Efficacy of Lamivudine in Patients with Hematologic Malignancies Receiving Chemotherapy and Precore Mutant Chronic Active Hepatitis B

Reactivation of hepatitis B virus (HBV), a well-known complication in patients receiving cytotoxic treatment for non-Hodgkin’s lymphoma (NHL), may result in hepatitis, hepatic failure and death [1]. Typically, patients with chronic hepatitis B are hepatitis B e antigen (HbeAg)-positive and HBV DNA-positive in serum during the active disease and often exhibit sustained disease remission if they lose detectable HbeAg and develop antibody to HbeAg (HbeAb). However, a proportion of patients with circulating HbeAb without detectable HbeAg remain or become HBV DNA-positive. This discrepancy is most frequently explained with the occurrence of a mutation at nucleoside 1896 in the precore region of the HBV DNA genome (precore mutant) [2]. This mutation results in the generation of a stop codon that blocks HbeAg synthesis but still permits HBV replication and hepatitis B core antigen production [3]. It is estimated that more than 95% of patients with HbeAg-negative chronic hepatitis B in the Mediterranean area are infected with the 1896 precore mutant HBV [4]. Recently, the oral nucleoside analogue lamivudine (a reverse transcriptase inhibitor approved for HIV therapy) was reported to be effective in the management of HbeAg-negative/HBV DNA-positive chronic hepatitis by incorporation of its monophosphate form into DNA, which results in chain termination [5, 6]. Here, we report our experience with the use of this drug in 5 patients with various hematologic malignancies receiving chemotherapy and concurrent precore mutant chronic active HBV infection.From May 2000, 3 patients affected by NHL (high grade, centroblastic), 1 by IgA multiple myeloma and 1 by B-chronic lymphocytic leukemia were submitted to chemotherapy at our institution. All of them also suffered from chronic active hepatitis B (all data are reported in table 1).Four patients were male aged 70, 52, 54 and 56 years, respectively, and one was a 56-year-old female, all HCV- and HIV-negative. In all patients, pretreatment HBV serology was as follows: HbsAg-positive, anti-HBs-negative, HbeAg-negative, anti-Hbe-positive and anti-HBc IgG-positive. One of them (patient 1) was treated with the standard CHOP regimen, two (patients 2 and 3) with the combination CHOP plus anti-CD20 monoclonal antibody (rituximab), one patient (patient 4) with the standard VAD regimen for multiple myeloma, whereas the patient with the B-chronic lymphocytic leukemia (patient 5) was treated with a combination of mitoxantrone plus chlorambucil/prednisone.Before starting chemotherapy transaminases were increased and HBV DNA, detected using nested polymerase chain reaction, was positive in all patients. A liver biopsy was performed in all patients. The histological examination revealed an active hepatitis with predominantly lymphocytic portal infiltrates with piece meal necrosis, apoptotic hepatocytes and ground-glass hepatocytes.In all 5 patients, lamivudine 100 mg/day was started 1 week before initiation of chemotherapy and continued after the end of the last chemotherapy course. During the follow-up period, patients were monitored with monthly blood counts, transaminase levels and HBV DNA; all these parameters remained normal throughout the observation period.Liver injury and jaundice in patients receiving cancer chemotherapeutic agents are caused by drug hepatotoxicity, shock, sepsis, or viral hepatitis. Reactivation of HBV has frequently been observed during chemotherapy of HBV carriers with NHL [5]. A clinical picture resembling that of acute hepatitis and even fatal fulminant hepatitis has been reported in HbsAg chronic carriers undergoing either standard or high-dose chemotherapy [1]. Therefore, treatment for the prevention of hepatitis B reactivation is needed to protect HBV carriers against chemotherapy-induced hepatic failure. In contrast to the recently published cases concerning protective therapy after viral reactivation in HBV carriers during chemotherapy [5, 7], we report 5 patients with chronic active disease due to the precore HBV mutant.In our study, HBV sequencing to confirm genotypic precore mutations was not performed. However, based on the serological profile at screening, patients were presumed to be infected with precore mutant HBV. Data from previous studies in similar patient populations indicate that more than 95% of patients in the Mediterranean area are infected with the 1896 precore mutant variant [2, 4]. Laras et al. [4]found that 100% (31 of 31) of a group of HbeAg-negative patients from Greece harbored the 1896 precore mutation and 20 (64%) also had a G to A mutation at nucleotide 1899.Of the several proposed methods for completion of chemotherapy programs in such patients, the use of lamivudine seems the best available option at present [7]. Our study supports lamivudine as an important new therapeutic option for the management of patients with hematologic malignancies and chronic active hepatitis B who are HbeAg-negative and HBV DNA-positive (i.e., patients presumably infected with the precore mutant HBV). To our knowledge, no other studies of protective lamivudine therapy in patients with hematologic malignancies and precore mutant chronic active HBV infection have been reported so far. Compared to famciclovir, lamivudine at a daily dose of 100 mg has recently been shown to be superior in terms of HBV DNA reduction and response [8]. Furthermore, 1 year of treatment with lamivudine was associated with a substantial histological improvement in patients with chronic hepatitis [9]. However, there have been several reports of the development of lamivudine resistance due to mutations in the YMDD motif of the hepatitis B virus polymerase [10], especially with long-term treatment [11]. Therefore, in published cases of HBV carriers, antiviral treatment was stopped 4–6 months after completion of chemotherapy in order to prevent the development of lamivudine resistance [6]. In contrast to HBV carriers, the optimal duration of treatment in patients with chronic active HBV infection has not been established so far and relapses of hepatitis B have been observed after treatment cessation [12]. Consequently, in all 5 patients, we continued with the lamivudine treatment after completion of chemotherapy.In conclusion, we suggest that lamivudine should be considered for prophylaxis against HBV reactivation and administered from the beginning of chemotherapy in patients undergoing chemotherapy for hematologic malignancies and chronic active precore mutant HBV infection.