Tumor Necrosis Factor Inhibitor Therapy for HBV Infected Individuals: How Loud is the Alarm Bell?
Robert P. Perrillo, MD Hepatology Division Baylor University Medical Center and University of Texas, Southwestern
E mail : [email protected]
Key words: Hepatitis B, reactivation, immunosuppression, chemotherapy, biologics
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27806 This article is protected by copyright. All rights reserved.
Hepatology
Page 2 of 13
2
Footnote page
Corresponding author: Robert P. Perrillo, M.D.
Address: 3410 Worth Street, Suite 860 Dallas, Texas 7546
Telephone: 214 820 2956 Fax:214 820 3565
E mail address: [email protected]
List of abbreviations: HBsAg: hepatitis B surface antigen Antibody to hepatitis B core antigen: anti-HBc HBV DNA: hepatitis B virus deoxyribonucleic acid Antibody to hepatitis B surface antigen: anti-HBs HBV reactivation: HBVr Immunosuppressive drug therapy: ISDT Tumor necrosis factor: TNF
Financial support: none
Hepatology This article is protected by copyright. All rights reserved.
Page 3 of 13
Hepatology
3
Reactivation of hepatitis B virus (HBVr) is a well recognized and potentially serious complication of immunosuppressive drug therapy (ISDT). Incidence rates of 20% to 50% are routinely reported in hepatitis B surface antigen (HBsAg) carriers undergoing chemotherapy for lymphoma or breast cancer, and it has been reported with many other malignancies. (1) The disorder is also a cause of considerable morbidity requiring hospitalization and frequent interruption of immunosuppressive medications. As it is preventable by antiviral prophylaxis in more than 85% of cases, the importance of universal screening for HBsAg when ISDT is needed cannot be overemphasized (1,2). Screening with antibody to hepatitis B core antigen (anti-HBc) is generally recommended because HBVr also occurs in patients with past infection. (1) Although HBVr during ISDT occurs much more commonly in HBsAg carriers, its occurrence in patients with resolved hepatitis B (HBsAg negative but anti-HBc-positive) has striking global health significance because worldwide the number of individuals in the latter group greatly exceeds those with active infection. This large pool of at risk individuals affirms a need to know an individual’s anti-HBc status when very intense or aggressive ISDT is planned, but it is controversial if screening for anti-HBc is always indicated in individuals receiving less potent forms of ISDT such as tumor necrosis factor (TNF) inhibitors, interleukin inhibitors, antilymphocyte agents, and other biologic agents (1) The decision to undertake anti-HBc screening in this population requires knowledge of the magnitude of risk for HBVr when ISDT is given. However, with the exception of B cell depletion therapy and bone marrow or hematopoietic stem cell transplantation, relatively little is known about the relative risk for HBVr in individuals with past hepatitis B given other forms of immunosuppression.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 4 of 13
4
The lack of information in this area is particularly relevant with TNF inhibitor therapy because millions of doses are prescribed annually for the treatment of autoimmune diseases including rheumatoid arthritis, anklylosing spondylitis, inflammatory bowel disease, plaque psoriasis, and psoriatic arthritis. During the past decade numerous reports have appeared of HBVr attributed to TNF inhibitor therapy in HBsAg carriers and less commonly, in individuals with resolved hepatitis B. However, much of the safety information comes from isolated case reports and small case series. The retrospective nature of many studies provides the potential for bias and the small sample sizes do not allow determination of risk factors, relationship to treatment duration, or assessment of possible differences in HBVr risk among the various TNF inhibitors. Observational studies with TNF inhibitors have generally suggested a low frequency of HBVr in HBsAg carriers (0 to 8%) and even lower (0-2%) in those with resolved infection. (1,3,4) However, discrepancies have been reported. A literature review found HBVr in 35 (39% )of 89 HBsAg carriers and 9 (5%) of 168 patients with resolved infection (5.) More than half were taking infliximab which resulted in fulminant liver failure in 5 cases. in this study looks quite alarming at first.
The frequency of HBVr
However, a closer look at the data reveal that two
thirds of the patients with HBVr were taking other immunosuppressive agents that could potentially cause reactivation (tacrolimus, cyclosporine, methotrexate, corticosteroids) including 7 of 9 cases with resolved hepatitis B. somewhat uncertain.
This makes implication of TNF inhibitor therapy
Multivariate analysis demonstrated that the proportion of patients with
HBVr was greater in patients previously treated with immunosuppressive agents (96% vs 70% without reactivation, p = 0.033).
The failure to respond to previous immunosuppression
probably explains why many of the patients were taking complex immunotherapy when they reactivated.
