Analytical Treatment Interruption (ATI) to Assess the Immune System's Ability to Control HIV in Participants Who Became HIV-infected During the HVTN 704/HPTN 085 AMP Study

Antiretroviral Analytical Treatment Interruption (ATI) to Assess Immunologic and Virologic Responses in Participants Who Received VRC01 or Placebo and Became HIV-infected During HVTN 704/HPTN 085

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 704/HPTN 085 (NCT02716675).

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.

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 704/HPTN 085 Antibody-Mediated Prevention (AMP) Study (NCT02716675).

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 extreme and 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 rectal and oral swab collection), blood draws, pregnancy testing for participants assigned female sex at birth that can become pregnant, HIV transmission risk reduction counseling, and interviews/questionnaires.

Inclusion Criteria:

• Estimated date of HIV-1 acquisition within 8 weeks of participant's last HVTN 704/HPTN 085 infusion.
• Initiated ART within 28 weeks of HVTN 704/HPTN 085 HIV-1 date of diagnosis.
• Receiving continuous ART for at least 1 year. ART interruptions of up to 7 days 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 until after confirmation of viral suppression following ART re-initiation.
• Willingness for CRS staff to contact primary HIV care provider to exchange information regarding HVTN 804/HPTN 095 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 704/HPTN 085 HIV diagnostic algorithm.

• Plasma HIV-1 RNA ≥ 1,000 copies/mL by any assay, prior to initiating ART.

• CD4+ 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 screening, within 90 days prior to enrollment; and
  • greater than 9 months prior to the screening HIV-1 RNA.

Hematology

• Hemoglobin (Hgb) ≥ 10.0 g/dL for volunteers who were assigned female sex at birth, ≥ 11.0 g/dL for volunteers who were assigned male sex at birth.
• Absolute neutrophil count (ANC) ≥ 750 cells/mm3
• Platelets ≥ 100,000 cells/mm3

Chemistry

• 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 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:

1. Any plasma HIV-1 RNA ≥ LLOQ (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: US volunteers must have results from a CLIA or VQA-approved assay. Non-US sites must have results from locally available assays that are approved as standard-of-care by their regional governing bodies.

2. History of AIDS-defining illnesses or US Centers for Disease Control (CDC) Category C events per the current list on the CDC website (see HVTN 804/HPTN 095 SSP).

3. 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).

4. 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).

5. Blood products received within 120 days before planned ART interruption.

6. Investigational research agents, other than experimental vaccine(s) (See Exclusion Criterion #7), received within 30 days before planned ART interruption.

7. HIV or non-HIV experimental vaccine(s) received within the last 1 year. Exceptions may be made by the HVTN 804/HPTN 095 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 804/HPTN 095 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 804/HPTN 095 PSRT on a case-by-case basis.

8. 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).

9. Licensed vaccines that are not live attenuated vaccines received within 14 days before planned ART interruption (eg, tetanus, pneumococcal, hepatitis A or B).

10. 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 804/HPTN 095 eligibility.

11. Significant or unstable cardiac or cerebrovascular disease (eg, angina, congestive heart failure [CHF], recent cerebrovascular accident [CVA], or myocardial infarction [MI]).

12. Hepatitis B surface antigen (HBsAg) or positive HCV RNA (Not exclusionary: positive HCV Ab with negative HCV RNA).

13. 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 COVID19, in the clinical judgement of the investigator)

14. Pregnant or breastfeeding

15. 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.

16. 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.

17. 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.

18. HIV dementia or other neurologic disease that, in the judgment of the investigator, would be a contraindication to study participation.

19. 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.

20. 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).

21. 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)

22. Untreated or incompletely treated syphilis, gonorrhea, or chlamydia infection