B-Enhancement of HBV Vaccination in Persons Living With HIV (BEe-HIVe): Evaluation of HEPLISAV-B

NCT04193189 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: ACTG A537938569
• Study Type: interventional
• Target: 638
• Locations: 10 countries
• Sites: 41

Brief Summary

The purpose of this study was to evaluate response to and safety of the HBV vaccine HEPLISAV-B in two study populations of people living with HIV: prior HBV vaccine recipients who are deemed non-responders and individuals who are naïve to HBV vaccination.

Conditions

HIV Infection; Hepatitis B

Keywords

vaccination; cytosine phosphoguanine adjuvant; seroprotection

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Primary Seroprotection Response

  Primary seroprotection response was defined as antibody titer against hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL at 8 weeks after 2-dose vaccination series and at 4 weeks after 3-dose vaccination series. If the completion of the vaccine series was delayed (a delay of ≤4 weeks was allowed), the trial protocol specified obtaining an antibody result at 8 weeks for the 2-dose series or at 4 weeks for the 3-dose series after vaccine completion for use in the primary outcome analysis. The study was designed separately for the two study populations (Groups A and B), and the analysis was conducted separately, as prespecified in the study protocol and Statistical Analysis Plan (SAP). In Group A, two-sided 97.5% confidence intervals (CI) were specified for the SPR differences between study arms (presented in the Statistical Analyses sections below). In Group B, two-sided 95% Wilson CI around the single-arm estimate was specified (presented in the Data Table below).

  Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B

• Percentage of Participants With Adverse Events (AEs)

  The protocol required reporting of (1) Grade ≥2 AEs, (2) AEs that led to a change in study treatment regardless of grade, (3) AEs meeting serious AE (SAE) definition or expedited AE (EAE) reporting requirement, (4) Grade ≥1 local and systemic injection reactions within 7 days of any study vaccine injection, (5) medically attended adverse events (MAAE) regardless of grade, and (6) potential immune-mediated AEs regardless of grade. Grading was per DAIDS AE Grading Table (Version 2.1): Grade 1 (mild), 2 (moderate), 3 (severe), 4 (life-threatening) and 5 (death). DAIDS EAE Manual (V1.0) was used. Wilson method was used for confidence intervals.

  From study entry to study discontinuation (Week 72 or premature discontinuation)

Secondary Outcomes (3)

• Percentage of Participants With Seroprotection Response

  Weeks 4, 8, 12, 24, 28, 32 (Group A 3-CpG and 3-alum and Group B), 48 (Group A 3-CpG and 3-alum and Group B), 52 (Group A 2-CpG) and 72. The visit schedule differed between the study arms.

• Count of Participants by Anti-HBs Titer Categories

  Weeks 4, 8, 12, 24, 28, 32 (Group A 3-CpG and 3-alum and Group B), 48 (Group A 3-CpG and 3-alum and Group B), 52 (Group A 2-CpG) and 72. The visit schedule differed between the study arms.

• Percentage of Participants With Grade ≥2 AEs Post-vaccination Adverse Events

  From study vaccination initiation to 4 weeks after last study vaccination (Week 8 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and Group B)

Other Outcomes (2)

• Percentage of Participants With Primary Seroprotection Response by Sex

  Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B

• Percentage of Participants With Primary Seroprotection Response by Race

  Week 12 in Group A 2-CpG, Week 28 in Group A 3-CpG and 3-alum and in Group B

Study Arms (4)

Group A, 2-CpG: HEPLISAV-B (two injections)

EXPERIMENTAL

Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by intramuscular (IM) injection at Weeks 0 and 4.

Biological: HEPLISAV-B

Group A, 3-CpG: HEPLISAV-B (three injections)

EXPERIMENTAL

Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by IM injection at Weeks 0, 4, and 24.

Biological: HEPLISAV-B

Group A, 3-alum: ENGERIX-B (three injections)

ACTIVE COMPARATOR

Participants were prescribed 1 mL of ENGERIX-B (conventional hepatitis B vaccine with an aluminum hydroxide adjuvant) by IM injection at Weeks 0, 4, and 24.

