Hepatitis B virus reactivation in patients undergoing cytotoxic chemotherapy for solid tumours: Precore/core mutations may play an important role

Abstract

Reactivation of the hepatitis B virus (HBV) is a rare, but well described complication of cytotoxic chemotherapy that may result in hepatic failure. Patients who are chronic carriers of the HBV and who have a G to A mutation at nucleotide 1896 in the precore region may develop more severe liver disease, possibly because of rapid selection and enhanced replication ability of the mutant strain. Such mutant viruses have been implicated occasionally in chemotherapy induced reactivation of hepatitis B virus. In this report, 5 patients with solid tumours were identified to have developed severe hepatitis B virus related liver disease during treatment with cytotoxic agents (with dexamethasone as anti-emetic). All had clinical and serological evidence of reactivation of the HBV. Three patients developed icteric hepatitis; 2 fully recovered, and 1 had died from progressive metastatic disease while recovering from the reactivation. The other two died from progressive liver failure. Direct sequencing of the polymerase chain reaction (PCR) products of the precore (preC) and precore promoter region of the HBV-DNA was carried out on the patients' serum samples taken during the episode of reactivation. In each case, similar mutations (G to A) in nucleotide 1896 of the preC region were found, together with additional mutations in the preC promoter. The present findings suggest that reactivation involving a mutant hepatitis B virus may lead to liver failure, which is possibly more severe than that caused by wild type HBV, and can be triggered by cytotoxic chemotherapy, or the administration of corticosteroids. In Eastern Asia the HBV carriage rate in adults is high. HBV reactivation and severe liver disease during cytotoxic treatment may become a serious and common problem in this region as cytotoxic chemotherapy is more widely used. Patients should be screened routinely for HBsAg in endemic areas of chronic hepatitis B virus infection prior to receiving cytotoxic treatment. The possibility of HBV reactivation should be considered in patients developing liver dysfunction. Patients who are HBeAg negative/Anti-HBe positive, and are suspected to be having an HBV reactivation, should have HBV-DNA levels measured for confirmation as they may carry a mutant HBV.

Comprehensive analysis of risk factors associating with Hepatitis B virus (HBV) reactivation in cancer patients undergoing cytotoxic chemotherapy

“…Although HBeAg positivity in immunocompromised cancer patients appears to be a risk factor for HBV reactivation (Liang et al, 1990;Yeo et al, 2000b), this has not been found to be universally the case (Lok et al, 1991;Nokamura et al, 1996), and an increased risk may be partly attributed to the presence of the precore/core promoter HBV mutant (i.e. HBeAg negative/anti-HBe positive), which had been associated with severe fulminant hepatitis (Omata et al, 1991;Ehata et al, 1993;Liang et al, 1994;Nokamura et al, 1996;Steinberg et al, 2000;Yeo et al, 2000a, b). In addition, consistent with other reports, the baseline (pretreatment) liver function including ALT, total bilirubin and albumin levels did not appear to be associated with the development of HBV reactivation.…”

Traditional Chinese medicine syndromes of chronic hepatitis B with precore mutant

“…It has been found that the patients with HBV precore mutation are subjected to develop not only severe hepatitis but also HCC [3,[24][25][26] . Therefore when doctors treat these patients, they should pay attention to more questions.…”

Hepatitis B reactivation after chemotherapy: two decades of clinical research

“…Almost all these patients had intense marrow suppression with a drastic reduction of white cell count, and the rebound of the white cell with immune recovery correlates with the initiation of liver damages [56]. Severe hepatitis due to HBV reactivation has also been reported in HBV-infected patients treated with chemotherapy for other malignancies such as breast cancer [10][11][12], hepatocellular carcinoma [18,57,58], small-cell lung cancer [59], and nasopharyngeal cancer [60]. The relative lack of report in other type of malignancy is probably related to their lower incidence in HBV endemic area, such as the Asia-Pacific region.…”

“…However, HBsAg-positive patients could suffer from reactivation even if they remain HBeAg negative. Sequence analysis of the HBV isolated from these patients had demonstrated the presence of point mutation in the precore region that inhibited the synthesis of HBeAg [59,[72][73][74]. Therefore, it would be more reliable to demonstrate the presence of HBV reactivation by showing an increase of serum HBV DNA by quantitation.…”