HIV Infections
Conditions
Keywords
Immunotherapy, mRNA, Lentivirus infection, Virus disease, Sexually transmitted disease, Immunodeficiency syndrome
Brief summary
iHIVARNA-01 is a novel therapeutic vaccine for the treatment of HIV-1-infected patients based on in vivo modification of DCs. It consists of HIVACAT-TriMix: mRNA encoding a mixture of APC activation molecules (CD40L, a constitutively active variant of TLR4 and CD70) and the HIV target antigens contained in HIVACAT to be administered through the intranodal route. iHIVARNA-01 aims to achieve the 'functional cure' of HIV infection, i.e. controlling viral replication in the absence of anti-retroviral therapy.
Detailed description
Objective: To evaluate the safety and immunogenicity of iHIVARNA-01 as a new therapeutic vaccine in HIV infected patients. Study design and duration: Phase IIa, multicentre double-blind placebo controlled intervention study. Each patient will be followed for 30 weeks. The study duration will be 38 weeks from inclusion of the first patient. Sites: Erasmus MC, Rotterdam The Netherlands (sponsor), Hospital Clínic de Barcelona and Institut de Recerca de la Sida - Caixa, Barcelona, Spain, Instituut voor Tropische Geneeskunde Antwerp, Belgium and Vrije Universiteit Brussel/UZ Brussel, Belgium Study population: Chronically HIV-1- infected patients under stable cART with plasma viral load (pVL) ≤ 50 copies/ml and stable CD4+ T-cell counts ≥ 450/μl, aged 18 years or above. Sample size: after recruitment and screening, 70 patients will be included and randomized to one of the study-arms. Intervention: One group (n=40) receives the HIVACAT-TriMix (300 microgram TriMix + 900 microgram HIVACAT) vaccine intranodally on three occasions with a two-week interval. One control group (n=15) receives TriMix only (300 microgram TriMix) and one group (n=15) receives saline intranodally on three occasions with a two-week interval. Two weeks after the last vaccination cART treatment will be interrupted. If plasma virus is detectable, cART will be re-initiated twelve weeks after treatment interruption. cART can always be re-initiated for medical reasons, as judged by the clinical investigator.
Interventions
BIOLOGICALiHIVARNA-01
Therapeutic vaccination, followed by treatment interruption
BIOLOGICALTriMix
Therapeutic vaccination, followed by treatment interruption
BIOLOGICALPlacebo
Therapeutic vaccination, followed by treatment interruption
Sponsors
Institut d'Investigacions Biomèdiques August Pi i Sunyer
IrsiCaixa
Institute of Tropical Medicine, Belgium
Vrije Universiteit Brussel
Synapse bv
Asphalion
eTheRNA immunotherapies
CR2O
Hospital Clinic of Barcelona
Germans Trias i Pujol Hospital
Universitair Ziekenhuis Brussel
Rob Gruters
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. ≥ 18 years of age; 2. Voluntarily signed informed consent; 3. Proven HIV-1 infection (with documented antibodies against HIV-1 and a detectable plasma HIV-1 RNA before initiation of therapy); 4. On stable treatment with cART regimen (antiretroviral therapy consisting of at least three registered antiretroviral agents) for at least 3 years; 5. Nadir CD4+ ≥ 350 cells/μl (up to 2 occasional determinations ≤ 350 cells/μl are allowed); 6. Current CD4+ cell count ≥ 450 cells/μl; 7. HIV-RNA below 50 copies/mL in the last 6 months prior to randomization, during at least two measurements (occasional so called 'blips' ≤ 500 copies/mL are permitted); 8. If sexually active, willing to use a reliable method of reducing the risk of transmission to their sexual partners during treatment interruption (including PrEP). 1. For heterosexually active female, using an effective method of contraception with partner (combined oral contraceptive pill; injectable or implanted contraceptive; IUD/IUS; consistent record with condoms; physiological or anatomical sterility (in self or partner) from 14 days prior to the first vaccination until 4 months after the last vaccination. For heterosexually active male, using an effective method of contraception with their partner from the first day of vaccination until 4 months after the last vaccination. -
