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Hepatitis A

Hepatitis

Hepatitis B

Liver Diseases

Gastrointestinal Diseases

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Hepatitis, Viral, Human

Anti-Infective Agents

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Tenofovir

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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

Rare Diseases

Disease Attributes

Enterovirus Infections

Picornaviridae Infections

RNA Virus Infections

Herpes Simiae (B Virus)

Entecavir

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 2\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for treatment of HBV may be utilized.

Best Practice

Tenofovir Alafenamide

Tenofovir Disoproxil Fumarate

Jessica P Hwang

This phase III trial studies the effect of hepatitis B antiviral (anti-HBV) therapy in preventing liver complications in patients with chronic or past hepatitis B virus (HBV) who are receiving anti-cancer therapy for solid tumors. People with chronic or past HBV who are undergoing therapy for cancer are at an increased risk for changes in the liver which could be minor or severe. Anti-HBV therapy acts against infections caused by HBV and may help reduce the chance that HBV gets worse or comes back in patients receiving anti-cancer therapy for solid tumors.

Co-Primary Objectives

1. To compare the effect of prophylactic anti-HBV therapy versus upon indication anti-HBV therapy on time-to-adverse liver outcomes of liver failure or liver-related death in patients with chronic HBV infection (HBsAg+ and anti-HBc+) receiving anti-cancer therapy for solid tumors.
2. To compare the effect of upon indication anti-HBV therapy versus usual care on time-to-adverse liver outcomes of liver failure or liver-related death in patients with past HBV infection (HBsAg- and anti-HBc+) receiving anti-cancer therapy for solid tumors.

Secondary Objectives

1. Using time-to-event analysis, to compare the effect of anti-HBV therapy versus upon indication anti-HBV therapy on HBV reactivation, on the combined endpoint of adverse liver outcomes (liver failure or liver-related death) and HBV reactivation, and on HBV flare by arm in patients with chronic HBV infection receiving anticancer therapy for solid tumors.
2. Using time-to-event analysis, to compare the effect of upon indication anti-HBV therapy versus usual care on HBV reactivation, on the combined endpoint of adverse liver outcomes (liver failure or liver-related death) and HBV reactivation, and on HBV flare by arm in patients with past HBV infection receiving anti-cancer therapy for solid tumors.

Translational Objectives

1. To compare baseline and changes in overall immune status and HBV-specific immune response in patients with solid tumors and chronic or past HBV infection receiving anti-cancer therapy, and to compare the differences in these immune responses by HBV reactivation status.
2. To identify demographic and clinical predictors and correlative immunologic biomarkers of HBV reactivation after receipt of anti-cancer therapy in patients with solid tumors and chronic or past HBV infection.

OUTLINE: Patients are recruited in two cohorts (Cohort 1: chronic HBV infection, Cohort 2: past HBV infection), with each cohort randomized equally to one of two potential treatment arms.

Chronic HBV Infection (Cohort 1) Arms:

Arm 1: Patients receive tenofovir alafenamide (TAF) orally (PO) once daily (QD) or tenofovir disoproxil fumarate (TDF) PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Arm 2: Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Past HBV infection (Cohort 2) Arms:

Arm 3: Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Arm 4: Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for HBV may be used.

(Cohort 1: Arm 2 and Cohort 2: Arm 3 follow the same treatment plan, but are considered part of separate parallel studies and are therefore identified as separate arms.)

Patients are followed for 24 months: every 4 weeks from randomization to week 24, then every 8 weeks thereafter up to week 104.

Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus Infection Receiving Anti-Cancer Therapy for Solid Tumors

A Phase III Randomized Trial of Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus (HBV) Infection Receiving Anti-Cancer Therapy for Solid Tumors

Adverse liver outcome: Defined as liver-related death or liver failure (ascites, hepatic encephalopathy or impaired hepatic synthetic function defined as total bilirubin ≥ 5 mg/dL or INR ≥ 2.0) not due to disease progression in the liver. Assessment of the primary endpoint will be made by sites and subsequently adjudicated by the research oversight team by blinded review.

