Infections

Digestive System Diseases

All Conditions

Symptoms and General Pathology

Hepatitis A

Hepatitis

Hepatitis B

Liver Diseases

Gastrointestinal Diseases

Communicable Diseases

Blood-Borne Infections

Hepadnaviridae Infections

Virus Diseases

DNA Virus Infections

Hepatitis, Viral, Human

Anti-Infective Agents

All Drugs and Chemicals

Tenofovir

Antiviral Agents

Reverse Transcriptase Inhibitors

Enzyme Inhibitors

Anti-HIV Agents

Anti-Retroviral Agents

Using TAF to prevent HBV reactivation for HBsAg-positive cancer patients

Tenofovir alafenamide 25 mg once per day for one year

Tenofovir alafenamide

Po-Yueh Chen, MD

Kuo-Chi Tseng, MD

Chi-Yi Chen, MD

Chu-Kuang Chou, MD

Li-Jen Chang, MD

Ching-Chu Lo, MD

Jyh-Jou Chen, MD

Yu-Jen Fang, MD

Tenofovir alafenamide (TAF) has been approved to prevent HBV reactivation for HBsAg-positive cancer patients receiving chemotherapy. However, the real-world effectiveness and safety of TAF for cancer patients was lacing. Therefore, we conduct a prospective single arm study to evaluate the efficacy and safety of TAF as a prophylactic antiviral agent for HBsAg-positive cancer patients receiving chemotherapy.

This prospective single arm study would be conducted in Taiwan. Patients who fulfill the inclusion criteria, will receive TAF before the initiation of systemic chemotherapy. Based on the guidance of NHI in Taiwan, prophylactic anti-viral agent should be prescribed within 7 days before chemotherapy and would be discontinued at 6 months after cessation of chemotherapy. The duration of TAF prophylaxis would be followed the guidance of NHI in Taiwan, however, the end of our observation would be at week 48 after TAF use. Patients will receive regular follow up at week 4, 12, 24, 36 and 48 (for T-bil, AST, ALT, creatinine, HBsAg, HBV DNA) till 1 year and the outcome will be collected. Platelet and HBcrAg would be examined at enrollment, 24 weeks and 48 weeks. HBeAg and anti-HBeAg will be examined at enrollment and 48 weeks.

TAF to Prevent HBV Reactivation in Cancer Patients

The Efficacy and Safety of TAF as a Prophylactic Antiviral Agent for HBsAg-positive Cancer Patients Receiving Chemotherapy

Definition of HBV reactivation :

1. HBV DNA increase 2 log (100-fold) compared to the baseline level
2. HBV DNA 3 log (1,000) IU/mL in a patient with previously undetectable level
3. HBV DNA 4 log (10,000) IU/mL if the baseline level is not available

record the dynamic change of eGFR from baseline to 48 weeks after TAF

St. Martin De Porress Hospital

Dalin Tzu Chi General Hospital

National Taiwan University Hospital, Yun-Lin Branch

Chi Mei Medical Hospital

Chiayi Christian Hospital

Musculoskeletal Diseases

Skin and Connective Tissue Diseases

Immune System Diseases

Rare Diseases

Necrosis

Arthritis

Arthritis, Rheumatoid

Enterovirus Infections

Picornaviridae Infections

RNA Virus Infections

Joint Diseases

Rheumatic Diseases

Collagen Diseases

Connective Tissue Diseases

Autoimmune Diseases

Herpes Simiae (B Virus)

Tin Fluorides

Entecavir

Participants will initiate entecavir 0.5 mg/day orally one week before biologic treatment. Entecavir treatment will be continued normally for 12 months (6 months after stopping biologic therapy or till restart another course of biologic treatment if the clinicians' judgment is minimal risk of reactivation after the first course of biologic agent treatment).

Patients will start entecavir therapy, 0.5 mg/day orally, when reactivation of HBV (defined as detectable HBV viral loads for 2 consecutive visits with at least one month apart), and continued entecavir treatment until undetectable HBV viral loads for 1 year (consistent with current APASL recommendation).