Hepatology This article is protected by copyright. All rights reserved.
Page 5 of 13
Hepatology
5
Another study looked at patients who were prescribed various types of ISDT for inflammatory bowel disease (glucocorticoids, azathioprine, infliximab, cyclosporine, adalimumab) .(6)
The
authors described HBVr in 9 (36%) of 25 HBsAg-positive patients most of whom were treated with combinations of glucocorticoids, azathioprine, and infliximab,
Reactivation only occurred
in 1 of 65 resolved cases and this individual took combination therapy. The authors of this study made two important observations: 1) treatment with ≥ 2 immunosuppressive agents was an independent predictor of HBV reactivation (OR 8.75, 95% CI 1.16 to 65.66) and 2) the majority of HBsAg-positive patients without reactivation were treated with only one immunosuppressant for a short period of time. Similar observations of a higher risk for HBVr when biologic agents are used with other immunosuppressive drugs have been published by other investigators (7). In this issue of HEPATOLOGY, a study by Barone and colleagues from Italy has provided important additional information on the reactivation risk in patients with resolved hepatitis B during biologic treatments for rheumatic disorders.(8) A total of 179 Caucasian patients were evaluated of which 14 were treated with rituximab, 146 with TNF inhibitors, and 19 with other biologics. Patients were monitored closely for ALT, HBsAg, and anti-HBc and serum HBV DNA testing was done annually. The authors describe that 115 (79%) of the TNF inhibitor patients also took disease modifying anti-rheumatic agents and 67 (46%) used low dose (< 7.5 mg) prednisone, both of which are associated with a low risk for HBVr.(1) Reactivated hepatitis B was not seen during the entire period of follow up (median of 34 ± 16 months for rituximab, and 56 ± 31 months for TNF inhibitor therapy). The findings are important in that they demonstrate a negligible risk of HBVr when patients with resolved hepatitis B are treated with TNF inhibitor therapy.
Further support for the limited potential of TNF inhibitor therapy to
induce HBVr is also found in a preliminary report from investigators at Kaiser Permanente in
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 6 of 13
6
which 4800 patients had baseline HBV screening. (9) In this retrospective analysis 4 (17%) of 23 HBsAg-positive patients and 1 of 440 (0.03%) with resolved infection developed reactivation during a median treatment period of 41 months (range 21-74). The use of other potentially immunosuppressive agents in these patients was not described. Taken together, the studies by Barone and others indicate that patients with resolved hepatitis B are most likely have a negligible risk of HBVr occurring during TNF inhibitor therapy. These are encouraging and important observations because they suggest that there is no need for routine anti-HBc screening, antiviral prophylaxis, or regular HBV DNA monitoring when TNF inhibitors are used in patients with resolved hepatitis B. However, the findings raise several questions that remain to be answered. If the risk of HBVr during TNF inhibitor therapy is negligible in patients with resolved infection why does this not seem the case for HBsAg carriers? Can we identify patients with resolved infection who are at higher risk from TNF inhibitor therapy and for whom anti-HBc screening might be beneficial? Does anti-HBs have a protective role in HBsAg negative patients when TNF inhibitor therapy is given? The answers to the first two questions above may be found from the above mentioned studies which demonstrate an increased risk of HBVr when TNF inhibitors are combined with other immunosuppressive drugs.
Glucocorticoids, calcineurin inhibitors, TNF inhibitors, anti-
interleukins, and methotrexate all have different mechanisms of action. Thus, the addition of TNF therapy to one or more of these agents can tip the immune system to a point in which it can no longer control viral replication. A management algorithm is depicted in Figure 1 which incorporates different screening and management decisions when caring for patients taking TNF inhibitor monotherapy as compared with persons taking a TNF inhibitor in combination with other immunosuppressive drugs. Additional studies specifically directed to the estimation of risk
Hepatology This article is protected by copyright. All rights reserved.
Page 7 of 13
Hepatology
7
for HBVr in these two different populations are likely to show that the reactivation alarm bell rings relatively softly for TNF inhibitor monotherapy, particularly in cases with resolved infection, but considerably louder for combinations of a TNF inhibitor with other ISDT.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 8 of 13
8
REFERENCES 1. Perrillo RP, Gish R, Falck-Ytter, Y. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148: 221-244.\
2. Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-528.
3. Caporali R, Pallavincini N, AtzenI F, et al Safety of tumor necrosis factor α blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases. Arthritis Care and Res 2010; 6:749-754.
