HIV Infection
Conditions
Keywords
HIV, Vaccine, Immune Therapy, DermaVir
Brief summary
* DermaVir is a plasmid DNA-containing synthetic nanomedicine. It is administered topically with DermaPrep to target Langerhans cells. Langerhans cells with DermaVir migrate to lymph nodes and express HIV-like particles that induce immune responses to kill HIV-infected cells. * Hypothesis: Single DermaVir immunization is safe and immunogenic measured by induction of HIV-specific precursor/memory T cell responses. * GIHU004 was a phase I dose escalation study conducted in Hungary. It evaluated the safety and immunogenicity of three dosing regimens of topical DermaVir immunization for the treatment of HIV-infected individuals on fully suppressive highly active antiretroviral therapy (HAART).
Detailed description
This study enrolled nine HIV-infected adult subjects in three sequential dose cohorts. All had durable suppression of HIV-RNA on HAART over the previous 6 months and CD4 count over 300 cells/mm3. Subjects, received on study Day 0 a single DermaVir immunization: * Low dose: 0.1 mg pDNA, 0.8 mL DermaVir administered under two DermaPrep patches. * Medium dose: 0.4 mg pDNA, 3.2 mL DermaVir administered under four DermaPrep patches. * High dose: 0.8 mg pDNA, 6.4 mL DermaVir administered under eight DermaPrep patches. Subjects were on study for a total of 28 days followed by a post-treatment safety follow-up for 48 weeks. HAART was not interrupted. All subjects completed the 28-day treatment and 48 weeks safety follow up phase.
Interventions
BIOLOGICALDermaVir
DermaVir is a synthetic pathogen-like nanomedicine. The active pharmaceutical ingredient is a plasmid DNA expressing fifteen HIV proteins that assemble into HIV-like particles. These particles are safe, cannot replicate, integrate or reverse transcribed. DermaVir is targeted to Langerhans cells with DermaPrep medical device. These DermaVir-containing Langerhans cells migrate to the lymph nodes, where induce HIV-specific cytotoxic T cells that can recognize and kill HIV-infected cells.
DRUGHAART
Three or more antiretroviral drugs that can fully suppress HIV RNA
Sponsors
Genetic Immunity
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Ability and willingness of subject or legal guardian/representative to give written informed consent * HIV-1 infection, as documented by any licensed ELISA test kit and confirmed by Western blot, HIV-1 culture, HIV-1 antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA * On a stable antiretroviral regimen without changes or interruptions for at least 12 weeks prior to study entry * Plasma HIV-1 RNA level of less than 50 copies/mL, obtained at least twice within the 12 weeks prior to study entry * Peak plasma HIV-1 RNA level before initiation of HAART \> 1000 copies/mL * CD4 cell count \> 300 cells/mm3 within the 12 weeks prior to study entry * Nadir (lowest) CD4+ cell count \> 250 cells/mm3 at any time prior to study entry * The following laboratory values, obtained within 30 days prior to study entry: * Absolute neutrophil count (ANC) \> 1000/mm3 * Hemoglobin \> 9.0 g/dL * Platelet count \> 50,000/mm3 * Serum creatinine \< upper limit of the laboratory normal range (ULN) * AST (SGOT), ALT (SGPT), and alkaline phosphatase \< 2.5 x ULN * Total bilirubin \< 2.5 x ULN * Anti-nuclear antibody (ANA) titer of 1:40 or lower and negative for serum anti-double-stranded DNA antibody (anti-ds-DNA) test result at screening. * All women of reproductive potential must have a negative urine beta-HCG pregnancy test performed within 14 days prior to study entry. * Female study volunteers who are not of reproductive potential or whose male partner has undergone successful vasectomy are eligible without requiring the use of contraception. Acceptable documentation of menopause, sterilization, and azoospermia is written or oral documentation communicated by clinician. * All subjects must not participate in a conception process (e.g. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) and, if participating in sexual activity that could lead to pregnancy, the study volunteer/ partner must use two reliable methods of contraception simultaneously while receiving the protocol-specified vaccination and for 3 months after the last vaccination. * Karnofsky performance score \> 90 within 30 days prior to study entry * Men and women age 18-50 years
Exclusion criteria
* Viral load measurement \> 50 copies/mL within the last 12 weeks prior to study entry * History of or evidence of active skin disease (e.g. atopic dermatitis), chronic autoimmune disease or any other significant active skin disease * Treatment with topical corticosteroids in close proximity to the proposed vaccination sites within 2 weeks prior to study entry * Excessive exposure to the sun (e.g. sunbathing) within 2 weeks prior to study entry * Use of any local skin treatments to the targeted vaccination sites within 7 days prior to study entry * History of diabetes and bleeding disorders * Previous CDC category C event * Pregnancy or breast-feeding * Use of immunomodulating therapy, including cyclosporin, IgG-containing products, interleukins, interferons, systemic glucocorticosteroids, or exposure to an experimental HIV vaccine within 6 months prior to study entry * Receipt of any vaccine within 30 days prior to study entry * Allergy/sensitivity to study vaccine products, including adhesives, will be excluded * Active drug or alcohol use or dependence * Serious illness until subject either completes therapy or is clinically stable on therapy, in the opinion of the site investigator, for at least 14 days prior to study entry * Hepatitis B surface antigen and/or anti-hepatitis C positive
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3 Adverse Event Related to DermaVir Treatment | 28 days | Occurrence of at least one grade 3 or higher adverse event including signs/symptoms, laboratory toxicities and clinical events possibly, probably or definitely related to study treatment as judged by the Principal Investigator or the site investigators during the 28 days after DermaVir administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CD4+ T Cell Counts/mm3 | 28 days | — |
| Number of Subjects With Detectable Anti-ds Antibody and ANA | 28 days | — |
| Number of Subjects Having More Than 50 Copies/mL HIV RNA | 28 days | — |
| Change in HIV-specific Memory T Cell Responses at Day 28 Compare to Baseline | 28 days | HIV-specific T cell precursors with high proliferative capacity (PHPC) were quantified as described earlier \[Calarota et al. J Immunol 2008\]. Gag-, Tat- and Rev-specific T cells were measured representing ca. 25% of HIV epitopes included in DermaVir. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in HIV-specific Memory T Cell Responses at Week 48 | 48 weeks | HIV-specific T cell precursors with high proliferative capacity (PHPC) were quantified as described earlier \[Calarota et al. J Immunol 2008\]. Gag-, Tat- and Rev-specific T cells were measured representing ca. 25% of HIV epitopes included in DermaVir. Note, group Single low-dose was measured at 24 weeks, for this group the 48 weeks data is not available |
Countries
Hungary
Participant flow
Recruitment details
Nine subjects were sequentially enrolled into each cohort. Participants were recruited from the Szent László Hospital, Budapest, Hungary.