Biological: ENGERIX-B

Group B: HEPLISAV-B (three injections)

EXPERIMENTAL

Participants were prescribed 0.5 mL of HEPLISAV-B (hepatitis B vaccine with a cytosine phosphoguanine adjuvant) by IM injection at Weeks 0, 4, and 24.

Biological: HEPLISAV-B

Interventions

HEPLISAV-B BIOLOGICAL

Administered by IM injection

Group A, 2-CpG: HEPLISAV-B (two injections); Group A, 3-CpG: HEPLISAV-B (three injections); Group B: HEPLISAV-B (three injections)

ENGERIX-B BIOLOGICAL

Administered by IM injection

Group A, 3-alum: ENGERIX-B (three injections)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• HIV-1 infection
• On current HIV-1 antiretroviral therapy (ART)
• CD4+ T-cell count ≥100 cells/mm\^3
• HIV-1 RNA \<1000 copies/mL
• Serum Hepatitis B antibody \<10 mlU/mL, non-reactive (negative), or indeterminate
• Documentation of HBV vaccination \>168 days prior to study entry
• Serum Hepatitis B antibody non-reactive (negative) within 45 days prior to study entry

You may not qualify if:

• Infection or prior exposure to HBV
• Serum HBsAb level ≥10 mlU/mL or positive at screening or any other time prior to screening
• Presence of any active or acute AIDS-defining opportunistic infections
• Solid organ transplantation
• History of ascites, encephalopathy, or variceal hemorrhage
• Diagnosis of chronic kidney disease (CKD) stage G4
• Cancer diagnosis within 5 years
• Currently receiving chemotherapy
• Chronic use and/or receipt of systemically administered immunosuppressive
• Known allergy/sensitivity or any hypersensitivity to any HBV vaccine or yeast
• Active, serious infection other than HIV-1
• Receipt of any inactivated virus vaccine within 14 days
• Receipt of any of the following within 45 days prior to study entry:
• Live virus vaccine
• Granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Dynavax Technologies Corporation: collaborator

Study Sites (41)

Alabama CRS

Birmingham, Alabama, 35222, United States

Location

UCLA CARE Center CRS

Los Angeles, California, 90035-4709, United States

Location

UCSD Antiviral Research Center

San Diego, California, 92103, United States

Location

Ucsf Hiv/Aids Crs

San Francisco, California, 94110, United States

Location

Harbor-UCLA CRS

Torrance, California, 90502, United States

Location

University of Colorado Hospital CRS

Aurora, Colorado, 80045, United States

Location

Whitman-Walker Health CRS

Washington D.C., District of Columbia, 20005, United States

Location

The Ponce de Leon Center CRS

Atlanta, Georgia, 30308-2012, United States

Location

Northwestern University CRS

Chicago, Illinois, 60611, United States

Location

Johns Hopkins University CRS

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital CRS (MGH CRS)

