• Chronic hepatitis B
• Hematology-oncology
• Hepatitis B reactivation
• Hepatitis B virus
• Occult B infection
• Oncology

• Acute infection
• Chronic infection
• Hepatitis B virus
• Monoclonal antibodies
• Reactivation

• Antiviral agents
• Bruton’s tyrosine kinase inhibitors
• Chimeric antigen receptor-T cell therapy
• Hematologic neoplasms
• Hepatitis B
• Monoclonal antibodies

• Humans
• Hepatitis B virus/genetics
• Hepatitis B Surface Antigens
• DNA, Viral
• Hepatitis B/complications
• Hepatitis B/diagnosis
• Hepatitis B/prevention & control
• Hematologic Neoplasms/complications
• Hematologic Neoplasms/therapy
• Antibodies, Monoclonal
• Antiviral Agents/therapeutic use

With a 5.3% of the global population involved, hepatitis B virus (HBV) is a major public health challenge requiring an urgent response. After a possible acute phase, the natural history of HBV infection can progress in chronicity. Patients with overt or occult HBV infection can undergo HBV reactivation (HBVr) in course of immunosuppressive treatments that, apart from oncological and hem-atological diseases, are also used in rheumatologic, gastrointestinal, neurological and dermatological settings, as well as to treat severe acute respiratory syndrome coronavirus 2 infection. The risk of HBV reactivation is related to the immune status of the patient and the baseline HBV infection condition. The aim of the present paper is to investigate the risk of HBVr in those not oncological settings in order to suggest strategies for preventing and treating this occurrence. The main studies about HBVr for patients with occult hepatitis B infection and chronic HBV infection affected by non-oncologic diseases eligible for immunosuppressive treatment have been analyzed. The occurrence of this challenging event can be reduced screening the population eligible for immunosuppressant to assess the best strategies according to any virological status. Further prospective studies are needed to increase data on the risk of HBVr related to newer immunomodulant agents employed in non-oncological setting.

• Hepatitis B Virus infection
• Reactivation
• Occult B infection
• Chronic B infection
• Immunosuppression
• Disease-modifying antirheumatic drugs

Hepatitis B virus (HBV) reactivation can lead to severe acute hepatic failure and death in patients with HBV infection. HBV reactivation (HBVr) most commonly develops in patients undergoing cancer chemotherapy, especially B cell-depleting agent therapy such as rituximab and ofatumumab for hematological or solid organ malignancies and that receiving hematopoietic stem cell transplantation without antiviral prophylaxis. In addition, the potential consequences of HBVr is particularly a concern when patients are exposed to either immunosuppressive or biologic therapies for the management of rheumatologic diseases, inflammatory bowel disease and dermatologic diseases. Thus, screening with HBV serological markers and prophylactic or pre-emptive antiviral treatment with nucleos(t)ide analogues should be considered in these patients to diminish the risk of HBVr. This review discusses the clinical manifestation, prognosis and management of HBVr, risk stratifications of cancer chemotherapy and immunosuppressive therapy and international guideline recommendations for the prevention of HBVr in patients with HBV infection and resolved hepatitis B.

• Hepatitis B virus
• Reactivation
• Chemotherapy
• Immunosuppression
• Prevention

• Hepatitis B virus
• Immunosuppression
• Inflammatory bowel disease
• Prophylaxis
• Reactivation
• Vaccination

• DNA, Viral
• Hepatitis B/diagnosis
• Hepatitis B/drug therapy
• Hepatitis B/epidemiology
• Hepatitis B Antibodies
• Hepatitis B Surface Antigens
• Hepatitis B virus/genetics
• Humans
• Inflammatory Bowel Diseases/complications
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/epidemiology
• Virus Activation

Reactivation of hepatitis B virus (HBV) replication is characterized by increased HBV-DNA serum values of about 1 log or by HBV DNA turning positive if previously undetectable in serum, possibly associated with liver damage and seldom life-threatening. Due to HBV reactivation, hepatitis B surface antigen (HBsAg)-negative/anti-HBc-positive subjects may revert to HBsAg-positive. In patients with hemo-lymphoproliferative disease, the frequency of HBV reactivation depends on the type of lymphoproliferative disorder, the individual's HBV serological status and the potency and duration of immunosuppression. In particular, it occurs in 10%-50% of the HBsAg-positive and in 2%-25% of the HBsAg- negative/anti-HBc-positive, the highest incidences being registered in patients receiving rituximab-based therapy. HBV reactivation can be prevented by accurate screening of patients at risk and by a pharmacological prophylaxis with anti-HBV nucleo(t)sides starting 2-3 wk before the beginning of immunosuppressive treatment and covering the entire period of administration of immunosuppressive drugs and a long subsequent period, the duration of which depends substantially on the degree of immunodepression achieved. Patients with significant HBV replication before immunosuppressive therapy should receive anti-HBV nucleo(t)sides as a long-term (may be life-long) treatment. This review article is mainly directed to doctors engaged every day in the treatment of patients with onco-lymphoproliferative diseases, so that they can broaden their knowledge on HBV infection and on its reactivation induced by the drugs with high immunosuppressive potential that they use in the care of their patients.

