HIV/AIDS
Conditions
Brief summary
Combination approaches will almost certainly be required to generate durable control of HIV in the absence of antiretroviral therapy (a "remission"). In this study, 20 individuals will receive a combination regimen administered during ART and then undergo an analytic treatment interruption (ATI).
Detailed description
The investigators will perform a single arm study of twenty individuals with HIV infection on effective ART. All participants will receive a combination regimen administered during ART and then undergo an analytic treatment interruption. Our strategy has five stages 1. IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4 2. IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12 3. MVA/HIV62B (MVA62B) boost at Week 20 4. single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses) 5. ATI with single dose of VRC07 and 10-1074 at Week 34 Follow-up off ART will occur through at least Week 46 (expected) and on or off ART (depending on outcome) through Week 86. Should this approach work, viral load would be expected to rebound in all individuals a few weeks after the bNAb levels decrease to sub-therapeutic levels. This acute rebound would be followed by a new lower viral load set-point and perhaps a long-term remission.
Interventions
1. IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4 2. IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12 3. MVA/HIV62B (MVA62B) boost at Week 20 4. single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses) 5. ATI with single dose of VRC07 and 10-1074 at Week 34
Sponsors
University of California, San Francisco
amfAR, The Foundation for AIDS Research
International AIDS Vaccine Initiative
Ichor Medical Systems Incorporated
National Institute of Allergy and Infectious Diseases (NIAID)
Rockefeller University
Mologen AG
GeoVax, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 67 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. Willing and able to provide written informed consent. 2. Age ≤67 years at the time of enrollment for those who started treatment during early infection and \<65 years for those who started treatment during chronic infection. 3. Documented HIV-1 infection. 4. On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days within the last 1 year, and on a stable regimen that does not include an non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks, without plans to modify ART during the study period. 5. Screening plasma HIV RNA levels below the level of quantification on all available determinations in past 24 months. 6. Screening CD4+ T-cell count ≥ 500 cells/mm3. Key
Exclusion criteria
1. Subjects receiving a non-nucleoside reverse transcriptase inhibitor 2. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study 3. High-level resistance to both 10-1074 and VRC-07 as defined using the PhenoSense Neutralizing Antibody Assay (Monogram Biosciences). 4. Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers. 5. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months. 6. CD4+ T cell nadir \<350 cells/mm3 during the chronic phase of infection (beginning 6 months following the estimated infection date and confirmed on repeat testing). 7. Active hepatitis B (HBV) infection defined as positive HBV surface antigen test. 9\. Active hepatitis C (HCV) infection. 10. Presence of significant abnormalities on electrocardiogram. 11. History of potential immune-mediated medical conditions. Individuals with isolated Raynaud's phenomenon or localized disease requiring topical therapy alone will not be excluded.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Grade 3 or Greater Adverse Event Count | Week 0 through 102 | Number of participants who experience a new grade 3 or greater adverse event |
| Proportion of Participants Achieving Post-treatment Control | Week 34 through 86 | This will be defined as: 1. Participants who fail to show any consistent rebound above 400 copies RNA/mL between Week 12 of the ATI (when bNAb levels wane) and Week 36 of the ATI 2. Participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Any Grade 2, 3 or 4 Adverse Event Through Week 62 | Week 0 through 62 | Occurrence of any unsolicited adverse events for 28 days after administration of each study agent |
| Any Serious Adverse Events, Medically Attended Adverse Event, and Potentially Immune-mediated Medical Condition | Week 0 through 86 | Occurrence of any serious adverse events, medically attended adverse event, and potentially immune-mediated medical condition from the time of administration of the first study injection through 12 months after administration of the final study injection |
| Magnitude of T Cell Responses | Week 22 | We measured the magnitude of the CD8+ T cells to gag conserved elements (CE) 2 weeks after MVA boost (Week 22). We measured new or boosted pre-existing interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses. The magnitude was determined based on intracellular cytokine staining (ICS) by measuring the frequency of interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses after 6 hour stimulation with peptide pools matching the CE immunogen. |
| Breadth of T Cell Responses | Week 22 | We measured the breadth of the vaccine-induced T cell response after DNA/MVA vaccination (two weeks after the MVA boost; Week 22). We defined breadth based on the number of conserved epitope (CE) pools with a positive CD8+ T cell responses, as defined by measuring the frequency of interferon (IFN)ɣ+ Gag/CE-specific CD8+ T cell responses after 6 hour stimulation with peptide pools matching the CE immunogen (using intracellular cytokine staining, ICS). Seven smaller CE pools were tested on each sample. Positive responses were determined based on a magnitude of IFNg+ cells greater than 0.001% of CD8+ T cells after peptide stimulation and after subtraction of background responses. |
| Intact Provirus DNA Levels | Baseline to pre-interruption (week 34) | The HIV-1 DNA reservoir was estimated using digital droplet PCR (Intact Proviral DNA Assay; IPDA). The frequency of intact proviruses (per million CD4+ T cells) was estimated at baseline and prior to the antiretroviral treatment interruption (Week 34). The change from baseline to Week 34 was calculated. A decrease (negative number) is a better outcome. The units are intact genomes/million CD4+ T cells. |
Countries
United States
Participant flow
Recruitment details
The final study included ten individuals who had initiated ART during the acute, early, or chronic phase of HIV infection (defined as \<30 days, between 1-6 months, or ≥6 months following estimated date of acquisition; n = 3, 4, and 3 participants, respectively). Participants were recruited from local clinics.
Pre-assignment details
The study enrolled 11 individuals. The study was terminated early for one participant as one of the investigational products was set to expire before planned dosing. Ten individuals received the complete set of interventions.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants |
| Race/Ethnicity, Customized Mixed | 1 Participants |
| Race/Ethnicity, Customized White Non-Hispanic | 6 Participants |
| Region of Enrollment United States | 11 participants |
| Sex/Gender, Customized Female | 0 Participants |
| Sex/Gender, Customized Male | 10 Participants |
| Sex/Gender, Customized Prefer not to state | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 11 / 11 |
| serious Total, serious adverse events | 3 / 11 |
Outcome results
None listed