Reducing HIV Persistence in Lymph Nodes by Interleukin-15 (IL-15) Receptor Super-agonist (N-803) in Acute HIV Infection

Study Overview
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Brief Summary
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Reducing HIV persistence in lymph nodes by Interleukin-15 (IL-15) Receptor super-agonist (N-803) in Individuals with Acute HIV Infection

Detailed Description
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This is a phase II, randomized, unblinded, controlled trial to investigate the safety, tolerability and immunomodulation effect of combining N-803 with antiretroviral therapy (ART) during acute HIV infection (AHI). The study will be conducted at one study site, the Thai Red Cross AIDS Research Centre (TRCARC) in Bangkok, Thailand. Eligible participants will be asked to undergo LN Bx at baseline (untreated AHI), prior to initiating dolutegravir-based ART. N-803 will be administered subcutaneously at weeks 0, 3, 6 (total 3 doses) and will be initiated together with ART. Participants will be asked to undergo a second inguinal LN Bx on the opposite groin approximately at week 6 (no later than 1 week after completion of study agents). They will be followed for safety parameters at weeks 8 and 12, after which they will roll over to the RV412, WRAIR#2178 safety monitoring protocol. The study duration for individual participants will be approximately 12 weeks. The study may include additional optional procedures at baseline and week 6 such as leukapheresis, brain MRI imaging and lumbar puncture, according to participants' consent. It is hypothesized that N-803 initiated with ART during AHI, will be safe, and will lead to a reduction of HIV reservoir size in LN, demonstrated by decreased frequencies of vRNA+ and vDNA+ cells in the LNs, in comparison with ART alone.

Official Title
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Reducing HIV Persistence in Lymph Nodes by Interleukin-15 (IL-15) Receptor Super-agonist (N-803) in Individuals With Acute HIV Infection

Conditions
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HIV/AIDS

Intervention / Treatment
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* Drug: N-803


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-40 years Acute HIV infection (Fiebig I to V: Fiebig I: RNA+, p24 antigen-; Fiebig II: p24 antigen+, IgM-; Fiebig III: IgM+, Western Blot-; Fiebig IV: Western Blot indeterminate; Fiebig V: Western Blot+ without p31 protein band) All female participants of childbearing potential must have a negative urine pregnancy test at the screening visit Women of child bearing potential and men with partners of child bearing potential must agree to use effective contraception (as defined in section 8.1.2 Pregnancy Risks) during therapy and for 4 months after completion of therapy Can read and write Thai and/or English language and must be able to understand and complete the informed consent process Must successfully complete a Test of Understanding (TOU) prior to enrollment as described in Section 7.1 Willing to undergo inguinal LN Bx at two time points (baseline and week 6) and blood draws during each study visit Willing to participate for the duration of the study visits and follow up. Exclusion Criteria: Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study Active or recent malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months; minor surgical removal of localized skin cancers (squamous cell carcinoma, basal cell carcinoma) are not exclusionary Receipt of any vaccine within 2 weeks prior to study enrollment and anticipated need for any vaccine within 2 weeks prior to or after any of the study agent administrations. Current or anticipated use of systemic steroid medications. Any clinically significant acute or chronic medical condition, including, pulmonary, hepatic, renal, gastrointestinal, genitourinary, hematological, coagulation, that in the opinion of the investigator would preclude participation (e.g., history of seizure disorders, cardiac disease, bleeding/clotting disorder, autoimmune disease, active malignancy, poorly controlled asthma, active tuberculosis or other systemic infections, etc.) Chronic liver disease Active and poorly controlled atherosclerotic cardiovascular disease (ASCVD), as defined by 2013 ACC/AHA guidelines, including a previous diagnosis of any of the following: (a) acute myocardial infarction, (b) acute coronary syndromes, (c) stable or unstable angina, (d) coronary or other arterial revascularization, (e) stroke, (f) transient ischemic attack, or (g) peripheral arterial disease presumed to be of atherosclerotic origin History of potential immune-mediated medical conditions Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment Major psychiatric illness and/or substance use during the past 12 months that in the opinion of the investigator would preclude participation Concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment Exposure to any experimental therapies within 90 days of study entry Pre-exposure prophylaxis (PrEP) use within 90 days of study entry

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N-803<br>N-803 at 6mcg/kg every 3 weeks for 3 doses plus ART (n=10) | Drug: N-803<br>* N-803 is a novel IL-15 superagonist complex that enhances NK cell and CD8+ T-cell proliferation and activation.<br>* Other names: ALT-803;|
| No Intervention: Control<br>ART alone (n=5) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of occurrence of ≥ grade 3 adverse events determined to be related (Safety) | Rate of occurrence of ≥ grade 3 adverse events determined to be related | at time of study completion at week 12 | 
| Frequency of vRNA+ and vDNA+ cells in LNs (Efficacy) | Frequency of vRNA+ and vDNA+ cells in LNs | at week 6 | 
| levels of vDNA and vRNA in LNs (Efficacy) | levels of vDNA and vRNA in LNs | at week 6 | 
| Frequency of CD8+ T cells in LNs (Efficacy) | Frequency of CD8+ T cells in LNs | at week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Immune cells in LN and blood | Frequency of Immune cells in LN and blood | at week 6 | 
| HIV-specific antibody levels | HIV-specific antibody levels | at week 12 | 
| HIV-specific antibody function as measured by Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and Antibody-dependent cell-mediated viral inhibition (ADCVI) levels. | HIV-specific antibody function as measured by Antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and Antibody-dependent cell-mediated viral inhibition (ADCVI) levels. | at week 12 | 
| Frequency of cells harboring vDNA, vRNA, intact genome and replication competent HIV-1 in peripheral blood mononuclear cell (PBMC) | Frequency of cells harboring vDNA, vRNA, intact genome and replication competent HIV-1 in peripheral blood mononuclear cell (PBMC) | at week 12 | 
| Differential expressed genes in LN and blood | Differential expressed genes in LN and blood | at week 12 | 
| Immune activation markers in blood | Immune activation markers in blood | at week 12 | 
| Immune activation markers in CSF | Immune activation markers in CSF | at week 6 | 
| Extent of cerebral inflammation in MR Spectroscopy (MRS) | Extent of cerebral inflammation in MR Spectroscopy (MRS) | at week 6 | 
| Viral load in the CSF | Viral load in the CSF | at week 6 |