4. Carroll MB, Forgione MA. Use of tumor necrosis factor α inhibitors in hepatitis B surface antigen-positive patients: a literature review and potential mechanisms of action. Clin Rheum 2010; 29:1021-1029.
5. Perez-Alvarez R, Diaz-Lagares C, Garcia-Hernandez F, et al. Hepatitis B virus (HBV)reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy:analysis of 257 cases. Medicine (Baltimore) 2011;90:359-371.
Hepatology This article is protected by copyright. All rights reserved.
Page 9 of 13
Hepatology
9
6. Loras C, Gisbert JP, Minguez M, et al. Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy. Gut 2010; 59:1340-1346.
7. Morisco F, Catiglione F, Rispo A, et al. Hepatitis B virus infection and immunosuppressive therapy in patients with inflammatory bowel disease. Dig Liv Dis 2011; 43S:S40-48.
8. Barone M, Lopalco G, Viggiani MT, et al. Safety of long term biologic therapy in rheumatologic patients with a previously resolved HBV infection. Hepatology 61:xxxx
9. Pauly MP, Tucker LY, Szpakowski JL, et al. Reactivation of hepatitis B (HBV) in patients treated with anti-tumor necrosis factor agents. Hepatology 2011; 60 (Suppl 4): 232 A (abstract 72).
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 10 of 13
10
Figure 1
TNF Inhibitor Monotherapy *
Use of TNF Inhibitor with Other Immunosuppressive Drugs**
Screen for HBsAg
Negative
Negligible risk
Routine Care
Screen for HBsAg PLUS
Positive
Moderate risk
Anti-HBc
HBsAg Positive
HBsAg Negative
HBsAg Negative
Anti-HBc Positive
Anti-HBc Positive
Anti-HBc Negative
Moderate risk
Antiviral Prophylaxis
Low risk
ALT every 2-3 mos;
No risk
Routine Care
test HBV DNA if ≥ 2 x baseline ___________________________________________________________________________________________________________ *Also can apply to patients receiving a second drug with very low risk for HBVr such as DMARD or low dose glucocorticoid. **This includes agents known or suspected to be independently associated with HBVr.
Hepatology This article is protected by copyright. All rights reserved.
Robert P. Perrillo, MD Hepatology Division Baylor University Medical Center and University of Texas, Southwestern
E mail : [email protected]
Key words: Hepatitis B, reactivation, immunosuppression, chemotherapy, biologics
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/hep.27806 This article is protected by copyright. All rights reserved.
Hepatology
Page 2 of 13
2
Footnote page
Corresponding author: Robert P. Perrillo, M.D.
Address: 3410 Worth Street, Suite 860 Dallas, Texas 7546
Telephone: 214 820 2956 Fax:214 820 3565
E mail address: [email protected]
List of abbreviations: HBsAg: hepatitis B surface antigen Antibody to hepatitis B core antigen: anti-HBc HBV DNA: hepatitis B virus deoxyribonucleic acid Antibody to hepatitis B surface antigen: anti-HBs HBV reactivation: HBVr Immunosuppressive drug therapy: ISDT Tumor necrosis factor: TNF
Financial support: none
Hepatology This article is protected by copyright. All rights reserved.
Page 3 of 13
Hepatology
3
Reactivation of hepatitis B virus (HBVr) is a well recognized and potentially serious complication of immunosuppressive drug therapy (ISDT). Incidence rates of 20% to 50% are routinely reported in hepatitis B surface antigen (HBsAg) carriers undergoing chemotherapy for lymphoma or breast cancer, and it has been reported with many other malignancies. (1) The disorder is also a cause of considerable morbidity requiring hospitalization and frequent interruption of immunosuppressive medications. As it is preventable by antiviral prophylaxis in more than 85% of cases, the importance of universal screening for HBsAg when ISDT is needed cannot be overemphasized (1,2). Screening with antibody to hepatitis B core antigen (anti-HBc) is generally recommended because HBVr also occurs in patients with past infection. (1) Although HBVr during ISDT occurs much more commonly in HBsAg carriers, its occurrence in patients with resolved hepatitis B (HBsAg negative but anti-HBc-positive) has striking global health significance because worldwide the number of individuals in the latter group greatly exceeds those with active infection. This large pool of at risk individuals affirms a need to know an individual’s anti-HBc status when very intense or aggressive ISDT is planned, but it is controversial if screening for anti-HBc is always indicated in individuals receiving less potent forms of ISDT such as tumor necrosis factor (TNF) inhibitors, interleukin inhibitors, antilymphocyte agents, and other biologic agents (1) The decision to undertake anti-HBc screening in this population requires knowledge of the magnitude of risk for HBVr when ISDT is given. However, with the exception of B cell depletion therapy and bone marrow or hematopoietic stem cell transplantation, relatively little is known about the relative risk for HBVr in individuals with past hepatitis B given other forms of immunosuppression.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 4 of 13
