Hepatitis B Reactivation Associated With Immune Suppressive and Biological Modifier Therapies: Current Concepts, Management Strategies, and Future Directions

Hepatitis B reactivation associated with immune-suppressive and biological therapies is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to hepatitis B virus (HBV) infection. The population at risk for HBV reactivation includes those who either currently are infected with HBV or have had past exposure to HBV. Because curative and eradicative therapy for HBV is not currently available, there is a large reservoir of individuals at risk for HBV reactivation in the general population. HBV reactivation with its potential consequences is particularly a concern when these people are exposed to either cancer chemotherapy, immunosuppressive or biologic therapies for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. With the advent of newer and emerging forms of targeted biologic therapies, it has become important to understand the mechanisms whereby certain therapies are more prone to HBV reactivation. This review provides a comprehensive update on the current concepts, risk factors, molecular mechanisms, prevention, and management of hepatitis B reactivation. In addition, we provide recommendations for future research in this area. Hepatitis B reactivation associated with immune-suppressive and biological therapies is emerging to be an important cause of morbidity and mortality in patients with current or prior exposure to hepatitis B virus (HBV) infection. The population at risk for HBV reactivation includes those who either currently are infected with HBV or have had past exposure to HBV. Because curative and eradicative therapy for HBV is not currently available, there is a large reservoir of individuals at risk for HBV reactivation in the general population. HBV reactivation with its potential consequences is particularly a concern when these people are exposed to either cancer chemotherapy, immunosuppressive or biologic therapies for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation. With the advent of newer and emerging forms of targeted biologic therapies, it has become important to understand the mechanisms whereby certain therapies are more prone to HBV reactivation. This review provides a comprehensive update on the current concepts, risk factors, molecular mechanisms, prevention, and management of hepatitis B reactivation. In addition, we provide recommendations for future research in this area. It is estimated that approximately 1 in every 3 individuals worldwide may have been exposed to hepatitis B virus (HBV) infection.1Dienstag J.L. Hepatitis B virus infection.N Engl J Med. 2008; 359: 1486-1500Crossref PubMed Scopus (787) Google Scholar, 2Liang T.J. Block T.M. McMahon B.J. et al.Present and future therapies of hepatitis B: from discovery to cure.Hepatology. 2015; 62: 1893-1908Crossref PubMed Scopus (227) Google Scholar Furthermore, HBV is one of the leading causes of chronic liver disease and hepatocellular carcinoma worldwide. Based on recent estimates, approximately 350 million people worldwide suffer from chronic hepatitis B (CHB) infection. In the United States, as many as 2.2 million Americans are estimated to have CHB.2Liang T.J. Block T.M. McMahon B.J. et al.Present and future therapies of hepatitis B: from discovery to cure.Hepatology. 2015; 62: 1893-1908Crossref PubMed Scopus (227) Google Scholar However, only a minority of these individuals know that they have CHB and receive medical care and treatment for CHB. The majority of infected patients either are unaware that they have chronic HBV infection, have been exposed to HBV, or have risk factors for acquiring HBV infection. Therefore, the risk and consequences of hepatitis B reactivation is increased significantly when these HBV-infected individuals are exposed to either immunosuppressive therapy or cancer chemotherapy. The population at risk for HBV reactivation includes those who either currently are infected with HBV or have had past exposure to HBV.3Hoofnagle J.H. Reactivation of hepatitis B.Hepatology. 