Analytical Treatment Interruption (ATI) to Assess the Immune System's Ability to Control HIV in Participants Who Became HIV-infected During the HVTN 703/HPTN 081 AMP Study

Antiretroviral Analytical Treatment Interruption (ATI) to Assess Immunologic and Virologic Responses in Participants Who Initiated ART in Early HIV Infection After Having Received VRC01 or Placebo in HVTN 703/HPTN 081

Status

Completed

Phases

Unknown

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04860323

Enrollment

Registered

2021-04-26

Start date

2021-05-28

Completion date

2025-02-04

Last updated

2026-03-13

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HIV Infection

Keywords

HIV, Antibody, LTNPs, ECs, VCs, Treatment interruption

Brief summary

The purpose of this study is to learn whether having the AMP Study antibody (called VRC01) in a person's body might help their immune system control HIV better, even without HIV medication called antiretroviral therapy or ART, if they get HIV. This study will evaluate the viral and immune system responses in an Analytical Treatment Interruption (ATI), in participants who received VRC01 or placebo and got HIV while enrolled in HVTN 703/HPTN 081 (NCT02568215). Participants in this study will stop taking their HIV medication. They will stay off HIV medication unless and until the HIV levels in their blood show that their immune system is unable to control the HIV or they meet other ART re-start criteria as noted in section "Detailed Description". While they are not taking HIV medication, their HIV levels will be tested frequently, and their health will be monitored closely. This is called an analytical treatment interruption, or an ATI. An ATI is an experimental procedure that is only used in carefully monitored research.

Detailed description

The purpose of this study is to evaluate immunologic and virologic responses in an Analytical Treatment Interruption (ATI), in participants who received VRC01 or placebo and got HIV while enrolled in the HVTN 703/HPTN 081 Antibody-Mediated Prevention (AMP) Study (NCT02568215). ATI begins with the cessation of ART on Schedule 1 (Monitoring ATI). Participants on Schedule 1 will attend study visits every week for the first 8 weeks and at least every 2 weeks for the next 16 weeks. After that, participants will attend study visits once a month for the next 6 months, if their body is controlling their HIV without ART. Participants on Schedule 1 for more than a year will have visits every 3 months. For participants on Schedule 1 (Monitoring ATI), a confirmed VL ≥ 200 copies/mL will trigger transition to Schedule 2 (ATI monitoring with viremia). Participants on Schedule 2 will attend study visits every week for the first 8 weeks and at least every 2 weeks for the next 28 weeks. After that, participants will attend study visits once a month for the next 4 months, if their body is controlling their HIV without ART. Participants on Schedule 2 for more than a year will have visits every 3 months. For participants on Schedule 1 (Monitoring ATI), any of the following non-virologic criteria will trigger re-initiation of ART and transition to Schedule 3 (Follow-up on ART): confirmed CD4+ T-cell count \< 350 cells/mm3, any HIV-related syndrome, pregnancy or breastfeeding, or ART re-initiation requested by participant or if deemed medically necessary by primary HIV provider or clinical research site Investigator of Record. Participants on Schedule 3 will attend study visits every 2 weeks for the first 12 weeks, once a month for the next 16 weeks, and on 2 occasions 3 months apart for the next 24 weeks. For participants on Schedule 2 (ATI monitoring with viremia), the following virologic criteria will trigger re-initiation of ART and transition to Schedule 3 (Follow-up on ART): viral load remains ≥ 1,000 copies/mL for ≥ 4 consecutive weeks AND viral load has not dropped 0.5 log from the previous week (Week 0 - Week 24), confirmed viral load ≥ 200 copies/mL (after Week 24). Or, the following non-virologic criteria will trigger re-initiation of ART and transition from Schedule 2 (ATI monitoring with viremia) to Schedule 3 (Follow-up on ART): confirmed CD4+ T-cell count \< 350 cells/mm3, any HIV-related syndrome, pregnancy or breastfeeding, or ART re-initiation requested by participant or if deemed medically necessary by primary HIV provider or clinical research site Investigator of Record. Study duration is potentially indefinite for participants maintaining extended viral control during ATI. Study duration for most participants is expected to be 13-18 months. The maximum anticipated duration for any participant is expected to be approximately 2 1/2 to 3 years. Visits may include medical history review, physical exam, HIV testing, other STI testing (blood, urine, and cervical/vaginal swab collection), blood draws, pregnancy testing for participants that can become pregnant, HIV transmission risk reduction counseling, and interviews/questionnaires.

Interventions

OTHERAnalytical Treatment Interruption

Participants will stop taking their HIV medication and will stay off HIV medication unless and until the HIV levels in their blood show that their immune system is not controlling their HIV or they meet other ART re-start criteria as noted in section "Detailed Description".

