Hepatitis B virus (HBV) reactivation is a well-recognized complication associated with cytotoxic therapy.1 Despite its clinical importance, data on the risk factors for HBV reactivation after chemotherapy are limited.2 As the hepatitis is preceded by enhanced HBV viral replication3 and intrahepatic covalently closed circular DNA (cccDNA) is a key intermediate in the replication of the virus,4 we investigated the association of intrahepatic HBV cccDNA and HBV-related hepatitis after chemotherapy.
Thirty-five hepatitis B surface antigen (HBsAg)–positive lymphoma patients treated at the Department of Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region (SAR), between January 2000 and March 2003 were included into this prospective study if they fulfilled the following criteria: (1) had nucleoside analogs or were chemotherapy naive; (2) were treated with intensive chemotherapy regimen; and (3) had no evidence of liver cirrhosis histologically. Thirteen patients were excluded due to previous chemotherapy (n = 12) and pre-existing liver cirrhosis (n = 1). Of the 22 patients included in the study, 15 patients had participated in a previous study.2
Serum alanine transaminase (ALT) and serological testing for hepatitis B e antigen (HBeAg), hepatitis B e antibody, and serum HBV DNA by Digene Hybrid Capture II assay (Digene Diagnostics, Beltsville, MD) were performed at the initiation of chemotherapy and then prospectively every 2 weeks until the end of chemotherapy. A percutaneous liver biopsy was performed on all patients 2 weeks before chemotherapy and the level of intrahepatic viral cccDNA was quantitated using selective HBV cccDNA primers by real-time polymerase chain reaction (PCR).5 HBV reactivation induced by chemotherapy was defined according to previously published criteria.6
Statistical analyses were performed using the SAS Release 8.02 system (SAS, Cary, NC). Independent factors in Table 1 were individually examined in relationship to hepatitis due to HBV reactivation in simple Cox proportional hazards regression analysis. Important determinants among these factors were also explored by a Cox proportional hazards regression model together with a forward stepwise variable selection procedure. P values less than .05 were considered to be significant throughout this study. The optimal cut-off value of intrahepatic cccDNA was determined by maximizing the Youden index, defined as sensitivity + specificity - 1.
Nine (40.9%) patients suffered from HBV reactivation during chemotherapy and were treated with 100 mg lamivudine daily with complete resolution of the liver disease. The baseline demographic data of patients with and without HBV reactivation are shown in Table 1. Only intrahepatic viral cccDNA was associated with HBV reactivation in both simple and multiple analyses (Table 1). Using receiver-operating characteristics, the overall accuracy of using viral cccDNA to predict HBV reactivation was 88.9% (95% confidence interval [CI] = 73.2%-100.0%); the optimal cutoff value being 2.1 copies per cell with the sensitivity, specificity, positive predictive value, and negative predictive value of 77.8% (95% CI = 40.0%-97.2%), 100% (95% CI = 75.3%-100%), 100% (95% CI = 59.0%-100%), and 86.7% (95% CI = 59.5%-98.3%), respectively. Our result suggests that a high intrahepatic viral cccDNA level is predictive of HBV reactivation in HbsAg-positive patients treated with chemotherapy. Therefore, quantifying intrahepatic cccDNA will help to identify patients at a high risk for HBV reactivation after chemotherapy so that they could be treated with preemptive anti-HBV therapy.