• Hepatitis B virus reactivation
• Hepatitis B virus infection
• Hemo-lymphoproliferative diseases
• Immunosuppressive therapy
• Hepatitis B virus therapy
• Hepatitis B virus prophylasis

• Antibiotic Prophylaxis/methods
• Antiviral Agents/therapeutic use
• DNA, Viral/blood
• Hepatitis B/immunology
• Hepatitis B/prevention & control
• Hepatitis B/virology
• Hepatitis B Antibodies/blood
• Hepatitis B Antibodies/immunology
• Hepatitis B Surface Antigens/blood
• Hepatitis B Surface Antigens/immunology
• Hepatitis B virus/genetics
• Hepatitis B virus/immunology
• Hepatitis B virus/isolation & purification
• Humans
• Immunosuppressive Agents/adverse effects
• Lymphoproliferative Disorders/drug therapy
• Lymphoproliferative Disorders/immunology
• Time Factors
• Virus Activation/drug effects
• Virus Activation/immunology

Hepatitis B viral (HBV) reactivation in the immunosuppressed is a significant problem even in patients who have achieved serological clearance due to the persistence of HBV as cccDNA. HBV reactivation will continue to pose a significant healthcare burden given the high prevalence of HBV and increasing use of immunosuppressants. Screening of hepatitis B surface antigen, antibody to Hepatitis B core antigen antibody and HBV DNA levels should be done routinely in all patients planned for significant immunosuppressant use. We aimed to examine the factors affecting reactivation risk. This depended on HBV disease status, the underlying disease requiring immunosuppression, and the specific immunosuppressive regime. While antiviral prophylaxis can prevent reactivation, it increases cost and still has risk of delayed reactivation after stopping antivirals and close follow-up and on-demand treatment is a good alternative for patients at risk of reactivation.

• Previous hepatitis B exposure
• Immunosuppression
• Cost-effectiveness
• Hepatitis B reactivation

Hepatitis B virus (HBV) poses a significant challenge for both dialysis patients and kidney transplant recipients despite its decreasing rates, especially in developed countries. The best preventive method is vaccination. Patients with chronic renal disease should ideally be vaccinated prior to dialysis, otherwise, reinforced vaccination practices and close antibody titer monitoring should be applied while on dialysis. HBV infected dialysis patients who are renal transplant candidates must be thoroughly examined by HBV-DNA, and liver enzyme testing and by liver biopsy. When needed, one must consider treating patients with tenofovir or entecavir rather than lamivudine. Depending on the cirrhosis stage, dialysis patients are eligible transplant recipients for either a combined kidney-liver procedure in the case of decompensated cirrhosis or a lone kidney transplantation since even compensated cirrhosis after sustained viral responders is no longer considered an absolute contraindication. Nucleoside analogues have led to improved transplantation outcomes with both long-term patient and graft survival rates nearing those of HBsAg(-) recipients. Moreover, in the cases of immunized HBsAg(-) potential recipients with concurrent prophylaxis, we are enabled today to safely use renal grafts from both HBsAg(+) and HBsAg(-)/anti-HBc(+) donors. In so doing, we avoid unnecessary organ discarding. Universal prophylaxis with entecavir is recommended in HBV kidney recipients and should start perioperatively. One of the most important issues in HBV(+) kidney transplantation is the duration of antiviral prophylaxis. In the absence of robust data, it seems that prophylactic treatment may be discontinued in selected stable, low-risk recipients during maintenance immunosuppression and should be reintroduced when the immune status is altered. All immunosuppressive agents in kidney transplantation can be used in HBV(+) recipients. Immunosuppression is intimately associated with increased viral replication; thus it is important to minimize the total immunosuppression burden long term.

