Strategy for preventing hepatitis B reactivation in patients with resolved hepatitis B virus infection after rituximab-containing chemotherapy
Authors: Shigeru Kusumoto, Yasuhito Tanaka, Masashi Mizokami, Ryuzo Ueda
Journal: Hepatology (2013)

In a recent article in Hepatology, Hsu et al.1 reported on a prospective study (NCT00931299) to determine the incidence of hepatitis B virus (HBV) reactivation in 150 patients with resolved HBV infection receiving rituximab/CHOP chemotherapy. The researchers indicated that HBV reactivation is not uncommon and can be managed with regular monitoring of HBV DNA in serum. However, there are some concerns regarding the management of HBV DNA monitoring as described in this report. First, Hsu et al.1 reported that no HBV-related death occurred during the study period, but that HBV-related severe hepatitis and chemotherapy delay occurred in 7 (4.6%) and 2 (1.3%) patients, respectively. Furthermore, patients with HBV reactivation may have a poorer prognosis than those without reactivation, suggesting that HBV DNA monitoring could not enable successful management of HBV reactivation in this setting. In fact, the researchers have already described the usefulness of a more-sensitive HBV DNA assay and they should show whether a second polymerase chain reaction assay (detection limit: 300 copies/mL, assay #2) could prevent severe hepatitis flare resulting from HBV reactivation by estimating, in their retrospective analysis, the exact time between early HBV DNA detection and onset of hepatitis. Second, Hsu et al.1 concluded that reappearance of hepatitis B surface antigen (HBsAg) was the most important predictor of HBV-related hepatitis flare, but there is no information regarding the sensitivity and specificity of the HBsAg assay and these might influence clinical outcome. The researchers should provide information regarding the HBsAg assay in the Methods section and specify the time between the reappearance of HBsAg and onset of HBV-related hepatitis. In addition, they should specify the incidence of reappearance of HBsAg with persistence for more than 6 months in patients with HBV reactivation, because the chronic HBV carrier state might negatively influence long-term outcomes, regardless of fulminant hepatitis and HBV-related death. Third, Hsu et al.1 discussed the importance of host factors associated with HBV reactivation, but several articles have reported that the development of fulminant hepatitis was associated with viral factors, which especially included high levels of replication associated with mutations in the precore region.2, 3 The researchers should specify whether the kinetics of HBV DNA and severe hepatitis were associated with precore and/or basal core promoter mutations in the patients with HBV reactivation, because general readers need to be aware of such important viral factors to perform safe monitoring of HBV DNA. Preemptive antiviral therapy guided by regular monitoring of HBV DNA is a reasonable strategy to prevent HBV reactivation in patients with resolved HBV infection,1, 4, 5 but a standard management according to the risk of HBV reactivation has not been established as yet. We hope that the additional information can help readers regarding the optimal interval and sensitivity of the HBV DNA monitoring assay. In addition, if the reappearance of HBsAg and viral mutations related to viral replication are good predictive markers for severe hepatitis resulting from HBV reactivation, we can recommend that antiviral treatment should be started immediately for those patients with HBV reactivation. Shigeru Kusumoto, M.D., Ph.D.1 Yasuhito Tanaka, M.D., Ph.D.2 Masashi Mizokami, M.D., Ph.D.3 Ryuzo Ueda, M.D., Ph.D.4 1Department of Medical Oncology and Immunology Nagoya City University Graduate School of Medical Sciences Nagoya, Japan 2Department of Virology and Liver Unit Nagoya City University Graduate School of Medical Sciences Nagoya, Japan 3The Research Center for Hepatitis and Immunology National Center for Global Health and Medicine Ichikawa, Japan 4Department of Tumor Immunology Aichi Medical University School of Medicine Aichi, Japan