2009; 49: S156-S165Crossref PubMed Scopus (475) Google Scholar Because curative and eradicative therapy for HBV is not currently available, there is a large reservoir of individuals at risk for HBV reactivation in the general population. HBV reactivation with its potential consequences is particularly a concern when these people are exposed to either cancer chemotherapy, immunosuppressive, or biologic therapies for the management of rheumatologic conditions, malignancies, inflammatory bowel disease, dermatologic conditions, or solid-organ or bone marrow transplantation.4Doo E.C. Hoofnagle J.H. Rodgers G.P. NIH consensus development conference: management of hepatitis B.Introduction. Hepatology. 2009; 49: S1-S3Crossref PubMed Scopus (7) Google Scholar With the advent of newer and emerging forms of targeted biologic therapies, it has become important to understand the mechanisms that make certain therapies more prone to HBV reactivation.5Di Bisceglie A.M. Lok A.S. Martin P. et al.Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?.Hepatology. 2015; 61: 703-711Crossref PubMed Scopus (163) Google Scholar, 6Lok A.S. Ward J.W. Perrillo R.P. et al.Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable.Ann Intern Med. 2012; 156: 743-745Crossref PubMed Scopus (73) Google Scholar In this review, we discuss the epidemiology, virology, and management of HBV reactivation in the setting of immune-suppressive and biological modifier therapy. Because of space constraints, we will not cover the risk of HBV reactivation after bone marrow transplant or solid-organ transplant and refer the readers to other reviews on the topic.3Hoofnagle J.H. Reactivation of hepatitis B.Hepatology. 2009; 49: S156-S165Crossref PubMed Scopus (475) Google Scholar, 6Lok A.S. Ward J.W. Perrillo R.P. et al.Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable.Ann Intern Med. 2012; 156: 743-745Crossref PubMed Scopus (73) Google Scholar, 7Nagington J. Reactivation of hepatitis b after transplantation operations.Lancet. 1977; 1: 558-560Abstract PubMed Scopus (134) Google Scholar, 8Hwang J.P. Vierling J.M. Zelenetz A.D. et al.Hepatitis B virus management to prevent reactivation after chemotherapy: a review.Support Care Cancer. 2012; 20: 2999-3008Crossref PubMed Scopus (33) Google Scholar, 9Perrillo R.P. Gish R. Falck-Ytter Y.T. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.Gastroenterology. 2015; 148: 221-244 e3Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar, 10Reddy K.R. Beavers K.L. Hammond S.P. et al.American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.Gastroenterology. 2015; 148 (quiz e16–e17): 215-219Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar In the United States, HBV reactivation-related acute liver failure increasingly is being recognized and has emerged as an important and preventable cause of acute liver failure.4Doo E.C. Hoofnagle J.H. Rodgers G.P. NIH consensus development conference: management of hepatitis B.Introduction. Hepatology. 2009; 49: S1-S3Crossref PubMed Scopus (7) Google Scholar HBV reactivation is defined as a sudden and rapid increase in HBV-DNA level by at least a 100-fold in patients with previously detectable HBV DNA or reappearance of HBV-DNA viremia in individuals who did not have viremia before the initiation of immune-suppressive or biological modifier therapy or cancer chemotherapy. HBV reactivation may be classified into 2 broad categories based on the baseline virologic profile: HBV reactivation in patients who are positive for hepatitis B surface antigen (HBsAg) in the serum with or without detectable HBV-DNA viremia in the blood; and reverse seroconversion is defined as a reappearance of HBsAg and HBV DNA in individuals who initially are negative for HBsAg and HBV DNA in the serum before immunosuppression and then become positive after exposure to immunosuppressive therapies. The natural history of HBV reactivation may be classified into the following stages (Figure 1). The first stage has an increase in viral replication from baseline. After initial exposure to immunosuppressive therapies, viral replication may increase abruptly and continue to increase. Early into this phase the patient still may be asymptomatic. Many patients may not go on to develop HBV reactivation-related hepatitis, which is described later and defined as an increase in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level to 3 or more times baseline values. The second stage has an increase in serum ALT and AST values. Approximately within a few weeks (or in