HIV InfectionPhase 3BEe-HIVeNCT04193189
B-Enhancement of HBV Vaccination in Persons Living With HIV (BEe-HIVe): Evaluation of HEPLISAV-B
A Phase 3 study testing HEPLISAV-B and ENGERIX-B in people with HIV Infection and Hepatitis B, run by National Institute of Allergy and Infectious Diseases (NIAID) at 41 sites in 10 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- HIV Infection, Hepatitis B
- What is being tested?
- HEPLISAV-B and ENGERIX-B
- Type of treatment
- Vaccines, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 638 participants
- Where
- 41 sitesin 10 countries
- Study dates
- 14 Dec 2020to 13 Aug 2024
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 21Show fewer
- 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)
- Any other investigational medicinal agent
- Receipt of immunoglobulin or blood products within 90 days prior to study entry
- Receipt of an injection of DNA plasmids or oligonucleotides within 60 days prior to study entry
- Hepatitis B virus vaccination ≤168 days prior to study entry
- Receipt of HEPLISAV-B vaccine at any time prior to study entry
- Known HBV vaccination prior to study entry
Trial locations and contacts
41 sites in 10 countries.
41 sites in 10 countries
United States28 sites
The Ponce de Leon Center CRS
Atlanta, Georgia, 30308-2012
University of Colorado Hospital CRS
Aurora, Colorado, 80045
Johns Hopkins University CRS
Baltimore, Maryland, 21287
Alabama CRS
Birmingham, Alabama, 35222
Massachusetts General Hospital CRS (MGH CRS)
Boston, Massachusetts, 02114
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS
Boston, Massachusetts, 02115
Chapel Hill CRS
Chapel Hill, North Carolina, 27599
Northwestern University CRS
Chicago, Illinois, 60611
Cincinnati Clinical Research Site
Cincinnati, Ohio, 45219
Case Clinical Research Site
Cleveland, Ohio, 44106
Ohio State University CRS
Columbus, Ohio, 43210
Greensboro CRS
Greensboro, North Carolina, 27401
Houston AIDS Research Team CRS
Houston, Texas, 77009
UCLA CARE Center CRS
Los Angeles, California, 90035-4709
Vanderbilt Therapeutics (VT) CRS
Nashville, Tennessee, 47183
Weill Cornell Chelsea CRS
New York, New York, 10010
Columbia P&S CRS
New York, New York, 10032
Weill Cornell Uptown CRS
New York, New York, 10065
New Jersey Medical School Clinical Research Center CRS
Newark, New Jersey, 07103
Penn Therapeutics CRS
Philadelphia, Pennsylvania, 19104
University of Pittsburgh CRS
Pittsburgh, Pennsylvania, 15213
University of Rochester Adult HIV Therapeutic Strategies Network CRS
Rochester, New York, 14642
UCSD Antiviral Research Center
San Diego, California, 92103
Ucsf Hiv/Aids Crs
San Francisco, California, 94110
University of Washington AIDS CRS
Seattle, Washington, 98104-9929
Washington University Therapeutics (WT) CRS
St Louis, Missouri, 63110-1010
Harbor-UCLA CRS
Torrance, California, 90502
Whitman-Walker Health CRS
Washington D.C., District of Columbia, 20005
South Africa3 sites
Durban International Clinical Research Site CRS
Durban, KwaZulu-Natal, 4052
Wits Helen Joseph Hospital CRS (Wits HJH CRS), Perth Road, Westdene
Johannesburg, Gauteng, 2092
Soweto ACTG CRS
Johannesburg, Soweto, 1862
Brazil2 sites
Hospital Nossa Senhora da Conceicao CRS
Porto Alegre, Rio Grande do Sul, 91350
Instituto de Pesquisa Clinica Evandro Chagas (IPEC) CRS
Rio de Janeiro, 21040-360
Thailand2 sites
Thai Red Cross AIDS Research Centre (TRC-ARC) CRS
Bangkok, 10330
Chiang Mai University HIV Treatment (CMU HIV Treatment) CRS
Chiang Mai, 50200
Kenya1 site
Kenya Medical Research Institute/Walter Reed Project Clinical Research Center (KEMRI/WRP) CRS
Kericho, Rift Valley, 20200
Philippines1 site
De La Salle Health Science Institute Angelo King Medical Research Center
Silang, 4118
Uganda1 site
Joint Clinical Research Centre (JCRC)/Kampala Clinical Research Site
Kampala, 10005
About this study
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.
