Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations A. Alexopoulou, 1 M. Theodorou, 2 S. P. Dourakis, 1 P. Karayiannis, 3 E. Sagkana, 2 K. Papanikolopoulos 1 and A. J. Archimandritis 1 1 2nd Department of Medicine, University of Athens Medical School, Hippokration General Hospital, Athens, Greece; 2 Microbiology Department, West Attica Hospital, Athens, Greece; and 3 Department of Medicine, Imperial College, St Mary’s Campus, London, UK Received March 2005; accepted for publication July 2005 SUMMARY. Hepatitis B virus (HBV) strains carrying the precore stop-codon mutation (A1896) have been considered among the predisposing factors for reactivation during che- motherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV sero- logical markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cyto- toxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regi- mens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO-LiPA HBV Pre- Core kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)-(+)/hepatitis B e antigen (HBeAg)-()) before che- motherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg-())/anti-HBs-(+)/anti- hepatitis B core (HBc)-(+)/HBeAg-()) before chemotherapy. One of them reverted to HBeAg-(+) status but remained HBsAg-()), while the other became HBsAg-(+)/HBeAg-(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild-type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop-codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild-type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg-()) patients who had been anti-HBs-(+). Keywords: basic core promoter mutations, chemotherapy, HBV reactivation, precore stop-codon mutation. INTRODUCTION Hepatitis B virus (HBV) flares during or shortly after che- motherapy have been reported to occur in 14–53% of chronic hepatitis B surface antigen (HBsAg) carriers [1–3]. Acute hepatitis may be severe with mortality rates from acute liver failure ranging from 4% to 41% [1]. Factors favouring HBV reactivation during chemotherapy include use of corticosteroid (CS)-containing regimens and HBV strains carrying the precore stop-codon (A1896) mutation [4,5]. An association of precore stop-codon variants with severe liver disease has been described [6,7]. An escalated cytotoxic T-lymphocyte response induced by the absence of hepatitis B e antigen (HBeAg) – which is thought to be an immune tolerogen – may be responsible for the severity of liver disease in patients with acute HBV infection possessing the precore stop-codon variant [8] . The T1762/A1764 BCP mutations have also been associated with fulminant disease in acute HBV infection, which may also be the result of defective HBeAg secretion [9]. The role of these mutations as a predisposing factor for HBV reactivation after chemother- apy for malignancies has not yet been fully investigated. Finally, the occurrence of occult HBV infection is char- acterized by the detection of HBV-DNA by polymerase chain reaction (PCR) in the absence of HBsAg, and often than not, of serological markers of resolved HBV infection [10]. Abbreviations: BCP, basic core promoter; HBc, hepatitis B core; HBV, hepatitis B virus; HBsAg, hepatitis B surface antigen; HBeAg, hepatitis B e antigen. CLL, chronic lymphocytic leukaemia. Correspondence: Alexandra Alexopoulou, 20 N. Politis St, 16346 Athens, Greece. E-mail: alexopou@ath.forthnet.gr Journal of Viral Hepatitis, 2006, 13, 591–596 doi:10.1111/j.1365-2893.2006.00728.x Ó 2006 Blackwell Publishing Ltd