some cases days) of an increase in HBV-DNA levels, serum ALT and AST concentrations start increasing. This stage also is classified as HBV reactivation-related hepatitis or a hepatic flare. Typically, serum ALT and AST levels may increase between 5 and 10 times the upper limit of normal or baseline levels. The majority of patients may remain asymptomatic but a small number of patients experiencing a more severe flare of hepatitis may experience constitutional symptoms, right upper-quadrant tenderness, and jaundice. The third stage has a spontaneous or on-treatment improvement/resolution. The next phase in the natural history in some patients is spontaneous improvement in the flare of serum ALT and AST levels in most cases resulting from completion of the course of the immunosuppressive therapy or cycle of cancer chemotherapy. In some cases, HBV reactivation is recognized and the start of antiviral therapy also may lead to resolution of the flare of hepatitis and then a reduction in serum HBV-DNA levels. The fourth stage has acute liver failure/persistent liver injury. A small minority of patients may continue to have a progressive decrease in the synthetic function of the liver, leading to worsening serum bilirubin levels, prolongation of the prothrombin time, and may develop acute liver failure with other features of hepatic decompensation such as ascites, altered sensorium, and sequelae of portal hypertension. Some of these individuals may need a liver transplant if they are candidates despite initiation of antiviral therapy. If unrecognized or untreated, these individuals have a high risk of death from liver failure. The fifth stage has a resolution with immune recovery: The majority of individuals will recover from HBV reactivation with the initiation of antiviral therapy or with the cessation of immunosuppressive therapy that led to the HBV reactivation. These stages do not necessarily follow each other as outlined earlier. Many individuals may develop only transient increased HBV viremia with or without an ALT increase, but do not show any clinical consequences. The mechanism by which individuals show varying severity of HBV reactivation is unclear and this variability in the severity of HBV reactivation probably relates to both host and viral factors as described later. The timing of onset of HBV reactivation can be variable depending on the host status, underlying disease, and the type of immunosuppressive therapies. It may occur as early as within the first 2 weeks of onset of chemotherapy or up to a year after the cessation of immunosuppression. Understanding the risk factors and mechanisms that cause HBV reactivation can help understand and quantify the magnitude of the risk of HBV reactivation and its consequences. The key risk factors for reactivation can be classified broadly into 3 categories: (1) host factors, (2) virologic factors, and (3) type and degree of immunosuppression. Host factors include male sex, older age, presence of cirrhosis, and type of disease needing immunosuppression (eg, lymphoma).11Loomba 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: 519-528Crossref PubMed Scopus (411) Google Scholar, 12Yeo W. Chan P.K. Zhong S. et al.Frequency of hepatitis B virus reactivation in cancer patients undergoing cytotoxic chemotherapy: a prospective study of 626 patients with identification of risk factors.J Med Virol. 2000; 62: 299-307Crossref PubMed Scopus (562) Google Scholar The virologic factors associated with an increased risk of reactivation include high baseline HBV-DNA level, hepatitis B e antigen positivity, and chronic hepatitis B.13Yeo W. Chan P.K. Ho W.M. et al.Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.J Clin Oncol. 2004; 22: 927-934Crossref PubMed Scopus (224) Google Scholar, 14Yeo W. Chan P.K. Hui P. et al.Hepatitis B virus reactivation in breast cancer patients receiving cytotoxic chemotherapy: a prospective study.J Med Virol. 2003; 70: 553-561Crossref PubMed Scopus (182) Google Scholar, 15Yeo W. Johnson P.J. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy.Hepatology. 2006; 43: 209-220Crossref PubMed Scopus (418) Google Scholar HBV genotype increasingly has been linked to treatment response, disease severity, and progression.16Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2411) Google Scholar, 17Tohme R.A. Bulkow L. Homan C.E. et al.Rates and risk factors for hepatitis B reactivation in a cohort of persons in the inactive phase of chronic hepatitis B-Alaska, 2001-2010.J Clin Virol. 