• Hepatitis B virus (+) donor
• Hepatitis B virus (+) recipient
• Renal transplantation
• Viral reactivation
• Immunosuppression
• Nucleoside analogues
• Antiviral discontinuation
• Antiviral prophylaxis
• Hepatitis B

Hepatitis due to hepatitis B virus (HBV) reactivation can be severe and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving cancer chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. All patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc). Patients found to be positive for HBsAg should be given prophylactic antiviral therapy to prevent HBV reactivation. For patients with resolved HBV infection, no standard strategy has yet been established to prevent HBV reactivation. There are usually two options. One is pre-emptive therapy guided by serial HBV DNA monitoring, whereby antiviral therapy is given as soon as HBV DNA becomes detectable. However, there is little evidence regarding the optimal interval and period of monitoring. An alternative approach is prophylactic antiviral therapy, especially for patients receiving high-risk therapy such as rituximab, newer generation of anti-CD20 monoclonal antibody, obinutuzumab or hematopoietic stem cell transplantation. This strategy may effectively prevent HBV reactivation and avoid the inconvenience of repeated HBV DNA monitoring. Entecavir or tenofovir are preferred over lamivudine as prophylactic therapy. Although there is no well-defined guideline on the optimal duration of prophylactic therapy, there is growing evidence to recommend continuing prophylactic antiviral therapy for at least 12 mo after cessation of chemotherapy, and even longer for those who receive rituximab or who had high serum HBV DNA levels before the start of immunosuppressive therapy. Many novel agents have recently become available for the treatment of hematological malignancies, and these agents may be associated with HBV reactivation. Although there is currently limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, especially the Bruton tyrosine kinase inhibitors and the phosphatidylinositol 3-kinase inhibitors, which are B-cell receptor signaling modulators and reduce proliferation of malignant B-cells. Further studies are needed to clarify the risk of HBV reactivation with these agents and the best prophylactic strategy in the era of targeted therapy for hematological malignancies.

• Hepatitis B virus reactivation
• Hematological malignancies
• Rituximab
• Hematopoietic stem cell transplant
• Prophylactic antiviral therapy

• Agammaglobulinaemia Tyrosine Kinase
• Antineoplastic Agents/therapeutic use
• Antiviral Agents/therapeutic use
• B-Lymphocytes/immunology
• DNA, Viral/blood
• Disease Management
• Hematologic Neoplasms/drug therapy
• Hepatitis B Antibodies/blood
• Hepatitis B Surface Antigens/blood
• Hepatitis B, Chronic/blood
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/prevention & control
• Humans
• Phosphoinositide-3 Kinase Inhibitors
• Protein-Tyrosine Kinases/antagonists & inhibitors
• Rituximab/therapeutic use
• Virus Activation

Rituximab is currently used not only in the treatment of B-cell lymphoma but also for various other diseases, including autoimmune diseases, post-transplant graft vs host disease, and rejection following kidney transplants. Due to rituximab’s widespread use, great progress has been made regarding research into complications that arise from its use, one of the most serious being the reactivation of hepatitis B virus (HBV), and efforts continue to establish guidelines for preventive treatment against this occurrence. This report discusses preventive measures against rituximab-induced HBV reactivation and future objectives.

• Rituximab
• Hepatitis B virus
• Reactivation
• Nucleoside analog
• Non-Hodgkin’s lymphoma

• Carcinoma, hepatocellular
• Guidelines
• Management

• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/therapy
• Evidence-Based Practice
• Hepatectomy
• Humans
• Liver Neoplasms/therapy
• Liver Transplantation
• Primary Prevention
• Republic of Korea
• Secondary Prevention

Due to the inherent relationship between the immune system and the hepatitis B virus (HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation (HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations’ guidelines and the best available evidence to date.

• Immunosuppression
• Hepatitis B
• Hepatitis B virus reactivation
• Prophylaxis
• Lamivudine
• Chemotherapy
• Entecavir
• Tenofovir
• Rituximab

Hepatitis B virus (HBV) infection affects a large part of the world population. Within the different virological HBV categories that have been identified, patients with occult HBV infection represent a peculiar group. These individuals harbor a replication competent virus, inhibited in its replicative function. Accordingly, cases of reactivations have been observed in immunosuppressed individuals who lose immunological control over the infection. Patients with hematological malignancies (HM) are treated with intense myelo- and immunosuppressive chemotherapy regimens which favor HBV reactivation. This event can have severe consequences, such as hepatitis flare, hepatic failure and even death. In addition, it can lead to delays or interruptions of curative treatments, resulting in a decreased disease free and overall survival. In this review, we will examine the event of HBV reactivation in patients with signs of resolved HBV infection undergoing treatment for HM and propose possible management strategies.

• Occult hepatitis B
• Hematological malignancies
• Hepatitis B virus
• Chemotherapy
• Hepatitis B reactivation