Immunologic and Virologic Parameters During Analytical Treatment Interruption Following Combination bNAb Therapy During Suppressive ART
- Conditions
- HIV
- Registration Number
- NCT06908083
- Brief Summary
Background:
Recent studies have shown bNAbs may help remove cells that are infected with HIV (HIV reservoir) from the body and may also change how the immune system fights HIV.
Objective:
The purpose of this research study is to see if and when HIV levels in the blood (viral load) rise after the participant stops their HIV medication. We will also measure the highest number (peak) of the virus before each participant starts their HIV medications again. For most people treated with standard HIV medications, the HIV virus amount will increase within 2 to 4 weeks after stopping their HIV medications. This study is only open to participants who have taken part in an earlier study (MCA-1034 or NIH number 001037). In the earlier study, participants either received a combination of 3BN117-LS and 10-1074-LS (two anti-HIV monoclonal antibodies) OR received placebo (salt water). In this new study, researchers will compare the participants who received the antibodies to those who did not to see what effect the antibodies may have had on the HIV reservoir.
Researchers will also look at:
* side effects people may have when they stop their HIV medications.
* changes in the number of blood cells carrying inactive HIV (the HIV reservoir size).
* the blood cells that can clear HIV before, following temporarily stopping, and after re-starting HIV medications.
* how well HIV may be controlled after a participant stops their HIV medication.
Eligibility:
People aged 18 to 70 years with HIV who completed protocol MCA-1034 (NIH Study 001037).
Design:
Participants will be screened. They will have a physical exam. They will answer questions about their health. Blood samples will be taken.
Participants will stop their HIV medications for a period of time. They will have blood tests every 2 weeks and clinic visits every 4 weeks for 24 weeks to check their HIV levels and to make sure they are not having side effects. There will be strict safety rules for restarting HIV medications. Some participants whose HIV levels remain low at 24 weeks may continue without ART for another 24 weeks; they will have blood tests every 2 to 4 weeks.
Participants may undergo leukapheresis up to 3 times: Leukapheresis is a several hours long procedure in which blood is collected from a vein in one arm, processed through an attached machine, and then returned to the person through a vein in the opposite arm.
Participants will have 4 follow-up visits over 24 weeks after they restart ART.
Participants will remain in the study up to 18 months.
- Detailed Description
Study Description:
This is an exploratory study to evaluate virologic and immunologic parameters during analytical treatment interruption (ATI) in people
with HIV (PWH) who participated in protocol MCA-1034 (NIH # 001037), which evaluated HIV-1 reservoir dynamics in peripheral blood during combination bNAb therapy plus ART or ART alone. MCA-1034 participants will be invited to participate in this study after completing all MCA-1034 follow up visits. MCA-1034 treatment assignment will not be known at enrollment in this study until unblinding of MCA-1034 occurs. Under MCA-1034, participants will have received two intravenous infusions of 3BNC117-LS (dosed at 30 mg/kg) and 10-1074-LS (dosed at 10 mg/kg) or placebo at weeks 0 and 20 while on standard ART and will have completed 80 weeks of follow up after the first antibody infusions. Participants will be eligible to enter this study from 12 to 24 weeks after the last MCA-1034 study visit.
Participants who enroll in this study will discontinue ART at study entry (week 0/day 0) and will be followed every other week until meeting pre-defined ART restart criteria. The ATI period will last up to 24 weeks (Step 1 weeks 0-24). Participants who do not meet ART restart criteria will be offered to remain off ART until meeting ART restart criteria for up to 24 additional weeks with monitoring every 4 weeks, unless HIV-1 RNA is \>= 200 copies/ml when monitoring will occur every 2 weeks (Step 2 weeks 25-48; i.e. maximum ATI period of 48 weeks).
At the end of the ATI period, all participants will be advised to resume ART even if they have not experienced return of viremia. Participants who experience return of viremia and/or meet ART resumption criteria will be followed for 24 weeks after resuming ART.
Objectives:
Primary Objectives:
- To evaluate the kinetics of plasma viral rebound during ATI in PWH who participated in protocol MCA-1034 (NIH # 001037) and received combination bNAb or placebo during suppressive ART.
Secondary Objectives:
* To evaluate the occurrence of adverse events following ART discontinuation.
* To evaluate changes in HIV-1 reservoir size in peripheral blood prior to, following ATI and after re-initiation of ART.
* To evaluate HIV-1 specific cellular immune responses prior to, following ATI and after re-initiation of ART.
* To evaluate levels of immune exhaustion and immune activation prior to, following ATI and after re-initiation of ART.
Exploratory Objectives:
* To evaluate the degree (magnitude) of plasma viral rebound during ATI in PWH who participated in protocol MCA-1034 (NIH # 001037) and received combination bNAb or placebo during suppressive ART.