Exclusion criteria
1. Treatment with non-cART regimen prior to cART regimen; 2. Previous failure to antiretroviral and/or mutations conferring genotypic resistance to antiretroviral therapy; 3. Non-subtype B HIV infection; 4. Active Hepatitis B virus and/or Hepatitis C virus co-infection; 5. History of a CDC class C event (see appendix A); 6. Pregnant female (screened with a positive pregnancy test), lactating or intending to become pregnant during the study; 7. Active malignancy ≤ 30 days (extended period on the clinical assessment of the investigator) prior to screening; 8. Active infection with fever (38°C or above) ≤ 10 days of screening and/or first vaccination; 9. Therapy with immunomodulatory agents (e.g. systemic corticosteroids), including cytokines (e.g. IL-2), immunoglobulins and/or cytostatic chemotherapy ≤ 90 days prior to screening. This does not include seasonal influenza, hepatitis B and/or other travel related vaccines; 10. Congenital, acquired or induced coagulation disorders, such as thrombocytopenia (thrombocytes \< 150x109/L) and/or current use of anti-coagulant medication (e.g. coumarins, inhibitors of Xa); Usage of NSAIDs (including acetylsalicylic acid) is allowed, however it is advised to interrupt therapy 10 days ahead of vaccination; 11. Usage of any investigational drug ≤ 90 days prior to study entry; 12. An employee of the investigator or study site, with direct involvement in the proposed study or other studies under the direction of that investigator or study site, or is a family member of an employee or the investigator Any other condition, which, in the opinion of the investigator, may interfere with the evaluation of the study objectives
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | week 6 | * Grade 3 or above local adverse event (pain, cutaneous reactions including induration). * Grade 3 or above systemic adverse event (temperature, chills, headache, nausea, vomiting, malaise, and myalgia). * Grade 3 or above other clinical or laboratory adverse event confirmed at examination or on repeat testing respectively. Any event attributable to vaccination leading to discontinuation of the immunisation regimen. |
| Immunogenicity as Measured by Elispot | week 6 and week 18 | Change from baseline immunogenicity as measured by ELISPOT at week 6 and 18, i.e. two weeks and 14 weeks after the last immunization compared to both control groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity as Measured by Intracellular Cytokine Staining (ICS) | week 10, 18 and 30 | HIV-specific CD4+ and CD8+ T cell responses after immunization by the number of poly-functional T cells as determined by intracellular cytokine staining, (ICS). |
| Time to Viral Rebound | week 6-18 | time until viral rebound (defined as two consecutive measurements of plasma viral load \> 1000 copies/mL separated by at least 15 days) after discontinuation at week 6. |
| Change in Plasma Viral Load | week 6-18 | difference in log10 copies/ml plasma viral load in vivo after analytical treatment interruption (ATI, week 6-restart ART), compared to placebo WFI |
| Functional Cure | week 18 | proportion of patients with viral load below detectable level of 50 copies/mL in plasma after ATI, week 18 |
| Primary Immune Response Against Vaccine | from baseline to week 6 | Change in frequency of at least 0.7log10 HIV-specific T-cell responses between baseline and week 6 |
| CD8 T Cell Mediated Viral Suppression | week 4 | The capacity of CD8 T cells to suppress virus production in HIV infected autologous CD4 T cells, after vaccination. For this purpose PBMC are isolated and separated in CD8 and CD4 T cells. CD4 cells are infected with HIV. Thereafter CD4 cells are co-cultured with pre-stimulated CD8 cells and the capacity to suppress virus production at different effector to target (E:T) ratios is measured, by the change of p24 Gag production. Pannus et al AIDS 2019, PMID: 30702513 |