HBV reactivation is is defined as one of the following:

* ≥ 2 log (100-fold) increase in HBV DNA compared to baseline in patients with detectable HBV DNA at baseline, or
* HBV DNA ≥ 3 log (1,000) IU/mL in a patient with previously undetectable HBV DNA, or
* HBV DNA ≥ 4 log (10,000) IU/mL if baseline HBV DNA not available, or
* HBsAg seroreversion (HBsAg- to HBsAg+) in a patient previously HBsAg-.

Hepatitis flare is defined as ALT \> 3 x baseline and \>100 U/L.

Adverse liver outcome: Defined as liver-related death or liver failure (ascites, hepatic encephalopathy or impaired hepatic synthetic function defined as total bilirubin ≥ 5 mg/dL or INR ≥ 2.0) not due to disease progression in the liver. Assessment of the primary endpoint will be made by sites and subsequently adjudicated by the research oversight team by blinded review.

HBV reactivation is defined as one of the following:

* ≥ 2 log (100-fold) increase in HBV DNA compared to baseline in patients with detectable HBV DNA at baseline, or
* HBV DNA ≥ 3 log (1,000) IU/mL in a patient with previously undetectable HBV DNA, or
* HBV DNA ≥ 4 log (10,000) IU/mL if baseline HBV DNA not available, or
* HBsAg seroreversion (HBsAg- to HBsAg+) in a patient previously HBsAg-.

The combined endpoint of adverse liver outcomes and HBV reactivation is the occurrence of either adverse liver outcome or HBV reactivation as defined above.

National Cancer Institute (NCI)

SWOG Cancer Research Network

No participants received experimental treatment on this study. No participants were registered in the Chronic HBV cohort \[Cohort 1\]. In the Past HBV cohort \[Cohort 2\]:

* no participants assigned to Arm 3 experienced HBV reactivation, which would have prompted treatment with the study-assigned anti-HBV therapy according to protocol
* one participant in Arm 4 (standard of care) began anti-HBV therapy at physician discretion.

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 1 (TAF, TDF, Entecavir: Prophylactic)

\[Cohort 1\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 2 (TAF, TDF, Entecavir: Upon Indication)

\[Cohort 2\] Patients receive TAF PO QD or TDF PO QD or entecavir PO QD after HBV reactivation during chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Arm 3 (TAF, TDF, Entecavir: Upon Indication)

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for HBV may be used.

Arm 4 (Anti-Viral Therapy: Usual Care)

\[Cohort 1\] Patients receive tenofovir alafenamide (TAF) orally (PO) once daily (QD) or tenofovir disoproxil fumarate (TDF) PO QD or entecavir PO QD immediately or within 42 days after initial dose of chemotherapy. Treatment continues for up to 6 months after the last dose of chemotherapy or a maximum of 24 months in the absence of disease progression or unacceptable toxicity.

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

There were no participants registered to the Chronic HBV infection cohort \[Cohort 1, Arms 1 and 2\]

On November 15, 2022, the study was discontinued with no further follow-up required after it was determined that the accrual goal could not be met. Four participants had been accrued to Cohort 2 and no participants to Cohort 1. No adverse liver events, hepatitis B flares, or hepatitis B reactivations had occurred at the time the study was discontinued. As a result, planned time-to-event analyses for these outcomes could not be completed.

SWOG Statistician

Number of Participants With Adverse Liver Outcome

\[Cohort 2\] Patients receive anti-HBV therapy at the discretion of the physician. Any Food and Drug Administration (FDA) approved anti-viral medication for treatment of HBV may be utilized.

Best Practice: Receive best practice

Entecavir: Given PO

Tenofovir Alafenamide: Given PO

Tenofovir Disoproxil Fumarate: Given PO

Number of Participants With Hepatitis B Virus (HBV) Reactivation

Number of Participants With Hepatitis B Virus (HBV) Flare

Combined Endpoint of Adverse Liver Outcomes and HBV Reactivation, Number of Participants

Overall Study

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Lymphoma

Leukemia

Leukemia, Lymphoid

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, Large B-Cell, Diffuse

Lymphoma, B-Cell

Lymphoma, Non-Hodgkin

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Hematologic Diseases

Leukemia, B-Cell

Chronic Disease

Lymphosarcoma

Chronic Graft Versus Host Disease

Chronic Lymphocytic Leukemia

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Antineoplastic Agents

Antirheumatic Agents

Rituximab

Antineoplastic Agents, Immunological

Immunologic Factors

Patients will receive Rituximab+Chemotherapy+TAF for 6 months, followed by TAF as monotherapy for further 12 months. All subjects will receive TAF 1-3 weeks before Rituximab+Chemotherapy and withdrawn 12 months after the completion of chemotherapy.

