Risk of Reverse Seroconversion of Hepatitis B Virus Surface Antigen in Rituximab-Treated Non-Hodgkin Lymphoma Patients

Abstract

Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20+ NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS.Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20+ NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS.For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk, the univariate and multivariate regression analyses showed that several factors were independently associated with the development of HBV-RS, including anti-HCV seronegativity, histological subtype of posttransplant lymphoproliferative disorders, ≥6 cycles of rituximab therapy, and succeeding hematopoietic stem cell transplantation.The findings of our study identify additional factors influencing the development of rituximab-associated HBV-RS in HBsAg-seronegative adults with CD20+ NHL.

Reactivation of hepatitis B virus infection following rituximab treatment in HBsAg‐negative, HBcAb‐positive rheumatoid arthritis patients: A long‐term, real‐world observation

“…The occurrence of late‐onset rHBV supports other previous studies showing that RTX therapy for more than six cycles increased the risk of rHBV with HBsAg seroreversion, and a higher cumulative dose of RTX was associated with increased risk of infection . In addition, the incidence rate (8.7%) of rHBV in our HBsAg‐negative patients is similar to the results (9.1%) of a recent study in Taiwan, although different from another study indicating that rHBV was rare in those with resolved HBV infection . This discrepancy might be related to the differences in characteristics of the enrolled patients and the duration of follow‐up period.…”

“…Rituximab (RTX), a monoclonal antibody directed against B‐cell marker CD20, is effective for treating B‐cell lymphoma and RA patients with inadequate response to anti‐tumor necrosis factor (TNF)‐α therapy . Although a previous study demonstrated no rHBV in RTX‐treated rheumatic patients with resolved HBV infection, rHBV has recently been recognized as a complication characterized by a seroreversion of HBsAg in HBsAg‐negative patients receiving RTX therapy . Despite these findings, there are limited data or even conflicting results on rHBV in RTX‐treated patients .…”

Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients

“… 2 Hepatitis B virus (HBV) reactivation has been noted in hepatitis B virus surface antigen (HBsAg)-seronegative patients with CD20 + NHL, and at 10% risk of reverse seroconversion of hepatitis B virus surface antigen (HBV-RS). 3 – 7 Clinically, hepatitis flares are frequently associated with the reappearance of HBsAg (i.e., HBV-RS). 5 Among the risk factors for HBV-RS in HBsAg-seronegative patients with CD20 + NHL, HBV serological status prior to rituximab therapy, including antibody to hepatitis B virus core antigen (anti-HBc) seropositivity and antibody to hepatitis B virus surface antigen (anti-HBs) seronegativity, has been shown to be associated with a significantly increased risk in some reports.…”

“… 5 , 8 A higher number of cycles of rituximab therapy has also been highlighted as a risk factor. 6 , 7 However, the anti-HBc and anti-HBs seropositivity rate is relatively high in unvaccinated HBsAg-seronegative adults in HBV-hyperendemic areas, 3 , 4 , 6 – 9 for example, at least 70% in Taiwan, 4 – 7 , 9 which was the 1st country to initiate universal HBV vaccination, in 1984. 10 Therefore, it is necessary to investigate whether human genetic factors are related to rituximab-associated HBV reactivation.…”

Severe Acute Hepatitis B in HBV-Vaccinated Partner of a Patient with Multiple Myeloma Treated with Cyclophosphamide, Bortezomib, and Dexamethasone and Autologous Stem Cell Transplant

“…While the precise mechanism within the host immune response is largely unknown, recent studies suggest that T-cells may not be the major players in the natural history of chronic HBV infection [5]. Importantly, since therapies targeted against CD20 can result in HBV reactivation even after HBsAg loss, this suggests that B-lymphocytes and plasma cells likely play a role in immunity against HBV infection [6]. In patients undergoing autologous stem cell transplant (ASCT), host immunity is presumably restored immediately after chemoablation of cancer cells [7].…”