rheum Dis 2005;64:788-9.   Back to cited text no. 12
    
13.Ueno Y, Tanaka S, Shimamoto M, Miyanaka Y, Hiyama T, Ito M, et al. Infliximab therapy for Crohn′s disease in patient with chronic hepatitis B. Dig Dis Sci 2005;50:163-6.   Back to cited text no. 13
    
14.Anelli MG, Torres DD, Manno C, Scioscia C, Iannone F, Covelli M, et al. Improvement of renal function and disappearance of hepatitis B Virus DNA in a patient with rheumatoid arthritis and renal amyloidosis following treatment with infliximab. Arthritis Rheum 2005;52:2519-20.   Back to cited text no. 14
    
15.Garcia-Sanchez MV, Gomez-Camacho F, Poyato-Gonzalez A, Iglesias-Flores EM, de Dios-Vega JF. Infliximab therapy in a patient with Crohn′s disease and chronic hepatitis B virus infection. Inflamm Bowel Dis 2004;10:701-2.   Back to cited text no. 15
    
16.Madonia S, Orlando A, Scimeca D, Olivo M, Rossi F, Cottone M. Occult hepatitis B and infliximab-induced HBV reactivation. Inflamm Bowel Dis 2007;13:508.   Back to cited text no. 16
    
17.Carroll MB, Bond MI. Use of tumor necrosis factor-α inhibitors in patients with chronic hepatitis B infection. Semin Arthritis Rheum 2008;38:208-17.   Back to cited text no. 17
    
18.Kaur PP, Chan VC, Berney SN. Histological evaluation of liver in two rheumatoid arthritis patients with chronic hepatitis B and C treated with TNF-alpha blockade: Case reports. Clin Rheumatol 2008;27:1069-71.   Back to cited text no. 18
    
19.Zingarelli S, Airò P, Frassi M, Bazzani C, Scarsi M, Puoti M. Prophylaxis and therapy of HBV infection in 20 patients treated with disease modifying antirheumatic drugs or with biological agents for rheumatic diseases. Reumatismo 2008;60:22-7.   Back to cited text no. 19
    
20.Robinson H and Walker-Bone K. Anti-TNF-α therapy for rheumatoid arthritis among patients with chronic hepatitis B infection. Rheumatology 2009;48:450-1.   Back to cited text no. 20
    
21.Li S, Kaur PP, Chan V. Use of tumor necrosis factor-α (TNF-α) antagonists infliximab, etanercept, and adalimumab in patients with concurrent rheumatoid arthritis and hepatitis B or hepatitis C: A retrospective record review of 11 patients. Clin Rheumatol 2009;28:787-91.  Back to cited text no. 21
    
22.Wendling D, Di Martino V, Prati C, Toussirot E, Herbein G. Spondyloarthropathy and chronic B hepatitis: Effect of anti-TNF therapy. Joint Bone Spine 2009;76:308-11.   Back to cited text no. 22
    
23.Sakellariou GT, Chatzigiannis I. Long-term anti-TNFα therapy for ankylosing spondylitis in two patients with chronic HBV infection. Clin Rheumatol 2007;26:950-2.   Back to cited text no. 23
    
24.Vassilopoulos D, Calabrese LH. Virally associated arthritis 2008: Clinical, epidemiologic, and pathophysiologic considerations. Arthritis Res Ther 2008;10:215-22.   Back to cited text no. 24
    
25.Saliu OY, Sofer C, Stein D, Schwander SK, Wallis RS. Tumor-necrosis-factor blockers: Differential effects on mycobacterial immunity. J Infect Dis 2006;194:486-92.   Back to cited text no. 25
    
26.Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, et al. Risk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy. Arthritis Rheum 2009;60:1884-94.   Back to cited text no. 26
    
27.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.   Back to cited text no. 27
    
28.Giles JT, Bathon JM. Serious infections associated with anticytokine therapies in the rheumatic diseases. J Intensive Care Med 2004;19:320-34.   Back to cited text no. 28
    
29.Desai SB, Furst DE. Problems encountered during anti-tumor necrosis factor therapy. Best Pract Res Clin Rheum 2006;20:757-90.   Back to cited text no. 29
    
30.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Infliximab Label Information." 5 May 2009. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/103772s5234lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 30
    