In the prophylactic group, participants will initiate entecavir 0.5 mg/day orally one week before biologic treatment. Entecavir treatment (adjust dosage according to renal function) will be continued normally for 12 months (6 months after stopping biologic therapy or till restart another course of biologic treatment if the clinicians' judgment is minimal risk of reactivation after the first course of biologic agent treatment).

Yi-Hsiang Huang, MD, Ph.D.

Antiviral prophylaxis can prevent the risk of biologic agents-associated HBV reactivation in hepatitis B inactive carriers and patients with past HBV infection

The risk of HBV reactivation is associated with the intensity of immunosuppression. Biological therapies block the action of biological products involved in immune-inflammatory pathogenesis of many diseases. However, these biologic agents induce a profound immunosuppression, and their use has been reported to be associated with HBV reactivation. Currently, the actual incidence of HBV reactivation in inflammatory arthritis patients who underwent biologic treatments (TNF-α blockades) is unclear, especially in inflammatory arthritis (IA) patients with past hepatitis B infection. In this study, we plan to enroll IA patients who are inactive HBV carriers (HBsAg-positive/ HBV viral loads \<2000 IU/ml; subgroup 1), or have past HBV infection (HBsAg-negative/anti-HBc-positive/ HBV viral loads \< 2000 IU/ml; subgroup 2); and first line biologic treatment (Humira or Enbrel or Simponi or Orencia or Mabthera or Actemra) is indicated. Patients will be randomized in a 1:1 ratio to receive either prophylactic or therapeutic entecavir treatment for each subgroup. In the prophylactic group, participants will initiate entecavir 0.5 mg/day orally one week before biologic treatment. Entecavir treatment will be continued normally for 12 months. In the therapeutic group, patients will start entecavir therapy, 0.5 mg/day orally, when reactivation of HBV (pre-emptive treatment). HBV reactivation is defined as HBV viral loads \> 2,000 IU/ml for 2 consecutive visits of one month apart. The main goal of the study is to delineate the incidence of HBV reactivation during and after biologic treatment in IA patients who are inactive HBV carriers or have past HBV infection, and tries to define the optimal HBV monitoring and antiviral prophylactic strategy in IA patients.

Entecavir for Biological Agents Associated HBV Reactivation in Inflammatory Arthritis Patients

Propylactic Use of Entecavir for Biological Agents Associated Hepatitis B Virus Reactivation in Inflammatory Arthritis Patients: a Randomized Controlled Trial

The main goal of the study is to delineate the incidence of HBV reactivation during and after biologic treatment in IA patients who are inactive HBV carriers or have past HBV infection, and tries to define the optimal HBV monitoring and antiviral prophylactic strategy in IA patients.

Taipei Veterans General Hospital, Taiwan

Professor: Yi-Hsiang Huang

Neoplasms

Blood and Lymph Conditions

Lymphoma

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

Lamivudine

Ye Guo, MD

The aim of this study is to prove the superiority of entecavir over lamivudine for preventing the risk of hepatitis B virus reactivation in patients with non-Hodgkin lymphoma on CHOP/R-CHOP.

In china, previous studies showed patients with non-Hodgkin lymphoma (NHL) are likely to have hepatitis B virus (HBV) infection. The risk of HBV reactivation is high when patients were treated with CHOP, especially in combination with rituximab. The aim of this study is to compare entecavir with lamivudine, 2 commonly used anti-virus agents, for preventing the risk of HBV reactivation in patients with NHL on CHOP/R-CHOP.

Entecavir Versus Lamivudine for Preventing the Risk of Hepatitis B Reactivation in NHL

Entecavir Versus Lamivudine for Preventing the Risk of Hepatitis B Virus Reactivation in Patients With Non-Hodgkin Lymphoma on CHOP/R-CHOP: a Randomized Phase II Study

Defined by increased level of alanine transaminase

Measured by information of treatment delay

Measured by information of HBV DNA level normalization

Fudan University

Antineoplastic Agents

Antirheumatic Agents

Anti-Inflammatory Agents

Antiemetics

Neuroprotective Agents

Gastrointestinal Agents

Cyclophosphamide

Doxorubicin

Liposomal doxorubicin

Rituximab

Vincristine

Prednisolone

Methylprednisolone

Methylprednisolone Acetate

Methylprednisolone Hemisuccinate

Prednisolone acetate

Prednisolone hemisuccinate

Prednisolone phosphate

All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines.