2013; 58: 396-400Crossref PubMed Scopus (31) Google Scholar Although its association with HBV reactivation is unknown, a few small studies have suggested infection with non-A genotype may be more prone to reactivation.17Tohme R.A. Bulkow L. Homan C.E. et al.Rates and risk factors for hepatitis B reactivation in a cohort of persons in the inactive phase of chronic hepatitis B-Alaska, 2001-2010.J Clin Virol. 2013; 58: 396-400Crossref PubMed Scopus (31) Google Scholar, 18Borentain P. Colson P. Coso D. et al.Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg-negative and anti-HBc antibodies-positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer.J Viral Hepat. 2010; 17: 807-815Crossref PubMed Scopus (75) Google Scholar, 19Hayashi K. Ishigami M. Ishizu Y. et al.Clinical characteristics and molecular analysis of hepatitis B virus reactivation in hepatitis B surface antigen-negative patients during or after immunosuppressive or cytotoxic chemotherapy.J Gastroenterol. 2016; 51: 1081-1089Crossref PubMed Scopus (21) Google Scholar The prevalence of HBV genotypes has a variable and divergent worldwide distribution. Thus, the association of HBV genotypes with HBV reactivation will be an important question to address. Co-infection of HBV with HCV, hepatitis D virus, or human immunodeficiency virus infection presents an unusual setting for potential HBV reactivation. Treatment of co-infected patients with antivirals directed at the virus, such as direct-acting antivirals for HCV, lonafarnib for hepatitis D virus, and non-B antiretroviral therapy for human immunodeficiency virus can result in HBV reactivation.20Puoti M. Torti C. Bruno R. et al.Natural history of chronic hepatitis B in co-infected patients.J Hepatol. 2006; 44: S65-S70Abstract Full Text Full Text PDF PubMed Scopus (173) Google Scholar, 21De Monte A. Courjon J. Anty R. et al.Direct-acting antiviral treatment in adults infected with hepatitis C virus: reactivation of hepatitis B virus coinfection as a further challenge.J Clin Virol. 2016; 78: 27-30Crossref PubMed Scopus (106) Google Scholar, 22Koh C. Canini L. Dahari H. et al.Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial.Lancet Infect Dis. 2015; 15: 1167-1174Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar These host and virologic factors are important considerations that may increase the likelihood of HBV reactivation further. Therefore, the assessment of host as well as virologic risk factors should be important caveats to help decide whether to initiate prophylactic therapy before initiating immunosuppression. The risk of reactivation can be divided broadly into high risk (if the rate of HBV reactivation is ≥10%), moderate risk (if the risk of reactivation is between 1%–10%), and low risk (if the risk of reactivation is <1%) based on the type of immunosuppressive therapy stratified by the presence of HBsAg or absence of HBsAg, but positive for anti–hepatitis B core (HBc) antibody (HBsAg-negative and anti-HBc positive with or without the antibody to hepatitis B surface antigen [anti-HBs]). Routine HBV screening is recommended by HBsAg and anti-HBc testing among all patients who are at risk of HBV reactivation.16Lok A.S. McMahon B.J. Chronic hepatitis B: update 2009.Hepatology. 2009; 50: 661-662Crossref PubMed Scopus (2411) Google Scholar Prophylactic therapy with potent oral anti-HBV therapies strongly is recommended for patients at a high or medium risk of reactivation (see the section on the Type of Anti-HBV Regimen for Prophylaxis). For patients at low risk of reactivation, either pre-emptive therapy or watchful monitoring is recommended. Table 1 provides a list of therapies stratified by their risk of reactivation. Among HBsAg-negative and anti-HBc positive patients, the evidence for risk of HBV reactivation and pre-emptive therapy is considerably controversial in many situations. In general, this risk for HBV reactivation is much lower in the HBsAg-negative and anti-HBc–positive patients than in HBsAg-positive patients. The greatest risk of reactivation that mandates pre-emptive therapy is the use of B-cell–depleting therapies, or in the