31.Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necorsis factor antagonist mechanisms of action: A comprehensive review. Pharmacol Therap 2008;117:244-79.   Back to cited text no. 31
    
32.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Etanercept Label Information." 23 June 2008. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/103795s5359lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 32
    
33.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Adalimumab Label Information." 21 February 2008. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125057s114lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 33
    
34.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Certolizumab Label Information." 22 April 2008. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125160s000lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 34
    
35.Bourne T, Fossati G, Nesbitt A. A PEGylated Fab′ fragment against tumor necrosis factor for the treatment of Crohn′s disease. Biodrugs 2008;22:331-7.   Back to cited text no. 35
    
36.Bingham CO. Emerging therapeutics for rheumatoid arthritis. Bull NYU Hosp Jt Dis 2008;66:210-5.   Back to cited text no. 36
    
37.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Golimumab Label Information." 24 April 2009. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125289s000lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 37
    
38.Chakder S. US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Certolizumab Review." 22 April 2008. pages 18-38. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/125160s000_PharmR_P1.pdf. [cited 2009 Aug 21].   Back to cited text no. 38
    
39.Furst DE, Beenhouwer O. Tumor necrosis factor antagonists: Different kinetics and/or mechanisms of action may explain differences in the risk for developing granulomatous infection. Semin Arthritis Rheum 2006;36:159-67.   Back to cited text no. 39
    
40.Scott DL, Cope A. New tumor necrosis factor inhibitors for rheumatoid arthritis: Are there benefits from extending choice? Ann Rheum Dis 2009;68:767-9.   Back to cited text no. 40
    
41.Fossati G, Nesbitt A. In vitro complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by the anti-TNF agents adalimumab, etanercept, infliximab, and certolizumab pegol (CDP870): 807. Am J Gastroenterol 2005;100:S299.   Back to cited text no. 41
    
42.Mitoma H, Horiuchi T, Tsukamoto H, Tamimoto Y, Kimoto Y, Uchino A, et al. Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor α-expressing cells: Comparison among infliximab, etanercept, and Adalimumab. Arthritis Rheum 2008;58:1248-57.   Back to cited text no. 42
    
43.Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-79.  Back to cited text no. 43
    
44.Weaver AL. Differentiating the new rheumatoid arthritis biologic therapies. J Clin Rheumatol 2003;9:99-114.   Back to cited text no. 44
    
45.Feldmann M, Ravinder NM. Anti-TNFα therapy of rheumatoid arthritis: What have we learned? Annu Rev Immunol 2001;19:163-96.   Back to cited text no. 45
    
46.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Infliximab Label Information." 17 December 2004. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2004/103772_5077_lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 46
    
47.Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American college of rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762-84.   Back to cited text no. 47
    
48.Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology 2005;44:157-63.   Back to cited text no. 48
    
49.British Society of Rheumatology. "BSR Guidelines". Available from: http://www.rheumatology.org.uk/guidelines/. [cited 2009 Aug 15].   Back to cited text no. 49
    
50.Lichtenstein GR, Abreu MT, Cohen R, Tremaine W. American gastroenterologic association institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology 2006;130:935-9.   Back to cited text no. 50
    
51.Carter MJ, Lobo AJ, Travis SPL. Guidelines for the management of inflammatory bowel disease in adults. Gut 2004;53:v1-16.   Back to cited text no. 51
    
52.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Adalimumab Label Information." 28 August 2006. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/125057s062lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 52
    
53.US food and drug administration-Center for drug evaluation and research "Drugs@FDA: Etanercept Label Information." 1 February 2007. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/103795s5322lbl.pdf. [cited 2009 Aug 8].   Back to cited text no. 53
    
54.European Medicines Agency. European Public Assessment Report-Humira Product Information [English]. 11 August 2009. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/humira/emea-combined-h481en.pdf. [cited 2009 Aug 15].   Back to cited text no. 54
    
55.European Medicines Agency. European Public Assessment Report-Enbrel Product Information [English]. 9 July 2009. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/Enbrel/emea-combined-h262en.pdf. [cited 2009 Aug 15].   Back to cited text no. 55
    
