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

Abstract

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.

Keywords: Chronic Hepatitis B; Cirrhosis; Fulminant Hepatic Failure; Guidelines; Liver Disease; Liver Failure; Mortality; Viral Hepatitis.

Figure 1. Course of HBV reactivation after receiving immunosuppressive therapy

The course of HBV reactivation is depicted above when a patient at risk is exposed to cancer chemotherapy (as an example). All patients may not follow these phases in this sequence but it underscores the point that there is an asymptomatic phase early on in HBV reactivation that provides a window of opportunity to initiate treatment. In HBsAg positive patients, this asymptomatic phase is characterized by a rapid rise in HBV DNA, which is followed by a rapid rise in serum ALT levels. In HBsAg-negative patients, this asymptomatic phase is characterized by first reappearance of HBsAg and then sudden rise in HBV DNA, followed by an increase in serum ALT. Within a few weeks, after rapid HBV replication and increase in serum ALT, the bilirubin starts increasing and once it is above 3 mg/dl scleral icterus becomes apparent, and then some patients may progress to acute liver failure characterized by an increase in prothrombin time, development of ascites, and hepatic encephalopathy. The risk of mortality is significantly increased in those who develop ALF. Once patients are started on anti-HBV therapy the HBV DNA as well as serum ALT decrease rapidly, and this can happen spontaneously in some patients (however, spontaneous improvement after ALF is rare). This figure illustrates the natural history of HBV reactivation.

Figure 2

HBV life cycle and mechanisms associated with hepatitis B reactivation linked to immunosuppressive therapies. HBV replication and propagation is controlled by various innate and adaptive immune mechanisms as shown in the figure. The epigenetic regulation of HBV transcription can be altered by the HDIs. The innate immune control mechanisms such as IFNA and TNF-like molecules (TNFL) and their signaling pathways can be blocked by various immunosuppressive therapies such as TNFA and kinase inhibitors. The adaptive immunity controlling HBV including antigen-presenting cells (dendritic cells and macrophages), T and B cells can be inhibited by various immunosuppressive therapies targeting at different steps of immune response. See text for more explanation.

Figure 3. Algorithm for management of hepatitis B reactivation

Screening with serological tests for hepatitis B with HBsAg, anti-HBs and anti-HBc should be done prior to initiation of cancer chemotherapy or above mentioned immunosuppressive therapies. Patients with chronic hepatitis B as defined by the presence of HBsAg in the serum, serum HBV DNA ≥ 2000 IU/ml, and an elevated ALT should initiate antiviral therapy based upon published AASLD guidelines. Inactive HBV carriers, as defined by presence of HBsAg, HBV DNA <2000 IU/mlL and normal ALT and AST, when exposed to high and moderate risk immunosuppressive therapy should undergo prophylaxis against HBV reactivation. Prophylaxis should ideally be started 2 to 4 weeks before the initiation of immunosuppressive therapy and maintained for at least 6 to 12 months after the last dose of immunosuppressive therapy. Among those who are inactive HBsAg carriers and exposed to low-risk immunosuppressive therapy and patients with HBsAg negative/anti-HBc positive (HBV infection in the past), monitoring with serum ALT and HBsAg (and HBV DNA in those who are HBsAg-positive) is recommended. In patients who are exposed to rituximab-containing or other high-risk regimens, we recommend routine prophylaxis in patients who are HBsAg-negative and anti-HBc positive to reduce the risk of reactivation. Watchful monitoring may also be a reasonable choice in most other scenarios in patients who are HBsAg-negative and anti-HBc positive. Those who have a moderate risk of reactivation but HBsAg negative/anti-HBc positive (HBV infection in the past), anti-HBV prophylaxis should be considered or they could also be monitored with serum ALT and HBsAg every 3 months until 6 months after the last dose of immunosuppressive therapy. However, the HBV reactivation may occur up to 1–2 years after the last dose of rituximab therapy. Therefore, patients exposed to rituximab the anti-HBV prophylaxis may be continued up to 2 years after the last dose of rituximab.