| Proviral DNA Reservoir | day 0-90 (week 4, week 4 + 1 day and week 5 and week 6) and day 90-130 (week 18) and day >130 (week 30) | effect on reservoir as measured by changes in the proviral DNA copy numbers per million cells during and after immunization |
| Viral Immune Escape | week 18 | viral immune escape: change in % mutated epitopes from pre-cART to post-ATI |
| Transcriptomics | week 6 and 18 | host protein mRNA expression profiles in whole blood |
| Cell-associated RNA Viral Reservoir | day 0-30 (week 4, week 4 + 1 day and week 5) and day 30-80 (week 6), 80-150 days (week 18) and >150 days (week 30) | effect on reservoir as measured by changes in the intracellular viral RNA copy numbers per million cells during and after immunization |
Countries
Belgium, Netherlands, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| iHIVARNA-01 Biological: 1200μg mRNA (900 μg HIV mRNA+300 μg TriMix mRNA) 3 vaccinations, two weeks interval
iHIVARNA-01: Therapeutic vaccination, followed by treatment interruption
TriMix: Therapeutic vaccination, followed by treatment interruption | 16 |
| TriMix Biological: TriMix\_300 μg TriMix mRNA 3 vaccinations, two weeks interval
TriMix: Therapeutic vaccination, followed by treatment interruption | 9 |
| Placebo Water for injection 3 vaccinations, two weeks interval
Placebo: Therapeutic vaccination, followed by treatment interruption | 8 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Analytical Treatment Interruption | Physician Decision | 10 | 6 | 5 |
Baseline characteristics
| Characteristic | iHIVARNA-01 | TriMix | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 9 Participants | 8 Participants | 33 Participants |
| CD4 T cell counts | 793 cells/microliter | 708 cells/microliter | 742 cells/microliter | 769 cells/microliter |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Belgium | 6 participants | 3 participants | 3 participants | 12 participants |
| Region of Enrollment Netherlands | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Spain | 9 participants | 5 participants | 5 participants | 19 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 15 Participants | 9 Participants | 8 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 9 | 0 / 8 |
| other Total, other adverse events | 16 / 16 | 9 / 9 | 8 / 8 |
| serious Total, serious adverse events | 2 / 16 | 0 / 9 | 1 / 8 |
Outcome results
Primary
Immunogenicity as Measured by Elispot
Change from baseline immunogenicity as measured by ELISPOT at week 6 and 18, i.e. two weeks and 14 weeks after the last immunization compared to both control groups
Time frame: week 6 and week 18
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| iHIVARNA-01 | Immunogenicity as Measured by Elispot | week 6 | -0.07 delta log difference spot forming units |
| iHIVARNA-01 | Immunogenicity as Measured by Elispot | week 18 | -0.08 delta log difference spot forming units |
| TriMix | Immunogenicity as Measured by Elispot | week 6 | 0.18 delta log difference spot forming units |
| TriMix | Immunogenicity as Measured by Elispot | week 18 | -0.12 delta log difference spot forming units |
| Placebo | Immunogenicity as Measured by Elispot | week 6 | 0.01 delta log difference spot forming units |
| Placebo | Immunogenicity as Measured by Elispot | week 18 | 0.45 delta log difference spot forming units |
Comparison: Analyzed for week 6, to provide statistical information for decision on execution of intracellular cytokine staining (ICS).p-value: 0.14Mixed Models Analysis
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
* Grade 3 or above local adverse event (pain, cutaneous reactions including induration). * Grade 3 or above systemic adverse event (temperature, chills, headache, nausea, vomiting, malaise, and myalgia). * Grade 3 or above other clinical or laboratory adverse event confirmed at examination or on repeat testing respectively. Any event attributable to vaccination leading to discontinuation of the immunisation regimen.
