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

Hepatitis B virus (HBV) infection, defined by the presence of HBV surface antigen (HBsAg), increases the risk of HBV reactivation and current guidelines recommend that patients who are HBV-infected should receive antiviral prophylaxis during and after chemotherapy. As HBV infection is endemic in Asia, a proportion of patients may have had past HBV infection unknowingly. These patients have cleared HBsAg and are HBsAg negative but anti-Hepatitis B core antibody (anti-HBc) positive. The risk of HBV reactivation in lymphoma patients with past HBV infection undergoing immunochemotherapy has not been previously studied. We accrued 430 consecutive patients from our prospectively maintained data-base and an ongoing prospective epidemiological study from May 2006 to May 2008. All patients were tested for HBsAg. Prior to May 2006, anti-HBc test was performed at the discretion of the treating physician. After May 2006, anti-HBc test was performed for all patients. Stored sera from consented patients were genotyped for HBV DNA. Hepatitis attributable to HBV reactivation was defined as an increase in HBV DNA levels of tenfold, or an absolute increase greater than 10⁵ copies/ml in the HBV DNA level. At presentation, characteristics of lymphomas and baseline liver function test in patients with HBV infection were similar to those with past HBV infection. Among the 430 patients tested for HBsAg, the prevalence of HBV infection is 7.2% (31/430). Overall, 233 patients had both tests performed and 80 (34%) were anti-HBc positive only. Among the 80 patients with past HBV infection, 67 patients received systemic treatment. Of these 67 patients, 58 had a HBV DNA test, which was positive in three (5.2%). 46 patients with past HBV infection were treated with rituximab immunochemotherapy. Of these 46 patients, one reactivated and died (1/46; 4.3%); this patient did not receive anti-viral prophylaxis and had undetectable HBV DNA at time of lymphoma diagnosis. Of the 26 patients with HBV infection receiving systemic treatment, 11 (42.3%) reactivated (p<0.0001). 90% of patients with HBV infection received antiviral prophylaxis compared to 10% with past HBV infection. Of note, all 4 patients with HBV infection with mutant HBV on genotyping reactivated despite prophylactic lamivudine usage. The incidence of past HBV infection (34%) is unexpectedly high and a small proportion (5.2%) had occult infection (detectable HBV DNA). These findings have further implications in terms of HBV screening in endemic regions. Our data is the first to suggest that although majority of patients with past infection do not reactivate, the risk is not negligible when rituximab is used (4%). Undetectable HBV DNA does not appear to preclude reactivation. This data is also provocative and suggests that anti-HBc should be routinely tested and those with past infection, with or without detectable HBV DNA, be monitored closely for reactivation. The optimal use of anti-viral prophylaxis, particularly if immunotherapy is given, should be further evaluated. This is particularly relevant in endemic regions where the incidence of past infection is likely to be high. Given the observation that all patients with mutant HBV reactivated despite lamivudine prophylaxis, the optimal anti-viral agents chosen should be further evaluated.