Originally published as JCO Early Release 10.1200/JCO.2009.21.9352 on April 13 2009

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Risk of Hepatitis B Virus Reactivation in Patients Who Are Hepatitis B Surface Antigen Negative/Antibody to Hepatitis B Core Antigen Positive and the Role of Routine Antiviral Prophylaxis

Yong Loo Lin School of Medicine, National University of Singapore; Department of Medical Oncology, National Cancer Centre Singapore, Singapore
Department of Medical Oncology, National Cancer Centre Singapore, Singapore

To the Editor:

In Journal of Clinical Oncology, Yeo et al¹ reported a study of 104 patients with CD20⁺ diffuse large B-cell lymphoma (DLBCL). Of the 80 patients who were hepatitis B surface antigen (HBsAg) negative, 46 (44.2%) had resolved hepatitis B virus (HBV; ie, they were HBsAg negative but antibody to hepatitis B core antigen [anti-HBc] positive). Twenty-five of these patients were treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP), and none had HBV reactivation; 21 were treated with rituximab plus CHOP (R-CHOP), and five (23.8%) developed HBV reactivation.

Our institution presented results of a similar study² at the 50th Annual Meeting of the American Society of Hematology (San Francisco, CA). In our cohort, 80 (34.3%) of 233 patients were found to be HBsAg negative/anti-HBc positive. Indeed, the high prevalence of resolved HBV among patients with non-Hodgkin's lymphoma (NHL) reported in both studies^1,2 suggests that testing for HBsAg status alone may be insufficient for the screening of HBV infection in endemic areas. Patients who are HBsAg negative should also be screened for anti-HBc status.

Nonetheless, the high incidence of HBV reactivation in patients with resolved HBV receiving R-CHOP chemotherapy reported by Yeo et al¹ is somewhat alarming. On the basis of the prevalence rate of resolved HBV of 44% and reactivation rate of 24% reported by the authors, one would expect HBV reactivation in approximately one of every nine patients with newly diagnosed DLBCL. This is somewhat contrary to the experience of many oncologists with regard to HBV endemic areas. In addition, the authors attribute the high incidence of HBV reactivation to the incorporation of rituximab into CHOP chemotherapy. None of the patients treated with CHOP experienced reactivation of HBV, whereas five patients treated with R-CHOP experienced HBV reactivation. However, it should be noted that one of these patients had equivocal HBsAg status at start of chemotherapy.

This high rate of reactivation does not reflect our experience.² Of the 80 patients with resolved HBV in our study, 46 were treated with full-course R-CHOP chemotherapy, and only one (2.17%) experienced reactivation. This patient also had DLBCL and experienced reactivation 2 months after completion of R-CHOP chemotherapy. It is of note that our results were consistent with those of a recent study by Targhetta et al³ involving 1,087 patients with NHL. In that study, risk of HBV reactivation was only 1% (four of 394 patients) among all patients receiving chemotherapy. More importantly—and consistent with our findings—only two (2.7%) of 74 patients treated with immunochemotherapy developed HBV reactivation. Thus, although risk of HBV reactivation in patients with resolved HBV is real, it may not be as high as Yeo et al¹ suggest. Yeo et al studied 104 patients with DLBCL who were treated at a single institute over a 4-year period, but it is uncertain whether these patients represented consecutive patients seen at the institute. It is also uncertain whether the high incidence of HBV reactivation could have resulted from the inclusion of patients who had been referred to the institute on development of HBV reactivation.

The standard criterion for HBV reactivation in the report by Yeo et al¹ was defined as detectable HBV DNA with ALT elevation during and for 6 months after anticancer therapy. In a previous report by Yeo et al,⁴ hepatitis attributable to HBV reactivation was defined as a 10-fold or more increase in HBV DNA levels compared with baseline levels or an absolute increase > 10⁵ copies/mL in the HBV DNA levels. Targhetta et al³ defined HBV reactivation as the re-emergence of HBsAg in HBsAg-negative/anti-HBc–positive patients (ie, reverse seroconversion).⁵ The heterogeneity in the criterion could have resulted in labeling of patients as having developed HBV reactivation, when a more appropriate term such as HBV exacerbation would have perhaps more adequately reflected the lesser degree of severity.

On the basis of the high risk of HBV reactivation reported in their study, Yeo et al¹ recommend prophylactic lamivudine as an alternative to close monitoring for HBV reactivation. Nonetheless, the routine use of prophylactic lamivudine remains to be evaluated in larger cohort studies. If prophylactic lamivudine were to be routinely administered as suggested, antiviral prophylaxis would have to be offered to almost half of all patients with DLBCL. In addition to increasing costs, such an approach could promote the development of resistant strains. Instead, it would be important to identify and verify potential risk factors—such as HBV DNA levels or absence of anti-HBs at diagnosis—that could predict for HBV reactivation, so selected high-risk patients could be identified for antiviral prophylaxis. Of note—and consistent with the patients in the report by Yeo et al—our patient who experienced HBV reactivation did not have anti-HBs at diagnosis. Furthermore, whereas all patients who experienced reactivation in the study by Yeo et al were men, our patient was an elderly woman.

In the report by Yeo et al,¹ three of the patients with resolved HBV developed HBV reactivation after completion of chemotherapy, with a median interval of 98 days (range, 78 to 110 days). Similarly, our patient experienced HBV reactivation 2 months after completion of R-CHOP chemotherapy. This observation is of particular importance in the context of maintenance rituximab, which is being increasingly incorporated into management of patients with low grade B-cell NHL, including follicular lymphoma. Conceivably, patients with resolved HBV receiving maintenance rituximab over a 2-year period could be at continuous risk of HBV reactivation. Therefore, it will be important to ascertain the actual risk of HBV reactivation in such patients receiving maintenance rituximab. Balancing the goal of prolonged disease control, risk of HBV reactivation, and the disadvantages of prolonged antiviral prophylaxis will be a challenge in this group of patients.

In conclusion, the optimal approach to management of patients with resolved HBV receiving immunochemotherapy remains to be elucidated. Routine prophylaxis for all patients with resolved HBV should be used with discretion.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Yeo W, Chan TC, Leung NW, et al: Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 27:605–611, 2009.[Abstract/Free Full Text]

2. Koo YX, Tan SW, Tan BH, et al: Risk of hepatitis B virus (HBV) reactivation and role of anti-viral prophylaxis in lymphoma patients with past HBV infection (HBV antigen negative but anti-hepatitis B core antibody positive) receiving chemo-immunotherapy. Blood 112: 2008 abstr 3768.

3. Targhetta C, Cabras MG, Mamusa AM, et al: Hepatitis B virus-related liver disease in isolated anti-hepatitis B-core positive lymphoma patients receiving chemo- or chemo-immunetherapy. Haematologica 93:951–952, 2008.[Free Full Text]

4. Yeo W, Chan PK, Ho WM, et al: Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy. J Clin Oncol 22:927–934, 2004.[Abstract/Free Full Text]

5. Marzano A, Angelucci E, Andreone P, et al: Prophylaxis and treatment of hepatitis B in immunocompromised patients. Digest Liver Dis 39:397–408, 2007.[CrossRef]

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