setting of bone marrow transplant or solid-organ transplantation. In most other scenarios, in patients who are HBsAg negative and anti-HBc positive, watchful monitoring may be a reasonable choice.Table 1Risk of Hepatitis B Reactivation Associated With Immunosuppressive TherapiesImmunosuppressive therapiesRisk of reactivation in HBsAg-positive patients High risk of reactivationB-cell–depleting agents including rituximab, ofatumumab, natalizumab, alemtuzumab, and ibritumomabHigh-dose corticosteroidsAnthracyclines including doxorubicin and epirubicinMore potent TNF-α inhibitors including infliximab, adalimumab, certolizumab, and golimumabLocal therapy for HCC including TACE Moderate risk of reactivationSystemic chemotherapyLess potent TNF-α inhibitors including etanerceptCytokine-based therapies including abatacept, ustekinumab, mogamulizumab, natalizumab, and vedolizumabImmunophilin inhibitors including cyclosporineTyrosine-kinase inhibitors including imatinib and nilotinibProteasome inhibitors such as bortezomibHDIsModerate-dose corticosteroids Low risk of reactivationAntimetabolites, azathioprine, 6-mercaptopurine, and methotrexateShort-term low-dose corticosteroidsIntra-articular steroid injections (extremely low risk)Risk of reactivation in HBsAg-negative and anti-HBc positive patientsaThe risk of HBV reactivation in patients who are HBsAg-negative and anti-HBc positive receiving B-cell–depleting therapies is the highest. For the moderate- and low-risk groups, the evidence for risk of HBV reactivation is considerably controversial. High risk of reactivationB-cell–depleting agents including rituximab, ofatumumab, natalizumab, alemtuzumab, ibritumomab Moderate risk of reactivationHigh-dose corticosteroidsAnthracyclines including doxorubicin and epirubicinMore potent TNF-α inhibitors including infliximab, adalimumab, certolizumab, and golimumabSystemic cancer chemotherapy including HCCCytokine-based therapies including abatacept, ustekinumab, mogamulizumab, natalizumab, and vedolizumabImmunophilin inhibitors including cyclosporineTyrosine-kinase inhibitors including imatinib and nilotinibProteasome inhibitors such as bortezomibHDIs Low risk of reactivationModerate- and low-dose prednisoneAntimetabolites, azathioprine, 6-mercaptopurine, and methotrexateHCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.a The risk of HBV reactivation in patients who are HBsAg-negative and anti-HBc positive receiving B-cell–depleting therapies is the highest. For the moderate- and low-risk groups, the evidence for risk of HBV reactivation is considerably controversial. Open table in a new tab HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization. Among patients who are HBsAg positive, the following therapies create a high risk of reactivation (incidence rate of HBV reactivation, ≥10%). First, B-cell depleting therapies such as rituximab and ofatumumab have increased the risk of reactivation significantly in both HBsAg-positive as well as in HBsAg-negative and anti-HBc–positive patients.23Evens A.M. Jovanovic B.D. Su Y.C. et al.Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports.Ann Oncol. 2011; 22: 1170-1180Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar, 24Mozessohn L. Chan K.K. Feld J.J. et al.Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis.J Viral Hepat. 2015; 22: 842-849Crossref PubMed Scopus (88) Google Scholar This class of drugs is most notorious for causing severe HBV reactivation, and can lead to increased risk of HBV reactivation-related liver failure and liver-related mortality if HBV reactivation is not promptly recognized and treated.24Mozessohn L. Chan K.K. Feld J.J. et al.Hepatitis B reactivation in HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma: a meta-analysis.J Viral Hepat. 2015; 22: 842-849Crossref PubMed Scopus (88) Google Scholar Patients with non-Hodgkin lymphoma routinely are prescribed rituximab and have high rates of reactivation owing to host as well as immunosuppression-related factors. Rituximab also is being used for the treatment of several rheumatologic conditions such as rheumatoid arthritis and vasculitides. The Food and Drug Administration recently placed a black-box warning for rituximab to increase awareness regarding HBV reactivation in patients exposed to rituximab.5Di Bisceglie A.M. Lok A.S. Martin P. et al.Recent US Food and Drug Administration warnings on hepatitis B reactivation with immune-suppressing and anticancer drugs: just the tip of the iceberg?.Hepatology. 