Reply
Authors: Chiun Hsu, Pei-Jer Chen, Ann-Lii Cheng
Journal: Hepatology (2013)

We thank Dr. Kusumoto and his colleagues for their comments on our study.1 Management of chemotherapy-induced hepatitis B virus (HBV) reactivation in lymphoma patients with resolved HBV infection is a challenging issue in endemic areas because 50%-60% of the general population in those areas have resolved HBV infection, and the clinical courses of HBV reactivation in this patient population vary greatly. Dr. Kusumoto pointed out several important points that warrant further investigation. With increasing sensitivity of the HBV DNA tests, chemotherapy-induced HBV reactivation can be detected in about 20% of lymphoma patients who receive rituximab/CHOP chemotherapy and can be detected earlier (median, 11.8 weeks earlier than the less-sensitive assay).1, 2 However, in our study, most of the additional HBV reactivations detected by the more-sensitive assay were asymptomatic. Only 1 patient had a hepatitis flare, which resolved spontaneously. It is difficult to analyze whether earlier use of antiviral therapy by a more-sensitive assay can further reduce the number of HBV-related hepatitis flares, given the small number of patients. Therefore, the clinical benefit of HBV reactivation detected by the more-sensitive assay for pre-emptive antivirals remains to be established. Reappearance of hepatitis B surface antigen (HBsAg), which can be measured conveniently in the clinic by chemiluminescent immunoassay, such as the Abbott Architect assay (Abbott Laboratories, Abbott Park, IL), was found, in our study, to be significantly associated with HBV-related hepatitis flares. The sensitivity of HBsAg tests currently used in the clinic can be as low as 0.05 IU/mL. Most of the patients were found to be HBsAg+ at the time of hepatitis flare. Therefore an assay for HBsAg during the chemotherapy course is strongly advocated, in addition to HBV DNA. Whether HBsAg assay is useful, and more cost-effective for managing HBV reactivations in lymphoma patients, warrants a prospective study. Finally, we agree with Dr. Kusumoto that persistence of HBsAg positivity for more than 6 months may negatively influence long-term outcome, and long-term follow-up of patients with reappearance of HBsAg is ongoing. Dr. Kusumoto pointed out the potential importance of viral factors, including the HBV replication levels and the presence of precore/basal core promoter mutations, in the development of severe hepatitis flare. Because the majority of the patients did not have detectable HBV DNA at baseline, we could not study the viral factors before therapy. For those patients with HBV reactivations, we are currently characterizing the viral genotypes and variants. However, because the patient number is still limited, studies of larger sample size and more-comprehensive evaluation of the viral and host factors that may contribute to HBV reactivation are definitely needed. Dr. Huang and his colleagues recently reported on a randomized trial of prophylactic antiviral therapy in lymphoma patients with resolved HBV infection.2 Although the short-term efficacy in preventing HBV viral reactivation was clearly demonstrated, future studies are warranted to evaluate the optimal duration of antiviral therapy, the high-risk patient population for whom prophylactic antiviral therapy is most indicated, and the effect of prophylactic antiviral therapy on long-term outcome. In the endemic area, the management strategies have to take additional factors, especially cost-effectiveness, into account. Chiun Hsu, M.D., Ph.D.1,4 Pei-Jer Chen, M.D., Ph.D.2,3 Ann-Lii Cheng, M.D., Ph.D.1,4 Departments of 1Oncology, Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan2Internal Medicine National Taiwan University Hospital Taipei, Taiwan 3Hepatitis Research Center, National Taiwan University College of Medicine, Taipei, Taiwan 4Graduate Institute of Oncology National Taiwan University College of Medicine Taipei, Taiwan