Utilization of Hepatitis B Virus NAT+ Donors for Hepatitis B Vaccinated Lung Transplant Candidates (INHIBITOR)

Utilization of Hepatitis B Virus Nucleic Acid Test Positive Donors for Hepatitis B Vaccinated Lung Transplant Candidates

The objective of this study is to determine the safety and efficacy of transplanting lungs from hepatitis B virus (HBV) nucleic acid test positive (NAT+) donors into HBV vaccinated HBV surface antibody positive (sAb+) lung transplant candidates, who will then be treated with Hepatitis B Immune Globulin (HBIG) and entecavir, tenofovir disoproxil, or tenofovir alafenamide.

Study Overview

• Status: Withdrawn
• Conditions: Hepatitis B; Lung Transplant
• Intervention / Treatment: Drug: Hepatitis B Immune Globulin and entecavir, tenofovir disoproxil, or tenofovir alafenamide

Detailed Description

Despite advances in organ preservation and the use of increasingly sophisticated bridge-to-transplant therapies, there is significant waitlist mortality among lung transplant candidates. Between 2017-2019, 637 patients died while awaiting donor lungs and 403 became too sick for transplant. To increase the pool of available donors, many transplant programs in the United States now accept donors with active hepatitis C virus (HCV) infections. Transplant recipients are then treated with anti-viral therapy in the post-operative period.

Some kidney and lung transplant programs have extended this strategy to include donors with hepatitis B virus (HBV) viremia. Following transplant, recipients are treated with Hepatitis B Immune Globulin (HBIG) and life-long antiviral therapy. Published studies have shown decreased waitlist mortality among kidney recipients who receive HBV nucleic acid test positive (NAT+) organs without adverse impact on allograft or hepatic function. It is unknown, however, whether this can be a safe and effective strategy for lung transplant candidates.

The aim of this phase II clinical trial is to assess the safety and efficacy of accepting lungs from HBV NAT+ donors for HBV vaccinated lung transplant candidates. The study will enroll 10 subjects, who will be treated with HBIG and entecavir, tenofovir disoproxil, or tenofovir alafenamide following transplant. Outcomes will include rates of HBV viremia and time to undetectable viral level; rates of acute HBV-associated hepatitis and persistent HBsAg positivity at one year; and 1-year patient and graft survival.

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19146
      • Hospital of University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age 18-70 years
• Able to provide informed consent
• Willing and able to travel to the University of Pennsylvania for routine post-transplant study visits
• Pre-menopausal women must agree to use birth control in accordance with the Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) following transplant
• Both men and women must agree to use at least one barrier method of birth control or remain abstinent following transplant due to risk of HBV transmission
• Appropriate HBV vaccine pre-transplant response, defined as HBV sAb ≥12.00 mIU/mL

Exclusion Criteria:

• Donor characteristics:

  • Donation after circulatory death donor
  • Hepatitis C Virus (HCV) NAT+
  • PaO2/FiO2 <300 on FiO2 = 100% and PEEP=5
  • Age >55 years
  • Smoking history >20 pack years

• Transplant candidate characteristics:

  • Age >70 years
  • Any chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD)) associated with persistently elevated liver enzymes
  • Significant fibrosis (≥F2 on Fibroscan or Fib4 ≥1.67 (for patients unable to complete Fibroscan and without liver disease risk factors))
  • Inadequate insurance coverage of entecavir, tenofovir disoproxil, or tenofovir alafenamide
  • Retransplant candidate
  • Current use of extracorporeal membrane oxygenation (ECMO) or mechanical ventilation as a bridge to lung transplantation
  • HIV infection
  • Chronic kidney disease with estimated glomerular filtrate rate less than 50 ml/min/1.73 m2
  • Small bowel dysmotility or plan for prolonged medications and/or nutrition via tube route in the post-transplant period
  • Significant human leukocyte antibody (HLA) sensitization (Calculated Panel Reactive Antibody (CPRA) ≥60%)
  • Planned or high likelihood of anti-thymocyte globulin induction immunosuppression or rituximab treatment
  • Known hypercoagulable states including positive antiphospholipid antibodies with prior venous or arterial thromboembolic events or Factor V Leiden or Prothrombin mutations with or without prior venous or arterial thromboembolic events
  • History of hypersensitivity or anaphylactic reaction to immune globulin or similar products
  • Receiving or anticipated to receive drugs with significant entecavir or tenofovir interactions including phenytoin/fosphenytoin, oxcarbazepine, phenobarbital, primidone, rifabutin, and rifampin

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Recipient of Hepatitis B NAT+ Donor; All subjects will then be treated with Hepatitis B Immune Globulin and entecavir, tenofovir disoproxil, or tenofovir alafenamide (choice of specific drug to be based on long-term cost, clinical response, and renal function)	Drug: Hepatitis B Immune Globulin and entecavir, tenofovir disoproxil, or tenofovir alafenamide; Anti-hepatitis B medications

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of HBV viremia	HBV viremia rate in HBV vaccinated patients who receive a lung transplant from a HBV NAT+ donor.	1 year
Time to undetectable HV DNA	Time to undetectable HBV DNA rate in HBV vaccinated patients who receive a lung transplant from a HBV NAT+ donor.	1 year
Rate of acute HBV-associated hepatitis	Rates of acute HBV-associated hepatitis in HBV vaccinated patients who receive a lung transplant from a HBV NAT+ donor.	1 year
Rate of persistent HBV surface antigen positivity	Rates of persistent HBV surface antigen (HBsAg) positivity at one year in HBV vaccinated patients who receive a lung transplant from a HBV NAT+ donor.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
One year patient survival	One year patient survival among lung transplant patients who receive an organ from a HBV NAT+ donor.	1 year
One year graft survival	One year graft survival among lung transplant patients who receive an organ from a HBV NAT+ donor.	1 year

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Andrew M Courtwright, MD, PhD, Hospital of University of Pennsyvlania

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2022
• Primary Completion (Actual): August 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: May 7, 2022
• First Submitted That Met QC Criteria: May 31, 2022
• First Posted (Actual): June 3, 2022

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: August 2, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Enterovirus Infections; Picornaviridae Infections; Hepatitis B; Hepatitis; Hepatitis A; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Immunologic Factors; Tenofovir; Antibodies; Entecavir; Immunoglobulins; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin
• Other Study ID Numbers: 851257

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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.: Yes