Prophylactic Use of Entecavir for Non-Hodgkin's Lymphoma Patients With Resolved Hepatitis B (HBVNHL)

Hepatitis B (HBV) reactivation and hepatitis flare induced by cytotoxic chemotherapy is common in cancer patients who have chronic HBV infection. Lymphoma patients who had previous infected by HBV but negative for HBsAg have a the risk of HBV reactivation during chemotherapy, but prophylactic antiviral treatment is not a routine by current American Association for the Study of Liver Diseases (AASLD) guideline. Prophylactic entecavir might reduce the risk of HBV reactivation in such patients.

Hepatitis B (HBV) reactivation and hepatitis flare induced by cytotoxic chemotherapy is common in cancer patients who have chronic HBV infection. It is best characterized in patients with hematological malignancies such as non-Hodgkin's lymphoma but also can occur in patients with solid tumors. Reactivation during the initiation of chemotherapy may cause delay in cancer treatment and decrease in overall survival. The direct mortality caused by HBV reactivation, predominantly acute liver failure, ranges from 4% to 60%. Based on currently available information, it is well documented that HBV carriers should receive antiviral agents to prevent hepatitis B flare before receiving immunosuppressive agents and chemotherapy. However, development of hepatitis, acute liver failure, and mortality can occur among patients who are HBsAg negative but anti-HBc positive at the time of chemotherapy. Therefore, before the initiation of cytotoxic chemotherapy in cases of non-Hodgkin's lymphoma, it is unknown whether patients previous infected by HBV but negative HBsAg should routinely receive antiviral agents for prevention of HBV flare. In addition, the major concern of long-term lamivudine use is the selection of drug-resistant mutations. Based on these, we designed this current study to address the above important issues. Eligible patients are newly diagnosed, histologically proven anti-CD20-positive non-Hodgkin's lymphoma at our hospital. Patients should be negative of HBsAg but positive of serum anti-HBc. After signing the patient consent form, serum samples will be stored for further genotyping and quantitative HBV DNA testing. Patients will be randomized into two groups to receive either prophylactic or therapeutic use of entecavir (0.5 mg/day) during the period of chemotherapy. The primary endpoint is the incidence of HBV reactivation during and within 12 months after chemotherapy. Hepatitis flare is defined as a greater than 3-fold increase of serum ALT level that exceeded 100 IU/L. The hepatitis flare will be attributed to HBV reactivation if it was preceded or accompanied by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA or by the reappearance of HBsAg in the serum. The secondary endpoints of this current study are the incidence of hepatitis, hepatic failure, and the objective response rate to chemotherapy.

• Non Hodgkin's Lymphoma
• Hepatitis B

• Drug: Entecavir prophylaxis
  Entecavir 0.5mg daily from day 1 of chemotherapy to 3 months after completing chemotherapy
  Other Name: Baraclude
• Drug: Therapeutic entecavir
  Entecavir 0.5cm daily since hepatitis flare and HBV reactivation, till hepatitis remission
  Other Name: Baraclude

• Experimental: Entecavir prophylaxis
  Participants will initiate entecavir 0.5 mg/day orally on day 1 of the first course of chemotherapy, and will be continued until 3 months after completion of the chemotherapy.
  Intervention: Drug: Entecavir prophylaxis
• Active Comparator: Therapeutic arm
  In patients with HBV reactivation and ALT flare > 100 U/L, entecavir 0.5mg daily will be prescribed for the cases till hepatitis remission
  Intervention: Drug: Therapeutic entecavir

Inclusion Criteria:

• CD20 positive lymphoma
• negative for HBsAg and positive for anti-HBc
• age over 16 years old
• alanine aminotransferase less than 2 times the upper limit of normal
• bilirubin < 2.5 mg/dL
• neutrophil > 2000/mm3
• platelet > 100,000/mm3
• creatinine < 1.5 mg/dL
• urea nitrogen < 25 mg/dL
• Eastern Cooperative Oncology Group performance score 0 to 2

Exclusion Criteria:

• Child-Pugh class B or C cirrhosis
• grade 2 or greater heart failure by the NYHA classification
• previous chemotherapy,radiotherapy, or concurrent glucocorticoid therapy for other reasons
• other primary liver diseases, such as chronic hepatitis C, hepatitis D, autoimmune hepatitis, or Wilsons' disease