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HBV reactivation
Finally, the immunosuppression regimen itself is of great importance in the risk of reactivation, and numerous studies have attempted to stratify this risk.25 High risk is considered to be greater than 10%, moderate between 1- 10%, and low risk less than 1%; the degree of risk has implications on management (Table 2). Low-risk regimens are limited to traditional immunosuppressive agents such as azathioprine and oral low-dose methotrexate without combination steroids, short-term low-dose steroids (≤20 mg/day prednisolone or equivalent for ≤7 days), and intra- articular steroids. The specific treatments relevant to hematologic disorders will be discussed in more detail below.
Specific immunosuppressive treatments
Systemic cancer chemotherapy
The earliest studies of HBV reactivation were in the con- text of systemic chemotherapy for breast cancer and lym- phoma. The greatest rates of reactivation were found in patients with lymphoma, likely due to the potency of immunosuppression offered by the chemotherapy regi- mens, as well as the immunosuppressive effect of the underlying disease. In one prospective study of patients treated for lymphoma with a variety of chemotherapy regimens, mostly based on CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), the rate of hepati- tis attributed to HBV reactivation was 48% in HBsAg-pos- itive patients (13 out of 27) and 4% in patients positive for anti-HBc and/or anti-HBs (2 out of 51 patients).11 A similar study of patients receiving chemotherapy for other solid tumors found HBV reactivation in 15 out of 78 HBsAg- positive patients.14 In a large meta-analysis, the risk of HBV reactivation was found to be highest with anthracy- cline-derived chemotherapy such as doxorubicin and epirubicin.26
Corticosteroids
The negative effect of corticosteroids on HBV infection has long been documented, with early studies from the
1980s that aimed to investigate a therapeutic role for prednisolone instead showing a hastened biochemical deterioration and increased complications, including death.27 The mechanism is potentially 2-fold: firstly, the HBV genome contains a glucocorticoid-responsive tran- scription regulatory element which is up-regulated by cor- ticosteroids resulting in increased viral replication, and secondly, a directly suppressive effect on cytotoxic T cells which are involved in HBV control.28 Reactivation has been reported with steroid monotherapy, with one meta- analysis concluding the risk to be at least 10% in HBsAg- positive patients receiving continuous systemic treatment for four weeks or more.25 It also concluded that doses of ≥20 mg daily of prednisolone or equivalent represented a high risk. In patients with hemato-oncological disorders, corticosteroids are often used in conjunction with other chemotherapy agents, where they have been shown to have an additive deleterious effect. In one randomized study, 50 HBsAg positive patients received the same chemotherapy regimens for NHL either with or without corticosteroids; the incidence of reactivation in the corti- costeroid group was significantly higher (18 out of 25 vs. 9 out of 25, respectively), with also a higher incidence of clinically significant hepatitis.29
Anti-CD20-directed monoclonal antibodies
This class of drugs is well-reported for causing severe HBV reactivation, with several published cases of fatal ful- minant hepatic failure.30-34 These reports and a formal eval- uation of the post-marketing data from the US Food and Drug Administration (FDA) adverse events reporting sys- tem resulted in a warning on the packaging of all mono- clonal antibodies against CD20 regarding the risk of HBV reactivation. Rituximab, ofatumumab and obinutuzumab are currently licensed and predominantly used to treat B- cell malignancies. The risk of reactivation is highest for HBsAg-positive patients, and it has even been suggested that almost all will develop reactivation at some point.25 Patients with resolved HBV infection are also likely to be at high risk. In one large analysis of 326 anti-HBc positive patients receiving rituximab or obinutuzumab as part of
Table 2. Risk groups in terms of immunosuppressive regimen and the recommended management to prevent hepatitis B virus (HBV) reactivation.
Risk group
High risk (>10%)
Moderate risk (1-10%)
Low risk (<1%)
Treatment regimen
B-cell-depleting anti-CD20-directed monoclonal antibodies (e.g. rituximab) HSCT +/- diagnosis of GvHD
Systemic cancer chemotherapy
- anthracycline derivatives (e.g. doxorubicin)
Tyrosine kinase inhibitors (e.g. imatinib, ibrutinib)
Corticosteroids ≥20mg prednisolone, ≥4 weeks
Traditional immunosuppressive monotherapy (e.g. azathioprine, methotrexate)
Corticosteroids ≤4 weeks
Recommended management
HBsAg positive
Treatment/prophylaxis* with TDF/entecavir
Treatment/prophylaxis* with TDF/entecavir
Treatment/prophylaxis* with TDF/entecavir if chronic hepatitis
HBsAg negative, anti-HBc positive
Prophylaxis with lamivudine, or TDF/entecavir if expected duration >12 months
Prophylaxis with lamivudine, or TDF/entecavir if expected duration >12 months
Monitor HBsAg, ALT and HBV DNA every 3 months
*HBsAg-positive patients with evidence of chronic HBV hepatitis (see Table 1) will require active treatment of HBV infection. HSCT: hematopoietic stem cell transplantation; GvHD: graft-versus-host disease; TDF: tenofovir disoproxil fumarate; HbsAg: hepatitis B surface antigen; anti-HBc: anti-hepatitis B core antibody; ALT: alanine transaminase.
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