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Eligibility

Sex/Gender

ALL

Healthy volunteers

Inclusion criteria

* Estimated date of HIV-1 acquisition within 8 weeks (ie, before or after) having received an HVTN 703/HPTN 081 infusion. * Initiated ART within 28 weeks of HVTN 703/HPTN 081 date of HIV-1 diagnosis. * Receiving continuous ART for at least 1 year. ART interruptions of up to 7 days in duration and ≥ 90 days prior to enrollment are acceptable. Within- and between-class changes in ART within the previous year are acceptable. * If on an NNRTI, willingness and ability to switch to a PI- or INSTI-containing regimen for at least 4 weeks prior to ART interruption. * Willingness to interrupt ART for up to 24 weeks or up to the time of meeting ART re-initiation criteria. * Willingness to re-initiate ART upon meeting study ART re-initiation criteria. * Willingness to use barrier protection (ie, male or female condoms) for all sexual activity during ATI and until confirmation of viral suppression following ART re-initiation. * Willingness for CRS staff to contact primary HIV care provider to exchange information regarding HVTN 805/HPTN 093 and participant medical history. * Site investigator anticipates that a fully active alternative ART regimen could be constructed and would be available in the event of virologic failure on the participant's current ART regimen. * Access to a participating CRS and willingness to adhere to study visit schedule and to be followed for the planned duration of the study. * Ability and willingness to provide informed consent. * Assessment of understanding: volunteer demonstrates understanding of this study; completes a questionnaire prior to enrollment with verbal demonstration of understanding of all questionnaire items answered incorrectly. * Agrees not to enroll in another study of an investigational research agent for the duration of the participant's trial participation. Laboratory Inclusion Values: Immunology/Virology * HIV-1 infection, with reactive HIV-1 antibody and any Multispot or Geenius HIV-1/HIV-2 results, documented by the HVTN 703/HPTN 081 HIV diagnostic algorithm. * Plasma HIV-1 RNA ≥ 1,000 copies/mL by any assay, prior to initiating ART. * CD4+ T cell count ≥ 450 cells/mm3 obtained within 90 days prior to enrollment. * One plasma HIV-1 RNA below the lower limit of quantitation (LLOQ) of an VQA-certified or DAIDS-approved assay and collected at each of the following: * at screening, within 90 days prior to enrollment; and * greater than 9 months prior to the screening HIV-1 RNA. Note: Sites must have results from locally available assays that are approved as standard-of-care by their regional governing bodies. Hematology * Hemoglobin (Hgb) ≥ 10.0 g/dL * Absolute neutrophil count (ANC) ≥ 750 cells/mm3 * Platelets ≥ 100,000 cells/mm3 Chemistry * Alanine aminotrasferase (ALT) \< 2.5 times the institutional upper limit of normal and direct bilirubin within the institutional range of normal. * Estimated glomerular filtration rate (eGFR) \> 60 mL/min/1.73m2 Reproductive Status * Volunteers capable of becoming pregnant: negative serum or urine beta human chorionic gonadotropin (β-HCG) pregnancy test performed at the screening visit and prior to enrollment. Persons who are NOT capable of becoming pregnant due to having reached menopause (no menses for 1 year) or having undergone total hysterectomy or bilateral oophorectomy or tubal ligation (verified by medical records) are not required to undergo pregnancy testing. * Reproductive status: A volunteer who is capable of becoming pregnant must agree to consistently use effective contraception (ie, IUD or hormonal) for sexual activity that could lead to pregnancy from at least 21 days prior to enrollment through confirmation of viral suppression following ART re-initiation. * Volunteers capable of becoming pregnant must also agree not to seek pregnancy through alternative methods, such as artificial insemination or in vitro fertilization, until after confirmation of viral suppression following ART re-initiation.