All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy. Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks.

entecavir

Tsang-Wu Liu, Ph.D

This is a single-arm study. Key eligibility criteria include (1) newly diagnosed, diffuse large B-cell or follicular cell non-Hodgkin's lymphoma; (2) negative test for hepatitis B surface antigen (HBsAg) and positive for antibody to hepatitis B core antigen (anti-HBc); (3) adequate bone marrow, liver, and kidney function. All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of hepatitis B virus (HBV) reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy. Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks. The secondary endpoints include the incidence of hepatitis flare, defined as a greater than 3 fold increase of serum alanine aminotransferase (ALT) level that exceeded 100 IU/L, and the efficacy and safety of rituximab-CHOP chemotherapy.

In the T1408 study we enrolled patients with newly diagnosed lymphoma who were HBsAg (-) and anti-HBc (+) and were to receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)-based chemotherapy. Key findings of this study included (1) HBV reactivation, defined as a greater than 10-fold increase in HBV DNA compared with previous nadir levels, occurred to 10-20% of patients, depending on the sensitivity of the HBV DNA tests; (2) no HBV-related death with the prompt anti-viral therapy upon HBV reactivation; (3) patients with HBV reactivation were associated with poorer progression-free survival and overall survival; (4) serological breakthrough (i.e., re-appearance of HBsAg) is an important predictor of HBV-related hepatitis flare.

In this amendment we will enroll more patients to clarify the above findings: (1) the association between HBV reactivation and survival; (2) diagnostic value of quantitative HBsAg and anti HBc tests on HBV reactivation; (3) whether host factors (DNA polymorphism) may help predict HBV reactivation. A larger patient cohort is needed to identify (1) baseline features that may help predict HBV reactivation, and (2) on-treatment features that may help timely anti-viral therapy.

Treatment plan:

A typical course of rituximab-CHOP chemotherapy is as follows:

rituximab 375 mg/m2 i.v., day 1, cyclophosphamide 750 mg/m2 i.v., day 1, doxorubicin 50 mg/m2 i.v., day 1, vincristine 1.4 mg/m2 (maximal 2 mg) i.v., day 1, prednisolone 40 mg/m2/day p.o., day 1 to day 5.

Typically the treatment will be repeated every 3 weeks. If the patients cannot recover from chemotherapy-induced toxicity at the schedule time of the next course of treatment, modification of chemotherapy dosage or delay of chemotherapy administration will be done according to local treatment standard and will be recorded.

The use of component therapy or granulocyte colony-stimulating factor will be at the discretion of individual investigator.

Auxiliary medication, such as anti-emetics, will be given according to local treatment guidelines.

Statistical consideration:

1. Database Management Procedures

   Standard module for description of standard operation procedures for data processing to ensure quality and validity of the data.
2. Presentation of Efficacy and safety Endpoints

   2.1. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA, during rituximab-CHOP chemotherapy and within 1 year after the last course of rituximab-CHOP chemotherapy.

   2.2. Secondary endpoints: Incidence of hepatitis , defined as a greater than 3 fold increase of serum ALT level that exceeded 100 IU/L.

   Incidence of severe hepatitis, defined as a hepatitis flare with an increase of ALT to more than 10 fold of ULN or bilirubin to more than 1.5 fold of ULN.