Pre-assignment details
The first three subjects received a single low-dose DermaVir immunization. Further enrolment of subjects into the medium and high dose cohorts began only after the safety data for cohorts low and medium doses, respectively were available, and the criteria for enrolling into the next cohort were met.
Participants by arm
| Arm | Count |
|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization Single low-dose DermaVir immunization
* 0.1 mg pDNA/subject, 0.8 mL total volume of DermaVir
* Administered topically with DermaPrep under two skin patches (0.4 mL/patch) | 3 |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization Single medium-dose DermaVir immunization
* 0.4 mg pDNA/subject, 3.2 mL total volume of DermaVir
* Administered topically with DermaPrep under four skin patches (0.8 mL/patch) | 3 |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization Single high-dose DermaVir immunization
* 0.8 mg pDNA/subject, 6.4 mL total volume of DermaVir
* Administered topically with DermaPrep under eight skin patches (0.4 mL/patch) | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | 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 | 3 Participants | 3 Participants | 3 Participants | 9 Participants |
| Age Continuous | 34 years STANDARD_DEVIATION 4 | 36 years STANDARD_DEVIATION 9 | 45 years STANDARD_DEVIATION 4.3 | 38 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment Hungary | 3 participants | 3 participants | 3 participants | 9 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 1 / 3 | 2 / 3 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 3 |
Outcome results
Primary
Grade 3 Adverse Event Related to DermaVir Treatment
Occurrence of at least one grade 3 or higher adverse event including signs/symptoms, laboratory toxicities and clinical events possibly, probably or definitely related to study treatment as judged by the Principal Investigator or the site investigators during the 28 days after DermaVir administration.
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | Grade 3 Adverse Event Related to DermaVir Treatment | 0 participants |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Grade 3 Adverse Event Related to DermaVir Treatment | 0 participants |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Grade 3 Adverse Event Related to DermaVir Treatment | 0 participants |
Secondary
CD4+ T Cell Counts/mm3
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | CD4+ T Cell Counts/mm3 | 893 CD4+ T cell counts/mm3 | Standard Deviation 461 |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | CD4+ T Cell Counts/mm3 | 845 CD4+ T cell counts/mm3 | Standard Deviation 68 |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | CD4+ T Cell Counts/mm3 | 621 CD4+ T cell counts/mm3 | Standard Deviation 185 |
Secondary
Change in HIV-specific Memory T Cell Responses at Day 28 Compare to Baseline
HIV-specific T cell precursors with high proliferative capacity (PHPC) were quantified as described earlier \[Calarota et al. J Immunol 2008\]. Gag-, Tat- and Rev-specific T cells were measured representing ca. 25% of HIV epitopes included in DermaVir.
Time frame: 28 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Day 28 Compare to Baseline | 325 PHPC count | Standard Deviation 266 |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Day 28 Compare to Baseline | 136202 PHPC count | Standard Deviation 162287 |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Day 28 Compare to Baseline | 50759 PHPC count | Standard Deviation 44792 |
Secondary
Number of Subjects Having More Than 50 Copies/mL HIV RNA
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | Number of Subjects Having More Than 50 Copies/mL HIV RNA | 0 participants |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Number of Subjects Having More Than 50 Copies/mL HIV RNA | 0 participants |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Number of Subjects Having More Than 50 Copies/mL HIV RNA | 0 participants |
Secondary
Number of Subjects With Detectable Anti-ds Antibody and ANA
Time frame: 28 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | Number of Subjects With Detectable Anti-ds Antibody and ANA | 0 participants |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Number of Subjects With Detectable Anti-ds Antibody and ANA | 0 participants |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Number of Subjects With Detectable Anti-ds Antibody and ANA | 0 participants |
Other Pre-specified
Change in HIV-specific Memory T Cell Responses at Week 48
HIV-specific T cell precursors with high proliferative capacity (PHPC) were quantified as described earlier \[Calarota et al. J Immunol 2008\]. Gag-, Tat- and Rev-specific T cells were measured representing ca. 25% of HIV epitopes included in DermaVir. Note, group Single low-dose was measured at 24 weeks, for this group the 48 weeks data is not available
Time frame: 48 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single Low-dose (0.1 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Week 48 | 3899 PHPC count | Standard Deviation 869 |
| Single Medium-dose (0.4 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Week 48 | 9878 PHPC count | Standard Deviation 10257 |
| Single High-dose (0.8 mg pDNA/Subject) DermaVir Immunization | Change in HIV-specific Memory T Cell Responses at Week 48 | 18382 PHPC count | Standard Deviation 21477 |