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

• ClinicalTrials.gov Identifier: NCT04860323
• Recruitment Status: Recruiting
• First Posted: April 26, 2021
• Last Update Posted: May 18, 2022
• Sponsor: HIV Vaccine Trials Network
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); HIV Prevention Trials Network; AIDS Clinical Trials Group
• Information provided by (Responsible Party): HIV Vaccine Trials Network

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV Infection	Other: Analytical Treatment Interruption	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: May 28, 2021
• Estimated Primary Completion Date: August 12, 2023
• Estimated Study Completion Date: August 12, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Analytical Treatment Interruption; Participants who received VRC01 or placebo and got HIV while enrolled in HVTN 703/HPTN 081 (NCT02568215).	Other: Analytical 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".

Outcome Measures

Primary Outcome Measures :

1. Time from the start of ATI to meeting ART re-initiation criteria [ Time Frame: Measured through participant's last visit on Schedule 1 or 2, on average 3 months ]
   Cumulative incidence of meeting ART re-initiation criteria
2. Percentage of participants who sustain post-treatment HIV control [ Time Frame: Measured at week 24 off ART ]
   Cumulative incidence of meeting ART re-initiation criteria
3. Percentage of participants who experience adverse events (AEs) [ Time Frame: Measured through participant's last study visit, on average 15 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
4. Percentage of participants who experience serious adverse events (SAEs) [ Time Frame: Measured through participant's last study visit, on average 15 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
5. Percentage of participants who terminate the study early [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Tabulated by reason and HVTN 704/HPTN 085 treatment group
6. Percentage of participants who discontinue ATI [ Time Frame: Measured through participant's last visit on Schedule 1 or 2, on average 3 months ]
   Tabulated by reason and HVTN 704/HPTN 085 treatment group

Secondary Outcome Measures :

1. Response rate of HIV-specific CD4+ and CD8+ T-cells [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by flow cytometry
2. Magnitude of HIV-specific CD4+ and CD8+ T-cells [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by flow cytometry
3. Polyfunctionality of HIV-specific CD4+ and CD8+ T-cells [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by flow cytometry
4. Magnitude of neutralizing antibodies (nAb) responses against autologous and heterologous HIV isolates [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by TZM-bl neutralization assay
5. Non-neutralizing, FcγR-mediated antibody effector functions [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by ADCC
6. Non-neutralizing, FcγR-mediated antibody effector functions [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by ADCP
7. Non-neutralizing, FcγR-mediated antibody effector functions [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by virion capture
8. Frequency of dendritic cell activation and maturation markers [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by flow cytometry or other cell phenotyping assays
9. Frequency of T- and B-cell activation and exhaustion markers [ Time Frame: Measured through participant's last study visit, on average 15 months ]
   Measured by flow cytometry or other cell phenotyping assays
10. Percentage of participants with viral load ≥ 200 copies/mL [ Time Frame: Measured at weeks 8, 16, and 24 for participants undergoing ATI ]
    Cumulative incidence
11. Frequency of CD4+ T cells carrying intact and/or total pro-viral HIV DNA, replication competent virus, and/or cell-associated HIV RNA [ Time Frame: Measured through participant's last study visit, on average 15 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.

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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 exclusion criteria.
• Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, would interfere with, or serve as a contraindication to, protocol adherence, assessment of safety, or a volunteer's ability to give informed consent.
• Any medical, psychiatric, occupational, or other condition that, in the judgment of the investigator, could be exacerbated by events associated with protocol participation, which include: ATI, low-level viremia, subsequent viral rebound, and ART re-initiation.
• HIV dementia or other neurologic disease that, in the judgment of the investigator, would be a contraindication to study participation.
• Psychiatric condition that precludes compliance with the protocol. Specifically excluded are persons with psychoses within the past 3 years, ongoing risk for suicide, or history of suicide attempt or gesture within the past 3 years.
• Malignancy (Not excluded from participation: Volunteer who has had malignancy excised surgically and who, in the investigator's judgment, has a reasonable assurance of sustained cure, or who is unlikely to experience recurrence of malignancy during the period of the study).
• Current untreated or incompletely treated active tuberculosis disease or current latent tuberculosis infection (Not excluded from participation: Volunteer who has latent tuberculosis infection and is undergoing treatment, with at least one month of treatment completed)
• Untreated or incompletely treated syphilis, gonorrhea, or chlamydia infection