2015; 61: 703-711Crossref PubMed Scopus (163) Google Scholar Second, anthracycline derivatives such as doxorubicin and epirubicin also are associated with a high risk of reactivation.25Paul S. Saxena A. Terrin N. et al.Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis.Ann Intern Med. 2016; 164: 30-40Crossref PubMed Scopus (122) Google Scholar, 26Kim M.K. Ahn J.H. Kim S.B. et al.Hepatitis B reactivation during adjuvant anthracycline-based chemotherapy in patients with breast cancer: a single institution's experience.Korean J Intern Med. 2007; 22: 237-243Crossref PubMed Scopus (38) Google Scholar Patients with hepatocellular carcinoma and hepatitis B undergoing transarterial chemoembolization therapy are a particular concern. Third, chronic prednisone therapy, either medium dose (10–20 mg/day orally) or high dose (>20 mg/day orally), for more than a 4-week duration, increases the likelihood of HBV reactivation into a high risk of reactivation.9Perrillo R.P. Gish R. Falck-Ytter Y.T. American Gastroenterological Association Institute technical review on prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy.Gastroenterology. 2015; 148: 221-244 e3Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar Fourth, patients receiving cancer chemotherapy for lymphomas, acute myeloid leukemias, and chemotherapy for breast cancer, pancreatic cancer, or lung cancer, may end up receiving either of the earlier-described therapies or high-dose pulse steroids and should be considered at high risk of reactivation and received screening and antiviral prophylaxis for the prevention of HBV reactivation.11Loomba 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: 519-528Crossref PubMed Scopus (411) Google Scholar, 25Paul S. Saxena A. Terrin N. et al.Hepatitis B virus reactivation and prophylaxis during solid tumor chemotherapy: a systematic review and meta-analysis.Ann Intern Med. 2016; 164: 30-40Crossref PubMed Scopus (122) Google Scholar Fifth, tumor necrosis factor-α (TNF-α) inhibitors such as infliximab, adalimumab, and certolizumab, have a high risk (range, 12%–39%) of HBV reactivation in HBsAg-positive patients.27Esteve M. Saro C. Gonzalez-Huix F. et al.Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis.Gut. 2004; 53: 1363-1365Crossref PubMed Scopus (449) Google Scholar, 28Lan J.L. Chen Y.M. Hsieh T.Y. et al.Kinetics of viral loads and risk of hepatitis B virus reactivation in hepatitis B core antibody-positive rheumatoid arthritis patients undergoing anti-tumour necrosis factor alpha therapy.Ann Rheum Dis. 2011; 70: 1719-1725Crossref PubMed Scopus (145) Google Scholar The risk is higher with infliximab (a more potent TNF-α blocker) than etanercept (a much lower risk, approximately 1%–5%). These therapies commonly are used in the treatment of inflammatory bowel disease and rheumatologic conditions such as rheumatoid arthritis. Treatment with a moderate risk of reactivation (incidence rate of HBV reactivation of 1%–10%) includes the following:1.Systemic chemotherapy other than the situation described earlier.2.Less potent TNF-α inhibitors such as etanercept have a moderate risk (approximately 1%–5%) of HBV reactivation in HBsAg-positive patients and even lower in HBsAg-negative and anti-HBc–positive patients.28Lan J.L. Chen Y.M. 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Doumba P.P. et al.Hepatitis B virus reactivation during therapy with ustekinumab for psoriasis in a hepatitis B surface-antigen-negative anti-HBs-positive patient.Br J Dermatol. 2013; 168: 679-680Crossref PubMed Scopus (40) Google Scholar, 35Nakano N. Kusumoto S. Tanaka Y. et al.Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.Hepatol Res. 2014; 44: 354-357Crossref PubMed Scopus (24) Google Scholar These therapies commonly are being used in the management of inflammatory bowel disease and in rheumatologic as well as dermatologic conditions.4.Tyrosine kinase inhibitors such as imatinib and nilotinib have been associated with a moderate risk of HBV reactivation in both HBsAg-positive as well as in HBsAg-negative and anti-HBc–positive patients.36Ikeda K. Shiga Y. 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