* To characterize the HIV-1 reservoir clonal composition in peripheral blood prior to, following ATI and after re-initiation of ART.
* To characterize host HIV-1 specific humoral and cellular immune responses prior to, following ATI and after reinitiation of ART.
* To genotypically and phenotypically characterize plasma rebound viruses.
* To correlate virologic outcomes with bNAb sensitivity of reservoir proviruses.
* To correlate virologic and immunologic outcomes with time to meeting ART restart criteria.
Endpoints: Primary Endpoint:
- The difference in the time to meet criteria to restart ART between protocol MCA-1034 bNAb and placebo recipients.
Secondary Endpoints:
* The difference in peak plasma viremia from ART discontinuation to meeting ART restart criteria between protocol MCA-1034 bNAb and placebo recipients.
* The occurrence of grade 3 or higher adverse events (AE) (including confirmed laboratory abnormalities) that are possibly, probably, or definitely related to ART discontinuation.
* The occurrence of serious adverse events, regardless of relationship to ART discontinuation.
* Change in the intact proviral reservoir size, measured by droplet digital PCR (ddPCR) or intact proviral deoxyribonucleic acid assay (IPDA) prior to, following ATI and after re-initiation of ART.
* Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by enzyme-linked immunospot (ELISpot) or intracellular cytokine staining (ICS) prior to, following ATI and after re-initiation of ART.
* Changes in immune exhaustion and immune activation cellular or soluble markers by flow cytometry or by ELISA methods prior to, following ATI and after re-initiation of ART.
Exploratory Endpoints:
* Clonal composition of the intact proviral reservoir before and after immunotherapy with 3BNC117-LS and 10-1074-LS during suppressive ART by quadruplex polymerase chain reaction (Q4PCR) or other appropriate assays that may become available prior to, following ATI and after re-initiation of ART.
* HIV-1 transcriptional activity as determined by spliced and unspliced HIV-1 ribonucleic acid (RNA) in circulating total CD4+ T cells and/or other appropriate assays prior to, following ATI and after re-initiation of ART.
* Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by assays such as epitope mapping, proliferation and viral inhibition assays prior to, following ATI and after re-initiation of ART.
* Changes in binding capacity and neutralizing activity of autologous antibody responses to pre-ATI and post-ATI proviruses and rebound plasma viruses.
* Env sequencing and neutralization sensitivity of plasma rebound viruses to 3BNC117-LS, 10-1074-LS and autologous IgG by TZM/bl.
* Correlation between bNAb sensitivity of baseline proviruses (i.e. MCA-1034 entry) and virological outcomes (e.g. time to meeting ART restart criteria and peak viremia during ATI).
* Correlation between pre-ATI virological (e.g. proviral reservoir size and transcriptional activity) and immunological measures (e.g. magnitude, breadth and functionality of HIV-1 specific T cell immune responses, and autologous neutralization titers) and time to meeting ART restart criteria.
Recruitment & Eligibility
- Status
- ENROLLING_BY_INVITATION
- Sex
- All
- Target Recruitment
- 50
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method Time to Restart ART Week 0 until Week 48 or when participant meets restart criteria Difference in number of days from stopping ART (Day 0) until participant meets restart criteria between MCA-1034/001037 (NIH) bNAb and placebo recipients
- Secondary Outcome Measures
Name Time Method Difference in Peak Plasma Viremia Week 0 until Week 48 or when participant meets restart criteria Number of grade 3 or higher adverse events that occur during Analytical Treatment The difference in peak plasma viremia from Week 0 until week 48 or when participant meets restart criteria between MCA-1034/001037 (NIH) bNAb and placebo recipients
Frequency of Grade 3 or higher Adverse Events Week 0 until Week 48 or when participant meets restart criteria Number of grade 3 or higher adverse events that occur during Analytical Treatment Interruption that are possibly, probably, or definitely related.
Frequency of Serious Adverse Events Week 0 until Week 48 or when participant meets restart criteria Number of serious adverse events that occur during the Analytical Treatment Interruption regardless of relatedness
Change in intact proviral reservoir size Throughout Change in the intact proviral reservoir size, measured by droplet digital PCR (ddPCR) or intact proviral deoxyribonucleic acid assay (IPDA) prior to, following ATI, and after re-initiation of ART.
Changes in HIV-1 Specific T Cell Immune Responses in Peripheral Blood Throughout Changes in HIV-1 specific T cell immune responses in peripheral blood, measured by enzyme-linked immunospot (ELISpot) or intracellular cytokine staining (ICS) prior to, following ATI, and after re-initiation of ART.
Changes in immune exhaustion and immune activation cellular or soluble markers Throughout Changes in immune exhaustion and immune activation cellular or soluble markers by flow cytometry or by ELISA methods prior to, following ATI, and after re-initiation of ART.
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Trial Locations
- Locations (2)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
Rockefeller Institute
🇺🇸New York, New York, United States