Optimizing HBV Management During Anti-CD20 Antibodies

May 1, 2018 updated by: Wai-Kay Seto, The University of Hong Kong

Establishing Monitoring Strategies in Individuals With Prior Hepatitis B Virus Exposure Undergoing Anti-CD20 Antibody Containing Chemotherapy: A Prospective Observational Study

Hepatitis B virus (HBV) reactivation is common during anti-CD20 containing chemotherapy, even in HBsAg-negative patients with only prior HBV exposure. The optimal timing of commencing antiviral therapy and the interval of clinical monitoring is uncertain. 25% of the Hong Kong population has prior HBV exposure. The investigators plan monitor this cohort of patients and determine (1) the optimal time point for starting antiviral therapy based on the progression of HBV reactivation, and (2) the optimal interval of clinical monitoring.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The use of immunosuppressive cytotoxic therapy in patients with chronic hepatitis B virus (HBV) infection is known to be associated with potentially fatal HBV reactivation. Prophylactic nucleoside analogue therapy has been shown to reduce the rates of HBV reactivation in hepatitis B surface antigen (HBsAg)-positive subjects, and is now recommended in current treatment guidelines.

Patients who are negative for HBsAg and anti-HBsAg antibody (anti-HBs) may be naïve to HBV. Nonetheless in HBV-endemic regions, such patients might have been infected with HBV and achieved HBsAg seroclearance. Prior HBV exposure is evidenced by the presence of positive antibody to the hepatitis B core antigen (anti-HBc). Hence although a HBsAg-negative, anti-HBc positive state may represent resolved HBV infection, it could also represent occult HBV infection with HBV persisting at low replicative levels following HBsAg seroclearance. Reactivation of HBV is then possible.

Rituximab, ofanumumab and obinutuzumab are chimeric monoclonal antibodies against the B-cell surface antigen CD20, and are used extensively in B-cell lymphoid malignancies and many non-malignant immune-mediated diseases in the fields of rheumatology, dermatology, neurology and nephrology.Previous retrospective and prospective studies have found the rates of HBV reactivation in HBsAg-negative, anti-HBc positive individuals who undergo anti-CD20 antibody containing chemotherapy to vary between 8.9 and 23.8%. This variation can be partially explained by the use of different definitions of HBV reactivation, including a combination of biochemical hepatitis, HBsAg seroreversion, or HBV DNA levels over a certain threshold. Another important factor was the lack of regular monitoring following commencement of anti-CD20 antibodies. In view of these discrepancies, our research team conducted a prospective study in which HBsAg-negative, anti-HBc positive lymphoma patients were monitored at 4-week intervals for up to 2 years following commencement of rituximab. Using a detectable serum HBV DNA level as the definition of HBV reactivation, the 2-year cumulative reactivation rate was 41.5%. Anti-HBs negativity was significantly associated with a higher risk of HBV reactivation.

Despite previous accurate description of the rate of HBV reactivation, many clinical questions remain :

  1. Which is the better strategy for HBsAg-negative, anti-HBc positive patients receiving anti-CD20 antibodies - prophylactic antiviral therapy for all patients, or regular clinical monitoring and prescription of antiviral therapy when needed? Although prophylactic antiviral therapy has been proven effective, one needs to consider the high seroprevalence of anti-HBc in the HBV-endemic regions of East Asia that could reach 40%. Based on our two studies of rituximab and hematopoietic stem cell transplantation, the seroprevalence of anti-HBc in Hong Kong was between 26.4 and 27.6%. Universal prescription of antiviral therapy for all HBsAg-negative, anti-HBc positive individuals might not be cost-effective. At the same time, a recent technical review by the American Gastroenterological Association stated that based on current evidence, they "had no comment" on whether routine clinical monitoring could substitute prophylactic antiviral therapy.
  2. If routine clinical monitoring were chosen, what is the optimal interval of monitoring? A current recommendation of every 1-3 months was based on expert opinion only. To answer this question, a prospective study is needed to observe the serial changes in HBV DNA levels over time in patients following the development of detectable HBV DNA, with each time epoch assessed for its suitability in monitoring.
  3. Are all HBV reactivations clinically relevant? Our previous study only provided the rate of HBV DNA detectability, and did not describe its subsequent clinical progression. Will patients continue to have serial increases in HBV DNA level leading to biochemical hepatitis and/or HBsAg seroreversion, or do HBV DNA levels remain relatively low? A recent study found discrepancies between the rates of HBsAg seroconversion and HBV DNA ≥2,000 IU/mL (10.3% and 17.9% respectively), implying not all patients with HBV DNA detectability proceed to a progressive increase in HBV DNA levels, HBsAg seroreversion or biochemical hepatitis. Serial prospective data on this with respect to the cyclical treatment regimen of anti-CD20 antibodies are lacking.

The investigators propose a prospective observational study to answer these clinical questions and provide a concise management strategy for the large number of patients prescribed anti-CD20 antibodies containing therapy for both malignant and non-malignant diseases

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
83

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • The University of Hong Kong

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

HBsAg-negative anti-HBc positive individuals with hematological malignancies undergoing anti-CD20 containing chemotherapy.

Description

Inclusion Criteria:

  1. Age ≥18 years.
  2. Eastern Cooperative Oncology Group (ECOG) performance score of ≤2.
  3. HBsAg-negative, anti-HBc positive patient receiving anti-CD20 containing chemotherapy with or without antibody to the hepatitis B surface antigen (anti-HBs).
  4. Baseline normal serum alanine amiontransferase (ALT) (≤30 U/L for men, ≤19 U/L for women).

Exclusion Criteria:

  1. Concomitant liver diseases including chronic hepatitis C and D infection, Wilson's disease, autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis.
  2. Significant alcohol intake (>30 grams per day).
  3. History of prior anti-HBV therapy, hematopoietic stem-cell transplantation, anti-CD20 antibody therapy, anti-CD52 antibody therapy or anti-tumour necrosis factor antibody therapy.
  4. Baseline detectable HBV DNA (≥10 IU/mL). These patients will be started on prophylactic entecavir.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Anti-CD20 antibody
Patients with hematological malignancies receiving anti-CD20 antibody therapy
Drug: Anti-CD20 antibody
All patients receiving anti-CD20 therapy (rituximab, ofanumumab, obinutuzumab) for hematological malignancies

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
HBV Reactivation
Time Frame: From commencement of anti-CD20 antibody therapy for up to 2 years
HBV DNA >= 10 IU/mL
From commencement of anti-CD20 antibody therapy for up to 2 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
HBV-related hepatitis
Time Frame: From commencement of anti-CD20 antibody therapy for up to 2 years
ALT >60 U/L for men; >38 U/L for women; and HBV DNA >2,000 IU/mL
From commencement of anti-CD20 antibody therapy for up to 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The University of Hong Kong

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Wai-Kay Seto, MD, wkseto@hku.hk

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
October 1, 2013

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2017

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 1, 2017

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 15, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 15, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 16, 2017

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 4, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 1, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • UW15-384

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

IPD Plan Description

No such plan

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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