Read the detailed description
This phase III/IV study evaluated the 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 (Group A) and individuals who are naïve to HBV vaccination (Group B). The analyses were conducted as separate evaluations of the two study populations for all primary and secondary objectives.
Group A (HBV vaccine non-responders)
The study was designed as an open-label three-arm study to evaluate whether:
- HEPLISAV-B vaccination given as a two-dose series achieves non-inferior seroprotection response (SPR) compared to standard dose ENGERIX-B.
- HEPLISAV-B vaccination given as a three-dose series achieves superior SPR compared to standard dose ENGERIX-B.
Participants were randomized in 1:1:1 ratio to the following study arms, stratified by sex at birth (male vs. female) and diabetes diagnosis status (yes vs. no):
2-CpG: Two doses of HEPLISAV-B at weeks 0 and 4.
3-CpG: Three doses of HEPLISAV-B at weeks 0, 4, and 24.
3-alum: Three doses of ENGERIX-B at weeks 0, 4, and 24.
The target sample size in Group A was 561 participants, 187 participants in each arm.
Group B (Naïve to HBV vaccination)
Group B study was a single arm evaluation of vaccine response and safety of three doses of HEPLISAV-B. The target sample size was 73 participants.
In both groups, participants were scheduled to attend several study visits through Week 72. All participants were to remain on their antiretroviral therapy (ART), not provided by the study, throughout the study. Visits included physical examinations and blood collection. For 7 days after each vaccination, participants were asked to record temperature and any reactions they experienced.
- Conditions
- HIV Infection, Hepatitis B
- Being tested
- HEPLISAV-B, ENGERIX-B
- Keywords
- vaccination, cytosine phosphoguanine adjuvant, seroprotection
- Medical subject headings
- HIV Infections, Hepatitis B
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
HEPLISAV-BBiological
Administered by IM injection
ENGERIX-BBiological
Administered by IM injection
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Biological: HEPLISAV-B |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: 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.
Measured: From study entry to study discontinuation (Week 72 or premature discontinuation)
Secondary outcomes (3)
Percentage of Participants With Seroprotection Response
Seroprotection response (SPR) was defined as antibody titer against hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL. Study visit weeks are according to protocol-specified visit windows; anti-HBs results outside visit windows were not included. These are snapshots at scheduled visits irrespective of delayed vaccinations, unlike the visits defined in Primary Outcome 1. 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 CIs around the single-arm estimates were specified (presented in the Data Table below).
Measured: 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
Count of participants by antibody titer against hepatitis B surface antigen (anti-HBs), categorized using cutoffs at 5, 10, 100 and 1000 mIU/mL. The testing assay lower limit of quantitation was 5 mIU/mL and upper limit 1000 mIU/mL. Study visit weeks are according to protocol-specified visit windows; anti-HBs results outside visit windows were not included. Because high proportions of participants achieved anti-HBs above the assay upper limit of quantitation, the planned geometric mean analysis was not conducted. Instead, anti-HBs were summarized according to the categories shown in the Data Table below.
Measured: 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
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. This outcome is limited to the Grade ≥2 AEs that occurred within 4 weeks after any study vaccination. 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.
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Dec 2019
- Study start14 Dec 2020
- Primary completion13 Aug 2024
- Study completion13 Aug 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- More trials run by National Institute of Allergy and Infectious Diseases (NIAID)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 638 participants (actual)
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
- Collaborators
- Dynavax Technologies Corporation
- Responsible party
- Sponsor
- Investigators
- Kenneth E. Sherman, MD, PhD, Study chair, Cincinnati CRSKristen Marks, MD, Study chair, Weill Cornell Chelsea CRS
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04193189
- Sponsor's protocol ID
- ACTG A5379
- Other IDs
- 38569
- Acronym
- BEe-HIVe
- Status last verified
- Jul 2025
- First submitted
- 6 Dec 2019
- Last updated
- 20 Jul 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie results in the publication, after deidentification.
Publications
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.
PubMed 37017075Marks 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.
PubMed 39616603Kang 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.
PubMed 40147293