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS

Boston, Massachusetts, 02115, United States

Location

Washington University Therapeutics (WT) CRS

St Louis, Missouri, 63110-1010, United States

Location

New Jersey Medical School Clinical Research Center CRS

Newark, New Jersey, 07103, United States

Location

Weill Cornell Chelsea CRS

New York, New York, 10010, United States

Location

Columbia P&S CRS

New York, New York, 10032, United States

Location

Weill Cornell Uptown CRS

New York, New York, 10065, United States

Location

University of Rochester Adult HIV Therapeutic Strategies Network CRS

Rochester, New York, 14642, United States

Location

Chapel Hill CRS

Chapel Hill, North Carolina, 27599, United States

Location

Greensboro CRS

Greensboro, North Carolina, 27401, United States

Location

Cincinnati Clinical Research Site

Cincinnati, Ohio, 45219, United States

Location

Case Clinical Research Site

Cleveland, Ohio, 44106, United States

Location

Ohio State University CRS

Columbus, Ohio, 43210, United States

Location

Penn Therapeutics CRS

Philadelphia, Pennsylvania, 19104, United States

Location

University of Pittsburgh CRS

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Therapeutics (VT) CRS

Nashville, Tennessee, 47183, United States

Location

Houston AIDS Research Team CRS

Houston, Texas, 77009, United States

Location

University of Washington AIDS CRS

Seattle, Washington, 98104-9929, United States

Location

Gaborone CRS

Gaborone, South-East District, Botswana

Location

Hospital Nossa Senhora da Conceicao CRS

Porto Alegre, Rio Grande do Sul, 91350, Brazil

Location

Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS

Rio de Janeiro, 21040-360, Brazil

Location

Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS

Kericho, Rift Valley, 20200, Kenya

Location

Blantyre CRS

Blantyre, Malawi

Location

De La Salle Health Science Institute Angelo King Medical Research Center

Silang, 4118, Philippines

Location

Wits Helen Joseph Hospital CRS (Wits HJH CRS), Perth Road, Westdene

Johannesburg, Gauteng, 2092, South Africa

Location

Durban International Clinical Research Site CRS

Durban, KwaZulu-Natal, 4052, South Africa

Location

Soweto ACTG CRS

Johannesburg, Soweto, 1862, South Africa

Location

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS

Bangkok, 10330, Thailand

Location

Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS

Chiang Mai, 50200, Thailand

Location

Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site

Kampala, 10005, Uganda

Location

Hanoi Medical University CRS

Đống Đa, Hanoi, 10000, Vietnam

Location

Related Publications (3)

• Marks KM, Kang M, Umbleja T, Avihingsanon A, Sugandhavesa P, Cox AL, Vigil K, Perazzo H, Price JC, Katsidzira L, Vernon C, Alston-Smith B, Sherman KE; ACTG 5379 Study Team. Immunogenicity and Safety of Hepatitis B Virus (HBV) Vaccine With a Toll-Like Receptor 9 Agonist Adjuvant in HBV Vaccine-Naive People With Human Immunodeficiency Virus. Clin Infect Dis. 2023 Aug 14;77(3):414-418. doi: 10.1093/cid/ciad201.

  PMID: 37017075 RESULT

• Marks KM, Kang M, Umbleja T, Cox A, Vigil KJ, Ta NT, Omoz-Oarhe A, Perazzo H, Kosgei J, Hatlen T, Price J, Katsidzira L, Supparatpinyo K, Knowles K, Alston-Smith BL, Rathod P, Sherman KE; ACTG 5379 (BEe-HIVe) Study Team. HepB-CpG vs HepB-Alum Vaccine in People With HIV and Prior Vaccine Nonresponse: The BEe-HIVe Randomized Clinical Trial. JAMA. 2025 Jan 28;333(4):295-306. doi: 10.1001/jama.2024.24490.

  PMID: 39616603 RESULT

• Kang M, Marks KM, Cox AL, Sherman KE. An efficient vaccine clinical trial: ACTG A5379 hepatitis B vaccine trial in persons with HIV. Vaccine. 2025 May 10;55:127028. doi: 10.1016/j.vaccine.2025.127028. Epub 2025 Mar 26.

  PMID: 40147293 RESULT

Related Links

• Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0, January 2010

MeSH Terms

Conditions

HIV Infections; Hepatitis B

Interventions

Heplisav-B; Engerix-B

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Viral, Human; Hepatitis; Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@fstrf.org

(301) 628-3348

Study Officials

• Kenneth E. Sherman, MD, PhD

  Cincinnati CRS

  STUDY CHAIR

• Kristen Marks, MD

  Weill Cornell Chelsea CRS

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 6, 2019
• First Posted: December 10, 2019
• Study Start: December 14, 2020
• Primary Completion: August 13, 2024
• Study Completion: August 13, 2024
• Last Updated: July 20, 2025
• Results First Posted: July 20, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections network (ACTG) by NIH.
• Access Criteria: * With whom? * Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG. * For what types of analyses? * To achieve aims in the proposal approved by the ACTG. * By what mechanism will data be made available? * Researchers may submit a request for access to data using the ACTG "Data Request" form at: https://submit.mis.s-3.net/ Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.

Locations

KE (1); BO (1); TH (2); ZA (3); PH (1); UG (1); US (28); VN (1); MA (1); BR (2)