Hepatitis B Virus Reactivation In Surface Antigen-Negative Patients with B-Cell Non-Hodgkin's Lymphoma Treated with Rituximab

Anti-CD20 monoclonal antibody - rituximab leads to hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-negative patients with B-cell non-Hodgkin¡&brkbar;s lymphoma (NHL), with the reported incidence ranged from 2% to 25%. Using a large cohort of HBsAg-negative B-cell NHL patients in one of HBV-endemic areas - Taiwan, we analyzed the clinical and virological features of de novo HBV reactivation following rituximab-contained immuno-chemotherapy.

Patients with the diagnosis of CD20 positive B-cell NHL who received rituximab-contained immunochemotherapy in Taipei Veterans General Hospital between 2002/1 and 2008/12 were collected. Clinical features, disease status, treatment and serological data of hepatitis virus (HBsAg, Antibody to HBsAg [HBsAb], anti-HBc, antibody to hepatic C virus [anti-HCV] through the period of rituximab administration were collected. The event of reverse seroconverion (RS, defined by the seroconversion from HBsAg negative to positive) was identified, with additional data collection of liver function tests. Serum HBV DNA was examined using nested and real-time PCR for a subset of patients with available sera through rituximab therapy, including those with and without RS.

A total of 517 B-cell NHL who once received rituximab were identified, including 71 HBsAg-positive (13.7%). For 446 HBsAg-patients, there were 27 (6%) with RS, which resulted in deaths in two patients (0.45% of total 446 patients; 7% of 27 patients with RS), with the characteristics shown in Table 1. Fifty-two percents of these patients (n=14) were female and fifty one percents have diffuse large B cell lymphoma. They have received a median of 8 doses rituximab (range, 3–20) before the development of RS. All of RS events developed within 6 months since last dose of rituximab alone or contained therapy, including those four (15% of all events) which appeared during rituximab maintenance therapy. Additional factors which also leaded the development of RS included previous transplantation in 4 patients (3 with hematopoietic stem cell transplantation and 1 with organ transplantation) and previous use of radioimmunotherapy in one patient. Among those patients without RS, sixty percents of these 94 patients (88% being anti-HBc positive) with available sera had a detectable level (> 50 copies/ml) of serum HBV-DNA through the period of rituximab-contained therapy, with the level up to 6 × 1,000 copies/ml.

In HBV endemic areas, HBV reactivation is common in HBsAg-negative patients with different subtypes of B-cell NHL through the period of rituximab-contained therapy. The degree of reactivation ranged from asymptomatic viremia to reverse sero-conversion, which may be asymptomatic or accompanied by clinical hepatitis. Using anti-viral agents, primary prophylaxis or preempting therapy during regular monitoring of HBV reactivation may decrease these insults. However, the impact is now more complicated by increased duration of rituximab therapy and subsequent use of additional immunosuppressant in these patients.

No relevant conflicts of interest to declare.