Clinical trial NCT00926757: Prophylactic Use of Entecavir for Non-Hodgkin's Lymphoma Patients With Resolved Hepatitis B
Official title: Prophylactic Use of Entecavir for Chemotherapy Associated With Hepatitis B Reactivation in HBsAg (-), Anti-HBc (+) Non-Hodgkin's Lymphoma Patients: a Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Non Hodgkin's Lymphoma
Hepatitis B
Keywords: lymphoma
CD20
Hepatitis B virus
reactivation
Rituximab
Lead sponsor: Taipei Veterans General Hospital, Taiwan
Sponsor class: OTHER_GOV
Collaborators: name: Bristol-Myers Squibb
First posted: 2009-06-24
Enrollment: 80
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

Detailed description: 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. In the prophylactic use group, participants will initiate entecavir 0.5 mg/day orally on day 1 of the first course of chemotherapy. Entecavir treatment will be continued until 3 months after the completion of chemotherapy and achieving the remission of the hepatitis (ALT normalization and undetectable HBV DNA). In the therapeutic use group, patients will start entecavir therapy, 0.5 mg/day orally, only when elevation of ALT (\>100 U/L) and HBV DNA (\>2000 IU/ml) developed during follow-up, or in the situation of HBsAg reverse seroconversion, and continued entecavir treatment until hepatitis resolved. The primary endpoint is the incidence of HBV reactivation during and within 12 months after completing chemotherapy in diffuse large B cell or follicular lymphoma patients who receive R-CHOP regimen. The secondary endpoint is the incidence of HBsAg reverse seroconversion during and within 12 months after completing chemotherapy.

Eligibility criteria: 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

Primary outcomes:
measure: The primary endpoint is the incidence of HBV reactivation during and within 12 months after chemotherapy
timeFrame: Monthly, and till 12 months after chemotherapy
Secondary outcomes:
measure: The incidence of HBsAg reverse seroconversion during and within 12 months after completing chemotherapy.
timeFrame: monthly, till 12 months after chemotherapy
Other outcomes:
Locations:
city: Taipei
country: Taiwan
facility: Taipei Veterans General Hospital-Division of Gastroenterology, Division of Oncology
Study officials:
affiliation: Taipei Veterans General Hospital, Taiwan
name: Yi-Hsiang Huang, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang YH, Hsiao LT, Hong YC, Chiou TJ, Yu YB, Gau JP, Liu CY, Yang MH, Tzeng CH, Lee PC, Lin HC, Lee SD. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013 Aug 1;31(22):2765-72. doi: 10.1200/JCO.2012.48.5938. Epub 2013 Jun 17.