   Association between HBV reactivation and serological breakthrough (i.e., re-appearance of HBsAg) during follow-up Association between HBV reactivation and levels of anti-HBc antibodies during follow-up Association between HBV reactivation and HLA germline polymorphism (HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1) / IL28B genotype of the patients Progression-free survival and overall survival for patients who receive rituximab-CHOP chemotherapy.
3. Hypotheses and Sample Size Determination

   It is estimated that in Taiwan the incidence of 'resolved' HBV infection in the general population is about 50%. A recent survey of HbsAg(-)blood donors indicated that 7% of the donors had detectable HBV DNA in serum. The incidence of diffuse large B-cell non-Hodgkin's lymphoma in Taiwan is 700-800 new patients/year (Taiwan Cancer Registry, http://crs.cph.ntu.edu.tw). We plan to enroll 150 patients in three years (50 new patients every year).
4. General Statistical considerations

   4.1 Randomization and stratification

   This is a single-arm study. No randomization will be done.

   4.2 Analysis population

   This study will enroll NHL patients with evidence of 'resolved' HBV infection. Eligible subjects must be negative for serum HBV surface antigen (HBsAg) and positive for at least one of the following in the serum: anti-core antigen (anti-HBc), anti-surface antigen (anti-HBs), or HBV DNA. Patients who receive at least 1 dose of rituximab-CHOP chemotherapy will be enrolled in to the intent-to-treat population and safety population. Patients who complete at least 1 course of rituximab-CHOP chemotherapy will be enrolled into the per-protocol analysis. The primary and secondary endpoints described in Section 2.1, 2.2, and 2.3 will be included in the per-protocol analysis.

   4.3 Dropout

   Taking into account 10% dropout rate, we need to enter 62 patients per year to the trial so that we may finish accrual of patients within 3 years.

   4.4 Baseline

   Before the first course of rituximab-CHOP chemotherapy, the baseline characteristics for each patient will be measured.

   4.5 Multicenter study

   This study will be conducted by all participating medical centers to the Lymphoma Disease Committee (14 centers in total). Since the rituximab-CHOP chemotherapy is the standard first-line treatment for patients with diffuse large B-cell NHL and follicular cell NHL, no center interaction on treatment is expected in this study.

   4.6 Adjustment for multiple testing

   Adjustment because of multiple testing is not needed in this study.

   4.7 Subgroup analysis

   Pre-specified subgroup analysis for the primary endpoint (HBV reactivation rate) will be done in the following sub-groups:
   1. baseline HBV DNA (+) vs. HBV DNA (-);
   2. baseline alanine transaminase (ALT) normal vs. abnormal.

   4.8 Patient Listings

   Individual patient listings should be also provided.
5. Interim analysis and data monitoring

   No interim analysis is planned for this study.
6. Final Analysis

For the final statistical analysis, this section should state the specific statistical procedures described in item 6 of this section in the analysis of every primary and secondary efficacy and safety endpoint.

Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients

Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients Who Receive Rituximab-containing Chemotherapy and Are Previously Infected With Hepatitis B Virus

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TAF to Prevent HBV Reactivation in Cancer Patients	NCT04619082	Hepatitis B Rea...	Tenofovir alafe...	20 Years -	Chiayi Christian Hospital
Entecavir for Biological Agents Associated HBV Reactivation in Inflammatory Arthritis Patients	NCT01907230	Rheumatoid Arth... Hepatitis B Rea... Exposure to Hep...	Entecavir	20 Years - 90 Years	Taipei Veterans General Hospital, Taiwan
Entecavir Versus Lamivudine for Preventing the Risk of Hepatitis B Reactivation in NHL	NCT01914744	Non-Hodgkin Lym... Hepatitis B Rea...	Entecavir Lamivudine	18 Years - 80 Years	Fudan University
Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients	NCT00931229	Non-Hodgkin's L...	entecavir	18 Years - 75 Years	National Health Research Institutes, Taiwan
Entecavir Versus Lamivudine for Preventing the Risk of Hepatitis B Reactivation in NHL	NCT01914744	Non-Hodgkin Lym... Hepatitis B Rea...	Entecavir Lamivudine	18 Years - 80 Years	Fudan University
Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients	NCT00931229	Non-Hodgkin's L...	entecavir	18 Years - 75 Years	National Health Research Institutes, Taiwan

Spots Global Cancer Trial Database for hepatitis b reactivation