4
The lack of information in this area is particularly relevant with TNF inhibitor therapy because millions of doses are prescribed annually for the treatment of autoimmune diseases including rheumatoid arthritis, anklylosing spondylitis, inflammatory bowel disease, plaque psoriasis, and psoriatic arthritis. During the past decade numerous reports have appeared of HBVr attributed to TNF inhibitor therapy in HBsAg carriers and less commonly, in individuals with resolved hepatitis B. However, much of the safety information comes from isolated case reports and small case series. The retrospective nature of many studies provides the potential for bias and the small sample sizes do not allow determination of risk factors, relationship to treatment duration, or assessment of possible differences in HBVr risk among the various TNF inhibitors. Observational studies with TNF inhibitors have generally suggested a low frequency of HBVr in HBsAg carriers (0 to 8%) and even lower (0-2%) in those with resolved infection. (1,3,4) However, discrepancies have been reported. A literature review found HBVr in 35 (39% )of 89 HBsAg carriers and 9 (5%) of 168 patients with resolved infection (5.) More than half were taking infliximab which resulted in fulminant liver failure in 5 cases. in this study looks quite alarming at first.
The frequency of HBVr
However, a closer look at the data reveal that two
thirds of the patients with HBVr were taking other immunosuppressive agents that could potentially cause reactivation (tacrolimus, cyclosporine, methotrexate, corticosteroids) including 7 of 9 cases with resolved hepatitis B. somewhat uncertain.
This makes implication of TNF inhibitor therapy
Multivariate analysis demonstrated that the proportion of patients with
HBVr was greater in patients previously treated with immunosuppressive agents (96% vs 70% without reactivation, p = 0.033).
The failure to respond to previous immunosuppression
probably explains why many of the patients were taking complex immunotherapy when they reactivated.
Hepatology This article is protected by copyright. All rights reserved.
Page 5 of 13
Hepatology
5
Another study looked at patients who were prescribed various types of ISDT for inflammatory bowel disease (glucocorticoids, azathioprine, infliximab, cyclosporine, adalimumab) .(6)
The
authors described HBVr in 9 (36%) of 25 HBsAg-positive patients most of whom were treated with combinations of glucocorticoids, azathioprine, and infliximab,
Reactivation only occurred
in 1 of 65 resolved cases and this individual took combination therapy. The authors of this study made two important observations: 1) treatment with ≥ 2 immunosuppressive agents was an independent predictor of HBV reactivation (OR 8.75, 95% CI 1.16 to 65.66) and 2) the majority of HBsAg-positive patients without reactivation were treated with only one immunosuppressant for a short period of time. Similar observations of a higher risk for HBVr when biologic agents are used with other immunosuppressive drugs have been published by other investigators (7). In this issue of HEPATOLOGY, a study by Barone and colleagues from Italy has provided important additional information on the reactivation risk in patients with resolved hepatitis B during biologic treatments for rheumatic disorders.(8) A total of 179 Caucasian patients were evaluated of which 14 were treated with rituximab, 146 with TNF inhibitors, and 19 with other biologics. Patients were monitored closely for ALT, HBsAg, and anti-HBc and serum HBV DNA testing was done annually. The authors describe that 115 (79%) of the TNF inhibitor patients also took disease modifying anti-rheumatic agents and 67 (46%) used low dose (< 7.5 mg) prednisone, both of which are associated with a low risk for HBVr.(1) Reactivated hepatitis B was not seen during the entire period of follow up (median of 34 ± 16 months for rituximab, and 56 ± 31 months for TNF inhibitor therapy). The findings are important in that they demonstrate a negligible risk of HBVr when patients with resolved hepatitis B are treated with TNF inhibitor therapy.