Chemotherapy

Paola Fazi

Enrico Crea

Giuseppe Gentile

Alessandra Micozzi

Daniela Pietrasanta

Guido Gini

Piero Galieni

Emanuela Chimienti

Francesco C Albano

Attilio Guarini

Domenico Pastore

Francesco Di Raimondo

Antonio Cuneo

Vincenza Fernanda Fesce

Nicola Di Renzo

Donato Mannina

Felicetto Ferrara

Fabrizio Pane

Gianluca Gaidano

Catello Califano

Caterina Patti

Luca U Arcaini

Elsa Pennese

Fiorella Ilariucci

Anna Merli

Roberta Battistini

Maria Cantonetti

Agostino Tafuri

Paolo De Fabritiis

Luca Laurenti

Nicola Cascavilla

Marta Coscia

Carlo Visco

Maria Chiara Tisi

In this study, we will evaluate the incidence of hepatitis B virus reactivation within the first 6 months of treatment with rituximab, standard chemotherapy and TAF in patients with diffuse Large B-Cell Lymphoma/Chronic Lymphoid Leukemia HBsAg-positive.

This is a prospective, multicenter, interventional, single arm, evaluating the incidence of hepatitis B virus (HBV) reactivation within the first 6 months treatment period in HBsAg positive patients treated for DLBCL/Chronic Lymphoid Leukemia with Rituximab, standard chemotherapy, and TAF.

Approximate duration of the recruitment period based on the number of patients available The duration of the recruitment period has been estimated at 12 months.

Patients will receive Rituximab+Chemotherapy+TAF for 6 months, followed by TAF as monotherapy for further 12 months. All subjects will receive TAF 1-3 weeks before Rituximab+Chemotherapy and withdrawn 12 months after the completion of chemotherapy. Then patients will be also observed for further12 months

The Incidence of Hepatitis B in Diffuse Large B-Cell Lymphoma/Chronic Lymphoid Leukemia HBsAg-positive Treated With Rituximab, Chemotherapy and Tenofovir Alafenamide

Prospective Study on the Incidence of Hepatitis B Virus Reactivation in Untreated Patients With Diffuse Large B-Cell Lymphoma/Chronic Lymphoid Leukemia HBsAg-positive Treated With Rituximab, Chemotherapy and Tenofovir Alafenamide

Assessment of the percentage of patients presenting HBV reactivation within 6 months following the start of treatment with Rituximab, chemotherapy and TAF in in DLBCL and Chronic Lymphoid Leukemia patients.

Assessment of the percentage of patients presenting HBV reactivation during and after the 12-month treatment of TAF as a single agent in in DLBCL and Chronic Lymphoid Leukemia patients

In terms of percentage of patients with a delay of at least 7 days between chemotherapy cycles stratified by DLBCL and chronic lymphoid leukemia.

Gruppo Italiano Malattie EMatologiche dell'Adulto

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
Prophylactic Antiviral Therapy in Patients With Current or Past Hepatitis B Virus Infection Receiving Anti-Cancer Therapy for Solid Tumors	NCT03887702	Hepatitis B Inf... Malignant Solid...	Best Practice Entecavir Tenofovir Alafe... Tenofovir Disop...	18 Years -	SWOG Cancer Research Network
The Incidence of Hepatitis B in Diffuse Large B-Cell Lymphoma/Chronic Lymphoid Leukemia HBsAg-positive Treated With Rituximab, Chemotherapy and Tenofovir Alafenamide	NCT03804372	Large-B-cell Di... Chronic Lymphoi...	Rituximab Chemotherapy Tenofovir alafe...	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto
The Incidence of Hepatitis B in Diffuse Large B-Cell Lymphoma/Chronic Lymphoid Leukemia HBsAg-positive Treated With Rituximab, Chemotherapy and Tenofovir Alafenamide	NCT03804372	Large-B-cell Di... Chronic Lymphoi...	Rituximab Chemotherapy Tenofovir alafe...	18 Years -	Gruppo Italiano Malattie EMatologiche dell'Adulto

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