Exclusion criteria

* Any plasma HIV-1 RNA ≥ LLOQ of VQA-certified or DAIDS-approved assay (LLOQ: 75, 50, 40, or 20 copies/mL) within 12 months prior to enrollment. NOTE: Two "blips" (ie, plasma HIV-1 RNA \> LLOQ) \< 400 copies/mL are allowed if preceded and followed by values \< LLOQ and if the blips occur more than 6 months prior to enrollment. Note: Sites must have results from locally available assays that are approved as standard-of-care by their regional governing bodies. * History of AIDS-defining illnesses or US Centers for Disease Control (CDC) Category C events per the current list on the CDC website. * Autoimmune disease, including Type I diabetes mellitus (Not excluded from participation: Volunteer with mild, stable and uncomplicated autoimmune disease that does not require consistent immunosuppressive medication and that, in the judgment of the site investigator, is likely not subject to exacerbation and likely not to complicate AE assessments). * Immunosuppressive medications received within 6 months before enrollment (Not exclusionary: \[1\] corticosteroid nasal spray; \[2\] inhaled corticosteroids; \[3\] topical corticosteroids for mild, uncomplicated dermatologic condition; or \[4\] a single course of oral/parenteral prednisone or equivalent at doses \< 60 mg/day and length of therapy \< 11 days with completion at least 30 days prior to enrollment). * Blood products received within 120 days before planned ART interruption. * Investigational research agents, other than experimental vaccine(s), received within 30 days before planned ART interruption. * HIV or non-HIV experimental vaccine(s) received within the last 1 year. Exceptions may be made by the HVTN 805/HPTN 093 PSRT for vaccines that have subsequently undergone licensure by the FDA or by the national regulatory authority where the volunteer is enrolling. For volunteers who have received control/placebo in an experimental vaccine trial, the HVTN 805/HPTN 093 PSRT will determine eligibility on a case-by-case basis. For volunteers who have received an experimental vaccine(s) greater than 1 year ago, eligibility for enrollment will be determined by the HVTN 805/HPTN 093 PSRT on a case-by-case basis. * Licensed live attenuated vaccines received within 30 days before planned ART interruption (eg, measles, mumps, and rubella \[MMR\]; oral polio vaccine \[OPV\]; varicella; yellow fever; live attenuated influenza vaccine). * Licensed vaccines that are not live attenuated vaccines received within 14 days before planned ART interruption (eg, tetanus, pneumococcal, hepatitis A or B, influenza). * Receipt of any emergency-use authorized, WHO emergency use listed, licensed or registered SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) vaccine within 4 weeks before planned ART interruption. Note: SARS-CoV-2 vaccination is not required for HVTN 805/HPTN 093 eligibility * Significant or unstable cardiac or cerebrovascular disease (eg, angina, congestive heart failure \[CHF\], recent cerebrovascular accident \[CVA\], or myocardial infarction \[MI\]). * Positive Hepatitis B surface antigen (HBsAg) or positive HCV RNA (Not exclusionary: positive HCV Ab with negative HCV RNA). * Pregnant or breastfeeding * Volunteers who have: * a SARS-CoV-2 positive test (direct viral detection, eg, viral nucleic acid or antigen detection) ≤ 14 days of enrollment, if asymptomatic OR * unresolved COVID-19 (ie, SARS-CoV-2 positive test AND symptoms) ≤ 14 days of enrollment (not excluded: individuals with symptoms consistent with residual sequelae of resolved COVID-19, in the clinical judgement of the investigator) * Clinically significant medical condition, physical examination findings, clinically significant abnormal laboratory results, or past medical history with clinically significant implications for current health. A clinically significant condition or process includes but is not limited to: * A process that would affect the immune response; * A process that would require medication that affects the immune response; * Any contraindication to repeated blood draws, including inability to establish venous access; * A condition that requires active medical intervention or monitoring to avert grave danger to the volunteer's health or well-being during the study period; or * Any condition specifically mentioned among the

Design outcomes

Primary

Measure	Time frame	Description
Time to Meeting Criteria for ART Re-initiation	Measured through participant's last visit on Schedule 1 or 2, up to 27 months.	From ART Re-Initiation Criteria form, calculated median and range of weeks of ATI meeting ART re-initiation criteria by HVTN 703/HPTN 081 treatment assignment. Note that participants with evidence of ARV use during ATI schedule are excluded
Frequency of Sustained Post-treatment HIV Control, Defined as ≥ 24 Weeks Off ART Without Meeting ART Re-initiation Criteria	Measured at week 24 of schedule 1- monitoring ATI	From ART Re-Initiation Criteria form, counts number of participants with ≥ 24 weeks of ART without meeting ART re-initiation criteria by HVTN 703/HPTN 081 treatment assignment. Note that participants with evidence of ARV use in ATI monitoring schedule are excluded from the analysis
Percentage of Participants Who Experience Adverse Events (AEs)	Measured through participant's last study visit, up to 39 months.	Graded according to the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017
Number of Participants Reporting Serious Adverse Events (SAEs)	Measured through participant's last study visit, up to 39 months.	Graded according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017
Percent of Participants Who Discontinue ATI	Measured through participant's last visit on Schedule 1 or 2, up to 27 months	Tabulated by reason and HVTN 703/HPTN 081 treatment group. Note that 1. participants (N= 2) with evidence of ARV use during ATI schedule are excluded; 2. Participants may meet more than one ART re-initiation criterion.
Number of Local Laboratory Values Meeting Grade 2 AE Criteria or Above	Measured through participant's last study visit, up to 39 months	The number (percentage) of participants with lab grade \> 1 for alanine aminotransferase (ALT), Estimated Glomerular Filtration Rate (eFGR), Absolute Neutrophil Count, Direct Bilirubin, Hemoglobin, Platelets was summarized by arm. Only measurements with at least 1 record of grade 2 AE or above were shown in the table.

