Incidence of Hepatitis B Reactivation in Association with Rituximab Therapy.
Authors: Hanbali Amr , Khaled Yasser , Ajrouche Hussein , Ansari Shan , Janakiraman Nalini 
Published: October 2019

Abstract
Introduction:
Hepatitis B reactivation and fulminant acute hepatitis has been described in association with Rituximab therapy. However, the incidence of these adverse effects is unknown and there are no established guidelines for hepatitis B screening prior to Rituximab therapy.
Method:
To study the incidence of hepatitis B reactivation in association with Rituximab, we reviewed the records of 456 patients treated with Rituximab between 1998 and 2004. We identified 32 patients with positive hepatitis B serology who received Rituximab alone (#14) or with chemotherapy (#18) for NHL (n#17), ITP (n#8), Waldenstrom Macroglobulinemia (n#2), CLL (n#2) and autoimmune diseases (n#3).
The patients were divided into 4 groups based on their hepatitis B serology as per table-1. Acute liver events were defined by acute elevation of liver enzymes, abnormal liver biopsy diagnostic of hepatitis or liver necrosis, hepatic encephalopathy or demonstration of active viral DNA replication by PCR.
Results:
Five patient developed hepatic failure, 2 of 12 in group A, 1 of 6 in group B, 0 of 8 in group C and 2 of 6 in group D. However, the patient in group B had a prior history of allogeneic related stem cell transplantation for Mantle cell lymphoma. The overall incidence of hepatic failure (5/32) was 15.6%.
Four patients developed biochemical hepatitis with elevated liver enzymes, two in group C, and one in group A and one in group B. Active hepatitis B viral replications occurred in 2 patients in group D with biochemical hepatitis. Hepatitis B viral replication and biochemical hepatitis were observed in (6/32) 19% of the patients. Overall, eleven of thirty two patients developed acute liver events as described above with overall incidence of 34%. Acute liver events occurred in 25%, 33%, 25% and 66% of the patients in group A, B, C and D respectively. Median duration of onset of acute liver events after Rituximab therapy was 6.2 months except for two patients who developed acute liver events 21 and 36 months latter.
In this retrospective review of single institution experience, one third of the patients with positive hepatitis B serology developed acute liver events when treated with Rituximab alone or with chemotherapy. This correlation was more evident in patients with hepatitis B surface antigen (66% of these patients). Surprisingly, acute liver events occurred as well in 25% of patients with negative HBsAg and positive HBcAb. Hepatitis B surface antibody did not provide protection against acute liver events in HBcAb positive patients with negative HBsAg.
Conclusion:
Hepatitis B serology screening is advisable prior to Rituxmab with or without chemotherapy treatment because of increase incidence of acute hepatitis and fulminant hepatic failure. Although positive hepatitis B surface antigen has the strongest correlation with acute liver events in our cohort, Hepatitis B reactivatioh was observed as well in patients with negative HBsAg and positive HBcAb. Hepatitis B DNA viral load monitoring may be helpful in directing the prophylaxis during Rituximab therapy. Further studies in larger patient’s population are needed to confirm these results.
The 4 groups based on their hepatitis B serology
GroupF # of Patients HBsAg HBsAb HBcAb Liver Event (%) *HBsAb, 4 patients negative, one patient positive and one patient not available.**HBcAb 4 patient positive and two patient’s negative A 12 Negative Positive Positive 3 (25) B 6 Negative Negative Positive 2 (33) C 8 Negative Not available Positive 2 (25) D 6 Positive *Variable **Variable 4 (66)