Reply to S. Kusumoto et al

Abstract

We appreciate the comments raised in the correspondence from Kusumoto et al regarding our recently published article. Recently, Kusumoto et al reported that hepatitis B virus (HBV) reactivation can occur in hepatitis B surface antigen–negative patients with a history of HBV infection on administration of rituximab combination chemotherapy (R-chemotherapy) for B-cell lymphoma. Therefore, among patients who receive R-chemotherapy, those who are negative for the hepatitis B surface antigen should be additionally tested for antibodies to the hepatitis B surface antigen and hepatitis B core antigen. We believe that it is best to measure the HBV-DNA level in all patients with B-cell lymphoma who are scheduled to receive R-chemotherapy. However, HBV-DNA testing is not covered by the National Health Care Insurance program in Japan. Because of the expense of this testing, HBV-DNA is not measured until the antibodies to the hepatitis B surface antigen decrease to a level of less than 200 mU/mL. In our study, HBV-DNA was measured in all patients with B-cell lymphoma before the start of chemotherapy. We believe that measurement of HBV-DNA before treatment can result in detection of an escape mutant. In a report by Westhoff et al, HBV-DNA was measured 15 months before the start of chemotherapy in a patient with lymphoma, and an HBV-DNA level of 1.7 log copies/mL (50 copies/mL) was detected. Therefore, it seems that escape mutants can be detected by measuring HBV-DNA just prior to administration of R-chemotherapy. With respect to the method of measurement of HBV-DNA: in the prospective HBV-DNA monitoring performed in our study, HBV-DNA was measured in plasma and serum samples at Saitama Medical University. Between October 2006 and January 2008, HBVDNA was measured with a real-time polymerase chain reaction (PCR) assay using the LightCycler DNA Master SYBR Green I kit (Roche Diagnostics Japan, Tokyo, Japan), which has a detection limit of 1.7 log copies/mL. Between February 2008 and July 2009, HBV-DNA was measured with the COBAS TaqMan HBV Test, version 1.0 (Roche Diagnostics Japan), and since July 2009, HBV-DNA has been measured with COBAS TaqMan HBV Test, version 2.0 (Roche Diagnostics Japan). The cutoff values of the TaqMan version 1.0 and version 2.0 PCR assays were set at 1.8 log copies/mL and 2.1 log copies/mL, respectively. Both version 1.0 and version 2.0 TaqMan PCR assays have a detection limit of 1.7 log copies/mL. In our study, the median follow-up period for the 314 patients with diffuse large B-cell lymphoma was 26 months. Two patients were observed for less than 2 years. One patient could not be observed because of relocation, and another patient died after 24 months of treatment. It is necessary to investigate how long HBV-DNA monitoring should be performed after the end of R-chemotherapy, and to investigate the ideal timing for the start of entecavir administration after serum HBV-DNA becomes detectable. For these reasons, we believe that a future multicenter prospective study is necessary.