Time frame: week 6
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| iHIVARNA-01 | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 0 Participants |
| TriMix | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 0 Participants |
| Placebo | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0 | 0 Participants |
Secondary
CD8 T Cell Mediated Viral Suppression
The capacity of CD8 T cells to suppress virus production in HIV infected autologous CD4 T cells, after vaccination. For this purpose PBMC are isolated and separated in CD8 and CD4 T cells. CD4 cells are infected with HIV. Thereafter CD4 cells are co-cultured with pre-stimulated CD8 cells and the capacity to suppress virus production at different effector to target (E:T) ratios is measured, by the change of p24 Gag production. Pannus et al AIDS 2019, PMID: 30702513
Time frame: week 4
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| iHIVARNA-01 | CD8 T Cell Mediated Viral Suppression | stimulated (E:T) 2:1 | 0.15 log(pg/ml) |
| iHIVARNA-01 | CD8 T Cell Mediated Viral Suppression | Stimulated (E:T) 0.1:1 | -0.65 log(pg/ml) |
| TriMix | CD8 T Cell Mediated Viral Suppression | stimulated (E:T) 2:1 | 0.22 log(pg/ml) |
| TriMix | CD8 T Cell Mediated Viral Suppression | Stimulated (E:T) 0.1:1 | -1.32 log(pg/ml) |
| Placebo | CD8 T Cell Mediated Viral Suppression | stimulated (E:T) 2:1 | 0.18 log(pg/ml) |
| Placebo | CD8 T Cell Mediated Viral Suppression | Stimulated (E:T) 0.1:1 | 0.41 log(pg/ml) |
Secondary
Cell-associated RNA Viral Reservoir
effect on reservoir as measured by changes in the intracellular viral RNA copy numbers per million cells during and after immunization
Time frame: day 0-30 (week 4, week 4 + 1 day and week 5) and day 30-80 (week 6), 80-150 days (week 18) and >150 days (week 30)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| iHIVARNA-01 | Cell-associated RNA Viral Reservoir | caRNA 0-30 days | -0.001 delta log copies RNA/ml |
| iHIVARNA-01 | Cell-associated RNA Viral Reservoir | caRNA 30-80 days | -0.006 delta log copies RNA/ml |
| iHIVARNA-01 | Cell-associated RNA Viral Reservoir | caRNA 80-150 days | 0.002 delta log copies RNA/ml |
| iHIVARNA-01 | Cell-associated RNA Viral Reservoir | caRNA >150 days | 0.002 delta log copies RNA/ml |
| TriMix | Cell-associated RNA Viral Reservoir | caRNA >150 days | -0.001 delta log copies RNA/ml |
| TriMix | Cell-associated RNA Viral Reservoir | caRNA 0-30 days | -0.002 delta log copies RNA/ml |
| TriMix | Cell-associated RNA Viral Reservoir | caRNA 80-150 days | 0.003 delta log copies RNA/ml |
| TriMix | Cell-associated RNA Viral Reservoir | caRNA 30-80 days | -0.001 delta log copies RNA/ml |
| Placebo | Cell-associated RNA Viral Reservoir | caRNA >150 days | -0.004 delta log copies RNA/ml |
| Placebo | Cell-associated RNA Viral Reservoir | caRNA 30-80 days | 0.032 delta log copies RNA/ml |
| Placebo | Cell-associated RNA Viral Reservoir | caRNA 80-150 days | -0.016 delta log copies RNA/ml |
| Placebo | Cell-associated RNA Viral Reservoir | caRNA 0-30 days | -0.004 delta log copies RNA/ml |
Secondary
Change in Plasma Viral Load
difference in log10 copies/ml plasma viral load in vivo after analytical treatment interruption (ATI, week 6-restart ART), compared to placebo WFI
Time frame: week 6-18
Population: One participant from the the iHIVARNA-01 group did not interrupt ART and therefor could not be analysed for time to viral rebound. Therefore the number in this group is 15 in stead of 16 at start of the trial.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| iHIVARNA-01 | Change in Plasma Viral Load | -0.17 log10 copies/ml |
| TriMix | Change in Plasma Viral Load | -0.14 log10 copies/ml |
| Placebo | Change in Plasma Viral Load | 1.26 log10 copies/ml |
Secondary
Functional Cure
proportion of patients with viral load below detectable level of 50 copies/mL in plasma after ATI, week 18
Time frame: week 18
Population: One participant from the the iHIVARNA-01 group did not interrupt ART and therefor could not be analysed for time to viral rebound. Therefore the number in this group is 15 in stead of 16 at start of the trial.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| iHIVARNA-01 | Functional Cure | 0 Participants |
| TriMix | Functional Cure | 0 Participants |
| Placebo | Functional Cure | 0 Participants |
Secondary
Immunogenicity as Measured by Intracellular Cytokine Staining (ICS)
HIV-specific CD4+ and CD8+ T cell responses after immunization by the number of poly-functional T cells as determined by intracellular cytokine staining, (ICS).
