Risk of Hepatitis B Virus (HBV) Reactivation and Efficacy of Antiviral Preemptive Therapy in Malignant Lymphoma Patients Who Have Resolved HBV.

Reactivation of hepatitis B virus (HBV) is a well-described complication for hepatitis B surface antigen (HBsAg) positive patients undergoing systemic chemotherapy or immunosuppressive therapy. Recently, especially under use of rituximab, HBV reactivation has been increasingly reported in patients who have resolved HBV (HBsAg negative and hepatitis B core antibody [HBcAb] positive and/or hepatitis B surface antibody [HBsAb] positive). However the risk of HBV reactivation in malignant lymphoma patients with past HBV infection has not been well studied.

Eight hundred and forty-eight (848) patients were newly diagnosed with malignant lymphoma at Kurashiki Central Hospital from January 2001 to December 2008. We analyzed patients who received both HBsAg and HBcAb test; who underwent systemic chemotherapy; who were alive for >100 days after treatment; who were not administered antiviral prophylaxis for HBV. A total of 582 patients fulfilled these criteria, HBsAg detected in 10 patients (1.7%) and 175 (30.1%) were HBcAb positive only. Of these 175patients, 72 had HBV DNA test prior to systemic chemotherapy, no patients showed a detectable level of HBV serum DNA. Serial monthly HBV DNA monitoring was performed in 46 patients. HBV reactivation was defined as the reappearance of HBsAg or HBV DNA.

Of the 175 HBsAg-negative/HBcAb-positive patients (Diffuse large B cell lymphoma [DLBCL]; 91, Follicular lymphoma [FL]; 29, Mantle cell lymphoma [MCL]; 8, Maltoma [MALT]; 6, Hodgkin lymphoma [HL]; 6, Adult T cell leukemia/lymphoma [ATLL]; 8, Peripheral T cell lymphoma [PTCL]; 8, others; 20), 135 were treated with chemotherapy including rituximab, 11 patients received stem cell tarnsplantation (7 autologus, 4 allogenic). HBV reactivation was found in 6 patients (DLBCL; 2, FL; 2, MCL; 1, MALT; 1), all of them were treated with rituximab. Although the rate of reactivation with and without use of rituximab was 4.1%, 0%, respectively, there was no apparent statistical difference (p=0.12), probably due to the smaller number of reactivated patients. Age at diagnosis, sex, subtype of lymphoma, pretreatment liver function test, and type of treatment including allogenic stem cell taransplantation were not significantly associated with HBV reactivation. Three patients had reactivation occurred during chemotherapy, whereas other 3 patients developed reactivation after completion of treatment at median interval of 42 days (range, 19-162 days). At the reactivation, 3 were HbsAg positive/HBV-DNA positive and others, under serial monitoring, were HbsAg negative/HBV-DNA positive. The former group developed de novo HBV hepatitis, among whom 1 died as a result of hepatic failure despite of antiviral therapy. None of the latter group developed hepatitis following antiviral preemptive therapy.

Rituximab-containig regimens may increase the risk of HBV reactivation in lymphoma patients who have resolved HBV. And when molecular reactivation is recognized, prompt administration of preemptive antiviral therapy may prevent the development of de novo HBV hepatitis. For patients who are planned to receive rituximab therapy, HbsAg and HBcAb should be routinely tested, and HBsAg-negative/HBcAb-positive patients should be closely monitored with HBV DNA during at least 6 months after the end of chemotherapy, because the most delayed onset occurred 162 days in our study. Further studies are required to determine optimal monitoring and preemptive therapy.

No relevant conflicts of interest to declare.