Adding lenacapavir to ART to try to shrink hidden HIV reservoirs

Lenacapavir Intensification to Disrupt HIV Reservoirs in Virologically Suppressed People With HIV Receiving Antiretroviral Therapy

This study will test whether giving lenacapavir in addition to a stable ART regimen can reduce hidden HIV reservoirs in adults who have had undetectable viral loads for at least three years.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Drugs / interventions: chemotherapy, radiation, prednisone
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT06819176 on ClinicalTrials.gov

What this trial studies

This is a Phase 1, randomized 2:1 study comparing continued ART plus lenacapavir versus continued ART alone in virologically suppressed adults with HIV. Up to 36 participants (approximately 24 on lenacapavir, 12 on ART alone) will receive scheduled subcutaneous and oral dosing of lenacapavir with clinic visits over two years. All participants will remain on their prescribed ART and undergo leukapheresis at baseline and at weeks 12, 24, 48, 72, and 96 to measure intact proviral DNA and residual viremia. The primary outcome is change in intact HIV proviral DNA reservoir size over time, with longitudinal monitoring of decay rates.

Who should consider this trial

Good fit: Adults aged 18–75 with confirmed HIV who have maintained viral suppression (<40 copies/mL) on continuous ART for more than three years, CD4 counts >200 cells/mm3, and a total HIV DNA reservoir >300 copies per 10^6 CD4+ T cells are eligible.

Not a fit: People with ongoing viremia, CD4 counts ≤200 cells/mm3, reservoir sizes ≤300 copies/10^6 CD4+ T cells, or those unwilling/unable to attend repeated leukapheresis visits are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, adding lenacapavir could reduce the size of hidden HIV reservoirs and provide information that helps move cure strategies forward.

How similar studies have performed: Lenacapavir is approved for treatment-resistant HIV, but using it specifically to shrink latent reservoirs is a novel approach with limited prior clinical data.

Eligibility criteria

* INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all of the following criteria:

1. Able to provide informed consent.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Aged 18 years to 75 years.
4. In generally good health with an identified primary health care provider for medical management of HIV infection and willing to maintain a relationship with a primary health care provider while participating in the study.
5. Confirmed HIV-1 infection.
6. Total HIV DNA reservoir size greater than 300 copies/106 CD4+ T cells.
7. CD4+ T cell count \>200 cells/mm\^3 at screening.
8. Documentation of continuous ART treatment \>3 years with suppression of plasma viral level below the limit of quantitation (\<40 copies/mL). Individuals with \<= 2 blips (\>40 copies/mL) over 48 weeks prior to screening may be included provided they satisfy the following criteria:

   1. The blips are \<=200 copies/mL.
   2. Succeeding viral levels return to below the limit of quantification (\<40 copies/mL) on subsequent testing.
9. For individuals who can become pregnant (ie, participants who have not been postmenopausal for at least 24 consecutive months, who have had menses within the preceding 24 months, or who have not undergone surgical sterilization, specifically hysterectomy and/or bilateral oophorectomy), must have a negative pregnancy test at screening and within 48 hours prior to day 0. Participant-reported history is acceptable as documentation of hysterectomy and bilateral oophorectomy, tubal ligation, tubal micro-inserts, and vasectomy.
10. Participants who can become pregnant must agree to use 1 acceptable method of contraception when engaging in sexual activities that can result in pregnancy from 10 days prior to the first dose of lenacapavir through study follow up. Acceptable methods of contraception include the following:

    1. Contraceptive subdermal implant.
    2. Intrauterine device or intrauterine system.
    3. Combined estrogen and progestogen oral contraceptive.
    4. Injectable progestogen.
    5. Contraceptive vaginal ring.
    6. Percutaneous contraceptive patches.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. History of AIDS-defining illness within 3 years prior to enrollment.
2. History of systemic corticosteroids (eg, an equivalent dose of prednisone of \>20 mg daily for \>14 days), immunosuppressive anti-cancer, interleukins, systemic interferons, systemic chemotherapy, or other medications considered significant by the principal investigator within the last 6 months.
3. Any clinically significant acute or chronic medical condition (eg, autoimmune diseases, cirrhosis, active malignancy that may require systemic chemotherapy or radiation therapy), other than HIV infection, that in the opinion of the investigator would preclude participation.
4. Hepatitis B or C infection as indicated by the presence of hepatitis B surface antigen or hepatitis C virus (HCV) RNA in blood.