Time frame: week 10, 18 and 30
Population: The data were not collected. In the protocol it was pre-specified, that ICS would not be done if Elispot results did not show immunogenicity of the study product. This analysis was not performed, because the results from the Elispot assay at the same time points showed no increase in the number of spot-forming units, also see primary outcome two.
Secondary
Primary Immune Response Against Vaccine
Change in frequency of at least 0.7log10 HIV-specific T-cell responses between baseline and week 6
Time frame: from baseline to week 6
| Arm | Measure | Value (MEAN) |
|---|---|---|
| iHIVARNA-01 | Primary Immune Response Against Vaccine | 0.01 delta log spot forming units |
| TriMix | Primary Immune Response Against Vaccine | 0.17 delta log spot forming units |
| Placebo | Primary Immune Response Against Vaccine | 2.65 delta log spot forming units |
Secondary
Proviral DNA Reservoir
effect on reservoir as measured by changes in the proviral DNA copy numbers per million cells during and after immunization
Time frame: day 0-90 (week 4, week 4 + 1 day and week 5 and week 6) and day 90-130 (week 18) and day >130 (week 30)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| iHIVARNA-01 | Proviral DNA Reservoir | proviral DNA 90-130 days | 0.004 delta log copies DNA /10E6 cel |
| iHIVARNA-01 | Proviral DNA Reservoir | proviral DNA 0-90 days | -0.002 delta log copies DNA /10E6 cel |
| iHIVARNA-01 | Proviral DNA Reservoir | proviral DNA >130 days | -0.001 delta log copies DNA /10E6 cel |
| TriMix | Proviral DNA Reservoir | proviral DNA 90-130 days | 0.004 delta log copies DNA /10E6 cel |
| TriMix | Proviral DNA Reservoir | proviral DNA 0-90 days | -0.001 delta log copies DNA /10E6 cel |
| TriMix | Proviral DNA Reservoir | proviral DNA >130 days | -0.002 delta log copies DNA /10E6 cel |
| Placebo | Proviral DNA Reservoir | proviral DNA 0-90 days | 0.007 delta log copies DNA /10E6 cel |
| Placebo | Proviral DNA Reservoir | proviral DNA >130 days | -0.003 delta log copies DNA /10E6 cel |
| Placebo | Proviral DNA Reservoir | proviral DNA 90-130 days | -0.003 delta log copies DNA /10E6 cel |
Secondary
Time to Viral Rebound
time until viral rebound (defined as two consecutive measurements of plasma viral load \> 1000 copies/mL separated by at least 15 days) after discontinuation at week 6.
Time frame: week 6-18
Population: One participant from the the iHIVARNA-01 group did not interrupt ART and therefor could not be analysed for time to viral rebound. Therefore the number in this group is 15 in stead of 16 at start of the trial.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| iHIVARNA-01 | Time to Viral Rebound | 50 days |
| TriMix | Time to Viral Rebound | 55.5 days |
| Placebo | Time to Viral Rebound | 58 days |
Secondary
Transcriptomics
host protein mRNA expression profiles in whole blood
Time frame: week 6 and 18
Population: data were not collected
Secondary
Viral Immune Escape
viral immune escape: change in % mutated epitopes from pre-cART to post-ATI
Time frame: week 18
Population: data were not collected