Contacts and Locations

Locations

Botswana

Gaborone CRS; Recruiting

Gaborone, Botswana

Contact: CRS Leader 267-3930335 gmasheto@bhp.org.bw

Contact: CRS Coordinator 267-3931353 tkakhu@bhp.org.bw

Malawi

Blantyre CRS; Recruiting

Blantyre, Malawi

Contact: CRS Leader 265-1811885 sufia@jhu.edu

Contact: CRS Coordinator 265-1811885 dhuwa@jhu.medcol.mw

Malawi CRS; Recruiting

Lilongwe, Malawi

Contact: CRS Leader 265-8614587 lchinula@unclilongwe.org

Contact: CRS Coordinator 265-1755056 tmakuhunga@unclilongwe.org

South Africa

CAPRISA eThekwini CRS; Recruiting

Durban, South Africa

Contact: CRS Leader 27-31-260-4550 nesri.padayatchi@caprisa.org

Contact: CRS Coordinator 27-31-6550658 Kieara.Ramtahal@caprisa.org

Vulindlela CRS; Not yet recruiting

Durban, South Africa

Contact: CRS Leader 27-31-2604208 Quarraisha.abdoolkarim@caprisa.org

Contact: CRS Coordinator 27-33-2606861 Hilton.Humphries@caprisa.org

Kliptown Soweto CRS; Recruiting

Johannesburg, South Africa

Contact: CRS Leader 27-11-3424075 lazaruse@phru.co.za

Contact: CRS Coordinator 27-11-9899876 masalam@phru.co.za

Ward 21 CRS; Recruiting

Johannesburg, South Africa

Contact: CRS Leader 27-11-3585414 sdelany@wrhi.ac.za

Contact: CRS Coordinator 27-11-3585856 achikandiwa@wrhi.ac.za

Rustenburg CRS; Not yet recruiting

Rustenburg, South Africa

Contact: CRS Leader 27-87-1351575 wbrumskine@auruminstitute.org

Contact: CRS Coordinator 27-87-1351587 tadonis@auruminstatute.org

Zimbabwe

Milton Park CRS; Not yet recruiting

Harare, Zimbabwe

Contact: CRS Leader 263-772-511104 jhakim@mweb.co.zw

Contact: CRS Coordinator 263-24-2701356 rmahachi@uzchs-ctrc.org

Seke South CRS; Not yet recruiting

Harare, Zimbabwe

Contact: CRS Leader 263-774-430144 phunidzarira@uzchs-ctrc.org

Contact: CRS Coorindator 263-24-2701356 tchirenda@uzchs-ctrc.org

Spilhaus CRS; Not yet recruiting

Harare, Zimbabwe

Contact: CRS Leader 263-772-335232 fmhlanga@uzchs-ctrc.org

Contact 263-772-882704 etahuringana@uzchs-ctrc.org

Sponsors and Collaborators

HIV Vaccine Trials Network

National Institute of Allergy and Infectious Diseases (NIAID)

HIV Prevention Trials Network

AIDS Clinical Trials Group

Investigators

• Study Chair: Shelly Karuna; HVTN Core, Fred Hutch
• Study Chair: Katharine Bar; University of Pennsylvania
• Study Chair: Simba Takuva; HVTN Core, Fred Hutch

More Information

• Responsible Party: HIV Vaccine Trials Network
• ClinicalTrials.gov Identifier: NCT04860323
• Other Study ID Numbers: HVTN 805/HPTN 093; UM1AI068614 ( U.S. NIH Grant/Contract )
• First Posted: April 26, 2021
• Last Update Posted: May 18, 2022
• Last Verified: May 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by HIV Vaccine Trials Network:

HIV; Antibody; LTNPs; ECs; VCs; Treatment interruption

Additional relevant MeSH terms:

Infections; HIV Infections; Acquired Immunodeficiency Syndrome; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases