Tumor necrosis factor inhibitor therapy for hepatitis B virus–infected individuals: How loud is the alarm bell?
Authors: Robert P. Perrillo
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article on Page 40 Reactivation of hepatitis B virus (HBVr) is a well‐recognized and potentially serious complication of immunosuppressive drug therapy (ISDT). Incidence rates of 20%‐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 Screening with antibody to hepatitis B core antigen (anti‐HBc) also 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 the number of 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 new biologic agents.1 The decision to undertake anti‐HBc screening in patients administered these drugs requires knowledge of the magnitude of risk for HBVr when a particular agent or regimen is given. However, with the exception of B‐cell depletion therapy and the immunologic conditioning regimens required for bone marrow or hematopoietic stem cell transplantation, relatively little is known about the relative risk for HBVr in individuals with past hepatitis B given ISDT. 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, ankylosing 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%‐8%) and even lower (0%‐2%) in those with resolved infection.1 However, discrepancies have been reported. A literature review found HBVr in 35 (39%) of 89 HBsAg carriers and nine (5%) of 168 patients with resolved infection.5 More than half were taking infliximab, which resulted in fulminant liver failure in five cases. The frequency of HBVr in this study looks quite alarming at first. 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 seven of nine cases with resolved hepatitis B. This makes the implication of TNF inhibitor therapy somewhat uncertain. Multivariate analysis demonstrated that the proportion of patients with HBVr was greater among patients previously treated with immunosuppressive agents (96% versus 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. 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 nine (36%) of 25 HBsAg‐positive patients, most of whom were treated with combinations of glucocorticoids, azathioprine, and infliximab. Biochemically silent reactivation occurred in only one of 65 resolved cases, and this individual had taken infliximab combined with azathioprine. The authors of this study made two important observations: (1) treatment with two or more immunosuppressive agents was an independent predictor of HBV reactivation (odds ratio = 8.75, 95% confidence interval 1.16‐65.66) 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 provides 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 whom 14 were treated with rituximab, 146 with TNF inhibitors, and 19 with other biologics. Patients were monitored closely for alanine aminotransferase, 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 antirheumatic agents and that 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 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 which 4800 patients had baseline HBV screening.9 In this retrospective analysis four (17%) of 23 HBsAg‐positive patients and one 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 et al. and others indicate that patients with resolved hepatitis B 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 to be 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 antibody to HBsAg have a protective role in HBsAg‐negative patients when TNF inhibitor therapy is given? The answers to the first two questions 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 at which it can no longer control viral replication. A management algorithm is depicted in Fig. 1, which incorporates different screening and management decisions when caring for patients taking TNF inhibitor monotherapy compared with persons taking a TNF inhibitor in combination with other immunosuppressive drugs. Additional studies specifically directed to the estimation of risk 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.Figure 1: Management algorithm. *Also can apply to patients receiving a second drug with very low risk for HBVr such as a disease‐modifying antirheumatic drug or low‐dose glucocorticoid. **This includes agents known or suspected to be independently associated with HBVr.