Secondary

Measure	Time frame	Description
Cumulative Incidence of Participants With First Viral Load ≥ 200 Copies/mL at Week 8, 16, and 24 of Schedule 1: Monitoring ATI	Measured for participants undergoing ATI at week 8, 16, and 24	The number (percentage) of participants with first viral load \>= 200 by Schedule 1 week 8, 16, and 24. 2 Participants from VRC01 10mg/kg group with evidence of ARV use during ATI schedule are excluded. Given only 3 VRC01 10mg/kg participants followed ATI schedule, VRC01 treatment arms are grouped in this analysis.
Response Rate of HIV-specific CD4+ and CD8+ T-cells	Measured through participant's last study visit, up to 39 months	The four entries in each table were the number of cells positive for IFN-γ and/or IL-2 for both the stimulated and the negative control data. If both negative control replicates were included, then the average number of total cells and the average number of positive cells were used. A one-sided Fisher's exact test was applied to the table, testing whether the number of cytokine-producing cells for the stimulated data was equal to that for the negative control data. Since multiple individual tests (for each peptide pool) were conducted simultaneously, a multiplicity adjustment was made to the two individual peptide pool p-values considered, using the Bonferroni-Holm adjustment method. If the adjusted p-value for a peptide pool was ≤ 0.00001, the response to the peptide pool for the T-cell subset was considered positive. If at least one peptide pool for a specific HIV-1 protein was positive, then the overall response to the protein was considered positive.
Magnitude of HIV-specific CD4+ and CD8+ T-cells	Measured through participant's last study visit, up to 39 months	PBMC samples were stimulated with synthetic peptide pools or left unstimulated as a negative control. For each sample, T-cell subset, and peptide pool, response magnitude is % cells expressing cytokines (IFNy and/or IL-2) after peptide stimulation minus % cells expressing markers after no stimulation.
Magnitude of Neutralizing Antibodies (nAb) Responses Against Autologous and Global HIV Panel Isolates	Measured at schedule 1 visit 4 (baseline, ATI initiation), schedule 3 visits 80 (ART re-initiation), 86 (12 weeks post ART re-initiation), and 89 (24 weeks post ART re-initiation)	NAb against HIV-1 were measured as a function of reductions in Tat-regulated luciferase (Luc) reporter gene expression in TZM-bl cells. Samples were processed using ART-Dex method to remove antiretrovirals in the specimens. An ART-resistant backbone was utilized to produce the viruses used for the study to further minimize potential virus inhibition by residual antiretrovirals. A titer was defined as the serum dilution that reduced relative luminescence units (RLUs) by 50% relative to the RLUs in virus control wells (cells + virus only) after subtraction of background RLU (cells only). Net titer was then calculated by subtracting the MLV values, where the titer was set to 25 if it is less then MLV titer. For T/F and rebound autologous isolates, if participants with multiple isolates detected at each dilution and timepoints, geometric means titer was calculated.
Non-neutralizing, FcγR-mediated Antibody Effector Functions Measured by ADCC	Measured through participant's last study visit, on average 15 months	Measured by ADCC
Non-neutralizing, FcγR-mediated Antibody Effector Functions Measured by ADCP	Measured through participant's last study visit, on average 15 months	Measured by ADCP
Non-neutralizing, FcγR-mediated Antibody Effector Functions Measured by Virion Capture	Measured through participant's last study visit, on average 15 months	Measured by virion capture
Frequency of Dendritic Cell Activation and Maturation Markers	Measured through participant's last study visit, up to 39 months	Peripheral blood mononuclear cells (PBMC) obtained as specified in AMP ATI protocols were used to examine the frequency of dendritic cells (DC) using a previously established DC high parameter flow cytometry panel that has been slightly modified to include Ki67, a marker of activation. This phenotyping was performed using PBMC that were thawed for the ICS assay for samples with sufficient cells for both ICS and phenotyping.
Frequency of T- and B-cell Activation and Exhaustion Markers	Measured through participant's last study visit, up to 39 months	Measured by flow cytometry or other cell phenotyping assays
Frequency of CD4+ T Cells Carrying Intact and/or Total Pro-viral HIV DNA, Replication Competent Virus, and/or Cell-associated HIV RNA	Measured through participant's last study visit, up to 39 months	Measured by Intact Proviral DNA Assay (IPDA), Tat/rev Induced Limiting Dilution Assay (TILDA), assays detecting replication-competent virus-bearing cells, and/or measures of total proviral DNA. Cell-associated HIV-RNA may be quantitated as a measure of the transcriptionally active reservoir.

Countries

Botswana, Malawi, South Africa, Zimbabwe

Contacts

STUDY_CHAIRShelly Karuna

HVTN Core, Fred Hutch

STUDY_CHAIRKatharine Bar

University of Pennsylvania

STUDY_CHAIRSimba Takuva