   NOTE: Participants with a positive test for HCV antibody and a negative test for HCV RNA are eligible.
5. Pregnancy or lactation.
6. Any licensed vaccine (eg, hepatitis B, influenza, pneumococcal polysaccharide) received within 2 weeks prior to the study enrollment.
7. Receipt of other investigational study agents within 28 days of enrollment and at any time during the study, including any experimental non-HIV vaccination within 2 weeks prior to enrollment.
8. Systemic immunosuppressive medications received within 3 months prior to enrollment. The following are not excluded:

   1. Corticosteroid nasal spray or inhaler.
   2. Topical corticosteroids for mild, uncomplicated dermatitis.
   3. Oral/parenteral corticosteroids administered for non-chronic conditions not expected to recur (length of therapy 10 days, with completion in 30 days prior to enrollment).
   4. Cyclosporine eye drops
9. Active drug or alcohol abuse or any other pattern of behavior that, in the opinion of the investigator, would interfere with adherence to study requirements.
10. Laboratory abnormalities in the parameters listed below:

    1. Absolute neutrophil count \<1,000 cells/mm\^3
    2. Hemoglobin \<10 g/dL
    3. Platelet count \<100,000 cells/mm\^3
    4. ALT \>1.5 x ULN
    5. AST \>1.5 x ULN
    6. Total bilirubin \>1.5 x ULN
    7. Estimated glomerular filtration rate \<30 mL/min/1.73m\^2
11. Inability to undergo leukapheresis due to poor venous access or other medical conditions.
12. Concurrent treatment with any of the medications listed below:

    1. Antiarrhythmics: digoxin
    2. Anticoagulants: direct oral anticoagulants (DOACs), rivaroxaban, dabigatran, edoxaban
    3. Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
    4. Antiretroviral Agents: atazanavir/cobicistat, atazanavir/ritonavir, efavirenz, nevirapine, tipranavir/ritonavir
    5. Antimycobacterials: Rifabutin, rifampin, rifapentine
    6. Corticosteroids (systemic): dexamethasone, hydrocortisone/cortisone
    7. Ergot derivatives: dihydroergotamine, ergotamine, methylergonovine
    8. Herbal products: St. John's wort c (Hypericum perforatum)
    9. HMG-CoA reductase inhibitors: lovastatin simvastatin
    10. Narcotic analgesics metabolized by CYP3A: fentanyl, oxycodone
    11. Tramadol
    12. Narcotic analgesic for treatment of opioid dependence: buprenorphine, methadone
    13. Opioid antagonist: naloxegol
    14. Phosphodiesterase-5 (PDE-5) inhibitors: sildenafil, tadalafil, vardenafil
    15. Sedatives/Hypnotics: midazolam (oral), triazolam
13. Past or current medical findings that are not listed above, which, in the opinion of the investigator, may pose additional risk from participation in the study, may interfere with the individual's ability to comply with study requirements, or that may impact the quality or interpretation of the data obtained from the study.

Co-enrollment guidelines: Co-enrollment in other trials or protocols involving apheresis is restricted, other than enrollment on observational studies. Co-enrollment in an interventional trial will require the approval of the principal investigator. Study staff should be notified of co-enrollment on any other protocol as it may require the approval of the principal investigator.

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Chuen-Yen C Lau, M.D. — National Institute of Allergy and Infectious Diseases (NIAID)
• Study coordinator: Kathleen R Gittens

Conditions Human Immunodeficiency Virus; HIV; ART intensification; Reservoir; lenacapavir; persistence