Reactivation of precore mutant hepatitis B virus in chemotherapy-treated patients

Background: A point mutation from G to A at nucleotide (nt) 1896 of the precore region of hepatitis B virus (HBV) DNA has been shown to be associated with fulminant and severe hepatitis. Further studies have suggested that this point mutation, together with additional mutations in the precore promoter, is probably linked to the reactivation of HBV in patients undergoing cytotoxic chemotherapy. Taiwan is an area with a high prevalence of HBV where hepatitis B flare-up has become a serious problem of HBV carriers who must rely on chemotherapy to treat their diseases. The purpose of this study was to examine if nt 1896 mutation was also present in Chinese patients in Taiwan who developed severe liver disease after chemotherapy. MATERIALS AND METHODS. Thirteen HBV carrier patients, including eight patients with lymphoma, two with germ cell tumors, two with breast carcinomas, and one with acute myeloid leukemia, received chemotherapy in the authors' hospital from February 1994 to May 2000. They all received steroid-containing regimens or antiemetics during chemotherapy. These patients were monitored closely for the development of severe hepatitis during or after chemotherapy. Their sera were harvested at different times for direct sequencing of the polymerase chain reaction products of the precore region of HBV DNA.

Results: Six of the 13 patients developed severe hepatitis with a fulminant course during or after the completion of chemotherapy. A point mutation from G to A at nt 1896 was detected in five of these six patients. Among those five patients, four had additional precore mutations. The other patient did not have the nt 1896 mutation but had mutations at nt 1835 (A to C). None of the other seven patients lacking the precore nt 1896 mutation developed severe hepatitis flare-up. One of those seven patients who developed moderate elevation of alanine aminotransferase (ALT) without hyperbilirubinemia did have precore mutations other than nt 1896. None of the other six patients had mutations over the precore region.

Conclusions: Nucleotide mutation of the precore region, notably at position 1896, is associated with reactivation of HBV with a fulminant course during or after chemotherapy. The current data, together with other investigators' findings, suggest that patients who are HBV carriers with HBV envelope antigen (HBeAg) (-)/anti-HBV envelope antibody (Anti-HBe)(+) status should be assayed to determine if they carry mutant HBV before chemotherapy. Prophylactic use of lamivudine is strongly recommended for patients who carry mutant HBV at precore region, especially at nt 1896 (G to A), before and during chemotherapy.