Monoclonal antibodies, used to treat a wide variety of medical conditions [
61], interfere with ligand binding cell surface receptors on either B or T cells, conferring immunomodulatory effects. Recent experience with regimens containing rituximab, a monoclonal antibody against the protein CD20 found on the surface of B cells, has demonstrated that when used in the treatment of malignancies in HBsAg-negative, anti-HBc-positive patients, there was an approximately six times higher odds ratio of HBVr compared to identical regimens without rituximab [
12,
62]. A preliminary analysis of the post-marketing data from the FDA Adverse Event Reporting System found 109 cases of fatal HBV-related liver failure associated with rituximab or the anti-CD20 monoclonal antibody ofatumumab (Arzerra, GlaxoSmithKline, Research Triangle Park, NC); in more than half, screening was either inadequate (testing for HBsAg but not anti-HBc) or had not been done [
63]. In September 2013, these findings prompted the FDA to add HBVr to the existing Boxed Warning of the Rituxan label, and to create a new Boxed Warning for the Arzerra label. In the
Warnings and Precautions section of the labels for both drugs it is now recommended that before starting treatment all patients be screened by measuring HBsAg and anti-HBc; that when screening identifies patients at risk of HBVr, a hepatitis expert be consulted regarding monitoring and use of HBV antiviral therapy; that patients with evidence of prior HBV infection be monitored for clinical and laboratory signs of HBVr during therapy and for several months thereafter since reactivation has occurred up to 12 months after therapy completion with these drugs; that in patients who develop HBVr while on therapy, the drugs be immediately discontinued and appropriate treatment for HBV be started; and that any chemotherapy the patient is receiving be discontinued until the HBV infection is controlled or resolved [
64•]. HBVr has also been reported in association with ibritumomab tiuxetan (Zevalin) [
65], a CD20-directed radiotherapeutic antibody approved for treatment of B-cell non-Hodgkin lymphoma, and with alemtuzumab (Campath) [
66], a monoclonal antibody directed against CD52 (expressed on B cells and T cells, natural killer cells, and macrophages) which is approved for refractory chronic lymphocytic leukemia [
67]; although there are no current label warnings related to reactivation with these two drugs, physicians should be aware of the possibility.