56.European Medicines Agency. European Public Assessment Report-Remicade Product Information [English]. 11 August 2009. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/Remicade/emea-combined-h240en.pdf. [cited 2009 Aug 15].   Back to cited text no. 56
    
57.European Medicines Agency. European Public Assessment Report. Available from: http://www.emea.europa.eu/htms/human/epar/eparintro.htm. [cited 2009 Aug 15].   Back to cited text no. 57
    
58.Vassilopoulos D, Calabrese LH. Risks of immunosuppressive therapies including biologic agents in patients with rheumatic diseases and co-existing chronic viral infections. Curr Opin Rheumatol 2007;19:619-25.   Back to cited text no. 58
    
59.Marignani M, Cox MC, Delle Fave G. Hepatitis B virus infection. N Engl J Med 2009;360:304-6.   Back to cited text no. 59
    
60.Tilg H, Kaser A, Moschen AR. How to modulate inflammatory cytokines in liver disease. Liver Int 2006;26:1029-39.   Back to cited text no. 60
    
61.Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: Assessment and preventive strategies. Ann Rheum Dis 2006;65:983-9.   Back to cited text no. 61
    
62.Di Marco V, Marzano A, Lampertico P, Andreone P, Santantonio T, Almasio PL, et al. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology 2004;40:883-91.   Back to cited text no. 62
    
63.Papatheodoridis GV, Hadziyannis SJ. Review article: Current management of chronic hepatitis B. Aliment Pharmacol Ther 2004;19:25-37.   Back to cited text no. 63
    
64.Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124:105-17.   Back to cited text no. 64
    
65.Calabrese LH, Zein N, Vassilopoulos D. Safety of antitumor necrosis factor (anti-TNF) therapy in patients with chronic viral infections: Hepatitis C, hepatitis B, and HIV infection. Ann Rheum Dis 2004;63:ii18-24.   Back to cited text no. 65
    
66.Simpson ND, Simpson PW, Ahmed AM, Nguyen MH, Garcia G, Keeffe EB, et al. Prophylaxis against chemotherapy-induced reactivation of hepatitis B virus infection with Lamivudine. J Clin Gastroenterol 2003;37:68-71.   Back to cited text no. 66
    
67.Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy: Report of a prospective study. Gastroenterology 1991;100:182-8.   Back to cited text no. 67
    
68.Tsai FC, Hsieh SC, Chen DS, Sheu JC, Chen DS. Reactivation of hepatitis B virus in rheumatologic patients receiving immunosuppressive agents. Dig Dis Sci 2006;51:1627-32.  Back to cited text no. 68
    
69.Ganem D, Prince AM. Hepatitis B virus infection: Natural history and clinical consequences. N Engl J Med 2004;350:1118-29.   Back to cited text no. 69
    
70.Höhler T, Kruger A, Gerken G, Schneider PM, Meyer Zum Büschenfelde KH, Rittner C. A tumour necrosis factor-alpha (TNF-α) promoter polymorphism is associated with chronic hepatitis B infection. Clin Exp Immunol 1998;111:579-82.   Back to cited text no. 70
    
71.Cheong JY, Cho SW, Hwang IL, Yoon SK, Lee JH, Park CS, et al. Association between chronic hepatitis B virus infection and interleukin-10, tumor necrosis factor-α gene promoter polymorphisms. J Gastroenterol Hepatolol 2006;21:1163-9.   Back to cited text no. 71
    
72.Thio CL, Thomas DL, Carrington M. Chronic viral hepatitis and the human genome. Hepatology 2000;31:819-27.   Back to cited text no. 72
    
73.Sheron N, Lau JY, Daniels HM, Webster J, Eddleston AL, Alexander GJ, et al. Tumour necrosis factor to treat chronic hepatitis B virus infection. Lancet 1990;336:321-2.  Back to cited text no. 73
    

Top
Correspondence Address:
Matthew B Carroll
United States Air Force, Keesler Medical Center, 301 Fisher Street, Keesler AFB, Biloxi, MS, 39534
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-9747.76907

Rights and Permissions




 

Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
    Introduction
    Methods
    Not all TNF-^...
    Current Recommen...
    Conclusions
    References

 Article Access Statistics
    Viewed10643    
    Printed580    
    Emailed4    
    PDF Downloaded570    
    Comments [Add]    

Recommend this journal