Further support for the limited potential of TNF inhibitor therapy to
induce HBVr is also found in a preliminary report from investigators at Kaiser Permanente in
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 6 of 13
6
which 4800 patients had baseline HBV screening. (9) In this retrospective analysis 4 (17%) of 23 HBsAg-positive patients and 1 of 440 (0.03%) with resolved infection developed reactivation during a median treatment period of 41 months (range 21-74). The use of other potentially immunosuppressive agents in these patients was not described. Taken together, the studies by Barone and others indicate that patients with resolved hepatitis B are most likely have a negligible risk of HBVr occurring during TNF inhibitor therapy. These are encouraging and important observations because they suggest that there is no need for routine anti-HBc screening, antiviral prophylaxis, or regular HBV DNA monitoring when TNF inhibitors are used in patients with resolved hepatitis B. However, the findings raise several questions that remain to be answered. If the risk of HBVr during TNF inhibitor therapy is negligible in patients with resolved infection why does this not seem the case for HBsAg carriers? Can we identify patients with resolved infection who are at higher risk from TNF inhibitor therapy and for whom anti-HBc screening might be beneficial? Does anti-HBs have a protective role in HBsAg negative patients when TNF inhibitor therapy is given? The answers to the first two questions above may be found from the above mentioned studies which demonstrate an increased risk of HBVr when TNF inhibitors are combined with other immunosuppressive drugs.
Glucocorticoids, calcineurin inhibitors, TNF inhibitors, anti-
interleukins, and methotrexate all have different mechanisms of action. Thus, the addition of TNF therapy to one or more of these agents can tip the immune system to a point in which it can no longer control viral replication. A management algorithm is depicted in Figure 1 which incorporates different screening and management decisions when caring for patients taking TNF inhibitor monotherapy as compared with persons taking a TNF inhibitor in combination with other immunosuppressive drugs. Additional studies specifically directed to the estimation of risk
Hepatology This article is protected by copyright. All rights reserved.
Page 7 of 13
Hepatology
7
for HBVr in these two different populations are likely to show that the reactivation alarm bell rings relatively softly for TNF inhibitor monotherapy, particularly in cases with resolved infection, but considerably louder for combinations of a TNF inhibitor with other ISDT.
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 8 of 13
8
REFERENCES 1. Perrillo RP, Gish R, Falck-Ytter, Y. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology 2015; 148: 221-244.\
2. Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med 2008;148:519-528.
3. Caporali R, Pallavincini N, AtzenI F, et al Safety of tumor necrosis factor α blockers in hepatitis B virus occult carriers (hepatitis B surface antigen negative/anti-hepatitis B core antigen positive) with rheumatic diseases. Arthritis Care and Res 2010; 6:749-754.
4. Carroll MB, Forgione MA. Use of tumor necrosis factor α inhibitors in hepatitis B surface antigen-positive patients: a literature review and potential mechanisms of action. Clin Rheum 2010; 29:1021-1029.
5. Perez-Alvarez R, Diaz-Lagares C, Garcia-Hernandez F, et al. Hepatitis B virus (HBV)reactivation in patients receiving tumor necrosis factor (TNF)-targeted therapy:analysis of 257 cases. Medicine (Baltimore) 2011;90:359-371.
Hepatology This article is protected by copyright. All rights reserved.
Page 9 of 13
Hepatology
9
6. Loras C, Gisbert JP, Minguez M, et al. Liver dysfunction related to hepatitis B and C in patients with inflammatory bowel disease treated with immunosuppressive therapy. Gut 2010; 59:1340-1346.
7. Morisco F, Catiglione F, Rispo A, et al. Hepatitis B virus infection and immunosuppressive therapy in patients with inflammatory bowel disease. Dig Liv Dis 2011; 43S:S40-48.
8. Barone M, Lopalco G, Viggiani MT, et al. Safety of long term biologic therapy in rheumatologic patients with a previously resolved HBV infection. Hepatology 61:xxxx
9. Pauly MP, Tucker LY, Szpakowski JL, et al. Reactivation of hepatitis B (HBV) in patients treated with anti-tumor necrosis factor agents. Hepatology 2011; 60 (Suppl 4): 232 A (abstract 72).
Hepatology This article is protected by copyright. All rights reserved.
Hepatology
Page 10 of 13
10
Figure 1
TNF Inhibitor Monotherapy *
Use of TNF Inhibitor with Other Immunosuppressive Drugs**
Screen for HBsAg
Negative
Negligible risk
Routine Care
Screen for HBsAg PLUS
Positive
Moderate risk
Anti-HBc
HBsAg Positive
HBsAg Negative
HBsAg Negative
Anti-HBc Positive
Anti-HBc Positive
Anti-HBc Negative
Moderate risk
Antiviral Prophylaxis
Low risk
ALT every 2-3 mos;
No risk
Routine Care
test HBV DNA if ≥ 2 x baseline ___________________________________________________________________________________________________________ *Also can apply to patients receiving a second drug with very low risk for HBVr such as DMARD or low dose glucocorticoid. **This includes agents known or suspected to be independently associated with HBVr.
Hepatology This article is protected by copyright. All rights reserved.
